2.3 Introduction
The current coronavirus disease 2019 (COVID-19) pandemic, caused by the Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) virus, represents an acute global health crisis. -Symptoms of the disease can range from mild to severe or fatal [44] and can affect a variety of organs and systems [45]. -Outcomes of infection can include acute respiratory distress (ARDS) and acute lung injury, as well as damage to other organ systems [45,46]. +Symptoms of the disease can range from mild to severe or fatal [46] and can affect a variety of organs and systems [47]. +Outcomes of infection can include acute respiratory distress (ARDS) and acute lung injury, as well as damage to other organ systems [47,48]. Understanding the progression of the disease, including these diverse symptoms, depends on understanding how the virus interacts with the host. Additionally, the fundamental biology of the virus can provide insights into how it is transmitted among people, which can, in turn, inform efforts to control its spread. As a result, a thorough understanding of the pathogenesis of SARS-CoV-2 is a critical foundation on which to build an understanding of COVID-19 and the pandemic as a whole.
-The rapid identification and release of the genomic sequence of the virus in January 2020 [10] provided early insight into the virus in a comparative genomic context. +
The rapid identification and release of the genomic sequence of the virus in January 2020 [12] provided early insight into the virus in a comparative genomic context. The viral genomic sequence clusters with known coronaviruses (order Nidovirales, family Coronaviridae, subfamily Orthocoronavirinae). Phylogenetic analysis of the coronaviruses reveals four major subclades, each corresponding to a genus: the alpha, beta, gamma, and delta coronaviruses. -Among them, alpha- and betacoronaviruses infect mammalian species, gammacoronaviruses infect avian species, and deltacoronaviruses infect both mammalian and avian species [47]. -The novel virus now known as SARS-CoV-2 was identified as a betacoronavirus belonging to the B lineage based on phylogenetic analysis of a polymerase chain reaction (PCR) amplicon fragment from five patients along with the full genomic sequence [48]. -This lineage also includes the Severe acute respiratory syndrome-related coronavirus (SARS-CoV-1) that caused the 2002-2003 outbreak of Severe Acute Respiratory Syndrome (SARS) in humans [48]. +Among them, alpha- and betacoronaviruses infect mammalian species, gammacoronaviruses infect avian species, and deltacoronaviruses infect both mammalian and avian species [49]. +The novel virus now known as SARS-CoV-2 was identified as a betacoronavirus belonging to the B lineage based on phylogenetic analysis of a polymerase chain reaction (PCR) amplicon fragment from five patients along with the full genomic sequence [50]. +This lineage also includes the Severe acute respiratory syndrome-related coronavirus (SARS-CoV-1) that caused the 2002-2003 outbreak of Severe Acute Respiratory Syndrome (SARS) in humans [50]. Because viral structure and mechanisms of pathogenicity are highly conserved within the order, this phylogenetic analysis provided a basis for forming hypotheses about how the virus interacts with hosts, including which tissues, organs, and systems would be most susceptible to SARS-CoV-2 infection. Coronaviruses that infect humans (HCoV) are not common, but prior research into other HCoV such as SARS-CoV-1 and Middle East respiratory syndrome-related coronavirus (MERS-CoV), as well as other viruses infecting humans such as a variety of influenza species, established a strong foundation that accelerated the pace of SARS-CoV-2 research.
Coronaviruses are large viruses that can be identified by their distinctive “crown-like” shape (Figure 1). -Their spherical virions are made from lipid envelopes ranging from 100 to 160 nanometers in which peplomers (protruding structures) of two to three spike (S) glycoproteins are anchored, creating the crown [49,50]. -These spikes, which are critical to both viral pathogenesis and to the response by the host immune response, have been visualized using cryo-electron microscopy [51]. +Their spherical virions are made from lipid envelopes ranging from 100 to 160 nanometers in which peplomers (protruding structures) of two to three spike (S) glycoproteins are anchored, creating the crown [51,52]. +These spikes, which are critical to both viral pathogenesis and to the response by the host immune response, have been visualized using cryo-electron microscopy [53]. Because they induce the human immune response, they are also the target of many proposed therapeutic agents. -Viral pathogenesis is typically broken down into three major components: entry, replication, and spread [52]. +Viral pathogenesis is typically broken down into three major components: entry, replication, and spread [54]. However, in order to draw a more complete picture of pathogenesis, it is also necessary to examine how infection manifests clinically, identify systems-level interactions between the virus and the human body, and consider the possible effects of variation or evolutionary change on pathogenesis and virulence. Thus, clinical medicine and traditional biology are both important pieces of the puzzle of SARS-CoV-2 presentation and pathogenesis.
2.4 Coronavirus Structure and Pathogenesis
@@ -785,12 +786,12 @@.
-The SARS-CoV-2 genome lies in the middle of this range at 29,903 bp [13].
-Genome organization is highly conserved within the order [53].
-There are three major genomic regions: one containing the replicase gene, one containing the genes encoding structural proteins, and interspersed accessory genes [53] (Figure 1).
-The replicase gene comprises about two-thirds of the genome and consists of two open reading frames that are translated with ribosomal frameshifting [53].
-This polypeptide is then translated into 16 non-structural proteins (nsp), except in gammacoronaviruses where nsp1 is absent, that form replication machinery used to synthesize viral RNA [54].
+Coronaviruses have large positive-sense RNA (ssRNA+) genomes ranging from 27 to 32 kilobases in length [15,55].
+The SARS-CoV-2 genome lies in the middle of this range at 29,903 bp [15].
+Genome organization is highly conserved within the order [55].
+There are three major genomic regions: one containing the replicase gene, one containing the genes encoding structural proteins, and interspersed accessory genes [55] (Figure 1).
+The replicase gene comprises about two-thirds of the genome and consists of two open reading frames that are translated with ribosomal frameshifting [55].
+This polypeptide is then translated into 16 non-structural proteins (nsp), except in gammacoronaviruses where nsp1 is absent, that form replication machinery used to synthesize viral RNA [56].
The remaining third of the genome encodes structural proteins, including the spike, membrane, envelope, and nucleocapsid proteins.
Additional accessory genes are sometimes present between these two regions, depending on the species or strain.
Much attention has been focused on the S protein, which is a critical structure involved in cell entry.
@@ -801,157 +802,157 @@ [53].
+Accessory genes can also be interspersed throughout the genome [55].
B) The physical structure of the coronavirus virion, including the components determined by the conserved structural proteins S, E, M and N.
2.4.2 Pathogenic Mechanisms of Coronaviruses
-
2.4.2 Pathogenic Mechanisms of Coronaviruses
-While, like most viruses, it is possible that SARS-CoV-1 and SARS-CoV-2 can enter cells through endocytosis, coronaviruses are also able to target cells for entry through fusion with the plasma membrane [55,56]. +
While, like most viruses, it is possible that SARS-CoV-1 and SARS-CoV-2 can enter cells through endocytosis, coronaviruses are also able to target cells for entry through fusion with the plasma membrane [57,58]. This process is conserved among coronaviruses and is closely associated with the content of their genomes. Cell entry proceeds in three steps: binding, cleavage, and fusion. First, the viral spike protein binds to a host cell via a recognized receptor or entry point. -Coronaviruses can bind to a range of host receptors [57,58], with binding conserved only at the genus level [47]. -Viruses in the betacoronavirus genus, to which SARS-CoV-2 belongs, are known to bind to the CEACAM1 protein, 5-N-acetyl-9-O-acetyl neuraminic acid, and to the angiotensin-converting enzyme 2 (ACE2) [57]. -SARS-CoV-2 has a high affinity for human ACE2, which is expressed in the vascular epithelium, other epithelial cells, and cardiovascular and renal tissues [59,60], as well as many others [61]. -The binding process is guided by the molecular structure of the spike protein, which is structured in three segments: an ectodomain, a transmembrane anchor, and an intracellular tail [62]. -The ectodomain forms the crown-like structures on the viral membrane and contains two subdomains known as the S1 and S2 subunits [63]. -The S1 (N-terminal) domain forms the head of the crown and contains the receptor binding motif, and the S2 (C-terminal) domain forms the stalk that supports the head [63]. -The S1 subunit guides the binding of the virus to the host cell, and the S2 subunit guides the fusion process [62].
-After the binding of the S1 subunit to an entry point, the spike protein is often cleaved at the S1-S2 boundary by a host protease [64,65,66]. -Similar to SARS-CoV-1, SARS-CoV-2 exhibits redundancy in which host proteases can cleave the S protein [67]. -Specifically, both transmembrane protease serine protease-2 (TMPRSS2) and cathepsins B/L have been shown to mediate SARS-CoV-2 S protein proteolytic priming, and small molecule inhibition of these enzymes fully inhibited viral entry in vitro [67,68]. -Proteolytic priming prepares the S protein for fusion [65,66]. -The two subunits remain bound by van der Waals forces, with the S1 subunit stabilizing the S2 subunit during the membrane fusion process [64]. -Electron microscopy suggests that in some coronaviruses, including SARS-CoV-1 and MERS-CoV, a six-helix bundle separates the two subunits in the postfusion conformation, and the unusual length of this bundle facilitates membrane fusion through the release of additional energy [47]. -Cleavage at a second site within S2 by these same proteases activates S for fusion by inducing conformational changes [64]. +Coronaviruses can bind to a range of host receptors [59,60], with binding conserved only at the genus level [49]. +Viruses in the betacoronavirus genus, to which SARS-CoV-2 belongs, are known to bind to the CEACAM1 protein, 5-N-acetyl-9-O-acetyl neuraminic acid, and to the angiotensin-converting enzyme 2 (ACE2) [59]. +SARS-CoV-2 has a high affinity for human ACE2, which is expressed in the vascular epithelium, other epithelial cells, and cardiovascular and renal tissues [61,62], as well as many others [63]. +The binding process is guided by the molecular structure of the spike protein, which is structured in three segments: an ectodomain, a transmembrane anchor, and an intracellular tail [64]. +The ectodomain forms the crown-like structures on the viral membrane and contains two subdomains known as the S1 and S2 subunits [65]. +The S1 (N-terminal) domain forms the head of the crown and contains the receptor binding motif, and the S2 (C-terminal) domain forms the stalk that supports the head [65]. +The S1 subunit guides the binding of the virus to the host cell, and the S2 subunit guides the fusion process [64].
+After the binding of the S1 subunit to an entry point, the spike protein is often cleaved at the S1-S2 boundary by a host protease [66,67,68]. +Similar to SARS-CoV-1, SARS-CoV-2 exhibits redundancy in which host proteases can cleave the S protein [69]. +Specifically, both transmembrane protease serine protease-2 (TMPRSS2) and cathepsins B/L have been shown to mediate SARS-CoV-2 S protein proteolytic priming, and small molecule inhibition of these enzymes fully inhibited viral entry in vitro [69,70]. +Proteolytic priming prepares the S protein for fusion [67,68]. +The two subunits remain bound by van der Waals forces, with the S1 subunit stabilizing the S2 subunit during the membrane fusion process [66]. +Electron microscopy suggests that in some coronaviruses, including SARS-CoV-1 and MERS-CoV, a six-helix bundle separates the two subunits in the postfusion conformation, and the unusual length of this bundle facilitates membrane fusion through the release of additional energy [49]. +Cleavage at a second site within S2 by these same proteases activates S for fusion by inducing conformational changes [66]. The viral membrane can then fuse with the endosomal membrane to release the viral genome into the host cytoplasm. Once the virus enters a host cell, the replicase gene is translated and assembled into the viral replicase complex. This complex then synthesizes the double-stranded RNA (dsRNA) genome from the genomic ssRNA(+). -The dsRNA genome is transcribed and replicated to create viral mRNAs and new ssRNA(+) genomes [53,69]. +The dsRNA genome is transcribed and replicated to create viral mRNAs and new ssRNA(+) genomes [55,71]. From there, the virus can spread into other cells. In this way, the genome of SARS-CoV-2 provides insight into the pathogenic behavior of the virus.
2.4.3 Immune Evasion Strategies
Research in other HCoV provides some indication of how SARS-CoV-2 infection proceeds in spite of the human immune response. -By infecting the epithelium, viruses such as SARS-CoV-1 are known to bypass the physical barriers, such as skin and mucus, that comprise the immune system’s first line of defense [70]. +By infecting the epithelium, viruses such as SARS-CoV-1 are known to bypass the physical barriers, such as skin and mucus, that comprise the immune system’s first line of defense [72]. Once the virus infiltrates host cells, it is adept at evading detection. -CD163+ and CD68+ macrophage cells are especially crucial for the establishment of SARS-CoV-1 in the body [70]. +CD163+ and CD68+ macrophage cells are especially crucial for the establishment of SARS-CoV-1 in the body [72]. These cells most likely serve as viral reservoirs that help shield SARS-CoV-1 from the innate immune response. -According to a study on the viral dissemination of SARS-CoV-1 in Chinese macaques, viral RNA could be detected in some monocytes throughout the process of differentiation into dendritic cells [70]. -This lack of active viral replication allows SARS-CoV-1 to escape the innate immune response because reduced levels of detectable viral RNA allow the virus to avoid both natural killer cells and Toll-like receptors [70]. +According to a study on the viral dissemination of SARS-CoV-1 in Chinese macaques, viral RNA could be detected in some monocytes throughout the process of differentiation into dendritic cells [72]. +This lack of active viral replication allows SARS-CoV-1 to escape the innate immune response because reduced levels of detectable viral RNA allow the virus to avoid both natural killer cells and Toll-like receptors [72]. Even during replication, SARS-CoV-1 is able to mask its dsRNA genome from detection by the immune system. -Although dsRNA is a pathogen-associated molecular pattern that would typically initiate a response from the innate immune system [71], in vitro analysis of nidoviruses including SARS-CoV-1 suggests that these viruses can induce the development of double-membrane vesicles that protect the dsRNA signature from being detected by the host immune system [72]. -This protective envelope can therefore insulate these coronaviruses from the innate immune system’s detection mechanism [33].
+Although dsRNA is a pathogen-associated molecular pattern that would typically initiate a response from the innate immune system [73], in vitro analysis of nidoviruses including SARS-CoV-1 suggests that these viruses can induce the development of double-membrane vesicles that protect the dsRNA signature from being detected by the host immune system [74]. +This protective envelope can therefore insulate these coronaviruses from the innate immune system’s detection mechanism [35].HCoVs are also known to interfere with the host immune response, rather than just evade it. -For example, the virulence of SARS-CoV-2 is increased by nsp1, which can suppress host gene expression by stalling mRNA translation and inducing endonucleolytic cleavage and mRNA degradation [73]. +For example, the virulence of SARS-CoV-2 is increased by nsp1, which can suppress host gene expression by stalling mRNA translation and inducing endonucleolytic cleavage and mRNA degradation [75]. SARS-CoV-1 also evades the immune response by interfering with type I IFN induction signaling, which is a mechanism that leads to cellular resistance to viral infections. -SARS-CoV-1 employs methods such as ubiquitination and degradation of RNA sensor adaptor molecules MAVS and TRAF3/6 [74]. -Also, MERS-CoV downregulates antigen presentation via MHC class I and MHC class II, which leads to a reduction in T cell activation [74]. +SARS-CoV-1 employs methods such as ubiquitination and degradation of RNA sensor adaptor molecules MAVS and TRAF3/6 [76]. +Also, MERS-CoV downregulates antigen presentation via MHC class I and MHC class II, which leads to a reduction in T cell activation [76]. These evasion mechanisms, in turn, can facilitate systemic infection. -Coronaviruses such as SARS-CoV-1 are also able to evade the humoral immune response through other mechanisms, such as inhibiting certain cytokine pathways or down-regulating antigen presentation by the cells [72].
+Coronaviruses such as SARS-CoV-1 are also able to evade the humoral immune response through other mechanisms, such as inhibiting certain cytokine pathways or down-regulating antigen presentation by the cells [74].2.4.4 Host Cell Susceptibility
-ACE2 and TMPRSS2 have been identified as the primary entry portal and as a critical protease, respectively, in facilitating the entry of SARS-CoV-1 and SARS-CoV-2 into a target cell [51,67,75,76,77]. +
ACE2 and TMPRSS2 have been identified as the primary entry portal and as a critical protease, respectively, in facilitating the entry of SARS-CoV-1 and SARS-CoV-2 into a target cell [53,69,77,78,79]. This finding has led to a hypothesized role for ACE2 and TMPRSS2 expression in determining which cells, tissues, and organs are most likely to be infected by SARS-CoV-2. -ACE2 is expressed in numerous organs, such as the heart, kidney, and intestine, but it is most prominently expressed in alveolar epithelial cells; this pattern of expression is expected to contribute to the virus’ association with lung pathology [59,78,79] as well as that of SARS [80]. -Clinical investigations of COVID-19 patients have detected SARS-CoV-2 transcripts in bronchoalveolar lavage fluid (BALF) (93% of specimens), sputum (72%), nasal swabs (63%), fibrobronchoscopy brush biopsies (46%), pharyngeal swabs (32%), feces (29%), and blood (1%) [81]. -Two studies reported that SARS-CoV-2 could not be detected in urine specimens [81,82]; however, a third study identified four urine samples (out of 58) that were positive for SARS-CoV-2 nucleic acids [83]. -Although respiratory failure remains the leading cause of death for COVID-19 patients [84], SARS-CoV-2 infection can damage many other organ systems including the heart [85], kidneys [86,87], liver [88], and gastrointestinal tract [89,90]. +ACE2 is expressed in numerous organs, such as the heart, kidney, and intestine, but it is most prominently expressed in alveolar epithelial cells; this pattern of expression is expected to contribute to the virus’ association with lung pathology [61,80,81] as well as that of SARS [82]. +Clinical investigations of COVID-19 patients have detected SARS-CoV-2 transcripts in bronchoalveolar lavage fluid (BALF) (93% of specimens), sputum (72%), nasal swabs (63%), fibrobronchoscopy brush biopsies (46%), pharyngeal swabs (32%), feces (29%), and blood (1%) [83]. +Two studies reported that SARS-CoV-2 could not be detected in urine specimens [83,84]; however, a third study identified four urine samples (out of 58) that were positive for SARS-CoV-2 nucleic acids [85]. +Although respiratory failure remains the leading cause of death for COVID-19 patients [86], SARS-CoV-2 infection can damage many other organ systems including the heart [87], kidneys [88,89], liver [90], and gastrointestinal tract [91,92]. As it becomes clear that SARS-CoV-2 infection can damage multiple organs, the scientific community is pursuing multiple avenues of investigation in order to build a consensus about how the virus affects the human body.
2.5 Clinical Presentation of COVID-19
SARS-CoV-2 pathogenesis is closely linked with the clinical presentation of the COVID-19 disease. Reports have described diverse symptom profiles associated with COVID-19, with a great deal of variability both within and between institutions and regions. -A large study from Wuhan, China conducted early in the pandemic identified fever and cough as the two most common symptoms that patients reported at hospital admission [34], while a retrospective study in China described the clinical presentations of patients infected with SARS-CoV-2 as including lower respiratory tract infection with fever, dry cough, and dyspnea (shortness of breath) [35]. -This study [35] noted that upper respiratory tract symptoms were less common, suggesting that the virus preferentially targets cells located in the lower respiratory tract. -However, data from the New York City region [36,37] showed variable rates of fever as a presenting symptom, suggesting that symptoms may not be consistent across individuals. -For example, even within New York City, one study [36] identified low oxygen saturation (<90% without the use of supplemental oxygen or ventilation support) in 20.4% of patients upon presentation, with fever being present in 30.7%, while another study [51] reported cough (79.4%), fever (77.1%), and dyspnea (56.5%) as the as the most common presenting symptoms; both of these studies considered only hospitalized patients. -A later study reported radiographic findings such as ground-glass opacity and bilateral patchy shadowing in the lungs of many hospitalized patients, with most COVID-19 patients having lymphocytopenia, or low levels of lymphocytes (a type of white blood cell) [34]. +A large study from Wuhan, China conducted early in the pandemic identified fever and cough as the two most common symptoms that patients reported at hospital admission [36], while a retrospective study in China described the clinical presentations of patients infected with SARS-CoV-2 as including lower respiratory tract infection with fever, dry cough, and dyspnea (shortness of breath) [37]. +This study [37] noted that upper respiratory tract symptoms were less common, suggesting that the virus preferentially targets cells located in the lower respiratory tract. +However, data from the New York City region [38,39] showed variable rates of fever as a presenting symptom, suggesting that symptoms may not be consistent across individuals. +For example, even within New York City, one study [38] identified low oxygen saturation (<90% without the use of supplemental oxygen or ventilation support) in 20.4% of patients upon presentation, with fever being present in 30.7%, while another study [51] reported cough (79.4%), fever (77.1%), and dyspnea (56.5%) as the as the most common presenting symptoms; both of these studies considered only hospitalized patients. +A later study reported radiographic findings such as ground-glass opacity and bilateral patchy shadowing in the lungs of many hospitalized patients, with most COVID-19 patients having lymphocytopenia, or low levels of lymphocytes (a type of white blood cell) [36]. Patients may also experience loss of smell, myalgias (muscle aches), fatigue, or headache. -Gastrointestinal symptoms can also present [91], and the CDC includes nausea and vomiting, as well congestion and runny nose, on its list of symptoms consistent with COVID-19 [44]. -A preprint using data from an app-based survey of 500,000 individuals in the US found that among those tested for SARS-CoV-2, a loss of taste or smell, fever, and a cough were significant predictors of a positive test result [92]. +Gastrointestinal symptoms can also present [93], and the CDC includes nausea and vomiting, as well congestion and runny nose, on its list of symptoms consistent with COVID-19 [46]. +A preprint using data from an app-based survey of 500,000 individuals in the US found that among those tested for SARS-CoV-2, a loss of taste or smell, fever, and a cough were significant predictors of a positive test result [94]. It is important to note that in this study, the predictive value of symptoms may be underestimated if they are not specific to COVID-19. This underestimation could occur because the outcome measured was a positive, as opposed to a negative, COVID-19 test result, meaning an association would be more easily identified for symptoms that were primarily or exclusively found with COVID-19. At the time the surveys were conducted, due to limits in US testing infrastructure, respondents typically needed to have some symptoms known to be specific to COVID-19 in order to qualify for testing. Widespread testing of asymptomatic individuals may therefore provide additional insight into the range of symptoms associated with COVID-19.
-Consistent with the wide range of symptoms observed and the pathogenic mechanisms described above, COVID-19 can affect diverse body systems in addition to causing respiratory problems [93]. -For example, COVID-19 can lead to acute kidney injury, especially in patients with severe respiratory symptoms or certain preexisting conditions [94]. -It can also cause neurological complications [95,96], potentially including stroke, seizures or meningitis [97,98]. -In fact, autopsy samples suggest that SARS-CoV-2 may be able to enter the central nervous system via the neural–mucosal interface [99]. -COVID-19 has also been associated with an increased incidence of large vessel stroke, particularly in patients under the age of 40 [100], and other thrombotic events including pulmonary embolism and deep vein thrombosis [101]. -The mechanism behind these complications has been suggested to be related to coagulopathy, with reports indicating the presence of antiphospholipid antibodies [102] and elevated levels of d-dimer and fibrinogen degradation products in deceased patients [103]. -Other viral infections have been associated with coagulation defects and changes to the coagulation cascade; notably, SARS was also found to lead to disseminated intravascular coagulation and was associated with both pulmonary embolism and deep vein thrombosis [104]. -The mechanism behind these insults has been suggested to be related to inflammation-induced increases in the von Willebrand factor clotting protein, leading to a pro-coagulative state [104]. -Abnormal clotting (thromboinflammation or coagulopathy) has been increasingly discussed recently as a possible key mechanism in many cases of severe COVID-19, and may be associated with the high d-dimer levels often observed in severe cases [105,106,107]. -This excessive clotting in lung capillaries has been suggested to be related to a dysregulated activation of the complement system, part of the innate immune system [108,109].
+Consistent with the wide range of symptoms observed and the pathogenic mechanisms described above, COVID-19 can affect diverse body systems in addition to causing respiratory problems [95]. +For example, COVID-19 can lead to acute kidney injury, especially in patients with severe respiratory symptoms or certain preexisting conditions [96]. +It can also cause neurological complications [97,98], potentially including stroke, seizures or meningitis [99,100]. +In fact, autopsy samples suggest that SARS-CoV-2 may be able to enter the central nervous system via the neural–mucosal interface [101]. +COVID-19 has also been associated with an increased incidence of large vessel stroke, particularly in patients under the age of 40 [102], and other thrombotic events including pulmonary embolism and deep vein thrombosis [103]. +The mechanism behind these complications has been suggested to be related to coagulopathy, with reports indicating the presence of antiphospholipid antibodies [104] and elevated levels of d-dimer and fibrinogen degradation products in deceased patients [105]. +Other viral infections have been associated with coagulation defects and changes to the coagulation cascade; notably, SARS was also found to lead to disseminated intravascular coagulation and was associated with both pulmonary embolism and deep vein thrombosis [106]. +The mechanism behind these insults has been suggested to be related to inflammation-induced increases in the von Willebrand factor clotting protein, leading to a pro-coagulative state [106]. +Abnormal clotting (thromboinflammation or coagulopathy) has been increasingly discussed recently as a possible key mechanism in many cases of severe COVID-19, and may be associated with the high d-dimer levels often observed in severe cases [107,108,109]. +This excessive clotting in lung capillaries has been suggested to be related to a dysregulated activation of the complement system, part of the innate immune system [110,111].
2.5.1 Cytokine Release Syndrome
Symptoms of a disease can be caused by a pathogen, but they can also be caused by the immune system’s reaction to the pathogen. -A dysregulated immune response can cause significant damage to the host [110,111,112]. +A dysregulated immune response can cause significant damage to the host [112,113,114]. The inflammatory response has received particular attention for its role in both a healthy response to infection and a pathogenic one. -Inflammation is one of the most visible components of the immune response, as it is responsible for the hallmarks of injury, such as pain, heat, and swelling [113]. -In response to injury or to signaling by pattern recognition receptors indicating the detection of a molecular pattern associated with a pathogen or foreign body, the immune system stimulates leukocytes that travel to the site of the threat, where they then produce cytokines [113]. -Cytokines are a diverse group of small proteins that play an important role in intercellular signaling [114]. -Cytokines can be both pro- and anti-inflammatory, which means they can either stimulate or inhibit the production of additional cytokines [114,115]. -Some notable pro-inflammatory cytokines include the interleukins IL-1β and IL-6 and tumor necrosis factor α (TNF-α) [115]. -Anti-inflammatory cytokines play an immunoregulatory role complementary to the cascading effect of pro-inflammatory cytokines [114,115]. -A number of interleukins and interferons play anti-inflammatory roles, and receptors or receptor antagonists for inflammatory cytokines are also important for regulating inflammation [115]. -IL-10 is an anti-inflammatory cytokine of particular note because it regulates the expression of TNF-α, IL-1, and IL-6 [115]. -When the pro- and anti-inflammatory responses are both commensurate with the threat posed, the immune system drives a shift back to homeostasis [116]. +Inflammation is one of the most visible components of the immune response, as it is responsible for the hallmarks of injury, such as pain, heat, and swelling [115]. +In response to injury or to signaling by pattern recognition receptors indicating the detection of a molecular pattern associated with a pathogen or foreign body, the immune system stimulates leukocytes that travel to the site of the threat, where they then produce cytokines [115]. +Cytokines are a diverse group of small proteins that play an important role in intercellular signaling [116]. +Cytokines can be both pro- and anti-inflammatory, which means they can either stimulate or inhibit the production of additional cytokines [116,117]. +Some notable pro-inflammatory cytokines include the interleukins IL-1β and IL-6 and tumor necrosis factor α (TNF-α) [117]. +Anti-inflammatory cytokines play an immunoregulatory role complementary to the cascading effect of pro-inflammatory cytokines [116,117]. +A number of interleukins and interferons play anti-inflammatory roles, and receptors or receptor antagonists for inflammatory cytokines are also important for regulating inflammation [117]. +IL-10 is an anti-inflammatory cytokine of particular note because it regulates the expression of TNF-α, IL-1, and IL-6 [117]. +When the pro- and anti-inflammatory responses are both commensurate with the threat posed, the immune system drives a shift back to homeostasis [118]. However, when the responses are disproportionate, the cytokine response can become dysregulated. -Too low of an inflammatory response will not eliminate the immune threat [116]. -In contrast, if the response is dysregulated towards excessive pro-inflammatory cytokine activity, inflammation can cascade [117] and cause cell damage, among other problems [113]. -Elevated levels of inflammation over the long-term are associated with many chronic health conditions, including type 2 diabetes, dementia and Alzheimer’s, and arthritis [118]. -On a shorter timescale, dysregulated systemic inflammation can cause sepsis, which can lead to multi-organ failure and death [114,119].
+Too low of an inflammatory response will not eliminate the immune threat [118]. +In contrast, if the response is dysregulated towards excessive pro-inflammatory cytokine activity, inflammation can cascade [119] and cause cell damage, among other problems [115]. +Elevated levels of inflammation over the long-term are associated with many chronic health conditions, including type 2 diabetes, dementia and Alzheimer’s, and arthritis [120]. +On a shorter timescale, dysregulated systemic inflammation can cause sepsis, which can lead to multi-organ failure and death [116,121].Cytokines have been investigated for their role in the immune response to lung infections long before the COVID-19 pandemic. -Dysregulation of the inflammatory response, including elevated levels of pro-inflammatory cytokines, is found in patients with ARDS, which is a severe condition that can arise from pneumonia, SARS, and COVID-19 [117]. -One study of patients with and at risk for ARDS, specifically those who were intubated for medical ventilation, found that shortly after the onset of ARDS, anti-inflammatory cytokine concentration in BALF increased relative to the concentration of pro-inflammatory cytokines [120]. -The results suggest that an increase in pro-inflammatory cytokines such as IL-6 may signal the onset of ARDS, but recovery depends on an increased anti-inflammatory response [120]. +Dysregulation of the inflammatory response, including elevated levels of pro-inflammatory cytokines, is found in patients with ARDS, which is a severe condition that can arise from pneumonia, SARS, and COVID-19 [119]. +One study of patients with and at risk for ARDS, specifically those who were intubated for medical ventilation, found that shortly after the onset of ARDS, anti-inflammatory cytokine concentration in BALF increased relative to the concentration of pro-inflammatory cytokines [122]. +The results suggest that an increase in pro-inflammatory cytokines such as IL-6 may signal the onset of ARDS, but recovery depends on an increased anti-inflammatory response [122]. However, patients with severe ARDS were excluded from this study. -Acute phase response to an infection can also cause damage to the capillary endothelium, allowing leaks that disrupt the balance between pro-inflammatory cytokines and their regulators [120]. -Hyperactivity of the pro-inflammatory response due to lung infection is commonly associated with acute lung injury and more rarely with the more severe manifestation, ARDS [114]. -The heightened inflammatory response in the lungs can also serve as a source for systemic inflammation, or sepsis, and potentially multi-organ failure [114]. -The shift from local to systemic inflammation is a phenomenon often referred to broadly as a cytokine storm [114] or, more precisely, as cytokine release syndrome [121]. -Sepsis is a known possible complication of pneumonia, and in an analysis of over 1,400 US pneumonia patients, IL-6, tumor necrosis factor (TNF), and IL-10 were found to be elevated at intake in patients who developed severe sepsis and/or ultimately deceased [122]. -However, unlike the study analyzing pro- and anti-inflammatory cytokines in ARDS patients [120], this study reported that unbalanced pro-/anti-inflammatory cytokine profiles were rare. +Acute phase response to an infection can also cause damage to the capillary endothelium, allowing leaks that disrupt the balance between pro-inflammatory cytokines and their regulators [122]. +Hyperactivity of the pro-inflammatory response due to lung infection is commonly associated with acute lung injury and more rarely with the more severe manifestation, ARDS [116]. +The heightened inflammatory response in the lungs can also serve as a source for systemic inflammation, or sepsis, and potentially multi-organ failure [116]. +The shift from local to systemic inflammation is a phenomenon often referred to broadly as a cytokine storm [116] or, more precisely, as cytokine release syndrome [123]. +Sepsis is a known possible complication of pneumonia, and in an analysis of over 1,400 US pneumonia patients, IL-6, tumor necrosis factor (TNF), and IL-10 were found to be elevated at intake in patients who developed severe sepsis and/or ultimately deceased [124]. +However, unlike the study analyzing pro- and anti-inflammatory cytokines in ARDS patients [122], this study reported that unbalanced pro-/anti-inflammatory cytokine profiles were rare. This discrepancy could be related to the fact that the sepsis study measured only three cytokines. Regardless of variation in the anti-inflammatory response, prior work has therefore made it clear that pulmonary infection and injury are associated with systemic inflammation and with sepsis. -While IL-6 is a biomarker sometimes used to assess cytokine storm activity in sepsis [114], the relationship between cytokine profiles and the risks associated with sepsis may be more complex. -In fact, although IL-6 has traditionally been considered pro-inflammatory, its pleiotropic effects via both classical and trans-signaling allow it to play an integral role in both the inflammatory and anti-inflammatory responses [123], leading it to be associated with both healthy and pathological responses to viral threat [124].
+While IL-6 is a biomarker sometimes used to assess cytokine storm activity in sepsis [116], the relationship between cytokine profiles and the risks associated with sepsis may be more complex. +In fact, although IL-6 has traditionally been considered pro-inflammatory, its pleiotropic effects via both classical and trans-signaling allow it to play an integral role in both the inflammatory and anti-inflammatory responses [125], leading it to be associated with both healthy and pathological responses to viral threat [126].The inflammatory response was identified early on as a potential driver of COVID-19 outcomes due to existing research in SARS and emerging research in COVID-19. -In addition to the known role of cytokines in ARDS and lung infection more broadly, immunohistological analysis at autopsy of patients deceased from SARS revealed that ACE2-expressing cells that were infected by SARS-CoV-1 showed elevated expression of IL-6, IL-1β, and TNF-α [125]. -Similarly, the introduction of the S protein from SARS-CoV-1 to mouse macrophages was found to increase production of IL-6 and TNF-α [126]. -For SARS-CoV-2 infection leading to COVID-19, early reports described a cytokine storm syndrome-like response in patients with particularly severe infections [78,127,128]. -Among patients hospitalized with COVID-19 in Wuhan, China, 112 out of 191 (59%) developed sepsis, including all 54 of the non-survivors [35]. -However, the argument has been made that while the cytokine levels observed in COVID-19 patients fall outside of the normal range, they are not as high as typically found in patients with ARDS [129]. -Regardless, inflammation has received significant interest both in regards to the pathology of COVID-19 as well as potential avenues for treatment, as the relationship between the cytokine storm and the pathophysiology of COVID-19 has led to the suggestion that a number of immunomodulatory pharmaceutical interventions could hold therapeutic value for the treatment of COVID-19 [130].
+In addition to the known role of cytokines in ARDS and lung infection more broadly, immunohistological analysis at autopsy of patients deceased from SARS revealed that ACE2-expressing cells that were infected by SARS-CoV-1 showed elevated expression of IL-6, IL-1β, and TNF-α [127]. +Similarly, the introduction of the S protein from SARS-CoV-1 to mouse macrophages was found to increase production of IL-6 and TNF-α [128]. +For SARS-CoV-2 infection leading to COVID-19, early reports described a cytokine storm syndrome-like response in patients with particularly severe infections [80,129,130]. +Among patients hospitalized with COVID-19 in Wuhan, China, 112 out of 191 (59%) developed sepsis, including all 54 of the non-survivors [37]. +However, the argument has been made that while the cytokine levels observed in COVID-19 patients fall outside of the normal range, they are not as high as typically found in patients with ARDS [131]. +Regardless, inflammation has received significant interest both in regards to the pathology of COVID-19 as well as potential avenues for treatment, as the relationship between the cytokine storm and the pathophysiology of COVID-19 has led to the suggestion that a number of immunomodulatory pharmaceutical interventions could hold therapeutic value for the treatment of COVID-19 [132].2.5.2 Pediatric Presentation
The presentation of COVID-19 infection can vary greatly among pediatric patients and, in some cases, manifests in distinct ways from COVID-19 in adults. -Evidence suggests that while children and adolescents tend to have mostly asymptomatic infections, those that are symptomatic typically exhibit a mild illness [131,132,133,134]. -One review examined symptoms reported in 17 studies of children infected with COVID-19 during the early months of the COVID-19 epidemic in China and one study from Singapore [135]. +Evidence suggests that while children and adolescents tend to have mostly asymptomatic infections, those that are symptomatic typically exhibit a mild illness [133,134,135,136]. +One review examined symptoms reported in 17 studies of children infected with COVID-19 during the early months of the COVID-19 epidemic in China and one study from Singapore [137]. In the more than a thousand cases described, the most common reports were for mild symptoms such as fever, dry cough, fatigue, nasal congestion and/or runny nose, while three children were reported to be asymptomatic. Severe lower respiratory infection was described in only one of the pediatric cases reviewed. Gastrointestinal symptoms such as vomiting or diarrhea were occasionally reported. -Radiologic findings were not always reported in the case studies reviewed, but when they were mentioned they included bronchial thickening, ground-glass opacities, and/or inflammatory lesions [135]. -Neurological symptoms have also been reported [136].
+Radiologic findings were not always reported in the case studies reviewed, but when they were mentioned they included bronchial thickening, ground-glass opacities, and/or inflammatory lesions [137]. +Neurological symptoms have also been reported [138].These analyses indicate that most pediatric cases of COVID-19 are not severe. -Indeed, it is estimated that less than 1% of pediatric cases result in critical illness [133,137]. -However, serious complications and, in rare cases, deaths have occurred [138]. +Indeed, it is estimated that less than 1% of pediatric cases result in critical illness [135,139]. +However, serious complications and, in rare cases, deaths have occurred [140]. Of particular interest, children have occasionally experienced a serious inflammatory syndrome, multisystem inflammatory syndrome in children (MIS-C), following COVID-19 infection. -This syndrome is similar in some respects to Kawasaki disease, including Kawasaki disease shock syndrome [139,140,141] and is thought to be a distinct clinical manifestation of SARS-CoV-2 due to its distinct cytokine profile and the presence of burr cells in peripheral blood smears [142,143]. -MIS-C has been associated with heart failure in some cases [144]. -One case study [145] described an adult who appeared to show symptoms similar to MIS-C after exposure to COVID-19, but cautioned against broad conclusions; a second possible adult case has also been reported [146]. +This syndrome is similar in some respects to Kawasaki disease, including Kawasaki disease shock syndrome [141,142,143] and is thought to be a distinct clinical manifestation of SARS-CoV-2 due to its distinct cytokine profile and the presence of burr cells in peripheral blood smears [144,145]. +MIS-C has been associated with heart failure in some cases [146]. +One case study [147] described an adult who appeared to show symptoms similar to MIS-C after exposure to COVID-19, but cautioned against broad conclusions; a second possible adult case has also been reported [148]. The presentation of SARS-CoV-2 infection is therefore likely to be largely distinct between adult and pediatric populations.
2.6 Systems-Level Effects
Systems biology provides a cross-disciplinary analytical paradigm through which the host response to an infection can be analyzed. This field integrates the “omics” fields (genomics, transcriptomics, proteomics, metabolomics, etc.) using bioinformatics and other computational approaches. -Over the last decade, systems biology approaches have been used widely to study the pathogenesis of diverse types of life-threatening acute and chronic infectious diseases [147]. -Omics-based studies have also provided meaningful information regarding host immune responses and surrogate protein markers in several viral, bacterial and protozoan infections [148]. +Over the last decade, systems biology approaches have been used widely to study the pathogenesis of diverse types of life-threatening acute and chronic infectious diseases [149]. +Omics-based studies have also provided meaningful information regarding host immune responses and surrogate protein markers in several viral, bacterial and protozoan infections [150]. Though the complex pathogenesis and clinical manifestations of SARS-CoV-2 infection are not yet fully understood, omics technologies offer the opportunity for discovery-driven analysis of biological changes associated with SARS-CoV-2 infection. For example, previous studies suggest that infection by coronaviruses, such as SARS-CoV-1 and MERS-CoV, as well as other viruses, is associated with the upregulation of ACE2. -In several preliminary assays and an analysis of microarray data, ACE2 expression was reported to be significantly upregulated following infection of human embryonic kidney cells and human airway epithelial cells [78]. -This study also reported that direct stimulation with inflammatory cytokines such as type I interferons (e.g., IFNβ) resulted in the upregulation of ACE2 in human bronchial epithelial cells, with treated groups showing four-fold higher ACE2 expression than control groups at 18 hours post-treatment [78]. +In several preliminary assays and an analysis of microarray data, ACE2 expression was reported to be significantly upregulated following infection of human embryonic kidney cells and human airway epithelial cells [80]. +This study also reported that direct stimulation with inflammatory cytokines such as type I interferons (e.g., IFNβ) resulted in the upregulation of ACE2 in human bronchial epithelial cells, with treated groups showing four-fold higher ACE2 expression than control groups at 18 hours post-treatment [80]. While it is still unclear whether SARS-CoV-2 facilitates the positive regulation of its own transmission between host cells, the host immune response itself likely plays a key role in mediating infection-associated pathologies. For this reason, the application of omics technologies to the process of characterizing the host response is expected to provide novel insights into how hosts respond to SARS-CoV-2 infection and how these changes might influence COVID-19 outcomes.
2.6.1 Transcriptomics
-In addition to the study described above [78], two other studies have profiled expression following SARS-CoV-2 infection using human cell lines. -The first study [149] compared transcriptional responses to SARS-CoV-2 and to other respiratory viruses, including MERS-CoV, SARS-CoV, Human parainfluenza virus 3, Respiratory syncytial virus, and Influenza A virus. +
In addition to the study described above [80], two other studies have profiled expression following SARS-CoV-2 infection using human cell lines. +The first study [151] compared transcriptional responses to SARS-CoV-2 and to other respiratory viruses, including MERS-CoV, SARS-CoV, Human parainfluenza virus 3, Respiratory syncytial virus, and Influenza A virus. The responses of three human cell lines were analyzed: A549 (adenocarcinomic human alveolar basal epithelial cells), Calu-3 (human airway epithelial cells derived from human bronchial submucosal glands), and MRC-5 (human fetal lung fibroblast cells). As the viral entry portal ACE2 has low expression in A549 cells, these cells were supplemented with adenovirus-based vectors expressing either mCherry (a fluorescent protein used as a control) or ACE2 (A549-ACE2). The authors also measured host transcriptional responses to SARS-CoV-2 in primary normal human bronchial epithelial cells (HBEC or NHBE cells), nasal washes from an animal model (ferret), and lung samples from two COVID-19 patients. @@ -964,119 +965,119 @@
[150] that showed that the SARS-CoV-2 ORF3b gene suppresses IFNB1 promoter activity (IFN-I induction) more efficiently than the SARS-CoV-1 ORF3b gene. +This hypothesis was further supported by a recent study [152] that showed that the SARS-CoV-2 ORF3b gene suppresses IFNB1 promoter activity (IFN-I induction) more efficiently than the SARS-CoV-1 ORF3b gene. Taken together, these findings suggest that a unique cytokine profile is associated with the response to the SARS-CoV-2 virus, and that this response differs depending on the extent of exposure. -
Another study [151] analyzed dynamic transcriptional responses to SARS-CoV-2 and SARS-CoV-1. +
Another study [153] analyzed dynamic transcriptional responses to SARS-CoV-2 and SARS-CoV-1. They characterized the response of three human cell lines, H1299 (human non-small cell lung carcinoma cell line), Calu-3, and Caco-2 (human epithelial colorectal adenocarcinoma cell line), at 4 to 36 hours post infection. Using poly(A) bulk RNA-seq, the authors found negligible susceptibility of H1299 cells (< 0.08 viral read percentage of total reads) compared to Caco-2 and Calu-3 cells (>10% of viral reads). This finding suggests that the risk of infection varies among cell types, and that cell type could influence which hosts are more or less susceptible. Based on visual inspection of microscopy images alongside transcriptional profiling, the authors also showed distinct responses among the host cell lines evaluated. In contrast to Caco-2, Calu-3 cells infected with SARS-CoV-2 showed signs of impaired growth and cell death at 24 hours post infection, as well as moderate IFN induction with a strong up-regulation of IFN-stimulated genes. -Interestingly, the results were similar to those reported in Calu-3 cells exposed to much higher levels of SARS-CoV-2 [149], as described above. +Interestingly, the results were similar to those reported in Calu-3 cells exposed to much higher levels of SARS-CoV-2 [151], as described above. This finding suggests that IFN induction in Calu-3 cells is not dependent on the level of exposure, in contrast to A549-ACE2 cells. -The discrepancy could be explained by the observations that Calu-3 cells are highly susceptible to SARS-CoV-2 and show rapid viral replication [68], whereas A549 cells are incompatible with SARS-CoV-2 infection [152]. +The discrepancy could be explained by the observations that Calu-3 cells are highly susceptible to SARS-CoV-2 and show rapid viral replication [70], whereas A549 cells are incompatible with SARS-CoV-2 infection [154]. This discrepancy raises the concern that in vitro models may vary in their similarity to the human response, underscoring the importance of follow-up studies in additional models.
2.6.2 Proteomics
-One early proteomics study investigated changes associated with in vitro SARS-CoV-2 infection using Caco-2 cells [153]. +
One early proteomics study investigated changes associated with in vitro SARS-CoV-2 infection using Caco-2 cells [155]. This study reported that SARS-CoV-2 induced alterations in multiple vital physiological pathways, including translation, splicing, carbon metabolism and nucleic acid metabolism in the host cells. Another area of interest is whether SARS-CoV-2 is likely to induce similar changes to other HCoV. -For example, because of the high level of sequence homology between SARS-CoV-2 and SARS-CoV-1, it has been hypothesized that sera from convalescent SARS-CoV-1 patients might show some efficacy in cross-neutralizing SARS-CoV-2-S-driven entry [67]. -However, despite the high level of sequence homology, certain protein structures might be immunologically distinct, which would be likely to prohibit effective cross-neutralization across different SARS species [154]. -Consequently, proteomic analyses of SARS-CoV-1 might also provide some essential information regarding the new pathogen [155,156].
-Considering the paucity of omics-level big data sets for SARS-CoV-2 currently available, existing data hubs that contain information for other coronaviruses such as UniProt [157], NCBI Genome Database [158], The Immune Epitope Database and Analysis Resource [159], and The Virus Pathogen Resource [160] will serve as useful resources for comparative bioinformatics research of SARS-CoV-2. +For example, because of the high level of sequence homology between SARS-CoV-2 and SARS-CoV-1, it has been hypothesized that sera from convalescent SARS-CoV-1 patients might show some efficacy in cross-neutralizing SARS-CoV-2-S-driven entry [69]. +However, despite the high level of sequence homology, certain protein structures might be immunologically distinct, which would be likely to prohibit effective cross-neutralization across different SARS species [156]. +Consequently, proteomic analyses of SARS-CoV-1 might also provide some essential information regarding the new pathogen [157,158].
+Considering the paucity of omics-level big data sets for SARS-CoV-2 currently available, existing data hubs that contain information for other coronaviruses such as UniProt [159], NCBI Genome Database [160], The Immune Epitope Database and Analysis Resource [161], and The Virus Pathogen Resource [162] will serve as useful resources for comparative bioinformatics research of SARS-CoV-2. Using such databases, the systems-level reconstruction of protein-protein interaction networks will enable the generation of hypotheses about the mechanism of action of SARS-CoV-2 and suggest potential drug targets. -In an initial study [161], 26 of the 29 SARS-CoV-2 proteins were cloned and expressed in HEK293T kidney cells, allowing for the identification of 332 high-confidence human proteins interacting with them. +In an initial study [163], 26 of the 29 SARS-CoV-2 proteins were cloned and expressed in HEK293T kidney cells, allowing for the identification of 332 high-confidence human proteins interacting with them. Notably, this study suggested that SARS-CoV-2 interacts with innate immunity pathways. Ranking pathogens by the similarity between their interactomes and that of SARS-CoV-2 suggested West Nile virus, Mycobacterium tuberculosis, and human papillomavirus infections as the top three hits. Therefore, given the lung symptoms associated with COVID-19, the Mycobacterium tuberculosis host-pathogen interactome in particular might provide new insights to the mechanism of SARS-CoV-2 infection. -Additionally, it was suggested that the envelope protein, E, could disrupt host bromodomain-containing proteins, i.e., BRD2 and BRD4, that bind to histones, and the spike protein could likely intervene in viral fusion by modulating the GOLGA7-ZDHHC5 acyl-transferase complex to increase palmitoylation, which is a post-translational modification that affects how proteins interact with membranes [162].
-Another study [163] used patient-derived peripheral blood mononuclear cells to identify 251 host proteins targeted by SARS-CoV-2. +Additionally, it was suggested that the envelope protein, E, could disrupt host bromodomain-containing proteins, i.e., BRD2 and BRD4, that bind to histones, and the spike protein could likely intervene in viral fusion by modulating the GOLGA7-ZDHHC5 acyl-transferase complex to increase palmitoylation, which is a post-translational modification that affects how proteins interact with membranes [164].
+Another study [165] used patient-derived peripheral blood mononuclear cells to identify 251 host proteins targeted by SARS-CoV-2. This study also reported that more than 200 host proteins were disrupted following infection. In particular, a network analysis showed that nsp9 and nsp10 interacted with NF-Kappa-B-Repressing Factor, which encodes a transcriptional repressor that mediates repression of genes responsive to Nuclear Factor kappa-light-chain-enhancer of activated B-cells. -These genes are important to pro-, and potentially also anti-, inflammatory signaling [164]. +These genes are important to pro-, and potentially also anti-, inflammatory signaling [166]. This finding could explain the exacerbation of the immune response that shapes the pathology and the high cytokine levels characteristic of COVID-19, possibly due to the chemotaxis of neutrophils mediated by IL-8 and IL-6. -Finally, it was suggested [165] that the E protein of both SARS-CoV-1 and SARS-CoV-2 has a conserved Bcl-2 Homology 3-like motif, which could inhibit anti-apoptosis proteins, e.g., BCL2, and trigger the apoptosis of T cells. +Finally, it was suggested [167] that the E protein of both SARS-CoV-1 and SARS-CoV-2 has a conserved Bcl-2 Homology 3-like motif, which could inhibit anti-apoptosis proteins, e.g., BCL2, and trigger the apoptosis of T cells. Several compounds are known to disrupt the host-pathogen protein interactome, largely through the inhibition of host proteins. Therefore, this research identifies candidate targets for intervention and suggests that drugs modulating protein-level interactions between virus and host could be relevant to treating COVID-19. By revealing which genes are perturbed during SARS-CoV-2 infection, proteomics-based analyses can thus provide novel insights into host-virus interaction and serve to generate new avenues of investigation for therapeutics.
2.7 Viral Virulence
-Like that of SARS-CoV-1, the entry of SARS-CoV-2 into host cells is mediated by interactions between the viral spike glycoprotein, S, and human ACE2 (hACE2) [64,67,166,167,168,169,170,171]. +
Like that of SARS-CoV-1, the entry of SARS-CoV-2 into host cells is mediated by interactions between the viral spike glycoprotein, S, and human ACE2 (hACE2) [66,69,168,169,170,171,172,173]. Differences in how the S proteins of the two viruses interact with hACE2 could partially account for the increased transmissibility of SARS-CoV-2. -Recent studies have reported conflicting binding constants for the S-hACE2 interaction, though they have agreed that the SARS-CoV-2 S protein binds with equal, if not greater, affinity than the SARS-CoV-1 S protein does [51,64,169]. -The C-terminal domain of the SARS-CoV-2 S protein in particular was identified as the key region of the virus that interacts with hACE2, and the crystal structure of the C-terminal domain of the SARS-CoV-2 S protein in complex with hACE2 reveals stronger interaction and a higher affinity for receptor binding than that of SARS-CoV-1 [170]. -Among the 14 key binding residues identified in the SARS-CoV-1 S protein, eight are conserved in SARS-CoV-2, and the remaining six are semi-conservatively substituted, potentially explaining variation in binding affinity [64,169]. -Recent crystal structures have shown that the receptor binding domain (RBD) of the SARS-CoV-2 S protein, like that of other coronaviruses, undergoes stochastic hinge-like movement that flips it from a “closed” conformation, in which key binding residues are hidden at the interface between protomers, to an “open” one [51,64]. +Recent studies have reported conflicting binding constants for the S-hACE2 interaction, though they have agreed that the SARS-CoV-2 S protein binds with equal, if not greater, affinity than the SARS-CoV-1 S protein does [53,66,171]. +The C-terminal domain of the SARS-CoV-2 S protein in particular was identified as the key region of the virus that interacts with hACE2, and the crystal structure of the C-terminal domain of the SARS-CoV-2 S protein in complex with hACE2 reveals stronger interaction and a higher affinity for receptor binding than that of SARS-CoV-1 [172]. +Among the 14 key binding residues identified in the SARS-CoV-1 S protein, eight are conserved in SARS-CoV-2, and the remaining six are semi-conservatively substituted, potentially explaining variation in binding affinity [66,171]. +Recent crystal structures have shown that the receptor binding domain (RBD) of the SARS-CoV-2 S protein, like that of other coronaviruses, undergoes stochastic hinge-like movement that flips it from a “closed” conformation, in which key binding residues are hidden at the interface between protomers, to an “open” one [53,66]. Because the RBD plays such a critical role in viral entry, blocking its interaction with ACE2 could represent a promising therapeutic approach. -Nevertheless, despite the high structural homology between the SARS-CoV-2 RBD and that of SARS-CoV-1, monoclonal antibodies targeting SARS-CoV-1 RBD failed to bind to SARS-CoV-2-RBD [51]. -However, in early research, sera from convalescent SARS patients were found to inhibit SARS-CoV-2 viral entry in vitro, albeit with lower efficiency than it inhibited SARS-CoV-1 [67].
+Nevertheless, despite the high structural homology between the SARS-CoV-2 RBD and that of SARS-CoV-1, monoclonal antibodies targeting SARS-CoV-1 RBD failed to bind to SARS-CoV-2-RBD [53]. +However, in early research, sera from convalescent SARS patients were found to inhibit SARS-CoV-2 viral entry in vitro, albeit with lower efficiency than it inhibited SARS-CoV-1 [69].Comparative genomic analysis reveals that several regions of the coronavirus genome are likely critical to virulence. -The S1 domain of the spike protein, which contains the receptor binding motif, evolves more rapidly than S’s S2 domain [57,58]. -However, even within the S1 domain, some regions are more conserved than others, with the receptors in S1’s N-terminal domain (S1-NTD) evolving more rapidly than those in its C-terminal domain (S1-CTD) [58]. -Both S1-NTD and S1-CTD are involved in receptor binding and can function as RBDs to bind proteins and sugars [57], but RBDs in the S1-NTD typically bind to sugars, while those in the S1-CTD recognize protein receptors [47]. -Viral receptors show higher affinity with protein receptors than sugar receptors [47], which suggests that positive selection on or relaxed conservation of the S1-NTD might reduce the risk of a deleterious mutation that would prevent binding. -The SARS-CoV-2 S protein also contains an RRAR furin recognition site at the S1/S2 junction [51,64], setting it apart from both bat coronavirus RaTG13, with which it shares 96% genome sequence identity, and SARS-CoV-1 [12]. -Such furin cleavage sites are commonly found in highly virulent influenza viruses, and as such may contribute to the heightened pathogenicity of SARS-CoV-2 [172,173]. +The S1 domain of the spike protein, which contains the receptor binding motif, evolves more rapidly than S’s S2 domain [59,60]. +However, even within the S1 domain, some regions are more conserved than others, with the receptors in S1’s N-terminal domain (S1-NTD) evolving more rapidly than those in its C-terminal domain (S1-CTD) [60]. +Both S1-NTD and S1-CTD are involved in receptor binding and can function as RBDs to bind proteins and sugars [59], but RBDs in the S1-NTD typically bind to sugars, while those in the S1-CTD recognize protein receptors [49]. +Viral receptors show higher affinity with protein receptors than sugar receptors [49], which suggests that positive selection on or relaxed conservation of the S1-NTD might reduce the risk of a deleterious mutation that would prevent binding. +The SARS-CoV-2 S protein also contains an RRAR furin recognition site at the S1/S2 junction [53,66], setting it apart from both bat coronavirus RaTG13, with which it shares 96% genome sequence identity, and SARS-CoV-1 [14]. +Such furin cleavage sites are commonly found in highly virulent influenza viruses, and as such may contribute to the heightened pathogenicity of SARS-CoV-2 [174,175]. The ongoing evolution of the spike protein can be seen from the genomic data. -For example, the mutation D614G became dominant by the end of May 2020, soon after its initial appearance in mid-March [174,175], and a variant carrying two mutations (N501Y and 69–70del) that was first observed in the UK in October 2020 [176] has quickly spread around the world [177,178]. +For example, the mutation D614G became dominant by the end of May 2020, soon after its initial appearance in mid-March [176,177], and a variant carrying two mutations (N501Y and 69–70del) that was first observed in the UK in October 2020 [178] has quickly spread around the world [179,180]. Effective cell entry is a critical component to pathogenesis and therefore an important process to understand when examining possible therapeutics.
2.8 Mechanism of Transmission
Once a human host is infected with a virus, person-to-person viral transmission can occur through several possible mechanisms. -The primary mechanisms associated with respiratory viruses are contact, droplet, and aerosol transmission [179]. -Contact transmission can occur through either contact with a contagious person or contact with active viral particles on a contaminated surface [180]. -This latter mode of transmission is also called fomite transmission [181]. -Viral particles can enter the body if they then come in contact with the oral, nasal, eye, or other mucus membranes [180]. -Droplet transmission occurs when a contagious individual sneezes, coughs, or exhales and produces respiratory droplets that can contain a large number of viral particles [180]. -Contact with these droplets can occur through direct exposure to the droplets, such as breathing in droplets produced by a sneeze [180]. -The droplets can also potentially settle on a surface and contribute to fomite transmission [180]. -Aerosol transmission refers to much smaller particles (less than 5 micrometers) that are also produced by sneezing, coughing, or exhaling [179,180]. -The small size of these particles allows them to remain suspended over a longer period of time and potentially to be moved by air currents [180]. -Additionally, viral particles deposited on surfaces via large respiratory droplets can also later be aerosolized [180]. -Droplet and/or contact transmission are both well-accepted modes of transmission for many viruses associated with common human illnesses, including influenza and rhinovirus [180]. +The primary mechanisms associated with respiratory viruses are contact, droplet, and aerosol transmission [181]. +Contact transmission can occur through either contact with a contagious person or contact with active viral particles on a contaminated surface [182]. +This latter mode of transmission is also called fomite transmission [183]. +Viral particles can enter the body if they then come in contact with the oral, nasal, eye, or other mucus membranes [182]. +Droplet transmission occurs when a contagious individual sneezes, coughs, or exhales and produces respiratory droplets that can contain a large number of viral particles [182]. +Contact with these droplets can occur through direct exposure to the droplets, such as breathing in droplets produced by a sneeze [182]. +The droplets can also potentially settle on a surface and contribute to fomite transmission [182]. +Aerosol transmission refers to much smaller particles (less than 5 micrometers) that are also produced by sneezing, coughing, or exhaling [181,182]. +The small size of these particles allows them to remain suspended over a longer period of time and potentially to be moved by air currents [182]. +Additionally, viral particles deposited on surfaces via large respiratory droplets can also later be aerosolized [182]. +Droplet and/or contact transmission are both well-accepted modes of transmission for many viruses associated with common human illnesses, including influenza and rhinovirus [182]. The extent to which aerosol transmission contributes to the spread of respiratory viruses is less clear. -In influenza A, for example, viral particles can be detected in aerosols produced by infected individuals, but the extent to which these particles drive the spread of influenza A infection remains under debate [179,180,182,183,184]. -Regardless of its role in the spread of influenza A, however, aerosol transmission likely played a role in outbreaks such as the 1918 Spanish Influenza (H1N1) and 2009 “swine flu” (pH1N1) [184]. +In influenza A, for example, viral particles can be detected in aerosols produced by infected individuals, but the extent to which these particles drive the spread of influenza A infection remains under debate [181,182,184,185,186]. +Regardless of its role in the spread of influenza A, however, aerosol transmission likely played a role in outbreaks such as the 1918 Spanish Influenza (H1N1) and 2009 “swine flu” (pH1N1) [186]. Contact, droplet, and aerosol transmission are therefore all worth evaluating when considering possible modes of transmission for a respiratory virus like SARS-CoV-2.
-All three of these mechanisms have been identified as possible contributors to the transmission of HCoVs [180], including the highly pathogenic coronaviruses SARS-CoV-1 and MERS-CoV [28,185]. -Transmission of SARS-CoV-1 is thought to proceed primarily through droplet transmission, but aerosol transmission is also considered possible [180], and fomite transmission may have also played an important role in some outbreaks [186]. -Similarly, the primary mechanism of MERS transmission is thought to be droplets because inter-individual transmission appears to be associated with close interpersonal contact (e.g., household or healthcare settings), but aerosolized particles of the MERS virus have been reported to persist much more robustly than influenza A under a range of environmental conditions [187,188]. -While droplet-based and contact transmission were initially put forward as the greatest concern for the spread of SARS-CoV-2 [189], as additional information has emerged, the possibility of aerosol transmission has also been raised [190,191,192]. -For example, the detection of SARS-CoV-2 viral particles in air samples taken from hospitals treating COVID-19 patients led to the concern that the virus could be spreading via aerosols [193]. -The stability of the virus both in aerosols and on a variety of surfaces appeared similar to that of SARS-CoV-1 [191]. -However, while the possibility of aerosol transmission seems plausible, the evidence suggests that droplet transmission is the dominant mechanism driving the spread of the virus [194], and the risk of fomite transmission under real-world conditions is likely to be substantially lower than the conditions used for experimental analyses [195]. +
All three of these mechanisms have been identified as possible contributors to the transmission of HCoVs [182], including the highly pathogenic coronaviruses SARS-CoV-1 and MERS-CoV [30,187]. +Transmission of SARS-CoV-1 is thought to proceed primarily through droplet transmission, but aerosol transmission is also considered possible [182], and fomite transmission may have also played an important role in some outbreaks [188]. +Similarly, the primary mechanism of MERS transmission is thought to be droplets because inter-individual transmission appears to be associated with close interpersonal contact (e.g., household or healthcare settings), but aerosolized particles of the MERS virus have been reported to persist much more robustly than influenza A under a range of environmental conditions [189,190]. +While droplet-based and contact transmission were initially put forward as the greatest concern for the spread of SARS-CoV-2 [191], as additional information has emerged, the possibility of aerosol transmission has also been raised [192,193,194]. +For example, the detection of SARS-CoV-2 viral particles in air samples taken from hospitals treating COVID-19 patients led to the concern that the virus could be spreading via aerosols [195]. +The stability of the virus both in aerosols and on a variety of surfaces appeared similar to that of SARS-CoV-1 [193]. +However, while the possibility of aerosol transmission seems plausible, the evidence suggests that droplet transmission is the dominant mechanism driving the spread of the virus [196], and the risk of fomite transmission under real-world conditions is likely to be substantially lower than the conditions used for experimental analyses [197]. These mechanisms may differ in their relevance to different types of transmission events, such as transmission within households, nosocomial transmissions, and transmission in indoor versus outdoor spaces.
2.8.1 Symptoms and Viral Spread
Other aspects of pathogenesis are also important to understanding how the virus spreads, especially the relationship between symptoms, viral shedding, and contagiousness. -Symptoms associated with reported cases of COVID-19 range from mild to severe [44], but some individuals who contract COVID-19 remain asymptomatic throughout the duration of the illness [196]. -The incubation period, or the time period between exposure and the onset of symptoms, has been estimated at five to eight days, with means of 4.91 (95% confidence interval (CI) 4.35-5.69) and 7.54 (95% CI 6.76-8.56) reported in two different Asian cities and a median of 5 (IQR 1 to 6) reported in a small number of patients in a Beijing hospital [197,198]. +Symptoms associated with reported cases of COVID-19 range from mild to severe [46], but some individuals who contract COVID-19 remain asymptomatic throughout the duration of the illness [198]. +The incubation period, or the time period between exposure and the onset of symptoms, has been estimated at five to eight days, with means of 4.91 (95% confidence interval (CI) 4.35-5.69) and 7.54 (95% CI 6.76-8.56) reported in two different Asian cities and a median of 5 (IQR 1 to 6) reported in a small number of patients in a Beijing hospital [199,200]. However, the exact relationship between contagiousness and viral shedding remains unclear. -Estimates suggest that viral shedding can, in some cases, begin as early as 12.3 days (95% CI 5.9-17.0) before the onset of symptoms, although this was found to be very rare, with less than 0.1% of transmission events occurring 7 or more days before symptom onset [199]. -Transmissibility appeared to peak around the onset of symptoms (95% CI -0.9 - 0.9 days), and only 44% (95% CI 30–57%) of transmission events were estimated to occur from presymptomatic contacts [199]. -As these trends became apparent, concerns arose due to the potential for individuals who did not yet show symptoms to transmit the virus [200]. +Estimates suggest that viral shedding can, in some cases, begin as early as 12.3 days (95% CI 5.9-17.0) before the onset of symptoms, although this was found to be very rare, with less than 0.1% of transmission events occurring 7 or more days before symptom onset [201]. +Transmissibility appeared to peak around the onset of symptoms (95% CI -0.9 - 0.9 days), and only 44% (95% CI 30–57%) of transmission events were estimated to occur from presymptomatic contacts [201]. +As these trends became apparent, concerns arose due to the potential for individuals who did not yet show symptoms to transmit the virus [202]. Recovered individuals may also be able to transmit the virus after their symptoms cease. -Estimates of the communicable period based on twenty-four individuals who tested positive for SARS-CoV-2 prior to or without developing symptoms estimated that individuals may be contagious for one to twenty-one days, but they note that this estimate may be low [196]. -In an early study, viral nucleic acids were reported to remain at observable levels in the respiratory specimens of recovering hospitalized COVID-19 patients for a median of 20 days and with a maximum observed duration through 37 days, when data collection for the study ceased [35]. +Estimates of the communicable period based on twenty-four individuals who tested positive for SARS-CoV-2 prior to or without developing symptoms estimated that individuals may be contagious for one to twenty-one days, but they note that this estimate may be low [198]. +In an early study, viral nucleic acids were reported to remain at observable levels in the respiratory specimens of recovering hospitalized COVID-19 patients for a median of 20 days and with a maximum observed duration through 37 days, when data collection for the study ceased [37]. As more estimates of the duration of viral shedding are released, they are beginning to converge around approximately three weeks from first positive PCR test and/or onset of symptoms (which, if present, are usually identified within three days of the initial PCR test). -For example, in later studies, viral shedding was reported for up to 28 days following symptom onset [201] and for one to 24 days from first positive PCR test, with a median of 12 days [82]. -On the other hand, almost 70% of patients were reported to still have symptoms at the time that viral shedding ceased, although all symptoms reduced in prevalence between onset and cessation of viral shedding [202]. -The median time that elapsed between the onset of symptoms and cessation of viral RNA shedding was 23 days and between first positive PCR test and cessation of viral shedding was 17 days [202]. +For example, in later studies, viral shedding was reported for up to 28 days following symptom onset [203] and for one to 24 days from first positive PCR test, with a median of 12 days [84]. +On the other hand, almost 70% of patients were reported to still have symptoms at the time that viral shedding ceased, although all symptoms reduced in prevalence between onset and cessation of viral shedding [204]. +The median time that elapsed between the onset of symptoms and cessation of viral RNA shedding was 23 days and between first positive PCR test and cessation of viral shedding was 17 days [204]. The fact that this study reported symptom onset to predate the first positive PCR test by an average of three days, however, suggests that there may be some methodological differences between it and related studies. -Furthermore, an analysis of residents of a nursing home with a known SARS-CoV-2 case measured similar viral load in residents who were asymptomatic regardless of whether they later developed symptoms, and the load in the asymptomatic residents was comparable to that of residents who displayed either typical of atypical symptoms [203]. -Taken together, these results suggest that the presence or absence of symptoms are not reliable predictors of viral shedding or of SARS-CoV-2 status (e.g, [204]). +Furthermore, an analysis of residents of a nursing home with a known SARS-CoV-2 case measured similar viral load in residents who were asymptomatic regardless of whether they later developed symptoms, and the load in the asymptomatic residents was comparable to that of residents who displayed either typical of atypical symptoms [205]. +Taken together, these results suggest that the presence or absence of symptoms are not reliable predictors of viral shedding or of SARS-CoV-2 status (e.g, [206]). However, it should be noted that viral shedding is not necessarily a robust indicator of contagiousness. -The risk of spreading the infection was low after ten days from the onset of symptoms, as viral load in sputum was found to be unlikely to pose a significant risk based on efforts to culture samples in vitro [201]. +The risk of spreading the infection was low after ten days from the onset of symptoms, as viral load in sputum was found to be unlikely to pose a significant risk based on efforts to culture samples in vitro [203]. The relationship between symptoms, detectable levels of the virus, and risk of viral spread is therefore complex.
The extent to which asymptomatic or presymptomatic individuals are able to transmit SARS-CoV-2 has been a question of high scientific and community interest. -Early reports (February and March 2020) described transmission from presymptomatic SARS-CoV-2-positive individuals to close family contacts [205,206]. -One of these reports [206] also included a description of an individual who tested positive for SARS-CoV-2 but never developed symptoms. -Later analyses also sought to estimate the proportion of infections that could be traced back to a presymptomatic or asymptomatic individual (e.g., [207]). +Early reports (February and March 2020) described transmission from presymptomatic SARS-CoV-2-positive individuals to close family contacts [207,208]. +One of these reports [208] also included a description of an individual who tested positive for SARS-CoV-2 but never developed symptoms. +Later analyses also sought to estimate the proportion of infections that could be traced back to a presymptomatic or asymptomatic individual (e.g., [209]). Estimates of the proportion of individuals with asymptomatic infections have varied widely. -The proportion of asymptomatic individuals on board the Diamond Princess cruise ship, which was the site of an early COVID-19 outbreak, was estimated at 17.9% [208]. -In contrast, a model using the prevalence of antibodies among residents of Wuhan, China estimated a much higher rate of asymptomatic cases, at approximately 7 in 8, or 87.5% [209]. -An analysis of the populations of care homes in London found that, among the residents (median age 85), the rate of asymptomatic infection was 43.8%, and among the caretakers (median age 47), the rate was 49.1% [210]. -The duration of viral shedding may also be longer in individuals with asymptomatic cases of COVID-19 compared to those who do show symptoms [211]. +The proportion of asymptomatic individuals on board the Diamond Princess cruise ship, which was the site of an early COVID-19 outbreak, was estimated at 17.9% [210]. +In contrast, a model using the prevalence of antibodies among residents of Wuhan, China estimated a much higher rate of asymptomatic cases, at approximately 7 in 8, or 87.5% [211]. +An analysis of the populations of care homes in London found that, among the residents (median age 85), the rate of asymptomatic infection was 43.8%, and among the caretakers (median age 47), the rate was 49.1% [212]. +The duration of viral shedding may also be longer in individuals with asymptomatic cases of COVID-19 compared to those who do show symptoms [213]. As a result, the potential for individuals who do not know they have COVID-19 to spread the virus raises significant concerns. -In Singapore and Tianjin, two cities studied to estimate incubation period, an estimated 40-50% and 60-80% of cases, respectively, were considered to be caused by contact with asymptomatic individuals [197]. -An analysis of viral spread in the Italian town of Vo’, which was the site of an early COVID-19 outbreak, revealed that 42.5% of cases were asymptomatic and that the rate was similar across age groups [212]. +In Singapore and Tianjin, two cities studied to estimate incubation period, an estimated 40-50% and 60-80% of cases, respectively, were considered to be caused by contact with asymptomatic individuals [199]. +An analysis of viral spread in the Italian town of Vo’, which was the site of an early COVID-19 outbreak, revealed that 42.5% of cases were asymptomatic and that the rate was similar across age groups [214]. The argument was thus made that the town’s lockdown was imperative for controlling the spread of COVID-19 because it isolated asymptomatic individuals. While more models are likely to emerge to better explore the effect of asymptomatic individuals on SARS-CoV-2 transmission, these results suggest that strategies for identifying and containing asymptomatic but contagious individuals are important for managing community spread.
2.8.2 Estimating the Fatality Rate
@@ -1086,66 +1087,66 @@[213].
-Estimates of CFR at the national and continental level and IFR at the content level is maintained by the Centre for Evidence-Based Medicine [214].
+IFR varies regionally, with some locations observed to have IFRs as low as 0.17% while others are as high as 1.7% [215].
+Estimates of CFR at the national and continental level and IFR at the content level is maintained by the Centre for Evidence-Based Medicine [216].
Several meta-analyses have also sought to estimate IFR at the global scale.
-These estimates have varied; one peer-reviewed study aggregated data from 24 other studies and estimated IFR at 0.68% (95% CI 0.53%–0.82%), but a preprint that aggregated data from 139 countries calculated a global IFR of 1.04% (95% CI 0.77%-1.38%) when false negatives were considered in the model [213,215].
-A similar prevalence estimate was identified through a repeated cross-sectional serosurvey conducted in New York City that estimated the IFR as 0.97% [216].
-Examination of serosurvey-based estimates of IFR identified convergence on a global IFR estimate of 0.60% (95% CI 0.42%–0.77%) [213].
-All of these studies note that IFR varies widely by location, and it is also expected to vary with demographic and health-related variables such as age, sex, prevalence of comorbidities, and access to healthcare and testing [217].
+These estimates have varied; one peer-reviewed study aggregated data from 24 other studies and estimated IFR at 0.68% (95% CI 0.53%–0.82%), but a preprint that aggregated data from 139 countries calculated a global IFR of 1.04% (95% CI 0.77%-1.38%) when false negatives were considered in the model [215,217].
+A similar prevalence estimate was identified through a repeated cross-sectional serosurvey conducted in New York City that estimated the IFR as 0.97% [218].
+Examination of serosurvey-based estimates of IFR identified convergence on a global IFR estimate of 0.60% (95% CI 0.42%–0.77%) [215].
+All of these studies note that IFR varies widely by location, and it is also expected to vary with demographic and health-related variables such as age, sex, prevalence of comorbidities, and access to healthcare and testing [219].
Estimates of infection rates are becoming more feasible as more data becomes available for modeling and will be bolstered as serological testing becomes more common and more widely available.
2.9 Dynamics of Transmission
Disease spread dynamics can be estimated using R0, the basic reproduction number, and Rt, the effective reproduction number. Accurate estimates of both are crucial to understanding the dynamics of infection and to predicting the effects of different interventions. -R0 is the average number of new (secondary) infections caused by one infected person, assuming a wholly susceptible population [218] and is one of the most important epidemiological parameters [219]. -A simple mechanistic model used to describe infectious disease dynamics is a susceptible-infected-recovered compartmental model [220,221]. -In this model, individuals move through three states: susceptible, infected, and recovered; two parameters, \(\gamma\) and \(\beta\), specify the rate at which the infectious recover, and the infection transmission rate, respectively, and R0 is estimated as the ratio of \(\beta\) and \(\gamma\) [219,222]. -A pathogen can invade a susceptible population only if R0 > 1 [219,223]. +R0 is the average number of new (secondary) infections caused by one infected person, assuming a wholly susceptible population [220] and is one of the most important epidemiological parameters [221]. +A simple mechanistic model used to describe infectious disease dynamics is a susceptible-infected-recovered compartmental model [222,223]. +In this model, individuals move through three states: susceptible, infected, and recovered; two parameters, \(\gamma\) and \(\beta\), specify the rate at which the infectious recover, and the infection transmission rate, respectively, and R0 is estimated as the ratio of \(\beta\) and \(\gamma\) [221,224]. +A pathogen can invade a susceptible population only if R0 > 1 [221,225]. The spread of an infectious disease at a particular time t can be quantified by Rt, the effective reproduction number, which assumes that part of the population has already recovered (and thus gained immunity to reinfection) or that mitigating interventions have been put into place. For example, if only a fraction St of the population is still susceptible, Rt = St x R0. When Rt is greater than 1, an epidemic grows (i.e., the proportion of the population that is infectious increases); when Rt is less than 1, the proportion of the population that is infectious decreases. R0 and Rt can be estimated directly from epidemiological data or inferred using susceptible-infected-recovered-type models. To accurately capture the dynamics of SARS-CoV-2, the addition of a fourth compartment, i.e. a susceptible-exposed-infectious-recovered model may be appropriate.
-Estimates of R0 for COVID-19 lie in the range R0=1.4-6.5 [224,225,226]. +
Estimates of R0 for COVID-19 lie in the range R0=1.4-6.5 [226,227,228]. Variation in R0 is expected between different populations, and the estimated values of R0 discussed below are for specific populations in specific environments. The different estimates of R0 should not necessarily be interpreted as a range of estimates of the same underlying parameter. -In one study of international cases, the predicted value was R0=1.7 [227]. -In China (both Hubei province and nationwide), the value was predicted to lie in the range R0=2.0-3.6 [224,228,229]. -Another estimate based on a cruise ship where an outbreak occurred predicted R0=2.28 [230]. -Susceptible-exposed-infectious-recovered model-derived estimates of R0 range from 2.0 - 6.5 in China [231,232,233,234] to R0=4.8 in France [235]. -Using the same model as for the French population, a study estimated R0=2.6 in South Korea [235], which is consistent with other studies [236]. -From a meta-analysis of studies estimating R0, [225] the median R0 was estimated to be 2.79 (IQR 1.16) based on twelve studies published between January 1 and February 7, 2020.
+In one study of international cases, the predicted value was R0=1.7 [229]. +In China (both Hubei province and nationwide), the value was predicted to lie in the range R0=2.0-3.6 [226,230,231]. +Another estimate based on a cruise ship where an outbreak occurred predicted R0=2.28 [232]. +Susceptible-exposed-infectious-recovered model-derived estimates of R0 range from 2.0 - 6.5 in China [233,234,235,236] to R0=4.8 in France [237]. +Using the same model as for the French population, a study estimated R0=2.6 in South Korea [237], which is consistent with other studies [238]. +From a meta-analysis of studies estimating R0, [227] the median R0 was estimated to be 2.79 (IQR 1.16) based on twelve studies published between January 1 and February 7, 2020.Inference of the effective reproduction number can provide insight into how populations respond to an infection and the effectiveness of interventions. -In China, Rt was predicted to lie in the range 1.6-2.6 in January 2020, before travel restrictions [237]. +In China, Rt was predicted to lie in the range 1.6-2.6 in January 2020, before travel restrictions [239]. Rt decreased from 2.35 one week before travel restrictions were imposed (January 23, 2020), to 1.05 one week after. Using their model, the authors also estimated the probability of new outbreaks occurring. Assuming individual-level variation in transmission comparable to that of MERS or SARS, the probability of a single individual exporting the virus and causing a large outbreak is 17-25%, and assuming variation like that of SARS and transmission patterns like those observed for COVID-19 in Wuhan, the probability of a large outbreak occurring after ≥4 infections exist at a new location is greater than 50%. -An independent study came to similar conclusions, finding Rt=2.38 in the two-week period before January 23 with a decrease to Rt = 1.34 (using data from January 24 to February 3) or Rt=0.98 (using data from January 24 to February 8) [226]. -In South Korea, Rt was inferred for February through March 2020 in two cities, Daegu (the center of the outbreak) and Seoul [236]. +An independent study came to similar conclusions, finding Rt=2.38 in the two-week period before January 23 with a decrease to Rt = 1.34 (using data from January 24 to February 3) or Rt=0.98 (using data from January 24 to February 8) [228]. +In South Korea, Rt was inferred for February through March 2020 in two cities, Daegu (the center of the outbreak) and Seoul [238]. Metro data was also analyzed to estimate the effects of social distancing measures. Rt decreased in Daegu from around 3 to <1 over the period that social distancing measures were introduced. In Seoul, Rt decreased slightly, but remained close to 1 (and larger than Rt in Daegu). These findings indicate that social distancing measures appeared to be effective in containing the infection in Daegu, but in Seoul, Rt remained above 1, meaning secondary outbreaks remained possible. The study also shows the importance of region-specific analysis: the large decline in case load nationwide was mainly due to the Daegu region and could mask persistence of the epidemic in other regions, such as Seoul and Gyeonggi-do. -In Iran, estimates of Rt declined from 4.86 in the first week to 2.1 by the fourth week after the first cases were reported [238]. -In Europe, analysis of 11 countries inferred the dynamics of Rt over a time range from the beginning of the outbreak until March 28, 2020, by which point most countries had implemented major interventions (such as stay-at-home orders, public gathering bans, and school closures) [239]. +In Iran, estimates of Rt declined from 4.86 in the first week to 2.1 by the fourth week after the first cases were reported [240]. +In Europe, analysis of 11 countries inferred the dynamics of Rt over a time range from the beginning of the outbreak until March 28, 2020, by which point most countries had implemented major interventions (such as stay-at-home orders, public gathering bans, and school closures) [241]. Across all countries, the mean Rt before interventions began was estimated as 3.87; Rt varied considerably, from below 3 in Norway to above 4.5 in Spain. After interventions, Rt decreased by an average of 64% across all countries, with mean Rt=1.43. The lowest predicted value was 0.97 for Norway and the highest was 2.64 for Sweden, which could be related to the fact that Sweden did not implement social distancing measures on the same scale as other countries. The study concludes that while large changes in Rt are observed, it is too early to tell whether the interventions put into place are sufficient to decrease Rt below 1.
-More generally, population-level epidemic dynamics can be both observed and modeled [222]. -Data and empirically determined biological mechanisms inform models, while models can be used to try to understand data and systems of interest or to make predictions about possible future dynamics, such as the estimation of capacity needs [240] or the comparison of predicted outcomes among prevention and control strategies [241,242]. -Many current efforts to model Rt have also led to tools that assist the visualization of estimates in real time or over recent intervals [243,244]. +
More generally, population-level epidemic dynamics can be both observed and modeled [224]. +Data and empirically determined biological mechanisms inform models, while models can be used to try to understand data and systems of interest or to make predictions about possible future dynamics, such as the estimation of capacity needs [242] or the comparison of predicted outcomes among prevention and control strategies [243,244]. +Many current efforts to model Rt have also led to tools that assist the visualization of estimates in real time or over recent intervals [245,246]. These are valuable resources, yet it is also important to note that the estimates arise from models containing many assumptions and are dependent on the quality of the data they use, which varies widely by region.
2.10 Molecular Signatures and Transmission
Genetic variation in SARS-CoV-2 has been used to elucidate patterns over time and space. -Mutations observed in individual SARS-CoV-2 genome sequences can be used to trace transmission patterns and have provided insights during outbreak investigations [14,245,246]. +Mutations observed in individual SARS-CoV-2 genome sequences can be used to trace transmission patterns and have provided insights during outbreak investigations [16,247,248]. Similar mutations observed in several patients may indicate that the patients belong to the same transmission group. The tracking of SARS-CoV-2 mutations is recognized as an essential tool for controlling future outbreaks and tracing the path of the spread of SARS-CoV-2. -Efforts vary widely by country: the UK has coordinated has coordinated a national database of viral genomes [247]; no such coordination has been achieved in the USA. -Several studies used phylogenetic analysis to determine the source of local COVID-19 outbreaks in Connecticut (USA), [248], the New York City area (USA) [249], and Iceland [250]. +Efforts vary widely by country: the UK has coordinated has coordinated a national database of viral genomes [249]; no such coordination has been achieved in the USA. +Several studies used phylogenetic analysis to determine the source of local COVID-19 outbreaks in Connecticut (USA), [250], the New York City area (USA) [251], and Iceland [252]. There is an ongoing effort to collect SARS-CoV-2 genomes throughout the COVID-19 outbreak, and as of January 18, 2021 more than 381,000 genome sequences have been collected from patients. -The sequencing data can be found at GISAID [251], NCBI [252], and COVID-19 data portal [253].
+The sequencing data can be found at GISAID [253], NCBI [254], and COVID-19 data portal [255].2.11 Conclusions
The novel coronavirus SARS-CoV-2 is the third HCoV to emerge in the 21st century, and research into previous HCoVs has provided a strong foundation for characterizing the pathogenesis and transmission of SARS-CoV-2. Critical insights into how the virus interacts with human cells have been gained from previous research into HCoVs and other viral infections. @@ -1154,10 +1155,10 @@
2.11
Many of the mechanisms that facilitate the pathogenesis of SARS-CoV-2 are currently under consideration as possible targets for the treatment or prevention of COVID-19.
Research in other viruses also provides a foundation for understanding the transmission of SARS-CoV-2 among people and can therefore inform efforts to control the virus’s spread.
The extent to which aerosol and fomite transmission contribute to the spread of SARS-CoV-2 remains a question: in general, much like SARS-CoV-1 and MERS-CoV, this virus seems to be spread primarily by droplet transmission.
-Asymptomatic transmission was also a concern in the SARS outbreak of 2002-03 and, as in current pandemic, presented challenges for estimating rates of infection [254].
+Asymptomatic transmission was also a concern in the SARS outbreak of 2002-03 and, as in current pandemic, presented challenges for estimating rates of infection [256].
However, in the current pandemic, we have been fortunate to be able to build on top of 18 years of SARS-CoV-1 research in order to rapidly ascertain the identity and behavior of the virus.
Even with the background obtained from research in SARS and MERS, COVID-19 has revealed itself to be a complex and difficult-to-characterize disease that has many possible presentations that vary with age.
-Variability in presentation, including cases with no respiratory symptoms or with no symptoms altogether, were also reported during the SARS epidemic at the beginning of the 21st century [254].
+Variability in presentation, including cases with no respiratory symptoms or with no symptoms altogether, were also reported during the SARS epidemic at the beginning of the 21st century [256].
The variability of both which symptoms present and their severity have presented challenges for public health agencies seeking to provide clear recommendations regarding which symptoms indicate SARS-CoV-2 infection and should prompt isolation.
Asymptomatic cases add complexity both to efforts to estimate statistics such as R0 and Rt, which are critical to understanding the transmission of the virus, and IFR, which is an important component of understanding its impact on a given population.
The development of diagnostic technologies over the course of the pandemic has facilitated more accurate identification, including of asymptomatic cases.
@@ -1165,13 +1166,13 @@
2.11
While many efforts have focused on adults, and especially older adults because of the susceptibility of this demographic, additional research is needed to understand the presentation of COVID-19 and MIS-C in pediatric patients.
As more information is uncovered about the pathogenesis of HCoV and SARS-CoV-2 specifically, the diverse symptomatology of COVID-19 has and likely will continue to conform with the ever-broadening understanding of how SARS-CoV-2 functions within a human host.
While the SARS-CoV-2 virus is very similar to other HCoV in several ways, including in its genomic structure and the structure of the virus itself, there are also some differences that may account for differences in the COVID-19 pandemic compared to the SARS and MERS epidemics of the past two decades.
-The R0 of SARS-CoV-2 has been estimated to be similar to SARS-CoV-1 but much higher than that of MERS-CoV [30,30].
+The R0 of SARS-CoV-2 has been estimated to be similar to SARS-CoV-1 but much higher than that of MERS-CoV [32,32].
While the structures of the viruses are very similar, evolution among these species may account for differences in their transmissibility and virulence.
For example, the acquisition of a furin cleavage site the S1/S2 boundary within the SARS-CoV-2 S protein may be associated with increased virulence.
Additionally, concerns have been raised about the accumulation of mutations within the SARS-CoV-2 species itself, and whether these could influence virulence.
The coming of age of genomic technologies has made these types of analyses feasible, and genomics research characterizing changes in SARS-CoV-2 along with temporal and spatial movement is likely to provide additional insights into whether within-species evolution influences the effect of the virus on the human host.
Additionally, the rapid development of sequencing technologies over the past decade has made it possible to rapidly characterize the host response to the virus.
-For example, proteomics analysis of patient-derived cells revealed candidate genes whose regulation is altered by SARS-CoV-2 infection, suggesting possible approaches for pharmaceutical invention and providing insight into which systems are likely to be disrupted in COVID-19 [163].
+For example, proteomics analysis of patient-derived cells revealed candidate genes whose regulation is altered by SARS-CoV-2 infection, suggesting possible approaches for pharmaceutical invention and providing insight into which systems are likely to be disrupted in COVID-19 [165].
As more patient data becomes available, the biotechnological advances of the 2000s are expected to allow for more rapid identification of potential drug targets than was feasible during the SARS, or even MERS, pandemic.
Thus, though the COVID-19 crisis is still evolving, the insights acquired over the past 20 years of HCoV research have provided a solid foundation for understanding the SARS-CoV-2 virus and the disease it causes.
As the scientific community continues to respond to COVID-19 and to elucidate more of the relationships between viral pathogenesis, transmission, and symptomatology, and as more data about the regulatory shifts associated with COVID-19 become available, this understanding will no doubt continue to evolve and to reveal additional connections among virology, pathogenesis, and health.
@@ -1182,52 +1183,52 @@
3.13.2 Introduction
3.3 Initial Characterization of SARS-CoV-2
The first genome sequence of the virus was released on January 3, 2020.
-It revealed that the cluster of pneumonia cases seen in Wuhan were caused by a novel coronavirus [10].
-Multiple research groups have drafted the genome sequence of SARS-CoV-2 based on sequences developed from clinical samples collected from the lower respiratory tract, namely bronchoalveolar lavage fluid (BALF), and the upper respiratory tract, in the form of throat and nasopharyngeal swabs [11,12,13].
-Analysis of the SARS-CoV-2 genome revealed significant sequence homology with two coronaviruses known to infect humans, with about 79% identity to SARS-CoV-1 and 50% to MERS-CoV [13].
-However, in this analysis, the highest degree of similarity was observed between SARS-CoV-2 and bat-derived SARS-like coronaviruses (bat-SL-CoVZC45 and bat-SL-CoVZXC21) [13].
-Other analyses have reported even greater similarity between SARS-CoV-2 and the bat coronavirus BatCoV-RaTG13, with identity as high as 96.2% [12,14], and the closely related pangolin coronavirus [15].
+It revealed that the cluster of pneumonia cases seen in Wuhan were caused by a novel coronavirus [12].
+Multiple research groups have drafted the genome sequence of SARS-CoV-2 based on sequences developed from clinical samples collected from the lower respiratory tract, namely bronchoalveolar lavage fluid (BALF), and the upper respiratory tract, in the form of throat and nasopharyngeal swabs [13,14,15].
+Analysis of the SARS-CoV-2 genome revealed significant sequence homology with two coronaviruses known to infect humans, with about 79% identity to SARS-CoV-1 and 50% to MERS-CoV [15].
+However, in this analysis, the highest degree of similarity was observed between SARS-CoV-2 and bat-derived SARS-like coronaviruses (bat-SL-CoVZC45 and bat-SL-CoVZXC21) [15].
+Other analyses have reported even greater similarity between SARS-CoV-2 and the bat coronavirus BatCoV-RaTG13, with identity as high as 96.2% [14,16], and the closely related pangolin coronavirus [17].
This evidence therefore suggests the SARS-CoV-2 virus is the result of zoonotic transfer of a virus from bats to humans.
Nevertheless, some fragments between SARS-CoV-2 and RATG13 differ by up to 17%, suggesting a complex natural selection process during zoonotic transfer.
-While the S region is highly similar to that of viruses found in pangolins [15], there is no consensus about the origin of S in SARS-CoV-2, as it could potentially be the result either of recombination or coevolution [14,16].
+While the S region is highly similar to that of viruses found in pangolins [17], there is no consensus about the origin of S in SARS-CoV-2, as it could potentially be the result either of recombination or coevolution [16,18].
Though the intermediate host serving as the source for the zoonotic introduction of SARS-CoV-2 to human populations has not yet been identified, the SARS-CoV-2 virus has been placed within the coronavirus phylogeny through comparative genomic analyses.
-Genomic analyses and comparisons to other known coronaviruses suggest that SARS-CoV-2 is unlikely to have originated in a laboratory – either purposely engineered and released, or escaped – and instead evolved naturally in an animal host [17].
-Indeed, the World Health Organization (WHO) have published their intentions to thoroughly investigate the origins of SARS-CoV-2 [255].
-While the position of the SARS-CoV-2 virus within the coronavirus phylogeny has been largely resolved, the functional consequences of molecular variation between this virus and other viruses, such as its bat and pangolin sister taxa or SARS-CoV-1, remain unknown [17].
+Genomic analyses and comparisons to other known coronaviruses suggest that SARS-CoV-2 is unlikely to have originated in a laboratory – either purposely engineered and released, or escaped – and instead evolved naturally in an animal host [19].
+Indeed, the World Health Organization (WHO) have published their intentions to thoroughly investigate the origins of SARS-CoV-2 [257].
+While the position of the SARS-CoV-2 virus within the coronavirus phylogeny has been largely resolved, the functional consequences of molecular variation between this virus and other viruses, such as its bat and pangolin sister taxa or SARS-CoV-1, remain unknown [19].
Fortunately, the basic genome structure of coronaviruses is highly conserved, and insight into the mechanisms the virus uses to enter cells, replicate, and spread is available from prior research on coronaviruses, which has been instrumental in the mobilization of global research to understand the biology of SARS-CoV-2.
Additionally, worldwide sequencing of viral samples has provided some preliminary insights into possible mechanisms of adaptation in the virus and the detection of novel variants, and omics-based analysis of patient samples has elucidated some of the biological changes the virus induces in its human hosts.
3.4 Coronaviruses and Animal Hosts
-Coronaviruses have long been known to infect animals and have been the subject of veterinary medical investigations and vaccine development efforts due to their effect on the health of companion and agricultural animals [18].
+
Coronaviruses have long been known to infect animals and have been the subject of veterinary medical investigations and vaccine development efforts due to their effect on the health of companion and agricultural animals [20].
Most coronaviruses show little to no transmission in humans.
-However, it is thought that approximately one-third of common cold infections are caused by four seasonal human coronaviruses (HCoV): Human coronavirus 229E (HCoV-229E), Human coronavirus NL63 (HCoV-NL63), Human coronavirus OC43 (HCoV-OC43), and Human coronavirus HKU1 (HCoV-HKU1) [19,20,256].
-The first HCoV were identified in the 1960s: HCoV-229E in 1965 [21] and HCoV-OC43 in 1967 [22].
-Both of these viruses typically cause cold-like symptoms, including upper and lower respiratory infections [23,24,257], but they have also been associated with gastrointestinal symptoms [258].
-Two additional HCoV were subsequently identified [25,26].
-In 2003, HCoV-NL63 [25] was first identified in a 7-month-old infant and then in clinical specimens collected from seven additional patients, five of whom were infants younger than 1 year old and the remainder of whom were adults.
-CoV-HKU1 was identified in samples collected from a 71-year-old pneumonia patient in 2004 and then found in samples collected from a second adult patient [26].
-These viruses are associated with respiratory diseases of varying severity, ranging from common cold to severe pneumonia, with severe symptoms mostly observed in immunocompromised individuals [27], and also have gastrointestinal involvement in some cases [258].
-In addition to these relatively mild HCoV, however, highly pathogenic human coronaviruses have been identified, including Severe acute respiratory syndrome-related coronavirus (SARS-CoV or SARS-CoV-1) and Middle East respiratory syndrome-related coronavirus (MERS-CoV) [19,28,29].
-At the time that SARS-CoV-1 emerged in the early 2000s, no HCoV had been identified in almost 40 years [28].
-The first case of SARS was reported in November 2002 in the Guangdong Province of China, and over the following month, the disease spread more widely within China and then into several countries across multiple continents [28,30].
-Unlike previously identified HCoV, SARS was much more severe, with an estimated death rate of 9.5% [30].
-It was also highly contagious via droplet transmission, with a basic reproduction number (R0) of 4 (i.e., each person infected was estimated to infect four other people) [30].
-However, the identity of the virus behind the infection remained unknown until April of 2003, when the SARS-CoV-1 virus was identified through a worldwide scientific effort spearheaded by the WHO [28].
-SARS-CoV-1 belonged to a distinct lineage from the two other HCoV known at the time [30].
-By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices [28].
+However, it is thought that approximately one-third of common cold infections are caused by four seasonal human coronaviruses (HCoV): Human coronavirus 229E (HCoV-229E), Human coronavirus NL63 (HCoV-NL63), Human coronavirus OC43 (HCoV-OC43), and Human coronavirus HKU1 (HCoV-HKU1) [21,22,258].
+The first HCoV were identified in the 1960s: HCoV-229E in 1965 [23] and HCoV-OC43 in 1967 [24].
+Both of these viruses typically cause cold-like symptoms, including upper and lower respiratory infections [25,26,259], but they have also been associated with gastrointestinal symptoms [260].
+Two additional HCoV were subsequently identified [27,28].
+In 2003, HCoV-NL63 [27] was first identified in a 7-month-old infant and then in clinical specimens collected from seven additional patients, five of whom were infants younger than 1 year old and the remainder of whom were adults.
+CoV-HKU1 was identified in samples collected from a 71-year-old pneumonia patient in 2004 and then found in samples collected from a second adult patient [28].
+These viruses are associated with respiratory diseases of varying severity, ranging from common cold to severe pneumonia, with severe symptoms mostly observed in immunocompromised individuals [29], and also have gastrointestinal involvement in some cases [260].
+In addition to these relatively mild HCoV, however, highly pathogenic human coronaviruses have been identified, including Severe acute respiratory syndrome-related coronavirus (SARS-CoV or SARS-CoV-1) and Middle East respiratory syndrome-related coronavirus (MERS-CoV) [21,30,31].
+At the time that SARS-CoV-1 emerged in the early 2000s, no HCoV had been identified in almost 40 years [30].
+The first case of SARS was reported in November 2002 in the Guangdong Province of China, and over the following month, the disease spread more widely within China and then into several countries across multiple continents [30,32].
+Unlike previously identified HCoV, SARS was much more severe, with an estimated death rate of 9.5% [32].
+It was also highly contagious via droplet transmission, with a basic reproduction number (R0) of 4 (i.e., each person infected was estimated to infect four other people) [32].
+However, the identity of the virus behind the infection remained unknown until April of 2003, when the SARS-CoV-1 virus was identified through a worldwide scientific effort spearheaded by the WHO [30].
+SARS-CoV-1 belonged to a distinct lineage from the two other HCoV known at the time [32].
+By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices [30].
A decade later, a second outbreak of severe respiratory illness associated with a coronavirus emerged, this time in the Arabian Peninsula.
This disease, known as Middle East respiratory syndrome (MERS), was linked to another novel coronavirus, MERS-CoV.
-The fatality rate associated with MERS is much higher than that of SARS, at almost 35%, but the disease is much less easily transmitted, with an R0 of 1 [30].
-Although MERS is still circulating, its low reproduction number has allowed for its spread to be contained [30].
+The fatality rate associated with MERS is much higher than that of SARS, at almost 35%, but the disease is much less easily transmitted, with an R0 of 1 [32].
+Although MERS is still circulating, its low reproduction number has allowed for its spread to be contained [32].
The COVID-19 pandemic is thus associated with the seventh HCoV to be identified and the fifth since the turn of the millennium, though additional HCoVs may be in circulation but remain undetected.
-SARS-CoV-1 and MERS-CoV were ultimately managed largely through infection management practices (e.g., mask wearing) and properties of the virus itself (i.e., low rate of transmission), respectively [28,30].
-Vaccines were not used to control either outbreak, although vaccine development programs were established for SARS-CoV-1 [31].
-In general, care for SARS and MERS patients focuses on supportive care and symptom management [30].
+
SARS-CoV-1 and MERS-CoV were ultimately managed largely through infection management practices (e.g., mask wearing) and properties of the virus itself (i.e., low rate of transmission), respectively [30,32].
+Vaccines were not used to control either outbreak, although vaccine development programs were established for SARS-CoV-1 [33].
+In general, care for SARS and MERS patients focuses on supportive care and symptom management [32].
Clinical treatments for SARS and MERS developed during the outbreaks generally do not have strong evidence supporting their use.
-Common treatments included Ribavirin, an antiviral, often in combination with corticosteroids or sometimes interferon (IFN) medications, which would both be expected to have immunomodulatory effects [28].
-However, retrospective and in vitro analyses have reported inconclusive results of these treatments on SARS and the SARS-CoV-1 virus, respectively [28].
-IFNs and Ribavirin have shown promise in in vitro analyses of MERS, but their clinical effectiveness remains unknown [28].
+Common treatments included Ribavirin, an antiviral, often in combination with corticosteroids or sometimes interferon (IFN) medications, which would both be expected to have immunomodulatory effects [30].
+However, retrospective and in vitro analyses have reported inconclusive results of these treatments on SARS and the SARS-CoV-1 virus, respectively [30].
+IFNs and Ribavirin have shown promise in in vitro analyses of MERS, but their clinical effectiveness remains unknown [30].
Therefore, only limited strategies can be adopted for the pharmaceutical management of COVID-19 from previous severe HCoV infections.
Research in response to prior outbreaks of HCoV-borne infections, such as SARS and MERS, have, however, provided a strong foundation for hypotheses about the pathogenesis of SARS-CoV-2 as well as potential diagnostic and therapeutic approaches.
3.5 Zoonotic Transfer of Coronaviruses
@@ -1237,90 +1238,90 @@
Evolution in SARS-CoV-2 has also been observed over a short timescale.
-After zoonotic transfer, SARS-CoV-2 continued evolving in the human population [245].
-The SARS-CoV-2 mutation rate is moderate compared to other RNA viruses [246], which likely restricts the pace of evolution in SARS-CoV-2.
+After zoonotic transfer, SARS-CoV-2 continued evolving in the human population [247].
+The SARS-CoV-2 mutation rate is moderate compared to other RNA viruses [248], which likely restricts the pace of evolution in SARS-CoV-2.
Nevertheless, genomic analyses have yielded statistical evidence of ongoing evolution.
-Initially, two known variants of the spike protein emerged that differed by a single amino acid at position 614 (G614 and D614), and there is evidence that G614 had become more prevalent than D614 by June 2020 [174].
-While there is a hypothesis that this genomic change increased the SARS-CoV-2 infectivity and virulence, this hypothesis has not yet been tested due to a lack of data [259].
-Another study [246] identified 198 recurrent mutations in a dataset of 7,666 curated sequences.
+Initially, two known variants of the spike protein emerged that differed by a single amino acid at position 614 (G614 and D614), and there is evidence that G614 had become more prevalent than D614 by June 2020 [176].
+While there is a hypothesis that this genomic change increased the SARS-CoV-2 infectivity and virulence, this hypothesis has not yet been tested due to a lack of data [261].
+Another study [248] identified 198 recurrent mutations in a dataset of 7,666 curated sequences.
This pattern of convergent evolution at some sites could indicate that certain mutations confer an adaptive advantage.
While it is evident that SARS-CoV-2 exhibits moderate potential for ongoing and future evolution, the relationship between mutations and pathogenicity is not yet known.
Additional data is needed in order to understand patterns of evolutionary change and whether they are likely to affect virulence.
Several factors could promote the evolution of SARS-CoV-2, including host immunodeficiency and transient exposure to antibodies directed against SARS-CoV-2 proteins.
-A single case study of SARS-CoV-2 infection in an immunocompromised female with chronic lymphocytic leukemia and hypogammaglobulinemia [260] suggested that an accelerated evolution of the virus could occur in conditions of immunodeficiency.
+A single case study of SARS-CoV-2 infection in an immunocompromised female with chronic lymphocytic leukemia and hypogammaglobulinemia [262] suggested that an accelerated evolution of the virus could occur in conditions of immunodeficiency.
A first administration of convalescent plasma did not clear the virus, and an ensuing increase in the genomic diversity in the samples was observed, suggesting an accelerated evolution due to selection pressure.
A second administration of convalescent plasma cleared the virus from the host 105 days after the initial diagnosis.
However, throughout the duration of infection, the patient was asymptomatic but contagious.
-A second single case study in a 45-year old male with antiphospholipid syndrome [261] confirmed the earlier results, providing evidence of persistent COVID-19 symptoms in an immunocompromised patient for 154 days following diagnosis, ultimately leading to the death of patient.
+A second single case study in a 45-year old male with antiphospholipid syndrome [263] confirmed the earlier results, providing evidence of persistent COVID-19 symptoms in an immunocompromised patient for 154 days following diagnosis, ultimately leading to the death of patient.
The treatments administered included remdesivir and the Regeneron anti-spike protein antibody cocktail.
Genomic analyses of the patient’s nasopharyngeal swabs confirmed an accelerated evolution of the virus through mutations in the spike gene and the receptor-binding domain.
In summary, these two case studies suggested an accelerated evolution and persistent shedding of the virus in conditions of immunodeficiency.
In particular, the first case highlighted the role of convalescent plasma in creating escape variants.
-In fact, one study [262] exposed the SARS-CoV-2 virus to convalescent plasma in vitro repeatedly to see how much plasma was required to neutralize the virus.
+In fact, one study [264] exposed the SARS-CoV-2 virus to convalescent plasma in vitro repeatedly to see how much plasma was required to neutralize the virus.
The results of the first six exposures were similar, but they reported that after the seventh exposure (on day 45), the amount of plasma required began to increase.
In analyzing the viral variants present, they found that this viral escape was promoted by the sudden accumulation of mutations, especially in the receptor-binding domain (RBD) and N-terminal domain (NTD), that quickly rose in frequency.
By the thirteenth exposure (day 85), the virus had evolved three mutations and could not longer be neutralized by the plasma used.
Taken together, these observations suggest that evolutionary analyses of SARS-CoV-2 can provide crucial information about the conditions that promote resistance in SARS-CoV-2 and the kinetics of how resistance develops, information which will be important for understanding the implications of how vaccine regimens are designed and whether/when next-generation vaccines will be needed.
When variants occur, they can rise in frequency by chance or through an adaptive process that confers a competitive advantage to the virus.
Variants that had the D614G mutation in the spike glycoprotein seemed to spread faster.
-However, it has been suggested that the mutation rose in frequency due to early chance events rather than by adaptive events [263].
+However, it has been suggested that the mutation rose in frequency due to early chance events rather than by adaptive events [265].
Another mutation, Y453F, that occurred in the receptor binding domain of S, was first detected in mink; however, the transmission to humans has been established.
-In mink, this mutation conferred an advantage by increasing the affinity towards ACE2 [264].
-Similarly, N501Y mutation induces an increased affinity towards human ACE2 and has been involved in the dominance of B.1.1.7 by outcompeting other variants [265].
-Therefore, genomic surveillance is essential to prevent the emergence of super-spreaders [266].
+In mink, this mutation conferred an advantage by increasing the affinity towards ACE2 [266].
+Similarly, N501Y mutation induces an increased affinity towards human ACE2 and has been involved in the dominance of B.1.1.7 by outcompeting other variants [267].
+Therefore, genomic surveillance is essential to prevent the emergence of super-spreaders [268].
Emerging methods are being applied to this problem in an effort to understand which mutations are most likely to be of significant concern.
Novel machine learning methods were developed to predict the mutations in the sequence that promote viral escape.
While they preserve the pathogenicity of the virus, escape mutations change the virus’s sequence to evade detection by the immune system.
-By using tools from natural language processing (NLP), viral escape was modeled as an NLP problem [267] where a modification makes a sentence grammatically correct but semantically different.
+By using tools from natural language processing (NLP), viral escape was modeled as an NLP problem [269] where a modification makes a sentence grammatically correct but semantically different.
Therefore, language models of viruses could predict mutations that change the presentation of the virus to the immune system but preserve its infectivity.
3.6.3 Variants of concern and variants under surveillance
-Viral replication naturally leads to the occurrence of mutations, and thus to genetic variation [268].
+
Viral replication naturally leads to the occurrence of mutations, and thus to genetic variation [270].
The emergence of new genetic variants of SARS-CoV-2 has attracted significant media attention since the detection of a variant of concern (VOC), a distinct phylogenetic cluster referred to as B.1.1.7/VOC 202012/01.
While the B.1.1.7 lineage garnered attention in November 2020, two genomes of the lineage were detected as early as September 20th, 2020 from routine genomic data sampled in Kent (U.K.) by the COVID-19 Genomics UK Consortium (COG-UK).
-The following day, a second B.1.1.7 genome was reported in greater London [263,269,270,271]
-Since then, B.1.1.7 has spread across the UK and internationally, and it has now been detected in at least 62 countries [272], despite several countries imposing travel restrictions on travelers from the UK.
-Of the twenty-three mutations that define B.1.1.7 from the original strain isolated in Wuhan (lineage A), fourteen are lineage-specific and three appear to be biologically consequential mutations associated with the spike protein, namely N501Y, P681H, and 69-70del [269,270].
-The latter is a 6-bp deletion that leads to the loss of two amino acids and has consequences for immune recognition; it may, in conjunction with N501Y, be responsible for the increased transmissibility of the B.1.1.7 VOC due to changes in the RBD that increase binding affinity with ACE2 [269,273].
+The following day, a second B.1.1.7 genome was reported in greater London [265,271,272,273]
+Since then, B.1.1.7 has spread across the UK and internationally, and it has now been detected in at least 62 countries [274], despite several countries imposing travel restrictions on travelers from the UK.
+Of the twenty-three mutations that define B.1.1.7 from the original strain isolated in Wuhan (lineage A), fourteen are lineage-specific and three appear to be biologically consequential mutations associated with the spike protein, namely N501Y, P681H, and 69-70del [271,272].
+The latter is a 6-bp deletion that leads to the loss of two amino acids and has consequences for immune recognition; it may, in conjunction with N501Y, be responsible for the increased transmissibility of the B.1.1.7 VOC due to changes in the RBD that increase binding affinity with ACE2 [271,275].
B.1.1.7 has increased transmissibility by up to 56%, leading to an R0 of approximately 1.4.
-While there is also the possibility that this VOC may be associated with increased disease severity, there is currently insufficient evidence to draw any conclusions [265,271,274,275].
-Other variants also express the 69-70del mutation [276,277], and public health officials in the United States and the UK have been able to use RT-PCR-based assays (ThermoFisher TaqPath COVID-19 assay) to identify sequences with this deletion because it occurs where the qPCR probe binds [271].
-In the UK, B.1.1.7 is present in more than 97% of diagnostic tests that return negative for S-gene targets and positive for the other targets; thus, the frequency of S-gene target failure can be used as a proxy for the detection of B.1.1.7 [269; https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/950823/Variant_of_Concern_VOC_202012_01_Technical_Briefing_3_-England.pdf].
-The FDA has highlighted that the performance of three diagnostic tests may be affected by the B.1.1.7 lineage because it could cause false negative tests [278].
-While B.1.1.7 is currently the main VOC, other genetic variants not designated VOCs have been detected, including B.1.351 (20H/501Y.V2) and P.1 (20J/501Y.V3), both of which emerged independently [279].
-B.1.351 was first detected in October 2020 in South Africa, was later detected in the EU on December 28th, 2020 and has now spread to at least 26 countries [280,281,282].
+While there is also the possibility that this VOC may be associated with increased disease severity, there is currently insufficient evidence to draw any conclusions [267,273,276,277].
+Other variants also express the 69-70del mutation [278,279], and public health officials in the United States and the UK have been able to use RT-PCR-based assays (ThermoFisher TaqPath COVID-19 assay) to identify sequences with this deletion because it occurs where the qPCR probe binds [273].
+In the UK, B.1.1.7 is present in more than 97% of diagnostic tests that return negative for S-gene targets and positive for the other targets; thus, the frequency of S-gene target failure can be used as a proxy for the detection of B.1.1.7 [271; https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/950823/Variant_of_Concern_VOC_202012_01_Technical_Briefing_3_-England.pdf].
+The FDA has highlighted that the performance of three diagnostic tests may be affected by the B.1.1.7 lineage because it could cause false negative tests [280].
+While B.1.1.7 is currently the main VOC, other genetic variants not designated VOCs have been detected, including B.1.351 (20H/501Y.V2) and P.1 (20J/501Y.V3), both of which emerged independently [281].
+B.1.351 was first detected in October 2020 in South Africa, was later detected in the EU on December 28th, 2020 and has now spread to at least 26 countries [282,283,284].
B.1.351 contains several mutations at the RBD including K417N, E484K, and N501Y.
-While the biological significance of these mutations are still under investigation, it does appear that this lineage may be associated with increased transmissibility [283] due to the N501Y mutation [270,273].
-The P.1 variant is a branch of the B.1.1.28 lineage that was first detected in Japan in samples obtained from four travelers from Brazil during a screening at a Tokyo airport on January 10, 2021 [284].
+While the biological significance of these mutations are still under investigation, it does appear that this lineage may be associated with increased transmissibility [285] due to the N501Y mutation [272,275].
+The P.1 variant is a branch of the B.1.1.28 lineage that was first detected in Japan in samples obtained from four travelers from Brazil during a screening at a Tokyo airport on January 10, 2021 [286].
Shortly thereafter, it was established that there was a concentration of cases of the P.1 variant in Manaus, in the Amazonas State, Brazil.
-In a small number of samples (n=31) sequenced in Manaus, 42% were identified as the P.1 variant as early as mid-December, but the variant seemed to be absent in genome surveillance testing prior to December [285].
-To date, at least eight countries have detected the P.1 lineage [286].
-While the majority of P.1 cases detected internationally have been linked to travel originating from Brazil, the UK has also reported evidence of community transmission detected via routine community sequencing [286,287].
-P.1 has eight lineage-specific mutations along with three concerning spike protein mutations in the RBD, including K417T, E484K, and N501Y [283].
-There have been multiple different SARS-CoV-2 lineages detected that have mostly been of no more clinical concern than the original devastating lineage originating in Wuhan [288].
+In a small number of samples (n=31) sequenced in Manaus, 42% were identified as the P.1 variant as early as mid-December, but the variant seemed to be absent in genome surveillance testing prior to December [287].
+To date, at least eight countries have detected the P.1 lineage [288].
+While the majority of P.1 cases detected internationally have been linked to travel originating from Brazil, the UK has also reported evidence of community transmission detected via routine community sequencing [288,289].
+P.1 has eight lineage-specific mutations along with three concerning spike protein mutations in the RBD, including K417T, E484K, and N501Y [285].
+There have been multiple different SARS-CoV-2 lineages detected that have mostly been of no more clinical concern than the original devastating lineage originating in Wuhan [290].
However, the spotlight has been cast on other variants of unknown clinical relevance due to the increase of cases observed that have been associated with B.1.1.7 in particular.
-Although early in its ascendency, CAL.20C (B.1.429) is a SARS-CoV-2 variant that was detected in California, USA [289].
+Although early in its ascendency, CAL.20C (B.1.429) is a SARS-CoV-2 variant that was detected in California, USA [291].
It was first detected in July 2020 but was not detected again until October 2020.
In December 2020, CAL.20C accounted for ~24% of the total cases in Southern California and ~36% of total cases in the Los Angeles area.
-CAL.20C has now been detected in New York and Washington, D.C., and some cases have been reported outside the USA in Oceania [289].
+CAL.20C has now been detected in New York and Washington, D.C., and some cases have been reported outside the USA in Oceania [291].
This variant is characterized by five lineage-specific mutations (ORF1a: I4205V, ORF1b:D1183Y, S: S13I;W152C;L452R).
-The latter spike mutation, L452R, is found in an area of the RBD known to resist monoclonal antibodies to the spike protein [290], and it is hypothesized that this mutation may resist polyclonal sera in convalescent patients or in individuals post-vaccination [289,291].
+The latter spike mutation, L452R, is found in an area of the RBD known to resist monoclonal antibodies to the spike protein [292], and it is hypothesized that this mutation may resist polyclonal sera in convalescent patients or in individuals post-vaccination [291,293].
CAL.20C is not a designated VOC; however, further research is required to determine the implications of the mutations encoded in this genetic variant.
-Another notable variant has recently been discovered in 35 patients in a Bavarian hospital in Germany; however, the sequencing data has not been published to date and it remains to be determined whether this variant is of any further concern [292].
-There are several shared mutations and deletions between the three lineages, P.1, B.1.1.7, and B.1.315 and indeed other variants of SARS-CoV-2 that are under investigation [285].
+Another notable variant has recently been discovered in 35 patients in a Bavarian hospital in Germany; however, the sequencing data has not been published to date and it remains to be determined whether this variant is of any further concern [294].
+There are several shared mutations and deletions between the three lineages, P.1, B.1.1.7, and B.1.315 and indeed other variants of SARS-CoV-2 that are under investigation [287].
For example, N501Y, which appears to have occurred independently in each of the three lineages.
-E484K is present in both B.1.351 and P.1 [293].
-The mutations N501Y and E484K are found in the RBD within the receptor-binding motif responsible for forming an interface with the ACE2 receptor, which seems to be consequential for ACE2 binding affinity [294].
-Indeed, N501Y is associated with increased virulence and infectivity in mouse models [295].
-E484K has also been associated with evasion from neutralizing antibodies [262,291,296].
+E484K is present in both B.1.351 and P.1 [295].
+The mutations N501Y and E484K are found in the RBD within the receptor-binding motif responsible for forming an interface with the ACE2 receptor, which seems to be consequential for ACE2 binding affinity [296].
+Indeed, N501Y is associated with increased virulence and infectivity in mouse models [297].
+E484K has also been associated with evasion from neutralizing antibodies [264,293,298].
The del69-70 (del:11288:9) is also shared between P.1 and B.1.1.7 and happens to be a common deletion found in the N terminal mutation of the spike protein.
-This deletion has also been associated with several RBD mutations [270,273,297].
-There is concern that mutations in the spike protein of variants may lead to clinical consequences for transmissibility, disease severity, re-infection, therapeutics, and vaccinations [262,291,298,299,300,301,302].
+This deletion has also been associated with several RBD mutations [272,275,299].
+There is concern that mutations in the spike protein of variants may lead to clinical consequences for transmissibility, disease severity, re-infection, therapeutics, and vaccinations [264,293,300,301,302,303,304].
Vaccine producers are working to determine whether the vaccines are still effective against the novel genetic variants.
Moderna recently published data for their mRNA-1273 vaccine that showed no significant impact of neutralization against the B.1.1.7 variant upon vaccination in humans and non-human primates.
-On the other hand, Moderna reported a reduced but significant neutralization against the B.1.351 variant upon vaccination [303].
-Indeed, Pfizer–BioNTech reported that sera from twenty participants vaccinated with the BNT162b COVID-19 vaccine in previous clinical trials [304,305] elicited equivalent neutralizing titers against isogenic Y501 SARS-CoV-2 on an N501Y genetic background in vitro [306].
-Another study has reported that the plasma neutralizing activity against SARS-CoV-2 variants encoding the combination of K417N:E484K:N501Y or E484K or N501Y was variably and significantly reduced in the sera of twenty participants who received either the Pfizer–BioNTech BNT162b (n = 6) vaccine or the Moderna’s mRNA-1273 vaccine (n =14) [307].
-For now, the consensus appears to be that the FDA approved vaccines still seem to be effective against the genetic variants of SARS-CoV-2 and their accompanying mutations, albeit with a slightly lower neutralizing capacity [303,306,307,308].
+On the other hand, Moderna reported a reduced but significant neutralization against the B.1.351 variant upon vaccination [305].
+Indeed, Pfizer–BioNTech reported that sera from twenty participants vaccinated with the BNT162b COVID-19 vaccine in previous clinical trials [306,307] elicited equivalent neutralizing titers against isogenic Y501 SARS-CoV-2 on an N501Y genetic background in vitro [308].
+Another study has reported that the plasma neutralizing activity against SARS-CoV-2 variants encoding the combination of K417N:E484K:N501Y or E484K or N501Y was variably and significantly reduced in the sera of twenty participants who received either the Pfizer–BioNTech BNT162b (n = 6) vaccine or the Moderna’s mRNA-1273 vaccine (n =14) [309].
+For now, the consensus appears to be that the FDA approved vaccines still seem to be effective against the genetic variants of SARS-CoV-2 and their accompanying mutations, albeit with a slightly lower neutralizing capacity [305,308,309,310].
Further research is required to discern the clinical, prophylactic, and therapeutic consequences of these genetic SARS-CoV-2 variants as the pandemic evolves.
3.7 Conclusions
As of October 2020 the SARS-CoV-2 virus remains a serious worldwide threat.
@@ -1334,7 +1335,7 @@
4.
Identifying individuals who have contracted COVID-19 is crucial to slowing down the global pandemic.
Given the high transmissibility of SARS-CoV-2, the development of reliable assays to detect SARS-CoV-2 infection even in asymptomatic carriers is vitally important.
For instance, the deployment of wide-scale diagnostic testing followed by the isolation of infected people has been a key factor in South Korea’s successful strategy for controlling the spread of the virus.
-Following the first release of the genetic sequence of the virus by Chinese officials on January 10, 2020, the first test was released about 13 days later [309].
+Following the first release of the genetic sequence of the virus by Chinese officials on January 10, 2020, the first test was released about 13 days later [311].
Diagnostic approaches utilizing a variety of methods are currently or have been developed.
There are two main classes of diagnostic tests: molecular tests, which can diagnose an active infection by identifying the presence of SARS-CoV-2, and serological tests, which can assess whether an individual was infected in the past via the presence or absence of antibodies against SARS-CoV-2.
Molecular tests are essential for identifying individuals for treatment and alerting their contacts to quarantine and be alert for possible symptoms.
@@ -1346,37 +1347,37 @@
4.
The innate immune system consists of barriers, such as the skin, mucous secretions, neutrophils, macrophages, and dendritic cells.
It also includes cell-surface receptors that can recognize the molecular patterns of pathogens.
The adaptive immune system utilizes antigen-specific receptors that are expressed on B and T lymphocytes.
-These components of the immune system typically act together; the innate response acts first, and the adaptive response begins to act several days after initial infection following the clonal expansion of T and B cells [32].
+These components of the immune system typically act together; the innate response acts first, and the adaptive response begins to act several days after initial infection following the clonal expansion of T and B cells [34].
After a virus enters into a host cell, its antigen is presented by major histocompatibility complex 1 (MHC 1) molecules and is then recognized by cytotoxic T lymphocytes.
In the case of COVID-19, there is also concern about the immune system becoming over-active.
One of the main immune responses contributing to the onset of acute respiratory distress syndrome (ARDS) in COVID-19 patients is cytokine storm syndrome (CSS), which causes an extreme inflammatory response due to a release of pro-inflammatory cytokines and chemokines by immune effector cells.
-In addition to respiratory distress, this mechanism can lead to organ failure and death in severe COVID-19 cases [33].
+In addition to respiratory distress, this mechanism can lead to organ failure and death in severe COVID-19 cases [35].
4.3 Molecular Tests
Molecular tests are used to identify distinct genomic subsequences of a viral molecule in a sample and thus to diagnose an active viral infection.
This first requires identifying which biospecimens are likely to contain the virus during infection and then acquiring these samples from the patient(s) to be tested.
-Common sampling sources for molecular tests include nasopharyngeal cavity samples, such as throat wash and saliva [310], and stool samples [311].
+Common sampling sources for molecular tests include nasopharyngeal cavity samples, such as throat wash and saliva [312], and stool samples [313].
Once a sample is acquired from a patient, molecular testing will utilize a number of steps, described below, to analyze a sample and identify whether evidence of SARS-CoV-2 is present.
When testing for RNA viruses like SARS-CoV-2, pre-processing is necessary in order to create DNA from the RNA sample.
The DNA can then be amplified with PCR.
Some tests use the results of the PCR itself to determine whether the pathogen is present, but in other cases, it may be necessary to sequence the amplified DNA.
Sequencing requires an additional pre-processing step: library preparation.
-Library preparation is the process of preparing the sample for sequencing, typically by fragmenting the sequences and adding adapters [312].
+Library preparation is the process of preparing the sample for sequencing, typically by fragmenting the sequences and adding adapters [314].
In some cases, library preparation can involve other modifications of the sample, such as adding “barcoding” to identify a particular sample in the sequence data, which is useful for pooling samples from multiple sources.
-There are different reagents used for library preparation that are specific to identifying one or more target sections with PCR [313].
+There are different reagents used for library preparation that are specific to identifying one or more target sections with PCR [315].
Sequential pattern matching is then used to identify unique subsequences of the virus that identify it in specific.
If sufficient subsequences are found, the test is considered positive.
4.3.1 RT-PCR
Real-Time Polymerase Chain Reaction (RT-PCR) tests determine whether a target is present by measuring the rate of amplification during PCR compared to a standard.
When the target is RNA, such as in the case of RNA viruses, the RNA must be converted into complementary DNA during pre-processing.
The Drosten Lab, from Germany, was the first lab to establish and validate a diagnostic test to detect SARS-CoV-2.
-This test uses RT-PCR with reverse transcription [309] to detect several regions of the viral genome: the ORF1b of the RNA-dependent RNA polymerase (RdRP), the Envelope protein gene (E), and the Nucleocapsid protein gene (N).
+This test uses RT-PCR with reverse transcription [311] to detect several regions of the viral genome: the ORF1b of the RNA-dependent RNA polymerase (RdRP), the Envelope protein gene (E), and the Nucleocapsid protein gene (N).
In collaboration with several other labs in Europe and in China, the researchers confirmed the specificity of this test with respect to other coronaviruses against specimens from 297 patients infected with a broad range of respiratory agents.
-Specifically this test utilizes two probes against RdRP, one of which is specific to SARS-CoV-2 [309].
+Specifically this test utilizes two probes against RdRP, one of which is specific to SARS-CoV-2 [311].
Importantly, this assay was not found to return false positive results.
4.3.2 qRT-PCR
-Chinese researchers developed a quantitative real-time reverse transcription PCR (qRT-PCR) test to identify two gene regions of the viral genome, ORF1b and N [314].
+
Chinese researchers developed a quantitative real-time reverse transcription PCR (qRT-PCR) test to identify two gene regions of the viral genome, ORF1b and N [316].
This assay was tested on samples coming two COVID-19 patients and a panel of positive and negative controls consisting of RNA extracted from several cultured viruses.
-The assay uses the N gene to screen patients, while the ORF1b gene region is used to confirm the infection [314].
+The assay uses the N gene to screen patients, while the ORF1b gene region is used to confirm the infection [316].
In this case the test was designed to detect sequences conserved across sarbecoviruses, or viruses within the same subgenus as SARS-CoV-2.
Considering that SARS-CoV-1 and SARS-CoV-2 are the only sarbecoviruses currently known to infect humans, a positive test can be assumed to indicate that the patient is infected with SARS-CoV-2.
However, this test is not able to discriminate the genetics of viruses within the sarbecovirus clade.
@@ -1384,15 +1385,15 @@ 4.3.2.1<
Digital PCR (dPCR) is a new generation of PCR technologies offering an alternative to traditional real-time quantitative PCR.
In dPCR, a sample is partitioned into thousands of compartments, such as nanodroplets (droplet dPCR or ddPCR) or nanowells, and a PCR reaction takes place in each compartment.
This design allows for a digital read-out where each partition is either positive or negative for the nucleic acid sequence being tested for, allowing for much higher throughput.
-While dPCR equipment is not yet as common as that for RT-PCR, dPCR for DNA targets generally achieves higher sensitivity than other PCR technologies while maintaining high specificity, though sensitivity is slightly lower for RNA targets [315].
+While dPCR equipment is not yet as common as that for RT-PCR, dPCR for DNA targets generally achieves higher sensitivity than other PCR technologies while maintaining high specificity, though sensitivity is slightly lower for RNA targets [317].
High sensitivity is particularly relevant for SARS-CoV-2 detection, since low viral load in clinical samples can lead to false negatives.
-Suo et al. [316] performed a double-blind evaluation of ddPCR for SARS-CoV-2 detection on 57 samples, comprised by 43 samples from suspected positive patients and 14 from supposed convalescents, that had all tested negative for SARS-CoV-2 using RT-PCR.
+Suo et al. [318] performed a double-blind evaluation of ddPCR for SARS-CoV-2 detection on 57 samples, comprised by 43 samples from suspected positive patients and 14 from supposed convalescents, that had all tested negative for SARS-CoV-2 using RT-PCR.
Despite the initial negative results, 33 out of 35 (94.3%) patients were later clinically confirmed positive.
All of these individuals tested positive using ddPCR.
Additionally, of 14 supposed convalescents who had received two consecutive negative RT-PCR tests, nine (64.2%) tested positive for SARS-CoV-2 using ddPCR.
Two symptomatic patients tested negative with both RT-PCR and ddPCR, but were later clinically diagnosed positive, and 5 of the 14 suspected convalescents tested negative by ddPCR.
While this study did not provide a complete head-to-head comparison to RT-PCR in all aspects, e.g., no samples testing positive using RT-PCR were evaluated by ddPCR, the study shows the potential of dPCR for viral detection even in highly diluted samples.
-In a second study, Dong et al. [317] compared the results of qRT-PCR and ddPCR testing for SARS-CoV-2 in 194 samples, including 103 samples from suspected patients, 75 from contacts and close contacts, and 16 from suspected convalescents.
+In a second study, Dong et al. [319] compared the results of qRT-PCR and ddPCR testing for SARS-CoV-2 in 194 samples, including 103 samples from suspected patients, 75 from contacts and close contacts, and 16 from suspected convalescents.
Of the 103 suspected patient samples, 29 were reported as positive, 25 as negative, and 49 as suspected by qRT-PCR; all patients were later confirmed to be SARS-CoV-2 positive.
Of the qRT-PCR negative or suspected samples, a total of 61 (17 negative and 44 suspected) were later confirmed to be positive by ddPCR, improving the overall detection rate among these patients from 28.2% to 87.4%.
Of 75 patient samples from contacts and close contacts, 48 tested negative with both methods, and these patients were observed to remain healthy.
@@ -1404,43 +1405,43 @@
4.3.2.1<
Overall, these studies suggest that dPCR is a promising tool for overcoming the problem of false-negative SARS-CoV-2 testing.
4.3.3 Pooled and Automated PCR Testing
Due to limited supplies and the need for more tests, several labs have found ways to pool or otherwise strategically design tests to increase throughput.
-The first such result came from Yelin et al. [318], who found they could pool up to 32 samples in a single qPCR run.
-This was followed by larger-scale pooling with slightly different methods [319].
+The first such result came from Yelin et al. [320], who found they could pool up to 32 samples in a single qPCR run.
+This was followed by larger-scale pooling with slightly different methods [321].
Although these approaches are also PCR based, they allow for more rapid scaling and higher efficiency for testing than the initial PCR-based methods developed.
4.3.3.1 CRISPR-based Detection
Two CRISPR-associated nucleases, Cas12 and Cas13, have been used for nucleic acid detection.
Multiple assays exploiting these nucleases have emerged as potential diagnostic tools for the rapid detection of SARS-CoV-2 genetic material and therefore SARS-CoV-2 infection.
-The SHERLOCK method (Specific High-sensitivity Enzymatic Reporter unLOCKing) from Sherlock Biosciences relies on Cas13a to discriminate between inputs that differ by a single nucleotide at very low concentrations [320].
+The SHERLOCK method (Specific High-sensitivity Enzymatic Reporter unLOCKing) from Sherlock Biosciences relies on Cas13a to discriminate between inputs that differ by a single nucleotide at very low concentrations [322].
The target RNA is amplified by RT-RPA and T7 transcription, and the amplified product activates Cas13a.
The nuclease then cleaves a reporter RNA, which liberates a fluorescent dye from a quencher.
Several groups have used the SHERLOCK method to detect SARS-CoV-2 viral RNA.
-An early study reported that the method could detect 7.5 copies of viral RNA in all 10 replicates, 2.5 copies in 6 out of 10, and 1.25 copies in 2 out of 10 runs [321].
+An early study reported that the method could detect 7.5 copies of viral RNA in all 10 replicates, 2.5 copies in 6 out of 10, and 1.25 copies in 2 out of 10 runs [323].
It also reported 100% specificity and sensitivity on 114 RNA samples from clinical respiratory samples (61 suspected cases, among which 52 were confirmed and nine were ruled out by metagenomic next-generation sequencing, 17 nCoV-/HCoV+ cases and 36 samples from healthy subjects), and a reaction turnaround time of 40 minutes.
A separate study screened four designs of SHERLOCK and extensively tested the best-performing assay.
-They determined the limit of detection to be 10 copies/μl using both fluorescent and lateral flow detection [322].
+They determined the limit of detection to be 10 copies/μl using both fluorescent and lateral flow detection [324].
Lateral flow test strips are simple to use and read, but there are limitations in terms of availability and cost per test.
-Another group therefore proposed the CREST protocol (Cas13-based, Rugged, Equitable, Scalable Testing), which uses a P51 cardboard fluorescence visualizer, powered by a 9V battery, for the detection of Cas13 activity instead of immunochromatography [323].
+Another group therefore proposed the CREST protocol (Cas13-based, Rugged, Equitable, Scalable Testing), which uses a P51 cardboard fluorescence visualizer, powered by a 9V battery, for the detection of Cas13 activity instead of immunochromatography [325].
CREST can be run, from RNA sample to result, with no need for AC power or a dedicated facility, with minimal handling in approximately 2 hours.
Testing was performed on 14 nasopharyngeal swabs.
CREST picked up the same positives as the CDC-recommended TaqMan assay with the exception of one borderline sample that displayed low-quality RNA.
The DETECTR method (DNA Endonuclease-Targeted CRISPR Trans Reporter) from Mammoth Biosciences involves purification of RNA extracted from patient specimens, amplification of extracted RNAs by loop-mediated amplification, which is a rapid, isothermal nucleic acid amplification technique, and application of their Cas12-based technology.
-In their assay, guide RNAs were designed to recognize portions of sequences corresponding to the SARS-CoV-2 genome, specifically the N2 and E regions [324].
+In their assay, guide RNAs were designed to recognize portions of sequences corresponding to the SARS-CoV-2 genome, specifically the N2 and E regions [326].
In the presence of SARS-CoV-2 genetic material, sequence recognition by the guide RNAs results in double-stranded DNA cleavage by Cas12, as well as cleavage of a single-stranded DNA molecular beacon.
The cleavage of this molecular beacon acts as a colorimetric reporter that is subsequently read out in a lateral flow assay and indicates the positive presence of SARS-CoV-2 genetic material and therefore SARS-CoV-2 infection.
The 40-minute assay is considered positive if there is detection of both the E and N genes or presumptive positive if there is detection of either of them.
The assay had 95% positive predictive agreement and 100% negative predictive agreement with the US Centers for Disease Control and Prevention SARS-CoV-2 real-time RT–PCR assay.
The estimated limit of detection was 10 copies per μl reaction, versus 1 copy per μl reaction for the CDC assay.
These results have been confirmed by other DETECTR approaches.
-Using RTRPA for amplification, another group detected 10 copies of synthetic SARS-CoV-2 RNA per μl of input within 60 minutes of RNA sample preparation in a proof-of-principle evaluation [325].
+Using RTRPA for amplification, another group detected 10 copies of synthetic SARS-CoV-2 RNA per μl of input within 60 minutes of RNA sample preparation in a proof-of-principle evaluation [327].
The DETECTR protocol was improved by combining RT-RPA and CRISPR-based detection in a one-pot reaction that incubates at a single temperature, and by using dual crRNAs (which increases sensitivity).
-This new assay, known as All-In-One Dual CRISPR-Cas12a (AIOD-CRISPR), detected 4.6 copies of SARS-CoV-2 RNA per μl of input in 40 minutes [326].
-Another single-tube, constant-temperature approach using Cas12b instead of Cas12a achieved a detection limit of 5 copies/μl in 40-60 minutes [327].
-It was also reported that electric field gradients can be used to control and accelerate CRISPR assays by co-focusing Cas12-gRNA, reporters, and target [328].
+This new assay, known as All-In-One Dual CRISPR-Cas12a (AIOD-CRISPR), detected 4.6 copies of SARS-CoV-2 RNA per μl of input in 40 minutes [328].
+Another single-tube, constant-temperature approach using Cas12b instead of Cas12a achieved a detection limit of 5 copies/μl in 40-60 minutes [329].
+It was also reported that electric field gradients can be used to control and accelerate CRISPR assays by co-focusing Cas12-gRNA, reporters, and target [330].
The authors generated an appropriate electric field gradient using a selective ionic focusing technique known as isotachophoresis (ITP) implemented on a microfluidic chip.
They also used ITP for automated purification of target RNA from raw nasopharyngeal swab samples.
Combining this ITP purification with loop-mediated isothermal amplification, their ITP-enhanced assay to achieved detection of SARS-CoV-2 RNA (from raw sample to result) in 30 minutes.
There is an increasing body of evidence that CRISPR-based assays offer a practical solution for rapid, low-barrier testing in areas that are at greater risk of infection, such as airports and local community hospitals.
-In the largest study to date, DETECTR was compared to qRT-PCR on 378 patient samples [329].
+In the largest study to date, DETECTR was compared to qRT-PCR on 378 patient samples [331].
The authors reported a 95% reproducibility.
Both techniques were equally sensitive in detecting SARS-CoV-2.
Lateral flow strips showed a 100% correlation to the high-throughput DETECTR assay.
@@ -1451,26 +1452,26 @@
False-negative responses, which can present a significant problem to large-scale testing.
-To reduce occurrence of false negatives, correct execution of the analysis is crucial [330].
-Uncertainty surrounding the SARS-CoV-2 viral shedding kinetics, which could affect the result of a test depending on when it was taken [330].
-Type of specimen, as it is not clear which clinical samples are best for detecting the virus [330].
-Expensive machinery, which might be present in major hospitals and/or diagnostic centers but is often not available to smaller facilities [331].
-Timing of the test, which might take up to 4 days to return results [331].
-The availability of supplies for testing, including swabs and testing media, has been limited [332].
+To reduce occurrence of false negatives, correct execution of the analysis is crucial [332].
+Uncertainty surrounding the SARS-CoV-2 viral shedding kinetics, which could affect the result of a test depending on when it was taken [332].
+Type of specimen, as it is not clear which clinical samples are best for detecting the virus [332].
+Expensive machinery, which might be present in major hospitals and/or diagnostic centers but is often not available to smaller facilities [333].
+Timing of the test, which might take up to 4 days to return results [333].
+The availability of supplies for testing, including swabs and testing media, has been limited [334].
Because the guide RNA can recognize other interspersed sequences on the patient’s genome, false positives and a loss of specificity can occur.
Similarly, in tests that use CRISPR, false positives can occur due to the specificity of the technique, as the guide RNA can recognize other interspersed sequences on the patient’s genome.
As noted above, false negatives are a significant concern for several reason.
-Importantly, clinical reports indicate that it is imperative to exercise caution when interpreting the results of molecular tests for SARS-CoV-2 because negative results do not necessarily mean a patient is virus-free [333].
+Importantly, clinical reports indicate that it is imperative to exercise caution when interpreting the results of molecular tests for SARS-CoV-2 because negative results do not necessarily mean a patient is virus-free [335].
4.4 Serological Tests
Although diagnostic tests based on the detection of genetic material can be quite sensitive, they cannot provide information about the extent of the disease over time.
Most importantly, they would not work on a patient who has fully recovered from the virus at the time of sample collection.
In this context, serological tests, which use serum to test for the presence of antibodies against SARS-CoV-2, are significantly more informative.
Additionally, serological tests can help scientists to understand why the disease has a different course among patients, as well as which strategies might work to manage the spread of the infection.
Furthermore, serological tests hold significant interest because of the possibility that they could provide information relevant to advancing economic recovery and allowing reopenings.
-For instance, people that had developed antibodies might be able to return to work, assuming (still-unproven) protective immunity [334].
+For instance, people that had developed antibodies might be able to return to work, assuming (still-unproven) protective immunity [336].
Some infectious agents can be controlled through “herd immunity”, which is when a critical mass within the population acquires immunity through vaccination and/or infection, preventing an infectious agent from spreading widely.
-A simple SIR model predicts that to achieve the required level of exposure for herd immunity to be effective, at least (1-(1/R0)) fraction of the population must be immune or, equivalently, less than (1/R0) fraction of the population susceptible [223].
+A simple SIR model predicts that to achieve the required level of exposure for herd immunity to be effective, at least (1-(1/R0)) fraction of the population must be immune or, equivalently, less than (1/R0) fraction of the population susceptible [225].
However, for SARS-CoV-2 and COVID-19, the R0 and mortality rates that have been observed suggest that relying on herd immunity without some combination of vaccines, proven treatment options, and strong non-pharmaceutical measures of prevention and control would likely result in a significant loss of life.
4.4.1 Sustained Immunity to COVID-19
In the process of mounting a response to a pathogen, the immune system produces antibodies specific to the pathogen.
@@ -1478,19 +1479,19 @@
[335].
-A two-year longitudinal study following convalesced SARS patients with a mean age of 29 found that IgG antibodies were detectable in all 56 patients surveyed for at least 16 months, and remained detectable in all but 4 (11.8%) of patients through the full two-year study period [336].
+IgG titers peaked by day 60, and persisted in all donors through the two-year duration of study [337].
+A two-year longitudinal study following convalesced SARS patients with a mean age of 29 found that IgG antibodies were detectable in all 56 patients surveyed for at least 16 months, and remained detectable in all but 4 (11.8%) of patients through the full two-year study period [338].
These results suggest that immunity to SARS-CoV-1 is sustained for at least a year.
The persistence of antibodies to SARS-CoV-2 remains under investigation.
-Circulating antibody titers to other coronaviruses have been reported to decline significantly after 1 year [337].
-Autopsies of lymph nodes and spleens from severe acute COVID-19 patients showed a loss of T follicular helper cells and germinal centers that may explain some of the impaired development of antibody responses [338].
-An early study (initially released on medRxiv on February 25, 2020) presented a chemiluminescence immunoassay to a synthetic peptide derived from the amino acid sequence of the SARS-CoV-2 S protein [339].
+Circulating antibody titers to other coronaviruses have been reported to decline significantly after 1 year [339].
+Autopsies of lymph nodes and spleens from severe acute COVID-19 patients showed a loss of T follicular helper cells and germinal centers that may explain some of the impaired development of antibody responses [340].
+An early study (initially released on medRxiv on February 25, 2020) presented a chemiluminescence immunoassay to a synthetic peptide derived from the amino acid sequence of the SARS-CoV-2 S protein [341].
This method was highly specific to SARS-CoV-2 and detected IgM in 57.2% and IgG in 71.4% and 57.2% of sera samples from 276 confirmed COVID-19 patients.
They reported that they could detect IgG within two days of the onset of fever and were not able to detect IgM any earlier, a pattern they compared to findings in MERS.
-Since then, several trials have reported the potential protective effect of antibodies in convalescent plasma obtained from recovered COVID-19 patients to treat critically ill COVID-19 patients [340,341,342].
+Since then, several trials have reported the potential protective effect of antibodies in convalescent plasma obtained from recovered COVID-19 patients to treat critically ill COVID-19 patients [342,343,344].
-Evidence to date suggests that sustained immunity to SARS-CoV-2 occurs for a period of at least 6-8 months [343,344,345].
-One study assessed sustained immunity using 245 blood samples from 188 COVID-19 positive patients [344].
+
Evidence to date suggests that sustained immunity to SARS-CoV-2 occurs for a period of at least 6-8 months [345,346,347].
+One study assessed sustained immunity using 245 blood samples from 188 COVID-19 positive patients [346].
The samples were collected at various time points between 6 and 240 days post-symptom onset, meaning some patients were assessed longitudinally.
Of the samples, 43 were collected at least 6 months after symptom onset.
After 1 month, 98% of patients were seropositive for Spike IgG.
@@ -1498,54 +1499,54 @@
[345,346], and this study confirms these finding and shows that these cells steadily increase over the 4-5 months post-symptom onset [344].
-Likewise, nucleocapsid-specific memory B cells seem to follow a similar pattern [344].
-SARS-CoV-2 memory CD8+ T cells were also detected in 70% of 169 COVID-19 patients after 1 month [344], which is consistent with previous research [347].
+RBD-specific memory B cells had been detected in COVID-19 patients 90 days post-symptom onset in previous studies [347,348], and this study confirms these finding and shows that these cells steadily increase over the 4-5 months post-symptom onset [346].
+Likewise, nucleocapsid-specific memory B cells seem to follow a similar pattern [346].
+SARS-CoV-2 memory CD8+ T cells were also detected in 70% of 169 COVID-19 patients after 1 month [346], which is consistent with previous research [349].
However, SARS-CoV-2 memory CD8+ T cells were slightly decreased (50%) 6 months post-symptom onset.
In this same subset of COVID-19 patients, 93% of subjects had detectable levels of SARS-CoV-2 memory CD4+ T cells, of which 42% had > 1% SARS-CoV-2-specific CD4+ T cells.
At 6 months, 92% of patients were positive for SARS-CoV-2 memory CD4+ T cells.
-Indeed, the spike-specific memory CD4+ T cells abundance over time were similar to the overall SARS-CoV-2-specific CD4+ T cells [344].
-T cell immunity to SARS-CoV-2 at 6-8 months post-symptom onset has also been confirmed by others [348,349].
+Indeed, the spike-specific memory CD4+ T cells abundance over time were similar to the overall SARS-CoV-2-specific CD4+ T cells [346].
+T cell immunity to SARS-CoV-2 at 6-8 months post-symptom onset has also been confirmed by others [350,351].
In another study, T cell reactivity to SARS-CoV-2 epitopes was also detected in some individuals never before exposed to SARS-CoV-2.
-This indicates that there is potential for cross-reactive T cell recognition between SARS-CoV-2 and pre-existing circulating coronaviruses that are responsible for the “common cold” [347], but further research is required.
-There is concern that immunity may wane over time, as there several reported cases of reinfection have been confirmed via genomic analysis that revealed distinct variants of SARS-CoV-2 within a single patient [350,351,352].
+This indicates that there is potential for cross-reactive T cell recognition between SARS-CoV-2 and pre-existing circulating coronaviruses that are responsible for the “common cold” [349], but further research is required.
+There is concern that immunity may wane over time, as there several reported cases of reinfection have been confirmed via genomic analysis that revealed distinct variants of SARS-CoV-2 within a single patient [352,353,354].
Further research is required to determine the full extent to which sustained immunity can be and is typically achieved following SARS-CoV-2 infection
-Furthermore, it is unclear whether previous infection may carry repercussions in terms of disease severity for patients [353] and what implications the possibility of reinfection holds for vaccine development and the long-term efficacy of vaccines [354,355].
+Furthermore, it is unclear whether previous infection may carry repercussions in terms of disease severity for patients [355] and what implications the possibility of reinfection holds for vaccine development and the long-term efficacy of vaccines [356,357].
4.4.2 Current Approaches
-
Several countries are now focused on implementing antibody tests, and in the United States, the FDA recently approved a serological test by Cellex for use under emergency conditions [356].
-Specifically, the Cellex qSARS-CoV-2 IgG/IgM Rapid Test is a chromatographic immunoassay designed to qualitatively detect IgM and IgG antibodies against SARS-CoV-2 in the plasma (from a blood sample) of patients suspected to have developed the SARS-CoV-2 infection [356].
+
Several countries are now focused on implementing antibody tests, and in the United States, the FDA recently approved a serological test by Cellex for use under emergency conditions [358].
+Specifically, the Cellex qSARS-CoV-2 IgG/IgM Rapid Test is a chromatographic immunoassay designed to qualitatively detect IgM and IgG antibodies against SARS-CoV-2 in the plasma (from a blood sample) of patients suspected to have developed the SARS-CoV-2 infection [358].
Such tests illuminate the progression of viral disease, as IgM are the first antibodies produced by the body and indicate that the infection is active.
-Once the body has responded to the infection, IgG are produced and gradually replace IgM, indicating that the body has developed immunogenic memory [357].
-The test cassette contains a pad of SARS-CoV-2 antigens and a nitrocellulose strip with lines for each of IgG and IgM, as well as a control (goat IgG) [356].
-In a specimen that contains antibodies against the SARS-CoV-2 antigen, the antibodies will bind to the strip and be captured by the IgM and/or IgG line(s), resulting in a change of color [356].
-With this particular assay, results can be read within 15-20 minutes [356].
-Other research groups, such as the Krammer lab of the Icahn School of Medicine at Mount Sinai, proposed an ELISA test that detects IgG and IgM that react against the receptor binding domain (RBD) of the spike proteins (S) of the virus [358].
-The authors are now working to get the assay into clinical use [359].
+Once the body has responded to the infection, IgG are produced and gradually replace IgM, indicating that the body has developed immunogenic memory [359].
+The test cassette contains a pad of SARS-CoV-2 antigens and a nitrocellulose strip with lines for each of IgG and IgM, as well as a control (goat IgG) [358].
+In a specimen that contains antibodies against the SARS-CoV-2 antigen, the antibodies will bind to the strip and be captured by the IgM and/or IgG line(s), resulting in a change of color [358].
+With this particular assay, results can be read within 15-20 minutes [358].
+Other research groups, such as the Krammer lab of the Icahn School of Medicine at Mount Sinai, proposed an ELISA test that detects IgG and IgM that react against the receptor binding domain (RBD) of the spike proteins (S) of the virus [360].
+The authors are now working to get the assay into clinical use [361].
4.4.3 Limitations of Serological Tests
-Importantly, false-positives can occur due to the cross-reactivity with other antibodies according to the clinical condition of the patient [356].
-Therefore, this test should be used in combination with RNA detection tests [356].
+
Importantly, false-positives can occur due to the cross-reactivity with other antibodies according to the clinical condition of the patient [358].
+Therefore, this test should be used in combination with RNA detection tests [358].
Due to the long incubation times and delayed immune responses of infected patients, serological tests are insufficiently sensitive for a diagnosis in the early stages of an infection.
The limitations due to timing make serological tests far less useful for enabling test-and-trace strategies.
4.5 Possible Alternatives to Current Practices for Identifying Active Cases
Clinical symptoms are too similar to other types of pneumonia to be sufficient as a sole diagnostics criterion.
In addition, as noted above, identifying asymptomatic cases is critical.
-Even among mildly symptomatic patients, a predictive model based on clinical symptoms had a sensitivity of only 56% and a specificity of 91% [360].
+Even among mildly symptomatic patients, a predictive model based on clinical symptoms had a sensitivity of only 56% and a specificity of 91% [362].
More problematic is that clinical symptom-based tests are only able to identify already symptomatic cases, not presymptomatic or asymptomatic cases.
They may still be important for clinical practice, and for reducing tests needed for patients deemed unlikely to have COVID-19.
-X-ray diagnostics have been reported to have high sensitivity but low specificity in some studies [361].
-Other studies have shown that specificity varies between radiologists [362], though the sensitivity reported here was lower than that published in the previous paper.
-However, preliminary machine-learning results have shown far higher sensitivity and specificity from analyzing chest X-rays than was possible with clinical examination [363].
+
X-ray diagnostics have been reported to have high sensitivity but low specificity in some studies [363].
+Other studies have shown that specificity varies between radiologists [364], though the sensitivity reported here was lower than that published in the previous paper.
+However, preliminary machine-learning results have shown far higher sensitivity and specificity from analyzing chest X-rays than was possible with clinical examination [365].
X-ray tests with machine learning can potentially detect asymptomatic or presymptomatic infections that show lung manifestations.
This approach would still not recognize entirely asymptomatic cases.
Given the above, the widespread use of X-ray tests on otherwise healthy adults is likely inadvisable.
4.6 Strategies and Considerations for Determining Whom to Test
-Early in the COVID-19 pandemic, testing was typically limited to individuals considered high risk for developing serious illness [364].
+
Early in the COVID-19 pandemic, testing was typically limited to individuals considered high risk for developing serious illness [366].
This approach often involved limiting testing to people with severe symptoms and people showing mild symptoms that had been in contact with a person who had tested positive.
Individuals who are asymptomatic (i.e., potential spreaders) and individuals who are able to recover at home are therefore often unaware of their status.
However, this method of testing administration misses a high proportion of infections and does not allow for test-and-trace methods to be used.
-For instance, a recent study from Imperial College estimates that in Italy, the true number of infections was around 5.9 million in a total population ~60 million, compared to the 70,000 detected as of March 28th [239].
-Another analysis, which examined New York state, indicated that as of May, 2020, approximately 300,000 cases had been reported in a total population of approximately 20 million [365].
-This corresponded to ~1.5% of the population, but ~12% of individuals sampled statewide were estimated as positive through antibody tests (along with indications of spatial heterogeneity at higher resolution) [365].
+For instance, a recent study from Imperial College estimates that in Italy, the true number of infections was around 5.9 million in a total population ~60 million, compared to the 70,000 detected as of March 28th [241].
+Another analysis, which examined New York state, indicated that as of May, 2020, approximately 300,000 cases had been reported in a total population of approximately 20 million [367].
+This corresponded to ~1.5% of the population, but ~12% of individuals sampled statewide were estimated as positive through antibody tests (along with indications of spatial heterogeneity at higher resolution) [367].
Technological advancements that facilitate widespread, rapid testing will therefore improve the potential to accurately assess the rate of infection and aid in controlling the virus’ spread.
4.7 Conclusions
Major advancements have been made in identifying diagnostic approaches.
@@ -1553,11 +1554,11 @@
4.7
As of October 2020, a range of diagnostic tests have become available.
One class of tests uses PCR (RT-PCR or qRT-PCR) to assess the presence of SARS-CoV-2 RNA, while another typically uses ELISA to test for the presence of antibodies to SARS-CoV-2.
The former approach is useful for identifying active infections, while the latter measures hallmarks of the immune response and therefore can detect either active infections or immunity gained from prior infection.
-Combining these tests leads to extremely accurate detection of SARS-CoV-2 infection (98.6%), but when used alone, PCR-based tests are recommended before 5.5 days after the onset of the illness and antibody tests after 5.5 days [366].
-Other strategies for testing can also influence the tests’ accuracy, such as the use of nasopharyngeal swabs versus BALF [366], which allow for trade-offs between patient’s comfort and test sensitivity.
+Combining these tests leads to extremely accurate detection of SARS-CoV-2 infection (98.6%), but when used alone, PCR-based tests are recommended before 5.5 days after the onset of the illness and antibody tests after 5.5 days [368].
+Other strategies for testing can also influence the tests’ accuracy, such as the use of nasopharyngeal swabs versus BALF [368], which allow for trade-offs between patient’s comfort and test sensitivity.
Additionally, technologies such as digital PCR may allow for scale-up in the throughput of diagnostic testing, facilitating widespread testing.
One major question that remains is whether people who recover from SARS-CoV-2 develop sustained immunity, and over what period this immunity is expected to last.
-Some reports have suggested that some patients may develop COVID-19 reinfections (e.g., [350]), but the rates of reinfection are currently unknown.
+Some reports have suggested that some patients may develop COVID-19 reinfections (e.g., [352]), but the rates of reinfection are currently unknown.
Serologic testing combined with PCR testing will be critical to confirming purported cases of reinfection and to identifying the duration over which immunity is retained and to understanding reinfection risks.
5 Identification and Development of Prophylactics and Therapeutics for COVID-19
5.1 Abstract
@@ -1566,7 +1567,7 @@ 5.1
5.2 Importance
@@ -1578,54 +1579,54 @@ 5.2<
This rapidly changing area of research provides important insight into how the ongoing pandemic can be managed and also demonstrates the power of interdisciplinary collaboration to rapidly understand a virus and match its characteristics with existing or novel pharmaceuticals.
5.3 Introduction
The novel coronavirus Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) emerged in late 2019 and quickly precipitated the worldwide spread of novel coronavirus disease 2019 (COVID-19).
-COVID-19 is associated with symptoms ranging from none (asymptomatic) to mild to severe, with approximately 2% of patients dying from COVID-19-related complications, such as acute respiratory disease syndrome (ARDS) [367].
-The virus is likely spread between people primarily by droplets, with the role of contact and aerosol transmission still in question [194,195].
+COVID-19 is associated with symptoms ranging from none (asymptomatic) to mild to severe, with approximately 2% of patients dying from COVID-19-related complications, such as acute respiratory disease syndrome (ARDS) [1].
+The virus is likely spread between people primarily by droplets, with the role of contact and aerosol transmission still in question [196,197].
As a result, public health guidelines have been critical to efforts to control the spread of the virus.
However, as of early 2021, COVID-19 remains a significant worldwide concern (Figure 2), with cases in some places surging far above the numbers reported during the initial outbreak in early 2020.
Due to the continued threat of the virus and the severity of the disease, the identification and development of prophylactic and therapeutic interventions have emerged as significant international priorities.
Both approaches hold valuable potential for controlling the impact of the disease.
Prophylactics bolster immunity to prevent an individual from contracting a disease, whereas therapeutics treat a disease in individuals who have already been infected.
While vaccine development programs have attracted significant attention and produced a number of promising candidates, there is also an immediate need for treatments that palliate symptoms and prevent the most severe outcomes from infection.
-Fortunately, prior developments during other recent pandemics, especially those caused by human coronaviruses (HCoV), has provided a number of hypotheses guiding a biomedical approach to the novel coronavirus infection.
+Fortunately, prior developments during other recent pandemics, especially those caused by human coronaviruses (HCoV), have provided a number of hypotheses guiding a biomedical approach to the novel coronavirus infection.
2,354,561 COVID-19 deaths had been reported worldwide as of February 10, 2021 (Figure 2).
Figure 2: Cumulative global COVID-19 deaths since January 22, 2020.
-Data are from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [368].
+Data are from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [369].
5.3.1 Lessons from Prior HCoV Outbreaks
SARS-CoV-2’s rapid shift from an unknown virus to a significant worldwide threat closely parallels the emergence of Severe acute respiratory syndrome-related coronavirus (SARS-CoV-1).
The first documented case of COVID-19 was reported in Wuhan, China in November 2019, and the disease quickly spread worldwide during the early months of 2020.
-Similarly, the first case of SARS was reported in November 2002 in the Guangdong Province of China, and it spread within China and then into several countries across continents over the following months [28,30].
-In fact, genome sequencing quickly revealed the virus causing COVID-19 to be a novel betacoronavirus closely related to SARS-CoV-1 [10].
+Similarly, the first case of SARS was reported in November 2002 in the Guangdong Province of China, and it spread within China and then into several countries across continents over the following months [30,32].
+In fact, genome sequencing quickly revealed the virus causing COVID-19 to be a novel betacoronavirus closely related to SARS-CoV-1 [12].
There are many similarities but also some differences in the characteristics of the two viruses that determine how they spread.
-SARS infection is severe, with an estimated death rate of 9.5% [30], while estimates of the death rate associated with COVID-19 are much lower, at approximately 2% [367].
-SARS-CoV-1 is highly contagious via droplet transmission and has a basic reproduction number (R0) of 4 (i.e., each person infected was estimated to infect four other people) [30].
-SARS-CoV-2 also appears to be spread primarily by droplet transmission [194,195], and most estimates of its R0 fall between 2.5 and 3 [367].
+SARS infection is severe, with an estimated death rate of 9.5% [32], while estimates of the death rate associated with COVID-19 are much lower, at approximately 2% [1].
+SARS-CoV-1 is highly contagious via droplet transmission and has a basic reproduction number (R0) of 4 (i.e., each person infected was estimated to infect four other people) [32].
+SARS-CoV-2 also appears to be spread primarily by droplet transmission [196,197], and most estimates of its R0 fall between 2.5 and 3 [1].
Furthermore, the 17-year difference in the timing of these two outbreaks has led to some major differences in the tools available for the international community’s response.
-At the time that SARS-CoV-1 emerged, no new HCoV had been identified in almost 40 years [28].
-The identity of the virus underlying the SARS disease remained unknown until April of 2003, when the SARS-CoV-1 virus was characterized through a worldwide scientific effort spearheaded by the WHO [28].
-In contrast, the SARS-CoV-2 genomic sequence was released on January 3, 2020 [10], only days after the international community became aware of the novel pneumonia-like illness now known as COVID-19.
-While SARS-CoV-1 belonged to a distinct lineage from the two other HCoV known at the time of its discovery [30], SARS-CoV-2 is closely related to SARS-CoV-1 and a more distant relative of another HCoV characterized in 2012, Middle East respiratory syndrome-related coronavirus [13,369].
-Thus, despite their phylogenetic similarity, SARS-CoV-2 emerged under very different circumstances than SARS-CoV-1 in terms of scientific knowledge about HCoV.
+At the time that SARS-CoV-1 emerged, no new HCoV had been identified in almost 40 years [30].
+The identity of the virus underlying the SARS disease remained unknown until April of 2003, when the SARS-CoV-1 virus was characterized through a worldwide scientific effort spearheaded by the World Health Organization (WHO) [30].
+In contrast, the SARS-CoV-2 genomic sequence was released on January 3, 2020 [12], only days after the international community became aware of the novel pneumonia-like illness now known as COVID-19.
+While SARS-CoV-1 belonged to a distinct lineage from the two other HCoV known at the time of its discovery [32], SARS-CoV-2 is closely related to SARS-CoV-1 and a more distant relative of another HCoV characterized in 2012, Middle East respiratory syndrome-related coronavirus [15,370].
+Despite their phylogenetic similarity, SARS-CoV-2 emerged under very different circumstances than SARS-CoV-1 in terms of scientific knowledge about HCoV.
The trajectories of the pandemics associated with each of the viruses have also diverged significantly.
-By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices such as mask wearing [28].
-In contrast, MERS is still circulating and remains a concern; although the fatality rate is very high at almost 35%, the disease is much less easily transmitted, as its R0 has been estimated to be 1 [30].
-The low R0 in combination with public health practices allowed for its spread to be contained [30].
+By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices such as mask wearing [30].
+In contrast, MERS is still circulating and remains a concern; although the fatality rate is very high at almost 35%, the disease is much less easily transmitted, as its R0 has been estimated to be 1 [32].
+The low R0 in combination with public health practices allowed for its spread to be contained [32].
Neither of these trajectories are comparable to that of SARS-CoV-2, which remains a serious threat worldwide more than a year after the first cases of COVID-19 emerged.
Early results suggest that pharmaceutical interventions for COVID-19 may be more successful than efforts to develop prophylactics and therapeutics for SARS and MERS were.
-Care for SARS and MERS patients prioritized supportive care and symptom management [30].
+Care for SARS and MERS patients prioritized supportive care and symptom management [32].
To the extent that clinical treatments for SARS and MERS were explored, there is generally a lack of evidence supporting their efficacy.
-For example, Ribavirin is an antiviral that was often used in combination with corticosteroids and sometimes interferon (IFN) medications to treat SARS and MERS [28], but its effects have been found to be inconclusive in retrospective and in vitro analyses of SARS and the SARS-CoV-1 virus, respectively [28].
-IFNs and Ribavirin have shown promise in in vitro analyses of MERS, but their clinical effectiveness remains unknown [28].
+For example, Ribavirin is an antiviral that was often used in combination with corticosteroids and sometimes interferon (IFN) medications to treat SARS and MERS [30], but its effects have been found to be inconclusive in retrospective and in vitro analyses of SARS and the SARS-CoV-1 virus, respectively [30].
+IFNs and Ribavirin have shown promise in in vitro analyses of MERS, but their clinical effectiveness remains unknown [30].
Therefore, only limited pharmaceutical advances from prior HCoV outbreaks can be adopted to COVID-19.
Importantly, though, prior analyses of the virological and pathogenic properties of SARS-CoV-1 and MERS-CoV provide a strong foundation for the development of hypotheses about SARS-CoV-2 that have served to accelerated the development and identification of potential prophylactic and therapeutic approaches.
5.3.2 Therapeutic Approaches
Therapeutic approaches to the current pandemic can utilize two potential avenues: they can reduce the symptoms that are harmful to COVID-19 patients, or they can directly target the virus to hinder the spread of infection.
The goal of the former is to reduce the severity and risks of an active infection, while for the latter, it is to inhibit the replication of the virus once an individual is infected.
A variety of symptom profiles with a range of severity are associated with COVID-19, many of which are not life-threatening.
-A study of COVID-19 patients in a hospital in Berlin, Germany found that the symptoms associated with the highest risk of death included infection-related symptoms, such as sepsis, respiratory symptoms such as ARDS, and cardiovascular failure or pulmonary embolism [370].
+A study of COVID-19 patients in a hospital in Berlin, Germany found that the symptoms associated with the highest risk of death included infection-related symptoms, such as sepsis, respiratory symptoms such as ARDS, and cardiovascular failure or pulmonary embolism [371].
Therapeutics that reduce the risks associated with these severe outcomes hold particular potential to reduce the pandemic death toll.
On the other hand, therapeutics that directly target the virus itself would hold the potential to prevent people infected with SARS-CoV-2 from developing potentially damaging symptoms.
These treatments typically fall into the broad category of antivirals.
@@ -1644,44 +1645,44 @@
[371].
+Trials data are from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [372].
5.4 Small Molecule Drugs
-
Small molecules are synthesized compounds of low molecular weight, typically less than 1 kilodalton (kDa) [372].
-Small-molecule pharmaceutical agents have been a backbone of drug development since the discovery of penicillin in the early twentieth century [373].
-It and other antibiotics have long been among the best known applications of small molecules to therapeutics, but biotechnological developments such as the prediction of protein-protein interactions have facilitated advances in precise targeting of specific structures using small molecules [373].
+
Small molecules are synthesized compounds of low molecular weight, typically less than 1 kilodalton (kDa) [373].
+Small-molecule pharmaceutical agents have been a backbone of drug development since the discovery of penicillin in the early twentieth century [374].
+It and other antibiotics have long been among the best known applications of small molecules to therapeutics, but biotechnological developments such as the prediction of protein-protein interactions have facilitated advances in precise targeting of specific structures using small molecules [374].
Small molecule drugs today encompass a wide range of therapeutics beyond antibiotics, including antivirals, protein inhibitors, and many broad-spectrum pharmaceuticals.
5.4.1 Small Molecule Antivirals
Antiviral drugs against SARS-CoV-2 are designed to inhibit replication of a virus within an epithelial host cell.
-This process requires inhibiting the replication cycle of a virus by disrupting one of six fundamental steps [374].
+This process requires inhibiting the replication cycle of a virus by disrupting one of six fundamental steps [375].
In the first of these steps, the virus attaches to and enters the host cell through endocytosis.
Then the virus undergoes uncoating, which is classically defined as the release of viral contents into the host cell.
Next, the viral genetic material enters the nucleus where it gets replicated during the biosynthesis stage.
During the assembly stage, viral proteins are translated, allowing new viral particles to be assembled.
In the final step new viruses are released into the extracellular environment.
Many antiviral drugs are designed to inhibit the replication of viral genetic material during the biosynthesis step.
-Unlike DNA viruses, which can use the host enzymes to propagate themselves, RNA viruses like SARS-CoV-2 depend on their own polymerase, the RNA-dependent RNA polymerase (RdRP), for replication [375,376].
-Targeting RdRP is therefore an effective strategy for antivirals against RNA viruses and is the proposed mechanism underlying the treatment of SARS and MERS with Ribavirin [377].
+Unlike DNA viruses, which can use the host enzymes to propagate themselves, RNA viruses like SARS-CoV-2 depend on their own polymerase, the RNA-dependent RNA polymerase (RdRP), for replication [376,377].
+Targeting RdRP is therefore an effective strategy for antivirals against RNA viruses and is the proposed mechanism underlying the treatment of SARS and MERS with Ribavirin [378].
However, although antivirals are designed to target a virus, they can also impact other processes in the host and may have unintended effects.
Therefore, these therapeutics must be evaluated for both efficacy and safety.
5.4.1.1 Nucleoside and Nucleotide Analogs
5.4.1.1.1 Favipiravir
-Favipiravir (Avigan), also known as T-705, was discovered by Toyama Chemical Co., Ltd. [378].
-The drug was found to be effective at blocking viral amplification in several influenza subtypes as well as other RNA viruses, such as Flaviviridae and Picornaviridae, through a reduction in plaque formation [379] and viral replication in Madin-Darby canine kidney cells [380].
-Furthermore, inoculation of mice with favipiravir was shown to increase survival of influenza infections [379,380].
-In 2014, the drug was approved in Japan for the treatment of influenza that was resistant to conventional treatments like neuraminidase inhibitors [381].
-Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) acts as a purine and purine nucleoside analogue that inhibits viral RNA polymerase in a dose-dependent manner across a range of RNA viruses, including influenza viruses [382,383,384,385,386].
+
Favipiravir (Avigan), also known as T-705, was discovered by Toyama Chemical Co., Ltd. [379].
+The drug was found to be effective at blocking viral amplification in several influenza subtypes as well as other RNA viruses, such as Flaviviridae and Picornaviridae, through a reduction in plaque formation [380] and viral replication in Madin-Darby canine kidney cells [381].
+Furthermore, inoculation of mice with favipiravir was shown to increase survival of influenza infections [380,381].
+In 2014, the drug was approved in Japan for the treatment of influenza that was resistant to conventional treatments like neuraminidase inhibitors [382].
+Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) acts as a purine and purine nucleoside analogue that inhibits viral RNA polymerase in a dose-dependent manner across a range of RNA viruses, including influenza viruses [383,384,385,386,387].
Nucleotides and nucleosides are the natural building blocks for RNA synthesis.
-Because of this, modifications to nucleotides and nucleosides can disrupt key processes including replication [387].
+Because of this, modifications to nucleotides and nucleosides can disrupt key processes including replication [388].
Biochemical experiments showed that favipiravir was recognized as a purine nucleoside analogue and incorporated into the viral RNA template.
-A single incorporation does not influence RNA transcription; however, multiple events of incorporation lead to the arrest of RNA synthesis [388].
-Evidence for T-705 inhibiting viral RNA polymerase are based on time-of-drug addition studies that found that viral loads were reduced with the addition of favipiravir in early times post-infection [382,385,386].
+A single incorporation does not influence RNA transcription; however, multiple events of incorporation lead to the arrest of RNA synthesis [389].
+Evidence for T-705 inhibiting viral RNA polymerase are based on time-of-drug addition studies that found that viral loads were reduced with the addition of favipiravir in early times post-infection [383,386,387].
The effectiveness of favipiravir for treating patients with COVID-19 is currently under investigation.
-An open-label, nonrandomized, before-after controlled study was recently conducted [389].
+An open-label, nonrandomized, before-after controlled study was recently conducted [390].
The study included 80 COVID-19 patients (35 treated with favipiravir, 45 control) from the isolation ward of the National Clinical Research Center for Infectious Diseases (The Third People’s Hospital of Shenzhen), Shenzhen, China.
The patients in the control group were treated with other antivirals, such as lopinavir and ritonavir.
-It should be noted that although the control patients received antivirals, two subsequent large-scale analyses, the WHO Solidarity trial and the RECOVERY trial, identified no effect of lopinavir or of a lopinavir-ritonavir combination, respectively, on the metrics of COVID-19-related mortality that each assessed [390,391,392].
+It should be noted that although the control patients received antivirals, two subsequent large-scale analyses, the WHO Solidarity trial and the RECOVERY trial, identified no effect of lopinavir or of a lopinavir-ritonavir combination, respectively, on the metrics of COVID-19-related mortality that each assessed [391,392,393].
Treatment was applied on days 2-14; treatment stopped either when viral clearance was confirmed or at day 14.
The efficacy of the treatment was measured by, first, the time until viral clearance using Kaplan-Meier survival curves, and, second, the improvement rate of chest computed tomography (CT) scans on day 14 after treatment.
The study found that favipiravir increased the speed of recovery, measured as viral clearance from the patient by RT-PCR, with patients receiving favipiravir recovering in four days compared to 11 days for patients receiving antivirals such as lopinavir and ritonavir.
@@ -1692,33 +1693,32 @@
[393].
-
In late 2020 and early 2021, the first randomized controlled trials of favipiravir for the treatment of COVID-19 released results [394,395,396].
-The first [394] used a randomized, controlled, open-label design to compare two drugs, favipiravir and baloxavir marboxil, to SOC alone.
+Additionally, it should be noted that this study was temporarily retracted and then restored without an explanation [394].
+In late 2020 and early 2021, the first randomized controlled trials of favipiravir for the treatment of COVID-19 released results [395,396,397].
+The first [395] used a randomized, controlled, open-label design to compare two drugs, favipiravir and baloxavir marboxil, to standard of care (SOC) alone.
Here, SOC included antivirals such as lopinavir/ritonavir and was administered to all patients.
The primary endpoint analyzed was viral clearance at day 14.
The sample size for this study was very small, with 29 total patients enrolled, and no significant effect of the treatments was found for the primary or any of the secondary outcomes analyzed, which included mortality.
The second study was larger, with 96 patients enrolled, and also utilized a randomized design.
-This study enrolled only patients with mild to moderate symptoms and randomized them into two groups: one receiving CQ in addition to SOC, and the other receiving favipiravir in addition to SOC.
+This study enrolled only patients with mild to moderate symptoms and randomized them into two groups: one receiving chloroquine (CQ) in addition to SOC, and the other receiving favipiravir in addition to SOC.
This study reported a non-significant trend for patients receiving favipiravir to have a shorter hospital stay and less likelihood of progressing to mechanical ventilation or to an oxygen saturation < 90%.
However, given the fact that favipiravir was being compared to CQ, which is now widely understood to be ineffective for treating COVID-19, these results do not suggest that favipiravir was likely to have had a strong effect on these outcomes.
-On the other hand, another trial of 60 patients reported a significant effect of favipiravir on viral clearance at four days (a secondary endpoint), but not at 10 days (the primary endpoint) [396].
-This study, as well as a prior study of favipiravir [397], also reported that the drug was generally well-tolerated.
+On the other hand, another trial of 60 patients reported a significant effect of favipiravir on viral clearance at four days (a secondary endpoint), but not at 10 days (the primary endpoint) [397].
+This study, as well as a prior study of favipiravir [398], also reported that the drug was generally well-tolerated.
Thus, in combination, these small studies suggest that the effects of favipiravir as a treatment for COVID-19 cannot be determined based on the available evidence, but additionally, none raise major concerns about the safety profile of the drug.
5.4.1.1.2 Remdesivir
Remdesivir (GS-5734) is an intravenous antiviral that was developed by Gilead Sciences to treat Ebola Virus Disease (EVD).
At the outset of the COVID-19 pandemic, it did not have any have any FDA-approved use.
-However, on May 1, 2020, the FDA issued an Emergency Use Authorization (EUA) for remdesivir for the treatment of hospitalized COVID-19 patients [398].
-The EUA was based on information from two clinical trials, NCT04280705 and NCT04292899 [399,400,401,402].
-Remdesivir is metabolized to GS-441524, an adenosine analog that inhibits a broad range of polymerases and then evades exonuclease repair, causing chain termination [403,404,405].
-A clinical trial in the Democratic Republic of Congo found some evidence of effectiveness against EVD, but two antibody preparations were found to be more effective, and remdesivir was not pursued [406].
-Although it was developed against EVD, remdesivir also inhibits polymerase and replication of the coronaviruses MERS-CoV and SARS-CoV-1 in cell culture assays with submicromolar IC50s [407].
-It has also been found to inhibit SARS-CoV-2, showing synergy with chloroquine in vitro [405].
-The effectiveness of remdesivir for treating patients with COVID-19 is currently under investigation.
-Remdesivir was first used on some COVID-19 patients under compassionate use guidelines [408,409].
+However, on May 1, 2020, the FDA issued an Emergency Use Authorization (EUA) for remdesivir for the treatment of hospitalized COVID-19 patients [399].
+The EUA was based on information from two clinical trials, NCT04280705 and NCT04292899 [400,401,402,403].
+Remdesivir is metabolized to GS-441524, an adenosine analog that inhibits a broad range of polymerases and then evades exonuclease repair, causing chain termination [404,405,406].
+A clinical trial in the Democratic Republic of Congo found some evidence of effectiveness against EVD, but two antibody preparations were found to be more effective, and remdesivir was not pursued [407].
+Although it was developed against EVD, remdesivir also inhibits polymerase and replication of the coronaviruses MERS-CoV and SARS-CoV-1 in cell culture assays with submicromolar IC50s [408].
+It has also been found to inhibit SARS-CoV-2, showing synergy with CQ in vitro [406].
+Remdesivir was first used on some COVID-19 patients under compassionate use guidelines [409,410].
All were in late stages of COVID-19 infection, and initial reports were inconclusive about the drug’s efficacy.
Gilead Sciences, the maker of remdesivir, led a recent publication that reported outcomes for compassionate use of the drug in 61 patients hospitalized with confirmed COVID-19.
-Here, 200 mg of remdesivir was administered intravenously on day 1, followed by a further 100 mg/day for 9 days [402].
+Here, 200 mg of remdesivir was administered intravenously on day 1, followed by a further 100 mg/day for 9 days [403].
There were significant issues with the study design, or lack thereof.
There was no randomized control group.
The inclusion criteria were variable: some patients only required low doses of oxygen, while others required ventilation.
@@ -1727,49 +1727,48 @@
There was a short follow-up period of investigation.
Some patients worsened, some patients died, and eight were excluded from the analysis mainly due to missing post-baseline information; thus, their health was unaccounted for.
Therefore, even though the study reported clinical improvement in 68% of the 53 patients ultimately evaluated, due to the significant issues with study design, it could not be determined whether treatment with remdesivir had an effect or whether these patients would have recovered regardless of treatment.
-Another study comparing 5- and 10-day treatment regimens reported similar results but was also limited because of the lack of a placebo control [411].
+Another study comparing 5- and 10-day treatment regimens reported similar results but was also limited because of the lack of a placebo control [412].
These studies did not alter the understanding of the efficacy of remdesivir in treating COVID-19, but the encouraging results provided motivation for placebo-controlled studies.
-Remdesivir was later tested in a double-blind placebo-controlled phase 3 clinical trial performed at 60 trial sites, 45 of which were in the United States [400,401].
+
Remdesivir was later tested in a double-blind placebo-controlled phase 3 clinical trial performed at 60 trial sites, 45 of which were in the United States [401,402].
The trial recruited 1,062 patients and randomly assigned them to placebo treatment or treatment with remdesivir.
-Patients were stratified for randomization based on site and the severity of disease presentation at baseline [401].
+Patients were stratified for randomization based on site and the severity of disease presentation at baseline [402].
The treatment was 200 mg on day 1, followed by 100 mg on days 2 through 10.
-Data was analyzed from a total of 1,059 patients who completed the 29-day course of the trial, with 517 assigned to remdesivir and 508 to placebo [401].
+Data was analyzed from a total of 1,059 patients who completed the 29-day course of the trial, with 517 assigned to remdesivir and 508 to placebo [402].
The two groups were well matched demographically and clinically at baseline.
Those who received remdesivir had a median recovery time of 10 days, as compared with 15 days in those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; p < 0.001).
The Kaplan-Meier estimates of mortality by 14 days were 6.7% with remdesivir and 11.9% with placebo, with a hazard ratio (HR) for death of 0.55 and a 95% CI of 0.36 to 0.83, and at day 29, remdesivir corresponded to 11.4% and the placebo to 15.2% (HR: 0.73; 95% CI: 0.52 to 1.03).
Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients in the placebo group (31.6%).
-This study also reported an association between remdesivir administration and both clinical improvement and a lack of progression to more invasive respiratory intervention in patients receiving non-invasive and invasive ventilation at randomization [401].
-Largely on the results of this trial, the FDA reissued and expanded the EUA for remdesivir for the treatment of hospitalized COVID-19 patients ages twelve and older [398].
-Additional clinical trials are currently underway to evaluate the use of remdesivir to treat COVID-19 patients at both early and late stages of infection and in combination with other drugs (Figure 3).
-These trials include [405,412,413,414,415].
-As of October 22, 2020, remdesivir received FDA approval based on three clinical trials [416].
-However, results suggesting no effect of remdesivir on survival were reported by the WHO Solidarity trial [390].
-This large-scale, open-label trial enrolled 11,330 adult in-patients at 405 hospitals in 30 countries around the world [390].
+This study also reported an association between remdesivir administration and both clinical improvement and a lack of progression to more invasive respiratory intervention in patients receiving non-invasive and invasive ventilation at randomization [402].
+Largely on the results of this trial, the FDA reissued and expanded the EUA for remdesivir for the treatment of hospitalized COVID-19 patients ages twelve and older [399].
+Additional clinical trials [406,413,414,415,416] are currently underway to evaluate the use of remdesivir to treat COVID-19 patients at both early and late stages of infection and in combination with other drugs (Figure 3).
+As of October 22, 2020, remdesivir received FDA approval based on three clinical trials [417].
+However, results suggesting no effect of remdesivir on survival were reported by the WHO Solidarity trial [391].
+This large-scale, open-label trial enrolled 11,330 adult in-patients at 405 hospitals in 30 countries around the world [391].
Patients were randomized in equal proportions into four experimental and a control conditions, corresponding to four candidate treatments for COVID-19 and SOC, respectively; no placebo was administered.
The 2,750 patients in the remdesivir group were administered 200 mg intravenously on the first day and 100 mg on each subsequent day until day 10 and assessed for in-hospital death (primary endpoint), duration of hospitalization, and progression to mechanical ventilation.
There were also 2,708 control patients who would have been eligible and able to receive remdesivir were they not assigned to the control group.
A total of 604 patients among these two cohorts deceased during initial hospitalization, with 301 in the remdesivir group and 303 in the control group.
The rate ratio of death between these two groups was therefore not significant (p = 0.50), suggesting that the administration of remdesivir did not affect survival.
The two secondary analyses similarly did not find any effect of remdesivir.
-Additionally, the authors compared data from their study with data from three other studies of remdesivir (including [401]) stratified by supplemental oxygen status.
+Additionally, the authors compared data from their study with data from three other studies of remdesivir (including [402]) stratified by supplemental oxygen status.
The adjusted rate ratio for death based on this meta-analysis was 0.91.
These results thus do not support the previous findings that remdesivir reduced median recovery time and mortality risk in COVID-19 patients.
-In response to the results of the Solidarity trial, Gilead, which manufactures remdesivir, released a statement pointing to the fact that the Solidarity trial was not placebo-controlled or double-blind and at the time of the statement had not been peer reviewed [417]; these sentiments have been echoed elsewhere [418].
-Other critiques of this study have noted that antivirals are not typically targeted at patients with severe illness, and therefore remdesivir could be more beneficial for patients with mild rather than severe cases [392,419].
-However, the publication associated with the trial sponsored by Gilead did purport an effect of remdesivir on patients with severe disease, identifying an 11 versus 18 day recovery period (rate ratio for recovery: 1.31, 95% CI 1.12 to 1.52), although the results of a significance test were not provided [401].
-Additionally, a smaller analysis of 598 patients, of whom two-thirds were randomized to receive remdesivir for either 5 or 10 days, reported a small effect of treatment with remdesivir for five days relative to standard of care in patients with moderate COVID-19 [420].
+
In response to the results of the Solidarity trial, Gilead, which manufactures remdesivir, released a statement pointing to the fact that the Solidarity trial was not placebo-controlled or double-blind and at the time of the statement had not been peer reviewed [418]; these sentiments have been echoed elsewhere [419].
+Other critiques of this study have noted that antivirals are not typically targeted at patients with severe illness, and therefore remdesivir could be more beneficial for patients with mild rather than severe cases [393,420].
+However, the publication associated with the trial sponsored by Gilead did purport an effect of remdesivir on patients with severe disease, identifying an 11 versus 18 day recovery period (rate ratio for recovery: 1.31, 95% CI 1.12 to 1.52), although the results of a significance test were not provided [402].
+Additionally, a smaller analysis of 598 patients, of whom two-thirds were randomized to receive remdesivir for either 5 or 10 days, reported a small effect of treatment with remdesivir for five days relative to standard of care in patients with moderate COVID-19 [421].
These results suggest that remdesivir could improve outcomes for patients with moderate COVID-19, but that additional information would be needed to understand the effects of different durations of treatment.
-Therefore, the arguments put forward in defense of remdesivir do not necessarily seem robust in light of the large sample size used in the Solidarity trial, especially since the broad international nature of the Solidarity clinical trial, which included countries with a wide range of economic profiles and a variety of healthcare systems, provides a much-needed global perspective in a pandemic [392].
-On the other hand, only 62% of patients in the Solidarity trial were randomized on the day of admission or one day afterwards [390], and concerns have been raised that differences in disease progression could influence the effectiveness of remdesivir [392].
+Therefore, the arguments put forward in defense of remdesivir do not necessarily seem robust in light of the large sample size used in the Solidarity trial, especially since the broad international nature of the Solidarity clinical trial, which included countries with a wide range of economic profiles and a variety of healthcare systems, provides a much-needed global perspective in a pandemic [393].
+On the other hand, only 62% of patients in the Solidarity trial were randomized on the day of admission or one day afterwards [391], and concerns have been raised that differences in disease progression could influence the effectiveness of remdesivir [393].
Despite the findings of the Solidarity trial, remdesivir remains available for the treatment of COVID-19 in many places.
-Follow-up studies are needed and, in many cases, are underway to further investigate remdesivir-related outcomes, with possibilities including combinations of remdesivir with other drugs such as baricitinib, which is an inhibitor of Janus kinase 1 and 2 [421].
+Follow-up studies are needed and, in many cases, are underway to further investigate remdesivir-related outcomes, with possibilities including combinations of remdesivir with other drugs such as baricitinib, which is an inhibitor of Janus kinase 1 and 2 [422].
Similarly, the extent to which the remdesivir dosing regimen could influence outcomes continues to be under consideration.
-In complement to the study that found that a 5-day course of remdesivir improved outcomes for patients with moderate COVID-19 but a 10-day course did not [420], a randomized, open-label trial compared the effect of remdesivir on 397 patients with severe COVID-19 over 5 versus 10 days [399,411].
+A randomized, open-label trial compared the effect of remdesivir on 397 patients with severe COVID-19 over 5 versus 10 days [400,412], complementing the study that found that a 5-day course of remdesivir improved outcomes for patients with moderate COVID-19 but a 10-day course did not [421].
Patients in the two groups were administered 200 mg of remdesivir intravenously on the first day, followed by 100 mg on the subsequent four or nine days, respectively.
The two groups differed significantly in their clinical status, with patients assigned to the 10-day group having more severe illness.
This study also differed from most because it included not only adults, but also pediatric patients as young as 12 years old.
It reported no significant differences across several outcomes for patients receiving a 5-day or 10-day course, when correcting for baseline clinical status.
-The data did suggest that the 10-day course might reduce mortality in the most severe patients at day 14, but the representation of this group in the study population was too low to justify any conclusions [411].
+The data did suggest that the 10-day course might reduce mortality in the most severe patients at day 14, but the representation of this group in the study population was too low to justify any conclusions [412].
Thus, additional research is also required to determine whether the dosage and duration of remdesivir administration influences outcomes.
In summary, remdesivir is a first in class drug due to its FDA approval.
Early investigations of this drug established proof of principle that drugs targeting the virus can benefit COVID-19 patients.
@@ -1781,43 +1780,43 @@
They are typically combined with protease inhibitors, integrase inhibitors, and even other polymerase inhibitors.
Additional clinical trials of remdesivir in different patient pools and in combination with other therapies will refine its use in the clinic.
5.4.1.2 Protease Inhibitors
-Several studies showed that viral proteases play an important role in the life cycle of viruses, including coronaviruses, by modulating the cleavage of viral polyprotein precursors [422].
+
Several studies showed that viral proteases play an important role in the life cycle of viruses, including coronaviruses, by modulating the cleavage of viral polyprotein precursors [423].
Several FDA-approved drugs target proteases, including lopinavir and ritonavir for HIV infection and simeprevir for hepatitis C virus infection.
-In particular, serine protease inhibitors were suggested for the treatment of SARS and MERS viruses [423].
-Recently, a study [67] suggested that camostat mesylate, an FDA-approved protease inhibitor (PI) could block the entry of SARS-CoV-2 into lung cells in vitro.
+In particular, serine protease inhibitors were suggested for the treatment of SARS and MERS viruses [424].
+Recently, a study [69] suggested that camostat mesylate, an FDA-approved protease inhibitor (PI) could block the entry of SARS-CoV-2 into lung cells in vitro.
Thus far, investigation of possible PIs that could work against SARS-CoV-2 has been driven by computational predictions.
Computer-aided design allowed for the development of a Michael acceptor inhibitor, now known as N3, to target a protease critical to SARS-CoV-2 replication.
-Discovery of the N3 mechanism arose from interest in the two polyproteins encoded by the SARS-CoV-2 replicase gene, pp1a and pp1ab, that are critical for viral replication and transcription [424].
+Discovery of the N3 mechanism arose from interest in the two polyproteins encoded by the SARS-CoV-2 replicase gene, pp1a and pp1ab, that are critical for viral replication and transcription [425].
These polyproteins must undergo proteolytic processing.
This processing is usually conducted by Mpro, a 33.8-kDa SARS-CoV-2 protease that is therefore fundamental to viral replication and transcription.
-N3 was designed computationally [425] to bind in the substrate binding pocket of the Mpro protease of SARS-like coronaviruses [426], therefore inhibiting proteolytic processing.
-Subsequently, the structure of N3-bound SARS-CoV-2 Mpro was solved [424], confirming the computational prediction.
-N3 was tested in vitro on SARS-CoV-2-infected Vero cells, which belong to a line of cells established from the kidney epithelial cells of an African green monkey, and was found to inhibit SARS-CoV-2 [424].
+N3 was designed computationally [426] to bind in the substrate binding pocket of the Mpro protease of SARS-like coronaviruses [427], therefore inhibiting proteolytic processing.
+Subsequently, the structure of N3-bound SARS-CoV-2 Mpro was solved [425], confirming the computational prediction.
+N3 was tested in vitro on SARS-CoV-2-infected Vero cells, which belong to a line of cells established from the kidney epithelial cells of an African green monkey, and was found to inhibit SARS-CoV-2 [425].
Although N3 is a strong inhibitor of SARS-CoV-2 in vitro, its safety and efficacy still need to be tested in healthy volunteers and patients.
-After the design and confirmation of N3 as a highly potent Michael acceptor inhibitor and the identification of Mpro’s structure [424,427], 10,000 compounds were screened for their in vitro anti-Mpro activity.
+After the design and confirmation of N3 as a highly potent Michael acceptor inhibitor and the identification of Mpro’s structure [425,428], 10,000 compounds were screened for their in vitro anti-Mpro activity.
The six leads that were identified were ebselen, disulfiram, tideglusib, carmofur, and PX-12.
-In vitro analysis revealed that Ebselen had the strongest potency in reducing the viral load in SARS-CoV-2-infected Vero cells [424].
-Ebselen is an organoselenium compound with anti-inflammatory and antioxidant properties [428].
-It has been proposed as a possible treatment for conditions ranging from bipolar disorder to diabetes to heart disease [428], and a preliminary investigation of ebselen as a treatment for noise-induced hearing loss provided promising reports of its safety [429].
-For COVID-19, the NSP5 in SARS-CoV-2 contains a cysteine at the active site of Mpro, and ebselen is able to inactivate the protease by bonding covalently with this cysteine to form a selenosulfide [428,430].
-Interestingly there has been some argument that selenium deficiency may be associated with more severe COVID-19 outcomes [431,432,433], possibly indicating that its antioxidative properties are protective [430].
-On the other hand, ebselen and the other compounds identified are likely to be promiscuous binders, which could diminish their therapeutic potential [424].
+In vitro analysis revealed that ebselen had the strongest potency in reducing the viral load in SARS-CoV-2-infected Vero cells [425].
+Ebselen is an organoselenium compound with anti-inflammatory and antioxidant properties [429].
+It has been proposed as a possible treatment for conditions ranging from bipolar disorder to diabetes to heart disease [429], and a preliminary investigation of ebselen as a treatment for noise-induced hearing loss provided promising reports of its safety [430].
+For COVID-19, the NSP5 in SARS-CoV-2 contains a cysteine at the active site of Mpro, and ebselen is able to inactivate the protease by bonding covalently with this cysteine to form a selenosulfide [429,431].
+Interestingly there has been some argument that selenium deficiency may be associated with more severe COVID-19 outcomes [432,433,434], possibly indicating that its antioxidative properties are protective [431].
+On the other hand, ebselen and the other compounds identified are likely to be promiscuous binders, which could diminish their therapeutic potential [425].
While there is clear computational and in vitro support for ebselen’s potential as a COVID-19 therapeutic, results from clinical trials are not yet available for this compound.
-However, as of July 2020, phase II clinical trials commenced to assess the effects of SPI-1005, an investigational drug from Sound Pharmaceuticals that contains ebselen [434], on 60 adults presenting with each of moderate [435] and severe [436] COVID-19.
+However, as of July 2020, phase II clinical trials commenced to assess the effects of SPI-1005, an investigational drug from Sound Pharmaceuticals that contains ebselen [435], on 60 adults presenting with each of moderate [436] and severe [437] COVID-19.
In summary, N3 is a computationally designed molecule that inhibits the viral transcription through inhibiting Mpro.
Ebselen is both a strong Mpro inhibitor and strong inhibitor of viral replication in vitro that was found to reduce SARS-CoV-2 viral load even more effectively than N3.
-Ebselen is a very promising compound since its safety has been demonstrated in other indications.
-However, ebselen may be a false positive, since it is a promiscuous compound that can have many targets [437].
+Ebselen is a promising compound since its safety has been demonstrated in other indications.
+However, ebselen may be a false positive, since it is a promiscuous compound that can have many targets [438].
Therefore, the results of ongoing clinical trials are expected to help establish whether compounds with higher specificity are required.
5.4.2 Broad-Spectrum Pharmaceuticals
-When a virus enters a host, the host becomes the virus’ environment.
+
When a virus enters a host, the host becomes the virus’s environment.
Therefore, the state of the host can also influence the virus’s ability to replicate and spread.
-Traditionally, viral targets have been favored for pharmaceutical interventions because altering host processes is likely to be less specific than targeting the virus directly [438].
-On the other hand, targeting the host offers potential for a complementary strategy to antivirals that could broadly limit the ability of viruses to replicate [438].
+Traditionally, viral targets have been favored for pharmaceutical interventions because altering host processes is likely to be less specific than targeting the virus directly [439].
+On the other hand, targeting the host offers potential for a complementary strategy to antivirals that could broadly limit the ability of viruses to replicate [439].
As a result, therapeutic approaches that target host proteins have become an area of interest for SARS-CoV-2.
Viral entry receptors in particular have been identified as a potential target.
-Entry of SARS-CoV-2 into the cell depends on binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which is catalyzed by the enzyme encoded by TMPRSS2 [67].
+Entry of SARS-CoV-2 into the cell depends on binding to angiotensin-converting enzyme 2 (ACE2), which is catalyzed by the enzyme encoded by TMPRSS2 [69].
In principle, drugs that reduce the expression of these proteins or sterically hinder viral interactions with them might reduce viral entry into cells.
Due to the urgent nature of the COVID-19 pandemic, many of the pharmaceutical agents that have been widely publicized as having possible therapeutic or prophylactic effects are broad-spectrum pharmaceuticals that pre-date the COVID-19 pandemic.
These treatments are not specifically targeted at the virus itself or at the host receptors it relies on, but rather induce broad shifts in host biology that are hypothesized to be potential inhibitors of the virus.
@@ -1825,56 +1824,56 @@
5.4.2.1 ACEi and ARB
-Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are among today’s most commonly prescribed medications [439,440].
+
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are among today’s most commonly prescribed medications [440,441].
In the United States, for example, they are prescribed well over 100,000,000 times annually.
-Data from some animal models suggest that several, but not all, ACE inhibitors and several ARBs increase ACE2 expression in the cells of some organs [441].
-Clinical studies have not established whether plasma ACE2 expression is increased in humans treated with these medications [442].
+Data from some animal models suggest that several, but not all, ACE inhibitors and several ARBs increase ACE2 expression in the cells of some organs [442].
+Clinical studies have not established whether plasma ACE2 expression is increased in humans treated with these medications [443].
While randomized clinical trials are ongoing, a variety of observational studies have examined the relationship between exposure to ACE inhibitors or ARBs and outcomes in patients with COVID-19.
-An observational study of the association of exposure to ACE inhibitors or ARB with outcomes in COVID-19 was retracted from the New England Journal of Medicine [443].
-Moreover, because observational studies are subject to confounding, randomized controlled trials are the standard means of assessing the effects of medications, and the findings of the various observational studies bearing on this topic cannot be interpreted as indicating a protective effect of the drug [444,445].
-Several clinical trials testing the effects of ACE inhibitors or ARBs on COVID-19 outcomes are ongoing [446,447,448,449,450,451].
+An observational study of the association of exposure to ACE inhibitors or ARB with outcomes in COVID-19 was retracted from the New England Journal of Medicine [444].
+Moreover, because observational studies are subject to confounding, randomized controlled trials are the standard means of assessing the effects of medications, and the findings of the various observational studies bearing on this topic cannot be interpreted as indicating a protective effect of the drug [445,446].
+Several clinical trials testing the effects of ACE inhibitors or ARBs on COVID-19 outcomes are ongoing [447,448,449,450,451,452].
These studies of randomized intervention will provide important data for understanding whether exposure to ACEis or ARBs is associated with COVID-19 outcomes.
-Additional information about ACE2, observational studies of ACE inhibitors and ARBs in COVID-19, and clinical trials on this topic have been summarized [452].
+Additional information about ACE2, observational studies of ACE inhibitors and ARBs in COVID-19, and clinical trials on this topic have been summarized [453].
5.4.2.2 Hydroxychloroquine and Chloroquine
-Chloroquine (CQ) and hydroxychloroquine (HCQ) are lysosomotropic agents, meaning they are weak bases that can pass through the plasma membrane.
-Both drugs increase cellular pH by accumulating in their protonated form inside lysosomes [453,454].
-This shift in pH inhibits the breakdown of proteins and peptides by the lysosomes during the process of proteolysis [454].
+
CQ and hydroxychloroquine (HCQ) are lysosomotropic agents, meaning they are weak bases that can pass through the plasma membrane.
+Both drugs increase cellular pH by accumulating in their protonated form inside lysosomes [454,455].
+This shift in pH inhibits the breakdown of proteins and peptides by the lysosomes during the process of proteolysis [455].
A number of mechanisms have been proposed through which these drugs could influence the immune response to pathogen challenge.
-For example, CQ/HCQ can interfere with digestion of antigens within the lysosome and inhibit CD4 T-cell stimulation while promoting the stimulation of CD8 T-cells [454].
-CQ/HCQ can also decrease the production of certain key cytokines involved in the immune response, including interleukin-6 (IL-6), and inhibit the stimulation of Toll-like receptors (TLR) and TLR signaling [454].
-The drugs also have anti-inflammatory and photoprotective effects and may also affect rates of cell death, blood clotting, glucose tolerance, and cholesterol levels [454].
+For example, CQ/HCQ can interfere with digestion of antigens within the lysosome and inhibit CD4 T-cell stimulation while promoting the stimulation of CD8 T-cells [455].
+CQ/HCQ can also decrease the production of certain key cytokines involved in the immune response, including interleukin-6 (IL-6), and inhibit the stimulation of Toll-like receptors (TLR) and TLR signaling [455].
+The drugs also have anti-inflammatory and photoprotective effects and may also affect rates of cell death, blood clotting, glucose tolerance, and cholesterol levels [455].
Interest in CQ and HCQ for treating COVID-19 was catalyzed by a mechanism observed in in vitro studies of both SARS-CoV-1 and SARS-CoV-2.
-In one study, CQ inhibited viral entry of SARS-CoV-1 into Vero E6 cells, a cell line that was derived from Vero cells in 1968, through the elevation of endosomal pH and the terminal glycosylation of the cellular entry receptor, ACE2 [455].
+In one study, CQ inhibited viral entry of SARS-CoV-1 into Vero E6 cells, a cell line that was derived from Vero cells in 1968, through the elevation of endosomal pH and the terminal glycosylation of ACE2 [456].
Increased pH within the cell, as discussed above, inhibits proteolysis, and terminal glycosylation of ACE2 is thought to interfere with virus-receptor binding.
-An in vitro study of SARS-CoV-2 infection of Vero cells found both HCQ and CQ to be effective in inhibiting viral replication, with HCQ being more potent [456].
-Additionally, an early case study of three COVID-19 patients reported the presence of antiphospholipid antibodies in all three patients [102].
-Antiphospholipid antibodies are central to the diagnosis of the antiphospholipid syndrome, a disorder that HCQ has often been used to treat [457,458,459].
-Because the 90% effective concentration (EC90) of CQ in Vero E6 cells (6.90 μM) can be achieved in and tolerated by rheumatoid arthritis (RA) patients, it was hypothesized that it might also be possible to achieve the effective concentration in COVID-19 patients [460].
-Additionally, HCQ has been found to be effective in treating HIV [461] and chronic Hepatitis C [462].
+An in vitro study of SARS-CoV-2 infection of Vero cells found both HCQ and CQ to be effective in inhibiting viral replication, with HCQ being more potent [457].
+Additionally, an early case study of three COVID-19 patients reported the presence of antiphospholipid antibodies in all three patients [104].
+Antiphospholipid antibodies are central to the diagnosis of the antiphospholipid syndrome, a disorder that HCQ has often been used to treat [458,459,460].
+Because the 90% effective concentration (EC90) of CQ in Vero E6 cells (6.90 μM) can be achieved in and tolerated by rheumatoid arthritis (RA) patients, it was hypothesized that it might also be possible to achieve the effective concentration in COVID-19 patients [461].
+Additionally, HCQ has been found to be effective in treating HIV [462] and chronic Hepatitis C [463].
Together, these studies triggered initial enthusiasm about the therapeutic potential for HCQ and CQ against COVID-19.
HCQ/CQ has been proposed both as a treatment for COVID-19 and a prophylaxis against SARS-CoV-2 exposure, and trials often investigated these drugs in combination with azithromycin (AZ) and/or zinc supplementation.
However, as more evidence has emerged, it has become clear that HCQ/CQ offer no benefits against SARS-CoV-2 or COVID-19.
5.4.2.2.1 Trials Assessing Therapeutic Administration of HCQ/CQ
-The initial study evaluating HCQ as a treatment for COVID-19 patients was published on March 20, 2020 by Gautret et al. [463].
-This non-randomized, non-blinded, non-placebo clinical trial compared HCQ to standard of care (SOC) in 42 hospitalized patients in southern France.
+
The initial study evaluating HCQ as a treatment for COVID-19 patients was published on March 20, 2020 by Gautret et al. [464].
+This non-randomized, non-blinded, non-placebo clinical trial compared HCQ to SOC in 42 hospitalized patients in southern France.
It reported that patients who received HCQ showed higher rates of virological clearance by nasopharyngeal swab on days 3-6 when compared to SOC.
This study also treated six patients with both HCQ + AZ and found this combination therapy to be more effective than HCQ alone.
However, the design and analyses used showed weaknesses that severely limit interpretability of results, including the lack of randomization, lack of blinding, lack of placebo, lack of Intention-To-Treat analysis, lack of correction for sequential multiple comparisons, trial arms entirely confounded by hospital, false negatives in outcome measurements, lack of trial pre-registration, and small sample size.
Two of these weaknesses are due to inappropriate data analysis and can therefore be corrected post hoc by recalculating the p-values (lack of Intention-To-Treat analysis and multiple comparisons).
However, all other weaknesses are fundamental design flaws and cannot be corrected for.
-Thus, conclusions cannot be generalized outside of the study.
-The International Society of Antimicrobial Chemotherapy, the scientific organization that publishes the journal where the article appeared, subsequently announced that the article did not meet its expected standard for publications [464], although it has not been officially retracted.
+Thus, the conclusions cannot be generalized outside of the study.
+The International Society of Antimicrobial Chemotherapy, the scientific organization that publishes the journal where the article appeared, subsequently announced that the article did not meet its expected standard for publications [465], although it has not been officially retracted.
Because of the preliminary data presented in this study, HCQ treatment was subsequently explored by other researchers.
-About one week later, a follow-up case study reported that 11 consecutive patients were treated with HCQ + AZ using the same dosing regimen [465].
+About one week later, a follow-up case study reported that 11 consecutive patients were treated with HCQ + AZ using the same dosing regimen [466].
One patient died, two were transferred to the intensive care unit (ICU), and one developed a prolonged QT interval, leading to discontinuation of HCQ + AZ administration.
As in the Gautret et al. study, the outcome assessed was virological clearance at day 6 post-treatment, as measured from nasopharyngeal swabs.
Of the ten living patients on day 6, eight remained positive for SARS-CoV-2 RNA.
Like in the original study, interpretability was severely limited by the lack of a comparison group and the small sample size.
However, these results stand in contrast to the claims by Gautret et al. that all six patients treated with HCQ + AZ tested negative for SARS-CoV-2 RNA by day 6 post-treatment.
This case study illustrated the need for further investigation using robust study design to evaluate the efficacy of HCQ and/or CQ.
-On April 10, 2020, a randomized, non-placebo trial of 62 COVID-19 patients at the Renmin Hospital of Wuhan University was released [466].
-This study investigated whether HCQ decreased time to fever break or time to cough relief when compared to SOC [466].
+
On April 10, 2020, a randomized, non-placebo trial of 62 COVID-19 patients at the Renmin Hospital of Wuhan University was released [467].
+This study investigated whether HCQ decreased time to fever break or time to cough relief when compared to SOC [467].
This trial found HCQ decreased both average time to fever break and average time to cough relief, defined as mild or no cough.
While this study improved on some of the methodological flaws in Gautret et al. by randomizing patients, it also had several flaws in trial design and data analysis that prevent generalization of the results.
These weaknesses include the lack of placebo, lack of correction for multiple primary outcomes, inappropriate choice of outcomes, lack of sufficient detail to understand analysis, drastic disparities between pre-registration and published protocol, and small sample size.
@@ -1883,67 +1882,67 @@
[467]
.
-The design limitations mean that the conclusions cannot be generalized outside of the study.
-A second randomized trial, conducted by the Shanghai Public Health Clinical Center, analyzed whether HCQ increased rates of virological clearance at day 7 in respiratory pharyngeal swabs compared to SOC [468].
+Additionally, the observation of drastic disparities between pre-registration and published protocol could indicate p-hacking [468].
+The design limitations mean that the conclusions cannot be generalized outside of the study.
+
A second randomized trial, conducted by the Shanghai Public Health Clinical Center, analyzed whether HCQ increased rates of virological clearance at day 7 in respiratory pharyngeal swabs compared to SOC [469].
This trial was published in Chinese along with an abstract in English, and only the English abstract was read and interpreted for this review.
The trial found comparable outcomes in virological clearance rate, time to virological clearance, and time to body temperature normalization between the treatment and control groups.
-A known weakness is small sample size, with only 30 patients enrolled and 15 in each arm.
+The small sample size is one weakness, with only 30 patients enrolled and 15 in each arm.
This problem suggests the study is underpowered to detect potentially useful differences and precludes interpretation of results.
Additionally, because only the abstract could be read, other design and analysis issues could be present.
Thus, though these studies added randomization to their assessment of HCQ, their conclusions should be interpreted very cautiously.
These two studies assessed different outcomes and reached differing conclusions about the efficacy of HCQ for treating COVID-19; the designs of both studies, especially with respect to sample size, meant that no general conclusions can be made about the efficacy of the drug.
Several widely reported studies on HCQ also have issues with data integrity and/or provenance.
-A Letter to the Editor published in BioScience Trends on March 16, 2020 claimed that numerous clinical trials have shown that HCQ is superior to control treatment in inhibiting the exacerbation of COVID-19 pneumonia [469].
-This letter has been cited by numerous primary literature, review articles, and media alike [470,471].
+A Letter to the Editor published in BioScience Trends on March 16, 2020 claimed that numerous clinical trials have shown that HCQ is superior to control treatment in inhibiting the exacerbation of COVID-19 pneumonia [470].
+This letter has been cited by numerous primary literature, review articles, and media alike [471,472].
However, the letter referred to 15 pre-registration identifiers from the Chinese Clinical Trial Registry.
When these identifiers are followed back to the registry, most trials claim they are not yet recruiting patients or are currently recruiting patients.
For all of these 15 identifiers, no data uploads or links to publications could be located on the pre-registrations.
At the very least, the lack of availability of the primary data means the claim that HCQ is efficacious against COVID-19 pneumonia cannot be verified.
-Similarly, a recent multinational registry analysis [472] analyzed the efficacy of CQ and HCQ with and without a macrolide, which is a class of antibiotics that includes Azithromycin, for the treatment of COVID-19.
+Similarly, a recent multinational registry analysis [473] analyzed the efficacy of CQ and HCQ with and without a macrolide, which is a class of antibiotics that includes Azithromycin, for the treatment of COVID-19.
The study observed 96,032 patients split into a control and four treatment conditions (CQ with and without a macrolide; HCQ with and without a macrolide).
They concluded that treatment with CQ and HCQ was associated with increased risk of de novo ventricular arrhythmia during hospitalization.
-However, this study has since been retracted by The Lancet due to an inability to validate the data used [473].
-These studies demonstrate that increased skepticism in evaluation of the HCQ/CQ and COVID-19 literature may be warranted, possible because of the significant attention HCQ and CQ have received as possible treatments for COVID-19 and the politicization of these drugs.
+However, this study has since been retracted by The Lancet due to an inability to validate the data used [474].
+These studies demonstrate that increased skepticism in evaluation of the HCQ/CQ and COVID-19 literature may be warranted, possibly because of the significant attention HCQ and CQ have received as possible treatments for COVID-19 and the politicization of these drugs.
Despite the fact that the study suggesting that CQ/HCQ increased risk of ventricular arrhythmia in COVID-19 patients has now been retracted, previous studies have identified risks associated with HCQ/CQ.
-A patient with systemic lupus erythematosus developed a prolonged QT interval that was likely exacerbated by use of HCQ in combination with renal failure [474].
-A prolonged QT interval is associated with ventricular arrhythmia [475].
-Furthermore, a separate study [476] investigated the safety associated with the use of HCQ with and without macrolides between 2000 and 2020.
+A patient with systemic lupus erythematosus developed a prolonged QT interval that was likely exacerbated by use of HCQ in combination with renal failure [475].
+A prolonged QT interval is associated with ventricular arrhythmia [476].
+Furthermore, a separate study [477] investigated the safety associated with the use of HCQ with and without macrolides between 2000 and 2020.
The study involved 900,000 cases treated with HCQ and 300,000 cases treated with HCQ + AZ.
The results indicated that short-term use of HCQ was not associated with additional risk, but that HCQ + AZ was associated with an enhanced risk of cardiovascular complications (15-20% increased risk of chest pain) and a two-fold increased risk of mortality.
Therefore, whether studies utilize HCQ alone or HCQ in combination with a macrolide may be an important consideration in assessing risk.
-As results from initial investigations of these drug combinations have emerged, concerns about the efficacy and risks of treating COVID-19 with HCQ and CQ has led to the removal of CQ/HCQ from SOC practices in several countries [477,478].
-As of May 25, 2020, WHO had suspended administration of HCQ as part of the worldwide Solidarity Trial [479], and later the final results of this large-scale trial that compared 947 patients administered HCQ to 906 controls revealed no effect on the primary outcome, mortality during hospitalization (rate ratio: 1.19; p = 0.23)
+As results from initial investigations of these drug combinations have emerged, concerns about the efficacy and risks of treating COVID-19 with HCQ and CQ has led to the removal of CQ/HCQ from SOC practices in several countries [478,479].
+As of May 25, 2020, WHO had suspended administration of HCQ as part of the worldwide Solidarity Trial [480], and later the final results of this large-scale trial that compared 947 patients administered HCQ to 906 controls revealed no effect on the primary outcome, mortality during hospitalization (rate ratio: 1.19; p = 0.23)
Additional research has emerged largely identifying HCQ/CQ to be ineffective against COVID-19 while simultaneously revealing a number of significant side effects.
-A randomized, open-label, non-placebo trial of 150 COVID-19 patients was conducted in parallel at 16 government-designated COVID-19 centers in China to assess the safety and efficacy of HCQ [480].
+A randomized, open-label, non-placebo trial of 150 COVID-19 patients was conducted in parallel at 16 government-designated COVID-19 centers in China to assess the safety and efficacy of HCQ [481].
The trial compared treatment with HCQ in conjunction with SOC to SOC alone in 150 infected patients who were assigned randomly to the two groups (75 per group).
The primary endpoint of the study was the negative conversion rate of SARS-CoV-2 in 28 days, and the investigators found no difference in this parameter between the groups.
The secondary endpoints were an amelioration of the symptoms of the disease such as axillary temperature ≤36.6°C, SpO2 >94% on room air, and disappearance of symptoms like shortness of breath, cough, and sore throat.
-The median time to symptom alleviation was similar across different conditions (19 days in HCQ+SOC vs. 21 days in SOC).
-Additionally, 30% of the patients receiving SOC+HCQ reported adverse outcomes compared to 8.8% of patients receiving only SOC, with the most common adverse outcome in the SOC+HCQ group being diarrhea (10% vs. 0% in the SOC group, p=0.004).
+The median time to symptom alleviation was similar across different conditions (19 days in HCQ + SOC versus 21 days in SOC).
+Additionally, 30% of the patients receiving SOC+HCQ reported adverse outcomes compared to 8.8% of patients receiving only SOC, with the most common adverse outcome in the SOC+HCQ group being diarrhea (10% versus 0% in the SOC group, p = 0.004).
However, there are several factors that limit the interpretability of this study.
Most of the enrolled patients had mild-to-moderate symptoms (98%), and the average age was 46.
SOC in this study included the use of antivirals (Lopinavir-Ritonavir, Arbidol, Oseltamivir, Virazole, Entecavir, Ganciclovir, and Interferon alfa), which appeared to introduce confounding effects.
Thus, to isolate the effect of HCQ, SOC would need to exclude the use of antivirals.
-In this trial, the samples used to test for the presence of the SARS-CoV-2 virus were collected from the upper respiratory tract, and the authors indicated that the use of upper respiratory samples may have introduced false negatives (e.g., [81]).
+In this trial, the samples used to test for the presence of the SARS-CoV-2 virus were collected from the upper respiratory tract, and the authors indicated that the use of upper respiratory samples may have introduced false negatives (e.g., [83]).
Another limitation of the study that the authors acknowledge was that the HCQ treatment began, on average, at a 16-day delay from the symptom onset.
The fact that this study was open-label and lacked a placebo limits interpretation, and additional analysis is required to determine whether HCQ reduces inflammatory response.
Therefore, despite some potential areas of investigation identified in post hoc analysis, this study cannot be interpreted as providing support for HCQ as a therapeutic against COVID-19.
-Additional evidence comes from a retrospective analysis [481] that examined data from 368 COVID-19 patients across all United States Veteran Health Administration medical centers.
+
Additional evidence comes from a retrospective analysis [482] that examined data from 368 COVID-19 patients across all United States Veteran Health Administration medical centers.
The study retrospectively investigated the effect of the administration of HCQ (n=97), HCQ + AZ (n=113), and no HCQ (n=158) on 368 patients.
The primary outcomes assessed were death and the need for mechanical ventilation.
Standard supportive care was rendered to all patients.
Due to the low representation of women (N=17) in the available data, the analysis included only men, and the median age was 65 years.
The rate of death in the HCQ-only treatment condition was 27.8% and in the HCQ + AZ treatment condition, it was 22.1%.
-In comparison to the 14.1% rate of death in the no-HCQ cohort, these data indicated a statistically significant elevation in the risk of death for the HCQ-only group compared to the no-HCQ group (adjusted HR: 2.61, p=0.03), but not for the HCQ + AZ group compared to the no-HCQ group (adjusted HR: 1.14; p=0.72).
+In comparison to the 14.1% rate of death in the no-HCQ cohort, these data indicated a statistically significant elevation in the risk of death for the HCQ-only group compared to the no-HCQ group (adjusted HR: 2.61, p = 0.03), but not for the HCQ + AZ group compared to the no-HCQ group (adjusted HR: 1.14; p = 0.72).
Further, the risk of ventilation was similar across all three groups (adjusted HR: 1.43, p = 0.48 (HCQ) and 0.43, p = 0.09 (HCQ + AZ) compared to no HCQ).
The study thus showed evidence of an association between increased mortality and HCQ in this cohort of COVID-19 patients but no change in rates of mechanical ventilation among the treatment conditions.
The study had a few limitations: it was not randomized, and the baseline vital signs, laboratory tests, and prescription drug use were significantly different among the three groups.
All of these factors could potentially influence treatment outcome.
Furthermore, the authors acknowledge that the effect of the drugs might be different in females and pediatric subjects, since these subjects were not part of the study.
-The reported result that HCQ + AZ is safer than HCQ contradicts the findings of the previous large-scale analysis of twenty years of records that found HCQ + AZ to be more frequently associated with cardiac arrhythmia than HCQ alone [476]; whether this discrepancy is caused by the pathology of COVID-19, is influenced by age or sex, or is a statistical artifact is not presently known.
+The reported result that HCQ + AZ is safer than HCQ contradicts the findings of the previous large-scale analysis of twenty years of records that found HCQ + AZ to be more frequently associated with cardiac arrhythmia than HCQ alone [477]; whether this discrepancy is caused by the pathology of COVID-19, is influenced by age or sex, or is a statistical artifact is not presently known.
Finally, findings from the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial were released on October 8, 2020.
-This study used a randomized, open-label design to study the effects of HCQ compared to SOC at 176 hospitals in the United Kingdom [482].
+This study used a randomized, open-label design to study the effects of HCQ compared to SOC at 176 hospitals in the United Kingdom [483].
This large study enrolled 11,197 hospitalized patients whose physicians believed it would not harm them to participate.
Patients were randomized into either the control group or one of the treatment arms, with twice as many patients enrolled in the control group as any treatment group.
Of the patients eligible to receive HCQ, 1,561 were randomized into the HCQ arm, and 3,155 were randomized into the control arm.
@@ -1958,14 +1957,14 @@
5.4.2.2.2 HCQ for the Treatment of Mild Cases
One additional possible therapeutic application of HCQ considered was the treatment of mild COVID-19 cases in otherwise healthy individuals.
-This possibility was assessed in a randomized, open-label, multi-center analysis conducted in Catalonia (Spain) [483].
+This possibility was assessed in a randomized, open-label, multi-center analysis conducted in Catalonia (Spain) [484].
This analysis enrolled adults 18 and older who had been experiencing mild symptoms of COVID-19 for fewer than five days.
Participants were randomized into an HCQ arm (N=136) and a control arm (N=157), and those in the treatment arm were administered 800 mg of HCQ on the first day of treatment followed by 400 mg on each of the subsequent six days.
The primary outcome assessed was viral clearance at days 3 and 7 following the onset of treatment, and secondary outcomes were clinical progression and time to complete resolution of symptoms.
They found no significant differences between the two groups.
This study thus suggests that HCQ does not improve recovery from COVID-19, even in otherwise healthy adult patients with mild symptoms.
5.4.2.2.3 Prophylactic Administration of HCQ
-An initial study of the possible prophylactic application of HCQ utilized a randomized, double-blind, placebo-controlled design to analyze the administration of HCQ prophylactically [484].
+
An initial study of the possible prophylactic application of HCQ utilized a randomized, double-blind, placebo-controlled design to analyze the administration of HCQ prophylactically [485].
Asymptomatic adults in the United States and Canada who had been exposed to SARS-CoV-2 within the past four days were enrolled in an online study to evaluate whether administration of HCQ over five days influenced the probability of developing COVID-19 symptoms over a 14-day period.
Of the participants, 414 received HCQ and 407 received a placebo.
No significant difference in the rate of symptomatic illness was observed between the two groups (11.8% HCQ, 14.3% placebo, p = 0.35).
@@ -1979,7 +1978,7 @@
-A second study [485] examined the effect of administering HCQ to healthcare workers as a pre-exposure prophylactic.
+
A second study [486] examined the effect of administering HCQ to healthcare workers as a pre-exposure prophylactic.
The primary outcome assessed was the conversion from SARS-CoV-2 negative to SARS-CoV-2 positive status over the 8 week study period.
This study was also randomized, double-blind, and placebo-controlled, and it sought to address some of the limitations of the first prophylactic study.
They aimed to enroll 200 healthcare workers, preferentially those working with COVID-19 patients, at two hospitals within the University of Pennsylvania hospital system in Philadelphia, PA.
@@ -1990,117 +1989,117 @@
5.4.2.2.4 Summary of HCQ/CQ Research Findings
Early in vitro evidence indicated that HCQ could be an effective therapeutic against SARS-CoV-2 and COVID-19, leading to significant media attention and public interest in its potential as both a therapeutic and prophylactic.
-Initially it was hypothesized that CQ/HCQ might be effective against SARS-CoV-2 in part because CQ and HCQ have both been found to inhibit the expression of CD154 in T-cells and to reduce TLR signaling that leads to the production of pro-inflammatory cytokines [486].
+Initially it was hypothesized that CQ/HCQ might be effective against SARS-CoV-2 in part because CQ and HCQ have both been found to inhibit the expression of CD154 in T-cells and to reduce TLR signaling that leads to the production of pro-inflammatory cytokines [487].
Clinical trials for COVID-19 have more often used HCQ rather than CQ because it offers the advantages of being cheaper and having fewer side effects than CQ.
However, research has not found support for a positive effect of HCQ on COVID-19 patients.
Multiple clinical studies have already been carried out to assess HCQ as a therapeutic agent for COVID-19, and many more are in progress.
To date, none of these studies have used randomized, double-blind, placebo-controlled designs with a large sample size, which would be the gold standard.
Despite the design limitations (which would be more likely to produce false positives than false negatives), initial optimism about HCQ has largely dissipated.
-The most methodologically rigorous analysis of HCQ as a prophylactic [484] found no significant differences between the treatment and control groups, and the WHO’s global Solidarity trial similarly reported no effect of HCQ on mortality [390].
+The most methodologically rigorous analysis of HCQ as a prophylactic [485] found no significant differences between the treatment and control groups, and the WHO’s global Solidarity trial similarly reported no effect of HCQ on mortality [391].
Thus, HCQ/CQ are not likely to be effective therapeutic or prophylactic agents against COVID-19.
-Additionally, one study identified an increased risk of mortality in older men receiving HCQ, and administration of HCQ and HCQ+AZ did not decrease the use of mechanical ventilation in these patients [481].
+Additionally, one study identified an increased risk of mortality in older men receiving HCQ, and administration of HCQ and HCQ + AZ did not decrease the use of mechanical ventilation in these patients [482].
HCQ use for COVID-19 could also lead to shortages for anti-malarial or anti-rheumatic use, where it has documented efficacy.
Despite significant early attention, these drugs appear to be ineffective against COVID-19.
Several countries have now removed CQ/HCQ from their SOC for COVID-19 due to the lack of evidence of efficacy and the frequency of adverse effects.
5.4.2.3 Dexamethasone
-Dexamethasone (9α-fluoro-16α-methylprednisolone) is a synthetic corticosteroid that binds to glucocorticoid receptors [487,488].
-It was first synthesized in the late 1950s as an anti-inflammatory and has been used to treat RA and other inflammatory conditions [489,490].
-Steroids such as dexamethasone are widely available and affordable, and they are often used to treat community-acquired pneumonia [491].
-A clinical trial that began in 2012 recently reported that dexamethasone may improve outcomes for patients with ARDS [492].
-However, a meta-analysis of a small amount of available data about dexamethasone as a treatment for SARS suggested that it may, in fact, be associated with patient harm [493]; however, these findings may have been biased by the fact that all of the studies examined were observational and a large number of inconclusive studies were not included [494].
-Dexamethasone works as an anti-inflammatory agent by binding to glucocorticoid receptors with higher affinity than endogenous cortisol [495].
+
Dexamethasone (9α-fluoro-16α-methylprednisolone) is a synthetic corticosteroid that binds to glucocorticoid receptors [488,489].
+It was first synthesized in the late 1950s as an anti-inflammatory and has been used to treat RA and other inflammatory conditions [490,491].
+Steroids such as dexamethasone are widely available and affordable, and they are often used to treat community-acquired pneumonia [492].
+A clinical trial that began in 2012 recently reported that dexamethasone may improve outcomes for patients with ARDS [493].
+However, a meta-analysis of a small amount of available data about dexamethasone as a treatment for SARS suggested that it may, in fact, be associated with patient harm [494]; however, these findings may have been biased by the fact that all of the studies examined were observational and a large number of inconclusive studies were not included [495].
+Dexamethasone works as an anti-inflammatory agent by binding to glucocorticoid receptors with higher affinity than endogenous cortisol [496].
In order to understand how dexamethasone reduces inflammation, it is necessary to consider the stress response broadly.
-In response to stress, corticotropin‐releasing hormone stimulates the release of neurotransmitters known as catecholamines, such as epinephrine, and steroid hormones known as glucocorticoids, such as cortisol [496,497].
-While catecholamines are often associated with the fight-or-flight response, the specific role that glucocorticoids play is less clear, although they are thought to be important to restoring homeostasis [498].
+In response to stress, corticotropin‐releasing hormone stimulates the release of neurotransmitters known as catecholamines, such as epinephrine, and steroid hormones known as glucocorticoids, such as cortisol [497,498].
+While catecholamines are often associated with the fight-or-flight response, the specific role that glucocorticoids play is less clear, although they are thought to be important to restoring homeostasis [499].
Immune challenge is a stressor that is known to interact closely with the stress response.
-The immune system can therefore interact with the central nervous system; for example, macrophages can both respond to and produce catecholamines [496].
-Additionally, the production of both catecholamines and glucocorticoids is associated with inhibition of proinflammatory cytokines such as IL-6, IL-12, and tumor necrosis factor-α (TNF‐α) and the stimulation of anti-inflammatory cytokines such as IL-10, meaning that the stress response can regulate inflammatory immune activity [497].
-Administration of dexamethasone has been found to correspond to dose-dependent inhibition of IL-12 production, but not to affect IL-10 [499]; the fact that this relationship could be disrupted by administration of a glucocorticoid-receptor antagonist suggests that it is regulated by the receptor itself [499].
+The immune system can therefore interact with the central nervous system; for example, macrophages can both respond to and produce catecholamines [497].
+Additionally, the production of both catecholamines and glucocorticoids is associated with inhibition of proinflammatory cytokines such as IL-6, IL-12, and tumor necrosis factor-α (TNF‐α) and the stimulation of anti-inflammatory cytokines such as IL-10, meaning that the stress response can regulate inflammatory immune activity [498].
+Administration of dexamethasone has been found to correspond to dose-dependent inhibition of IL-12 production, but not to affect IL-10 [500]; the fact that this relationship could be disrupted by administration of a glucocorticoid-receptor antagonist suggests that it is regulated by the receptor itself [500].
Thus, the administration of dexamethasone for COVID-19 is likely to simulate the release of glucocorticoids endogenously during stress, resulting in binding of the synthetic steroid to the glucocorticoid receptor and the associated inhibition of the production of proinflammatory cytokines.
-In this model, dexamethasone reduces inflammation by stimulating the biological mechanism that reduces inflammation following a threat such as immune challenge.
-Immunosuppressive drugs such as steroids are typically contraindicated in the setting of infection [500], but because COVID-19 results in hyperinflammation that appears to contribute to mortality via lung damage, immunosuppression may be a helpful approach to treatment [127].
-The decision of whether and/or when to counter hyperinflammation with immunosuppression in the setting of COVID-19 was an area of intense debate, as the risks of inhibiting antiviral immunity needed to be weighed against the beneficial anti-inflammatory effects [501].
-As a result, guidelines early in the pandemic typically recommended avoiding treating COVID-19 patients with corticosteroids such as dexamethasone [493].
-The application of dexamethasone for the treatment of COVID-19 was evaluated as part of the multi-site RECOVERY trial in the United Kingdom [502].
+In this model, dexamethasone reduces inflammation by stimulating the biological mechanism that reduces inflammation following a threat such as immune challenge.
+Immunosuppressive drugs such as steroids are typically contraindicated in the setting of infection [501], but because COVID-19 results in hyperinflammation that appears to contribute to mortality via lung damage, immunosuppression may be a helpful approach to treatment [129].
+The decision of whether and/or when to counter hyperinflammation with immunosuppression in the setting of COVID-19 was an area of intense debate, as the risks of inhibiting antiviral immunity needed to be weighed against the beneficial anti-inflammatory effects [502].
+As a result, guidelines early in the pandemic typically recommended avoiding treating COVID-19 patients with corticosteroids such as dexamethasone [494].
+The application of dexamethasone for the treatment of COVID-19 was evaluated as part of the multi-site RECOVERY trial in the United Kingdom [503].
Over 6,000 hospitalized COVID-19 patients were assigned into the SOC or treatment (dexamethasone) arms of the trial with a 2:1 ratio.
At the time of randomization, some patients were ventilated (16%), others were on non-invasive oxygen (60%), and others were breathing independently (24%).
Patients in the treatment arm were administered dexamethasone either orally or intravenously at 6 mg per day for up to 10 days.
The primary end-point was the patient’s status at 28-days post-randomization (mortality, discharge, or continued hospitalization), and secondary outcomes analyzed included the progression to invasive mechanical ventilation over the same period.
The 28-day mortality rate was found to be lower in the treatment group than in the SOC group (21.6% vs 24.6%, p < 0.001).
However, this finding was driven by differences in mortality among patients who were receiving mechanical ventilation or supplementary oxygen at the start of the study.
-The report indicated that dexamethasone reduced 28-day mortality relative to SOC in patients who were ventilated (29.3% vs. 41.4%) and among those who were receiving oxygen supplementation (23.3% vs. 26.2%) at randomization, but not in patients who were breathing independently (17.8% vs. 14.0%).
+The report indicated that dexamethasone reduced 28-day mortality relative to SOC in patients who were ventilated (29.3% versus 41.4%) and among those who were receiving oxygen supplementation (23.3% versus 26.2%) at randomization, but not in patients who were breathing independently (17.8% versus 14.0%).
One possible confounder is that patients receiving mechanical ventilation tended to be younger than patients who were not receiving respiratory support (by 10 years on average) and to have had symptoms for a longer period.
However, adjusting for age did not change the conclusions, although the duration of symptoms was found to be significantly associated with the effect of dexamethasone administration.
These findings also suggested that dexamethasone may have reduced progression to mechanical ventilation, especially among patients who were receiving oxygen support at randomization.
Thus, this large, randomized, and multi-site, albeit not placebo-controlled, study suggests that administration of dexamethasone to patients who are unable to breathe independently may significantly improve survival outcomes.
Additionally, dexamethasone is a widely available and affordable medication, raising the hope that it could be made available to COVID-19 patients globally.
-The results of the RECOVERY trial’s analysis of dexamethasone suggest that this therapeutic is effective primarily in patients who had been experiencing symptoms for at least seven days and patients who were not breathing independently [503].
-A meta-analysis that evaluated the results of the RECOVERY trial alongside trials of other corticosteroids, such as hydrocortisone, similarly concluded that corticosteroids may be beneficial to patients with severe COVID-19 who are receiving oxygen supplementation [504].
-Thus, it seems likely that dexamethasone is useful for treating inflammation associated with immunopathy or cytokine release syndrome.
-In fact, corticosteroids such as dexamethasone are sometimes used to treat cytokine release syndrome (CRS) [505].
+
The results of the RECOVERY trial’s analysis of dexamethasone suggest that this therapeutic is effective primarily in patients who had been experiencing symptoms for at least seven days and patients who were not breathing independently [504].
+A meta-analysis that evaluated the results of the RECOVERY trial alongside trials of other corticosteroids, such as hydrocortisone, similarly concluded that corticosteroids may be beneficial to patients with severe COVID-19 who are receiving oxygen supplementation [505].
+Thus, it seems likely that dexamethasone is useful for treating inflammation associated with immunopathy or cytokine release syndrome (CRS).
+In fact, corticosteroids such as dexamethasone are sometimes used to treat CRS [506].
It is not surprising that administration of an immunosuppressant would be most beneficial when the immune system was dysregulated towards inflammation.
However, it is also unsurprising that care must be taken in administering an immunosuppressant to patients fighting a viral infection.
-In particular, the concern has been raised that treatment with dexamethasone might increase patient susceptibility to concurrent (e.g., nosocomial) infections [506].
-Additionally, the drug could potentially slow viral clearance and inhibit patients’ ability to develop antibodies to SARS-CoV-2 [493,506], and the lack of data about viral clearance has been put forward as a major limitation of the RECOVERY trial [507].
-Furthermore, dexamethasone has been associated with side effects that include psychosis, glucocorticoid-induced diabetes, and avascular necrosis [493], and the RECOVERY trial did not report outcomes with enough detail to be able to determine whether they observed similar complications.
-The effects of dexamethasone have also been found to differ among populations, especially in high-income versus middle- or low-income countries [508].
-However, since the RECOVERY trial’s results were released, strategies have been proposed for administering dexamethasone alongside more targeted treatments to minimize the likelihood of negative side effects [506].
+In particular, the concern has been raised that treatment with dexamethasone might increase patient susceptibility to concurrent (e.g., nosocomial) infections [507].
+Additionally, the drug could potentially slow viral clearance and inhibit patients’ ability to develop antibodies to SARS-CoV-2 [494,507], and the lack of data about viral clearance has been put forward as a major limitation of the RECOVERY trial [508].
+Furthermore, dexamethasone has been associated with side effects that include psychosis, glucocorticoid-induced diabetes, and avascular necrosis [494], and the RECOVERY trial did not report outcomes with enough detail to be able to determine whether they observed similar complications.
+The effects of dexamethasone have also been found to differ among populations, especially in high-income versus middle- or low-income countries [509].
+However, since the RECOVERY trial’s results were released, strategies have been proposed for administering dexamethasone alongside more targeted treatments to minimize the likelihood of negative side effects [507].
Given the available evidence, dexamethasone is currently the most promising treatment for severe COVID-19.
5.5 Biologics
Biologics are produced from components of living organisms or viruses.
-They include treatments such as humanized monoclonal antibodies (mAb) tocilizumab (TCZ), and neutralizing antibodies (nAbs), and can also include prophylactics such as vaccines.
-Historically produced from animal tissue, biologics have become increasingly feasible to produce as recombinant DNA technologies have advanced [509].
-Often, they are glycoproteins or peptides [510], but whole viruses can also be used therapeutically or prophylactically, not only for vaccines but also as vectors for gene therapy or therapeutic proteins or for oncolytic virotherapy [511].
-They are typically catabolized by the body to their amino acid components [510].
+They include treatments such as humanized monoclonal antibodies (mAb), tocilizumab (TCZ), and neutralizing antibodies (nAbs), and can also include prophylactics such as vaccines.
+Historically produced from animal tissue, biologics have become increasingly feasible to produce as recombinant DNA technologies have advanced [510].
+Often, they are glycoproteins or peptides [511], but whole viruses can also be used therapeutically or prophylactically, not only for vaccines but also as vectors for gene therapy or therapeutic proteins or for oncolytic virotherapy [512].
+They are typically catabolized by the body to their amino acid components [511].
There are many differences on the development side between biologics and synthesized pharmaceuticals, such as small molecule drugs.
-Biologics are typically orders of magnitude larger than small molecule drugs, and their physiochemical properties are often much less understood [510].
-They are often heat sensitive, and their toxicity can vary, as it is not directly associated with the primary effects of the drug [510].
+Biologics are typically orders of magnitude larger than small molecule drugs, and their physiochemical properties are often much less understood [511].
+They are often heat sensitive, and their toxicity can vary, as it is not directly associated with the primary effects of the drug [511].
However, this class includes some extremely significant medical breakthroughs, including insulin for the management of diabetes and the smallpox vaccine.
As a result, biologics are another possible avenue through which the pharmacological management of SARS-CoV-2 infection can be approached.
5.5.1 Tocilizumab
-TCZ is a receptor antibody that was developed to manage chronic inflammation caused by the continuous synthesis of the cytokine IL-6 [512].
+
TCZ is a receptor antibody that was developed to manage chronic inflammation caused by the continuous synthesis of the cytokine IL-6 [513].
IL-6 is a pro-inflammatory cytokine belonging to the interleukin family, which is comprised by immune system regulators that are primarily responsible for immune cell differentiation.
-Often used to treat conditions such as RA [512], TCZ has become a pharmaceutical of interest for the treatment of COVID-19 because of the role IL-6 plays in this disease.
-While secretion of IL-6 can be associated with chronic conditions, it is a key player in the innate immune response and is secreted by macrophages in response to the detection of pathogen-associated molecular patterns and damage-associated molecular patterns [512].
+Often used to treat conditions such as RA [513], TCZ has become a pharmaceutical of interest for the treatment of COVID-19 because of the role IL-6 plays in this disease.
+While secretion of IL-6 can be associated with chronic conditions, it is a key player in the innate immune response and is secreted by macrophages in response to the detection of pathogen-associated molecular patterns and damage-associated molecular patterns [513].
An analysis of 191 in-patients at two Wuhan hospitals revealed that blood concentrations of IL-6 differed between patients who did and did not recover from COVID-19.
-Patients who ultimately deceased had higher IL-6 levels at admission than those who recovered [35].
-Additionally, IL-6 levels remained higher throughout the course of hospitalization in the patients who ultimately deceased [35].
-This finding provided some early evidence that COVID-19 deaths may be induced by the hyperactive immune response, often referred to as CRS or cytokine storm syndrome (CSS), as IL-6 plays a key role in this response [114].
+Patients who ultimately deceased had higher IL-6 levels at admission than those who recovered [37].
+Additionally, IL-6 levels remained higher throughout the course of hospitalization in the patients who ultimately deceased [37].
+This finding provided some early evidence that COVID-19 deaths may be induced by the hyperactive immune response, often referred to as CRS or cytokine storm syndrome (CSS), as IL-6 plays a key role in this response [116].
In this context, the observation of elevated IL-6 in patients who died may reflect an over-production of proinflammatory interleukins, suggesting that TCZ could potentially palliate some of the most severe symptoms of COVID-19 associated with increased cytokine production.
Human IL-6 is a 26-kDa glycoprotein that consists of 184 amino acids and contains two potential N-glycosylation sites and four cysteine residues.
-It binds to a type I cytokine receptor (IL-6Rα or glycoprotein 80) that exists in both membrane-bound (IL-6Rα) and soluble (sIL-6Rα) forms [513].
-It is not the binding of IL-6 to the receptor that initiates pro- and/or anti-inflammatory signaling, but rather the binding of the complex to another subunit, known as IL-6Rβ or glycoprotein 130 (gp13) [513,514].
-Unlike membrane-bound IL-6Rα, which is only found on hepatocytes and some types of leukocytes, gp130 is found on most cells [515].
-When IL-6 binds to sIL-6Rα, the complex can then bind to a gp130 protein on any cell [515].
-The binding of IL-6 to IL-6Rα is termed classical signaling, while its binding to sIL-6Rα is termed trans-signaling [515,516,517].
+It binds to a type I cytokine receptor (IL-6Rα or glycoprotein 80) that exists in both membrane-bound (IL-6Rα) and soluble (sIL-6Rα) forms [514].
+It is not the binding of IL-6 to the receptor that initiates pro- and/or anti-inflammatory signaling, but rather the binding of the complex to another subunit, known as IL-6Rβ or glycoprotein 130 (gp13) [514,515].
+Unlike membrane-bound IL-6Rα, which is only found on hepatocytes and some types of leukocytes, gp130 is found on most cells [516].
+When IL-6 binds to sIL-6Rα, the complex can then bind to a gp130 protein on any cell [516].
+The binding of IL-6 to IL-6Rα is termed classical signaling, while its binding to sIL-6Rα is termed trans-signaling [516,517,518].
These two signaling processes are thought to play different roles in health and illness.
-For example, trans-signaling may play a role in the proliferation of mucosal T-helper TH2 cells associated with asthma, while an earlier step in this proliferation process may be regulated by classical signaling [515].
-Similarly, IL-6 is known to play a role in Crohn’s Disease via trans-, but not classical, signaling [515].
-Both classical and trans-signaling can occur through three independent pathways: the Janus-activated kinase-STAT3 pathway, the Ras/Mitogen-Activated Protein Kinases (MAPK) pathway and the Phosphoinositol-3 Kinase/Akt pathway [513].
-These signaling pathways are involved in a variety of different functions, including cell type differentiation, immunoglobulin synthesis, and cellular survival signaling pathways, respectively [513].
-The ultimate result of the IL-6 cascade is to direct transcriptional activity of various promoters of pro-inflammatory cytokines, such as IL-1, TFN, and even IL-6 itself, through the activity of NF-κB [513].
-IL-6 synthesis is tightly regulated both transcriptionally and post-transcriptionally, and it has been shown that viral proteins can enhance transcription of the IL-6 gene by strengthening the DNA-binding activity between several transcription factors and IL-6 gene-cis-regulatory elements [518].
+For example, trans-signaling may play a role in the proliferation of mucosal T-helper TH2 cells associated with asthma, while an earlier step in this proliferation process may be regulated by classical signaling [516].
+Similarly, IL-6 is known to play a role in Crohn’s Disease via trans-, but not classical, signaling [516].
+Both classical and trans-signaling can occur through three independent pathways: the Janus-activated kinase-STAT3 pathway, the Ras/Mitogen-Activated Protein Kinases (MAPK) pathway and the Phosphoinositol-3 Kinase/Akt pathway [514].
+These signaling pathways are involved in a variety of different functions, including cell type differentiation, immunoglobulin synthesis, and cellular survival signaling pathways, respectively [514].
+The ultimate result of the IL-6 cascade is to direct transcriptional activity of various promoters of pro-inflammatory cytokines, such as IL-1, TFN, and even IL-6 itself, through the activity of NF-κB [514].
+IL-6 synthesis is tightly regulated both transcriptionally and post-transcriptionally, and it has been shown that viral proteins can enhance transcription of the IL-6 gene by strengthening the DNA-binding activity between several transcription factors and IL-6 gene-cis-regulatory elements [519].
Therefore, drugs inhibiting the binding of IL-6 to IL-6Rα or sIL-6Rα are of interest for combating the hyperactive inflammatory response characteristic of CRS and CSS.
TCZ is a humanized monoclonal antibody that binds both to the insoluble and soluble receptor of IL-6, providing de facto inhibition of the IL-6 immune cascade.
Tocilizumab is being administered either as an intervention or as concomitant medication in 84 COVID-19 clinical trials (Figure 3).
No randomized, placebo-controlled studies of TCZ have currently released results.
Therefore, no conclusions can be drawn about its efficacy for the treatment of COVID-19.
-However, early interest in TCZ as a possible treatment for COVID-19 emerged from a very small retrospective study in China that examined 20 patients with severe symptoms in early February 2020 and reported rapid improvement in symptoms following treatment with TCZ [519].
+However, early interest in TCZ as a possible treatment for COVID-19 emerged from a very small retrospective study in China that examined 20 patients with severe symptoms in early February 2020 and reported rapid improvement in symptoms following treatment with TCZ [520].
Subsequently, a number of retrospective studies have been conducted in several countries.
Many studies use a retrospective, observational design, where they compare outcomes for COVID-19 patients who received TCZ to those who did not over a set period of time.
-For example, one of the largest retrospective, observational analysis released to date [520] compared the rates at which patients who received TCZ deceased or progressed to invasive medical ventilation over a 14-day period compared to patients receiving only SOC.
+For example, one of the largest retrospective, observational analysis released to date [521] compared the rates at which patients who received TCZ deceased or progressed to invasive medical ventilation over a 14-day period compared to patients receiving only SOC.
Under this definition, SOC could include other drugs such as HCQ, azithromycin, lopinavir-ritonavir or darunavir-cobicistat, or heparin.
While this study was not randomized, a subset of patients who were eligible to receive TCZ were unable to obtain it due to shortages; however, these groups were not directly compared in the analysis.
After adjusting for variables such as age, sex, and SOFA (sequential organ failure assessment) score, they found that patients treated with TCZ were less likely to progress to invasive medical ventilation and/or death (adjusted HR = 0.61, CI 0.40-0.92, p = 0.020), although analysis of death and ventilation separately suggests that this effect may have been driven by differences in the death rate (20% of control versus 7% of TCZ-treated patients).
They reported particular benefits for patients whose PaO2/FiO2 ratio, also known as the Horowitz Index for Lung Function, fell below a 150 mm Hg threshold.
They found no differences between groups administered subcutaneous versus intravenous TCZ.
-Another retrospective observational analysis of interest examined the charts of patients at a hospital in Connecticut, USA where 64% of all 239 COVID-19 patients in the study period were administered TCZ based on assignment by a standardized algorithm [521].
+
Another retrospective observational analysis of interest examined the charts of patients at a hospital in Connecticut, USA where 64% of all 239 COVID-19 patients in the study period were administered TCZ based on assignment by a standardized algorithm [522].
They found that TCZ administration was associated with more similar rates of survivorship in patients with severe versus nonsevere COVID-19 at intake, defined based on the amount of supplemental oxygen needed.
They therefore proposed that their algorithm was able to identify patients presenting with or likely to develop CRS as good candidates for TCZ.
This study also reported higher survivorship in Black and Hispanic patients compared to white patients when adjusted for age.
The major limitation with interpretation for these studies is that there may be clinical characteristics that influenced medical practitioners decisions to administer TCZ to some patients and not others.
-One interesting example therefore comes from an analysis of patients at a single hospital in Brescia, Italy, where TCZ was not available for a period of time [522].
+One interesting example therefore comes from an analysis of patients at a single hospital in Brescia, Italy, where TCZ was not available for a period of time [523].
This study compared COVID-19 patients admitted to the hospital before and after March 13, 2020, when the hospital received TCZ.
Therefore, patients who would have been eligible for TCZ prior to this arbitrary date did not receive it as treatment, making this retrospective analysis something of a natural experiment.
Despite this design, demographic factors did not appear to be consistent between the two groups, and the average age of the control group was older than the TCZ group.
@@ -2111,113 +2110,114 @@
5.5
However, this study also holds a significant limitation: the time delay between the two groups means that knowledge about how to treat the disease likely improved over this timeframe as well.
All the same, the results of these observational retrospective studies provide support for TCZ as a pharmaceutical of interest for follow-up in clinical trials.
In addition to the retrospective observational studies, other analysis have utilized a retrospective case-control design to match pairs of patients with similar baseline characteristics, only one of whom received TCZ for COVID-19.
-In one such study, TCZ was significantly associated with a reduced risk of progression to ICU admission or death [523].
+In one such study, TCZ was significantly associated with a reduced risk of progression to ICU admission or death [524].
This study examined only 20 patients treated with TCZ (all but one of the patients treated with TCZ in the hospital during the study period) and compared them to 25 patients receiving SOC.
For the combined primary endpoint of death and/or ICU admission, only 25% of patients receiving TCZ progressed to an endpoint compared to 72% in the SOC group (p = 0.002, presumably based on a chi-square test based on the information provided in the text).
When the two endpoints were examined separately, progression to invasive medical ventilation remained significant (32% SOC compared to 0% TCZ, p = 0.006) but not for mortality (48% SOC compared to 25% TCZ, p = 0.066).
-In contrast, a study that compared 96 patients treated with TCZ to 97 patients treated with SOC only in New York City found that differences in mortality did not differ between the two groups, but that this difference did become significant when intubated patients were excluded from the analysis [524].
+In contrast, a study that compared 96 patients treated with TCZ to 97 patients treated with SOC only in New York City found that differences in mortality did not differ between the two groups, but that this difference did become significant when intubated patients were excluded from the analysis [525].
Taken together, these findings suggest that future clinical trials of TCZ may want to include intubation as an endpoint.
However, these studies should be approached with caution, not only because of the small number of patients enrolled and the retrospective design, but also because they performed a large number of statistical tests and did not account for multiple hypothesis testing.
These last findings highlight the need to search for a balance between impairing a harmful immune response, such as the one generated during CRS and CSS, and preventing the worsening of the clinical picture of the patients by potential new viral infections.
Though data about TCZ for COVID-19 is still only just emerging, some meta-analyses and systematic reviews have investigated the available data.
-One meta-analysis [525] evaluated 19 studies published or released as preprints prior to July 1, 2020 and found that the overall trends were supportive of the frequent conclusion that TCZ does improve survivorship, with a significant HR of 0.41 (p < 0.001).
+One meta-analysis [526] evaluated 19 studies published or released as preprints prior to July 1, 2020 and found that the overall trends were supportive of the frequent conclusion that TCZ does improve survivorship, with a significant HR of 0.41 (p < 0.001).
This trend improved when they excluded studies that administered a steroid alongside TCZ, with a significant HR of 0.04 (p < 0.001).
They also found some evidence for reduced invasive ventilation or ICU admission, but only when excluding all studies except a small number whose estimates were adjusted for the possible bias introduced by the challenges of stringency during the enrollment process.
-A systematic analysis of sixteen case-control studies of TCZ estimated an odds ratio of 0.453 (95% CI 0.376–0.547, p < 0.001), suggesting possible benefits associated with TCZ treatment [526].
+A systematic analysis of sixteen case-control studies of TCZ estimated an odds ratio of 0.453 (95% CI 0.376–0.547, p < 0.001), suggesting possible benefits associated with TCZ treatment [527].
Although these estimates are similar, it is important to note that they are drawing from the same literature and are therefore likely to be affected by the same biases in publication.
-A second systematic review of studies investigating TCZ treatment for COVID-19 analyzed 31 studies that had been published or released as pre-prints and reported that none carried a low risk of bias (RoB) [527].
+A second systematic review of studies investigating TCZ treatment for COVID-19 analyzed 31 studies that had been published or released as pre-prints and reported that none carried a low risk of bias [528].
Therefore, the present evidence is not likely to be sufficient for conclusions about the efficacy of TCZ.
Additionally, there are possible risks associated with the administration of TCZ for COVID-19.
-TCZ has been used for over a decade to treat RA [528], and a recent study found the drug to be safe for pregnant and breastfeeding women [529].
-However, TCZ may increase the risk of developing infections [528], and RA patients with chronic hepatitis B infections had a high risk of hepatitis B virus reactivation when TCZ was administered in combination with other RA drugs [530].
-As a result, TCZ is contraindicated in patients with active infections such as tuberculosis [531].
-Previous studies have investigated, with varying results, a possible increased risk of infection in RA patients administered TCZ [532,533], although another study reported that the incidence rate of infections was higher in clinical practice RA patients treated with TCZ than in the rates reported by clinical trials [534].
-In the investigation of 544 Italian COVID-19 patients, the group treated with TCZ was found to be more likely to develop secondary infections, with 24% compared to 4% in the control group [520].
+TCZ has been used for over a decade to treat RA [529], and a recent study found the drug to be safe for pregnant and breastfeeding women [530].
+However, TCZ may increase the risk of developing infections [529], and RA patients with chronic hepatitis B infections had a high risk of hepatitis B virus reactivation when TCZ was administered in combination with other RA drugs [531].
+As a result, TCZ is contraindicated in patients with active infections such as tuberculosis [532].
+Previous studies have investigated, with varying results, a possible increased risk of infection in RA patients administered TCZ [533,534], although another study reported that the incidence rate of infections was higher in clinical practice RA patients treated with TCZ than in the rates reported by clinical trials [535].
+In the investigation of 544 Italian COVID-19 patients, the group treated with TCZ was found to be more likely to develop secondary infections, with 24% compared to 4% in the control group [521].
Reactivation of hepatitis B and herpes simplex virus 1 was also reported in a small number of patients in this study, all of whom were receiving TCZ.
-A July 2020 case report described negative outcomes of two COVID-19 patients after receiving TCZ, including one death; however, both patients were intubated and had entered septic shock prior to receiving TCZ [535], likely indicating a severe level of cytokine production.
-Additionally, D-dimer and sIL2R levels were reported by one study to increase in patients treated with TCZ, which raised concerns because of the potential association between elevated D-dimer levels and thrombosis and between sIL2R and diseases where T-cell regulation is compromised [521].
-An increased risk of bacterial infection was also identified in a systematic review of the literature, based on the unadjusted estimates reported [525].
-In summary, TCZ administration to COVID-19 patients is not without risks, may introduce additional risk of developing secondary infections, and should be approached especially cautiously for patients who have latent viral infections.
-In summary, approximately 25% of coronavirus patients develop ARDS, which is caused by an excessive early response of the immune system which can be a component of cytokine release syndrome [521] and cytokine storm syndrome [531].
+A July 2020 case report described negative outcomes of two COVID-19 patients after receiving TCZ, including one death; however, both patients were intubated and had entered septic shock prior to receiving TCZ [536], likely indicating a severe level of cytokine production.
+Additionally, D-dimer and sIL2R levels were reported by one study to increase in patients treated with TCZ, which raised concerns because of the potential association between elevated D-dimer levels and thrombosis and between sIL2R and diseases where T-cell regulation is compromised [522].
+An increased risk of bacterial infection was also identified in a systematic review of the literature, based on the unadjusted estimates reported [526].
+TCZ administration to COVID-19 patients is not without risks, may introduce additional risk of developing secondary infections, and should be approached especially cautiously for patients who have latent viral infections.
+In summary, approximately 25% of coronavirus patients develop ARDS, which is caused by an excessive early response of the immune system which can be a component of CRS [522] and CSS [532].
This overwhelming inflammation is triggered by IL-6.
TCZ is an inhibitor of IL-6 and therefore may neutralize the inflammatory pathway that leads to the cytokine storm.
While the mechanism suggests TCZ could be beneficial for the treatment of COVID-19 patients experiencing excessive immune activity, no randomized controlled trials are available assessing its effect.
However, small initial studies have found preliminary indications that TCZ may reduce progression to invasive medical ventilation and/or death.
It should be noted that SOC varied widely across retrospective studies, with one study administering HCQ, lopinavir-ritonavir, antibiotics, and/or heparin as part of SOC.
-Interest in TCZ as a treatment for COVID-19 was supported by two meta-analyses [525,536], but a third meta-analysis found that all of the available literature carries a risk of bias, with even the largest available TCZ studies to date carrying a moderate risk of bias under the ROBINS-I criteria [527].
-Additionally, different studies used different dosages, number of doses, and methods of administration; ongoing research may be needed to optimize administration of TCZ [537], although similar results were reported by one study for intravenous and subcutaneous administration [520].
+Interest in TCZ as a treatment for COVID-19 was supported by two meta-analyses [526,537], but a third meta-analysis found that all of the available literature carries a risk of bias, with even the largest available TCZ studies to date carrying a moderate risk of bias under the ROBINS-I criteria [528].
+Additionally, different studies used different dosages, number of doses, and methods of administration.
+Ongoing research may be needed to optimize administration of TCZ [538], although similar results were reported by one study for intravenous and subcutaneous administration [521].
Clinical trials that are in progress are likely to provide additional insight into the effectiveness of this drug for the treatment of COVID-19 along with how it should be administered.
5.5.2 Neutralizing Antibodies
Monoclonal antibodies have revolutionized the way we treat human diseases.
-They have become some of the best-selling drugs in the pharmaceutical market in recent years [538].
-There are currently 79 FDA approved mAbs on the market, including antibodies for viral infections (e.g. Ibalizumab for HIV and Palivizumab for RSV) [538,539].
-Virus-specific neutralizing antibodies commonly target viral surface glycoproteins or host structures, thereby inhibiting viral entry through receptor binding interference [540,541].
-This section discusses current efforts in developing neutralizing antibodies against SARS-CoV-2 and how expertise gained from previous approaches for MERS-CoV and SARS-CoV-1 may benefit antibody development.
+They have become some of the best-selling drugs in the pharmaceutical market in recent years [539].
+There are currently 79 FDA approved mAbs on the market, including antibodies for viral infections (e.g. Ibalizumab for HIV and Palivizumab for RSV) [539,540].
+Virus-specific nAbs commonly target viral surface glycoproteins or host structures, thereby inhibiting viral entry through receptor binding interference [541,542].
+This section discusses current efforts in developing nAbs against SARS-CoV-2 and how expertise gained from previous approaches for MERS-CoV and SARS-CoV-1 may benefit antibody development.
5.5.2.1 Spike (S) Neutralizing Antibody
-During the first SARS epidemic in 2002, nAbs were found in SARS-CoV-1-infected patients [542,543].
-Several studies following up on these findings identified various S-glycoprotein epitopes as the major targets of neutralizing antibodies against SARS-CoV-1 [544].
-The passive transfer of immune serum containing nAbs from SARS-CoV-1-infected mice resulted in protection of naïve mice from viral lower respiratory tract infection upon intranasal challenge [545].
-Similarly, a meta-analysis suggested that administration of plasma from recovered SARS-CoV-1 patients reduced mortality upon SARS-CoV-1 infection [546].
+
During the first SARS epidemic in 2002, nAbs were found in SARS-CoV-1-infected patients [543,544].
+Several studies following up on these findings identified various S-glycoprotein epitopes as the major targets of nAbs against SARS-CoV-1 [545].
+The passive transfer of immune serum containing nAbs from SARS-CoV-1-infected mice resulted in protection of naïve mice from viral lower respiratory tract infection upon intranasal challenge [546].
+Similarly, a meta-analysis suggested that administration of plasma from recovered SARS-CoV-1 patients reduced mortality upon SARS-CoV-1 infection [547].
Similar results were observed in MERS-CoV infection during the second coronavirus-related epidemic of the 21st century.
-In these cases, neutralizing antibodies were identified against various epitopes of the receptor binding domain (RBD) of the S glycoprotein [547,548].
-Coronaviruses use trimeric spike (S) glycoproteins on their surface to bind to the host cell, allowing for cell entry [64,67].
+In these cases, nAbs were identified against various epitopes of the receptor binding domain (RBD) of the S glycoprotein [548,549].
+Coronaviruses use trimeric spike (S) glycoproteins on their surface to bind to the host cell, allowing for cell entry [66,69].
Each S glycoprotein protomer is comprised of an S1 domain, also called the RBD, and an S2 domain.
-The S1 domain binds to the host cell while the S2 domain facilitates the fusion between the viral envelope and host cell membranes [544].
-Although targeting of the host cell enzyme ACE2 shows efficacy in inhibiting SARS-CoV-2 infection [75], given the physiological relevance of ACE2 [549], it would be favorable to target virus-specific structures rather than host receptors.
-This concern underlies the rationale for developing neutralizing antibodies against the S glycoprotein, disrupting its interaction with ACE2 and other potential entry points and thereby inhibiting viral entry.
-The first human neutralizing antibody against SARS-CoV-2 targeting the S glycoproteins was developed using hybridoma technology [550], where antibody-producing B-cells developed by mice can be inserted into myeloma cells to produce a hybrid cell line (the hybridoma) that is grown in culture.
+The S1 domain binds to the host cell while the S2 domain facilitates the fusion between the viral envelope and host cell membranes [545].
+Although targeting of the host cell enzyme ACE2 shows efficacy in inhibiting SARS-CoV-2 infection [77], given the physiological relevance of ACE2 [550], it would be favorable to target virus-specific structures rather than host receptors.
+This concern underlies the rationale for developing nAbs against the S glycoprotein, disrupting its interaction with ACE2 and other potential entry points and thereby inhibiting viral entry.
+The first human nAb against SARS-CoV-2 targeting the S glycoproteins was developed using hybridoma technology [551], where antibody-producing B-cells developed by mice can be inserted into myeloma cells to produce a hybrid cell line (the hybridoma) that is grown in culture.
The 47D11 clone was able to cross-neutralize SARS-CoV-1 and SARS-CoV-2 by a mechanism that is different from receptor binding interference.
-The exact mechanism of how this clone neutralizes SARS-CoV-2 and inhibits infection in vitro remains unknown, but a potential mechanism might be antibody-induced destabilization of the membrane prefusion structure [550,551].
-The ability of this antibody to prevent infection at a feasible dose needs to be validated in vivo, especially since in vitro neutralization effects have been shown to not be reflective of in vivo efficacy [552].
-Only a week later, a different group successfully isolated multiple nAbs targeting the RBD of the S glycoprotein from blood samples taken from COVID-19 patients in China [154].
+The exact mechanism of how this clone neutralizes SARS-CoV-2 and inhibits infection in vitro remains unknown, but a potential mechanism might be antibody-induced destabilization of the membrane prefusion structure [551,552].
+The ability of this antibody to prevent infection at a feasible dose needs to be validated in vivo, especially since in vitro neutralization effects have been shown to not be reflective of in vivo efficacy [553].
+Only a week later, a different group successfully isolated multiple nAbs targeting the RBD of the S glycoprotein from blood samples taken from COVID-19 patients in China [156].
Interestingly, the patient-isolated antibodies did not cross-react with RBDs from SARS-CoV-1 and MERS-CoV, although cross-reactivity to the trimeric spike proteins of SARS-CoV-1 and MERS-CoV was observed.
This finding suggests that the RBDs between the three coronavirus species are immunologically distinct and that the isolated nAbs targeting the RBD of SARS-CoV-2 are species specific.
While this specificity is desirable, it also raises the question of whether these antibodies are more susceptible to viral escape mechanisms.
-Viral escape is a common resistance mechanism to nAb therapy due to selective pressure from neutralizing antibodies [553,554].
-For HIV, broadly neutralizing antibodies (bnAbs) targeting the CD4 binding site (CD4bs) show greater neutralization breadth than monoclonal antibodies, which target only specific HIV strains [555].
-For MERS-CoV, a combination of multiple neutralizing antibodies targeting different antigenic sites prevented neutralization escape [556].
-It was found that the different antibody isolates did not target the same epitopes, suggesting that using them in combination might produce a synergistic effect that prevents viral escape [154].
+Viral escape is a common resistance mechanism to nAb therapy due to selective pressure from nAbs [554,555].
+For HIV, broadly neutralizing antibodies (bnAbs) targeting the CD4 binding site (CD4bs) show greater neutralization breadth than monoclonal antibodies, which target only specific HIV strains [556].
+For MERS-CoV, a combination of multiple nAbs targeting different antigenic sites prevented neutralization escape [557].
+It was found that the different antibody isolates did not target the same epitopes, suggesting that using them in combination might produce a synergistic effect that prevents viral escape [156].
It was also demonstrated that binding affinity of the antibodies does not reflect their capability to compete with ACE2 binding.
-Furthermore, no conclusions about correlations between the severity of disease and the ability to produce neutralizing antibodies can be drawn at this point.
-Rather, higher neutralizing antibody titers were more frequently found in patients with severe disease.
-Correspondingly, higher levels of anti-spike IgG were observed in patients that deceased from infection compared to patient that recovered [557].
-Results from the SARS and MERS epidemics thus provide valuable lessons for the design of neutralizing antibodies for the current outbreak.
+Furthermore, no conclusions about correlations between the severity of disease and the ability to produce nAbs can be drawn at this point.
+Rather, higher nAb titers were more frequently found in patients with severe disease.
+Correspondingly, higher levels of anti-spike IgG were observed in patients that deceased from infection compared to patient that recovered [558].
+Results from the SARS and MERS epidemics thus provide valuable lessons for the design of nAbs for the current outbreak.
The findings for SARS-CoV-1 and MERS-CoV can aid in identifying which structures constitute suitable targets for nAbs, despite the fact that the RBD appears to be distinct between the three coronavirus species.
-These studies also suggest that a combination of nAbs targeting distinct antigens might be necessary to provide protection [556].
+These studies also suggest that a combination of nAbs targeting distinct antigens might be necessary to provide protection [557].
The biggest challenge remains identifying antibodies that not only bind to their target, but also prove to be beneficial for disease management.
-On that note, a recently published study indicates that anti-spike antibodies could make the disease worse rather than eliminating the virus [557].
+On that note, a recently published study indicates that anti-spike antibodies could make the disease worse rather than eliminating the virus [558].
These findings underscores our current lack of understanding the full immune response to SARS-CoV-2.
5.5.3 Interferons
IFNs are a family of cytokines critical to activating the innate immune response against viral infections.
-Interferons are classified into three categories based on their receptor specificity: types I, II and III [114].
-Specifically, IFNs I (IFN-𝛼 and 𝛽) and II (IFN-𝛾) induce the expression of antiviral proteins [558].
-Among these IFNs, IFN-𝛽 has already been found to strongly inhibit the replication of other coronaviruses, such as SARS-CoV-1, in cell culture, while IFN-𝛼 and 𝛾 were shown to be less effective in this context [558].
+Interferons are classified into three categories based on their receptor specificity: types I, II and III [116].
+Specifically, IFNs I (IFN-𝛼 and 𝛽) and II (IFN-𝛾) induce the expression of antiviral proteins [559].
+Among these IFNs, IFN-𝛽 has already been found to strongly inhibit the replication of other coronaviruses, such as SARS-CoV-1, in cell culture, while IFN-𝛼 and 𝛾 were shown to be less effective in this context [559].
There is evidence that patients with higher susceptibility to ARDS indeed show deficiency in IFN-𝛽.
-For instance, infection with other coronaviruses impairs IFN-𝛽 expression and synthesis, allowing the virus to escape the innate immune response [559].
-On March 18 2020, Synairgen plc received approval to start a phase II trial for SNG001, an IFN-𝛽-1a formulation to be delivered to the lungs via inhalation [560].
-SNG001, which contains recombinant interferon beta-1a, was previously shown to be effective in reducing viral load in an in vivo model of swine flu and in vitro models of other coronavirus infections [561].
-In July, a press release from Synairgen stated that SNG001 reduced progression to ventilation in a double-blind, placebo-controlled, multi-center study of 101 patients with an average age in the late 50s [562].
-These results were subsequently published in November 2020 [563].
+For instance, infection with other coronaviruses impairs IFN-𝛽 expression and synthesis, allowing the virus to escape the innate immune response [560].
+On March 18 2020, Synairgen plc received approval to start a phase II trial for SNG001, an IFN-𝛽-1a formulation to be delivered to the lungs via inhalation [561].
+SNG001, which contains recombinant interferon beta-1a, was previously shown to be effective in reducing viral load in an in vivo model of swine flu and in vitro models of other coronavirus infections [562].
+In July, a press release from Synairgen stated that SNG001 reduced progression to ventilation in a double-blind, placebo-controlled, multi-center study of 101 patients with an average age in the late 50s [563].
+These results were subsequently published in November 2020 [564].
The study reports that the participants were assigned at a ratio of 1:1 to receive either SNG001 or a placebo that lacked the active compound, by inhalation for up to 14 days.
The primary outcome they assessed was the change in patients’ score on the WHO Ordinal Scale for Clinical Improvement (OSCI) at trial day 15 or 16.
SNG001 was associated with an odds ratio (OR) of 2.32 (95% CI 1.07 – 5.04, p = 0.033) in the intention-to-treat analysis and 2.80 (95% CI 1.21 – 6.52, p = 0.017) in the per-protocol analysis, corresponding to significant improvement in the SNG001 group on the OSCI at day 15/16.
Some of the secondary endpoints analyzed also showed differences: at day 28, the OR for clinical improvement on the OSCI was 3.15 (95% CI 1.39 – 7.14, p = 0.006), and the odds of recovery at day 15/16 and at day 28 were also significant between the two groups.
Thus, this study suggested that IFN-𝛽1 administered via SNG001 may improve clinical outcomes.
-In contrast, the WHO Solidarity trial reported no significant effect of IFN-𝛽1a on patient survival during hospitalization [390].
-Here, the primary outcome analyzed was in-hospital mortality, and the rate ratio for the two groups was 1.16 (95% CI, 0.96 to 1.39; p = 0.11) administering IFN-𝛽-1a to 2050 patients and comparing their response to 2050 controls..
+
In contrast, the WHO Solidarity trial reported no significant effect of IFN-𝛽1a on patient survival during hospitalization [391].
+Here, the primary outcome analyzed was in-hospital mortality, and the rate ratio for the two groups was 1.16 (95% CI, 0.96 to 1.39; p = 0.11) administering IFN-𝛽-1a to 2050 patients and comparing their response to 2,050 controls.
However, there are a few reasons that the different findings of the two trials might not speak to the underlying efficacy of this treatment strategy.
One important consideration is the stage of COVID-19 infection analyzed in each study.
-The Synairgen trial enrolled only patients who were not receiving invasive ventilation, corresponding to a less severe stage of disease than many patients enrolled in the SOLIDARITY trial, as well as a lower overall rate of mortality [564].
-Additionally, the methods of administration differed between the two trials, with the SOLIDARITY trial administering IFN-𝛽-1a subcutaneously [564].
+The Synairgen trial enrolled only patients who were not receiving invasive ventilation, corresponding to a less severe stage of disease than many patients enrolled in the SOLIDARITY trial, as well as a lower overall rate of mortality [565].
+Additionally, the methods of administration differed between the two trials, with the SOLIDARITY trial administering IFN-𝛽-1a subcutaneously [565].
The differences in findings between the studies suggests that the method of administration might be relevant to outcomes, with nebulized IFN-𝛽-1a more directly targeting receptors in the lungs.
-A trial that analyzed the effect of subcutaneously administered IFN-β-1a on patients with ARDS between 2015 and 2017 had also reported no effect on 28-day mortality [565], while a smaller study analyzing the effect of subcutaneous IFN administration did find a significant improvement in 28-day mortality for COVID-19 [566].
-At present, several ongoing clinical trials are investigating the potential effects of IFN-𝛽-1a, including in combination with therapeutics such as remdesivir [567] and administered via inhalation [560].
+A trial that analyzed the effect of subcutaneously administered IFN-β-1a on patients with ARDS between 2015 and 2017 had also reported no effect on 28-day mortality [566], while a smaller study analyzing the effect of subcutaneous IFN administration did find a significant improvement in 28-day mortality for COVID-19 [567].
+At present, several ongoing clinical trials are investigating the potential effects of IFN-𝛽-1a, including in combination with therapeutics such as remdesivir [568] and administered via inhalation [561].
Thus, as additional information becomes available, a more detailed understanding of whether and under which circumstances IFN-𝛽-1a is beneficial to COVID-19 patients should develop.
5.6 Discussion
-With the emergence of the COVID-19 pandemic caused by the coronavirus SARS-CoV-2, the development and/or identification of therapeutic and prophylactic interventions became an issue of international urgency.
+
With the emergence of the COVID-19 pandemic caused by the coronavirus SARS-CoV-2, the development and identification of therapeutic and prophylactic interventions became issues of international urgency.
In previous outbreaks of HCoV, namely SARS and MERS, the development of these interventions was very limited.
-As research has progressed, several potential approaches to treatment have emerged (Figure 4)..
+As research has progressed, several potential approaches to treatment have emerged (Figure 4).
Most notably, remdesivir has been approved by the FDA for the treatment of COVID-19, and dexamethasone, which was approved by the FDA in 1958, has been found to improve outcomes for patients with severe COVID-19.
Other potential therapies are being still being explored and require additional data (Figure 3).
As more evidence becomes available, the potential for existing and novel therapies to improve outcomes for COVID-19 patients will become better understood.
@@ -2228,12 +2228,12 @@ 5.6
-Insights into the pathogenesis of and immune response to SARS-CoV-2 (see [367]) have also guided the identification of potential prophylactics and therapeutics.
+
Insights into the pathogenesis of and immune response to SARS-CoV-2 (see [1]) have also guided the identification of potential prophylactics and therapeutics.
As cases have become better characterized, it has become evident that many patients experience an initial immune response to the virus that is typically characterized by fever, cough, dyspnea, and related symptoms.
-However, the most serious concern is cytokine release syndrome, when the body’s immune response becomes dysregulated, resulting in an extreme inflammatory response.
-The RECOVERY trial, a large-scale, multi-arm trial enrolling about 15% of all COVID-19 patients in the United Kingdom, was the first to identify that the widely available steroid dexamethasone seems to be beneficial for patients suffering from this immune dysregulation [502].
+However, the most serious concern is CRS, when the body’s immune response becomes dysregulated, resulting in an extreme inflammatory response.
+The RECOVERY trial, a large-scale, multi-arm trial enrolling about 15% of all COVID-19 patients in the United Kingdom, was the first to identify that the widely available steroid dexamethasone seems to be beneficial for patients suffering from this immune dysregulation [503].
The results of efforts to identify therapeutic treatments to treat patients early in the course of infection have been more ambiguous.
-Early interest in the drugs hydroxychloroquine and chloroquine yielded no promising results from studies with robust experimental designs.
+Early interest in the drugs HCQ and CQ yielded no promising results from studies with robust experimental designs.
On the other hand, the experimental drug remdesivir, which was developed as a candidate therapeutic for EVD, has received enough support from early analyses to receive FDA approval, although results have been mixed.
The potential for other drugs, such as tocilizumab, to reduce recovery time remains unclear, but some early results were promising.
One additional concern is that the presentation of COVID-19 appears to be heterogeneous across the lifespan.
@@ -2245,33 +2245,33 @@
[568]
.
-Several other anti-inflammatory agents used for the treatment of autoimmune diseases may also be able to counter the effects of the cytokine storm induced by the virus, and some of these, such as cyclosporine, are likely to be more cost-effective and readily available than biologics [569].
+At the doses used for RA patients, the cost for tocilizumab ranges from $179.20 to $896 per dose for the IV form and $355 for the pre-filled syringe [569].
+Several other anti-inflammatory agents used for the treatment of autoimmune diseases may also be able to counter the effects of the cytokine storm induced by the virus, and some of these, such as cyclosporine, are likely to be more cost-effective and readily available than biologics [570].
While tocilizumab targets IL-6, several other inflammatory markers could be potential targets, including TNF-α.
-Inhibition of TNF-α by a compound such as Etanercept was previously suggested for treatment of SARS-CoV-1 [570] and may be relevant for SARS-CoV-2 as well.
-Another anti-IL-6 antibody, sarilumab, is also being investigated [571,572].
-Baricitinib and other small molecule inhibitors of the Janus-activated kinase pathway also curtail the inflammatory response and have been suggested as potential options for SARS-CoV-2 infections [573].
-Baricitinib, in particular, may be able to reduce the ability of SARS-CoV-2 to infect lung cells [574].
-Clinical trials studying baricitinib in COVID-19 have already begun in the US and in Italy [575,576].
+Inhibition of TNF-α by a compound such as Etanercept was previously suggested for treatment of SARS-CoV-1 [571] and may be relevant for SARS-CoV-2 as well.
+Another anti-IL-6 antibody, sarilumab, is also being investigated [572,573].
+Baricitinib and other small molecule inhibitors of the Janus-activated kinase pathway also curtail the inflammatory response and have been suggested as potential options for SARS-CoV-2 infections [574].
+Baricitinib, in particular, may be able to reduce the ability of SARS-CoV-2 to infect lung cells [575].
+Clinical trials studying baricitinib in COVID-19 have already begun in the US and in Italy [576,577].
Identification and targeting of further inflammatory markers that are relevant in SARS-CoV-2 infection may be of value for curtailing the inflammatory response and lung damage.
In addition to immunosuppressive treatments, which are most beneficial late in disease progression, much research is focused on identifying therapeutics for early-stage patients.
-For example, although studies of hydroxychloroquine have not supported the early theory-driven interest in this antiviral treatment, alternative compounds with related mechanisms may still have potential.
-Hydroxyferroquine derivatives of HCQ have been described as a class of bioorganometallic compounds that exert antiviral effects with some selectivity for SARS-CoV-1 in vitro [577].
+For example, although studies of HCQ have not supported the early theory-driven interest in this antiviral treatment, alternative compounds with related mechanisms may still have potential.
+Hydroxyferroquine derivatives of HCQ have been described as a class of bioorganometallic compounds that exert antiviral effects with some selectivity for SARS-CoV-1 in vitro [578].
Future work could explore whether such compounds exert antiviral effects against SARS-CoV-2 and whether they would be safer for use in COVID-19.
Another potential approach is the development of antivirals, which could be broad-spectrum, specific to coronaviruses, or targeted to SARS-CoV-2.
Development of new antivirals is complicated by the fact that none have yet been approved for human coronaviruses.
Intriguing new options are emerging, however.
-Beta-D-N4-hydroxycytidine (NHC) is an orally bioavailable ribonucleotide analog showing broad-spectrum activity against RNA viruses, which may inhibit SARS-CoV-2 replication in vitro and in vivo in mouse models of HCoVs [578].
+Beta-D-N4-hydroxycytidine (NHC) is an orally bioavailable ribonucleotide analog showing broad-spectrum activity against RNA viruses, which may inhibit SARS-CoV-2 replication in vitro and in vivo in mouse models of HCoVs [579].
A range of other antivirals are also in development.
Development of antivirals will be further facilitated as research reveals more information about the interaction of SARS-CoV-2 with the host cell and host cell genome, mechanisms of viral replication, mechanisms of viral assembly, and mechanisms of viral release to other cells; this can allow researchers to target specific stages and structures of the viral life cycle.
Finally, antibodies against viruses, also known as antiviral monoclonal antibodies, could be an alternative as well and are described in detail in an above section.
-The goal of antiviral antibodies is to neutralize viruses through either cell-killing activity or blocking of viral replication [579].
+The goal of antiviral antibodies is to neutralize viruses through either cell-killing activity or blocking of viral replication [580].
They may also engage the host immune response, encouraging the immune system to hone in on the virus.
-Given the cytokine storm that results from immune system activation in response to the virus, which has been implicated in worsening of the disease, a neutralizing antibody (nAb) may be preferable.
+Given the cytokine storm that results from immune system activation in response to the virus, which has been implicated in worsening of the disease, an nAb may be preferable.
Upcoming work may explore the specificity of nAbs for their target, mechanisms by which the nAbs impede the virus, and improvements to antibody structure that may enhance the ability of the antibody to block viral activity.
Some research is also investigating potential therapeutics and prophylactics that would interact with components of the innate immune response.
-For example, TLRs are PRRs that recognize pathogen- and damage-associated molecular patterns and contribute to innate immune recognition and, more generally, promotion of both the innate and adaptive immune responses [110].
-In mouse models, poly(I:C) and CpG, which are agonists of Toll-like receptors TLR3 and TLR9, respectively, showed protective effects when administered prior to SARS-CoV-1 infection [580].
+For example, TLRs are pattern recognition receptors that recognize pathogen- and damage-associated molecular patterns and contribute to innate immune recognition and, more generally, promotion of both the innate and adaptive immune responses [112].
+In mouse models, poly(I:C) and CpG, which are agonists of Toll-like receptors TLR3 and TLR9, respectively, showed protective effects when administered prior to SARS-CoV-1 infection [581].
Therefore, TLR agonists hold some potential for broad-spectrum prophylaxis.
Given that a large number of clinical trials are currently in progress, more information about the potential of these and other therapeutics should become available over time.
This information, combined with advances in understanding the molecular structure and viral pathogenesis of SARS-CoV-2, may lead to a more complete understanding of how the virus affects the human host and what strategies can improve outcomes.
@@ -2280,11 +2280,12 @@
[424,581]
, and efforts are already in place to perform screens for small molecule inhibitors of the main protease, which have yielded potential hits [424].
+Currently, crystal structures of the SARS-CoV-2 main protease have recently been resolved [425,582], and efforts are already in place to perform screens for small molecule inhibitors of the main protease, which have yielded potential hits [425].
Much work remains to be done to determine further crystal structures of other viral components, understand the relative utility of targeting different viral components, perform additional small molecule inhibitor screens, and determine the safety and efficacy of the potential inhibitors.
While still nascent, work in this area is promising.
-Over the longer term, this approach and others may lead to the development of novel therapeutics specifically for COVID-19 and SARS-CoV-2.
-5.6.2 Conclusions of the Present Analysis
+Over the longer term, this approach and others may lead to the development of novel therapeutics specifically for COVID-19 and SARS-CoV-2.
+
+5.6.2 Conclusions
Due to the large number of clinical trials currently under examination (Figure 3), not all candidates are examined here.
Instead, this review seeks to provide an overview of the range of mechanisms that have been explored and to examine some prominent candidates in the context of the pathogenesis of and immune response to SARS-CoV-2.
As more research becomes available, this review will be updated to include additional therapeutics that emerge and to include new findings that are released about those discussed here.
@@ -2315,140 +2316,140 @@
6.
This rapid effort led to the identification of some promising pharmaceutical therapies for hospitalized patients, such as remdesivir and dexamethasone.
Furthermore, most societies have adopted non-pharmacological preventative measures such as utilizing public health strategies that reduce the transmission of SARS-CoV-2.
However, during this time, many individuals sought additional protections via the consumption of various dietary supplements and nutraceuticals that they believed to confer beneficial effects.
-While a patient’s nutritional status does seem to play a role in COVID-19 susceptibility and outcomes [582,583,584,585,586], the beginning of the pandemic saw sales of vitamins and other supplements to soar despite a lack of any evidence supporting their use against COVID-19.
-In the United States, for example, dietary supplement and nutraceutical sales have shown modest annual growth in recent years (approximately 5%, or a $345 million increase in 2019), but during the six-week period preceding April 5, 2020, they increased by 44% ($435 million) relative to the same period in 2019 [587].
-While growth subsequently leveled off, sales continued to boom, with a further 16% ($151 million) increase during the six weeks preceding May 17, 2020 relative to 2019 [587].
-In France, New Zealand, India, and China, similar trends in sales were reported [588,589,590,591].
-The increase in sales was driven by a consumer perception that dietary supplements and nutraceuticals would protect consumers from infection and/or mitigate the impact of infection due to the various “immune-boosting” claims of these products [592,593].
+While a patient’s nutritional status does seem to play a role in COVID-19 susceptibility and outcomes [583,584,585,586,587], the beginning of the pandemic saw sales of vitamins and other supplements to soar despite a lack of any evidence supporting their use against COVID-19.
+In the United States, for example, dietary supplement and nutraceutical sales have shown modest annual growth in recent years (approximately 5%, or a $345 million increase in 2019), but during the six-week period preceding April 5, 2020, they increased by 44% ($435 million) relative to the same period in 2019 [588].
+While growth subsequently leveled off, sales continued to boom, with a further 16% ($151 million) increase during the six weeks preceding May 17, 2020 relative to 2019 [588].
+In France, New Zealand, India, and China, similar trends in sales were reported [589,590,591,592].
+The increase in sales was driven by a consumer perception that dietary supplements and nutraceuticals would protect consumers from infection and/or mitigate the impact of infection due to the various “immune-boosting” claims of these products [593,594].
Due to the significant interest from the general public in dietary additives, whether and to what extent nutraceuticals or dietary supplements can provide any prophylactic or therapeutic benefit remains a topic of interest for the scientific community.
Nutraceuticals and dietary supplements are related but distinct non-pharmaceutical products.
-Nutraceuticals are classified as supplements with health benefits beyond their basic nutritional value [594,595].
-The key difference between a dietary supplement and a nutraceutical is that nutraceuticals should not only supplement the diet, but also aid in the prophylaxis and/or treatment of a disorder or disease [596].
+Nutraceuticals are classified as supplements with health benefits beyond their basic nutritional value [595,596].
+The key difference between a dietary supplement and a nutraceutical is that nutraceuticals should not only supplement the diet, but also aid in the prophylaxis and/or treatment of a disorder or disease [597].
However, dietary supplements and nutraceuticals, unlike pharmaceuticals, are not subject to the same regulatory protocols that protect consumers of medicines.
-Indeed, nutraceuticals do not entirely fall under the responsibility of the Food and Drug Administration (FDA), but they are monitored as dietary supplements according to the Dietary Supplement, Health and Education Act 1994 (DSHEA) [597] and the Food and Drug Administration Modernization Act 1997 (FDAMA) [598].
+Indeed, nutraceuticals do not entirely fall under the responsibility of the Food and Drug Administration (FDA), but they are monitored as dietary supplements according to the Dietary Supplement, Health and Education Act 1994 (DSHEA) [598] and the Food and Drug Administration Modernization Act 1997 (FDAMA) [599].
Due to increases in sales of dietary supplements and nutraceuticals, in 1996 the FDA established the Office of Dietary Supplement Programs (ODSP) to increase surveillance.
Novel products or nutraceuticals must now submit a new dietary ingredient notification to the ODSP for review.
-There are significant concerns that these legislations do not adequately protect the consumer as they ascribe responsibility to the manufacturers to ensure the safety of the product before manufacturing or marketing [599].
+There are significant concerns that these legislations do not adequately protect the consumer as they ascribe responsibility to the manufacturers to ensure the safety of the product before manufacturing or marketing [600].
Manufacturers are not required to register or even seek approval from the FDA to produce or sell food supplements or nutraceuticals.
-Health or nutrient content claims for labeling purposes are approved based on an authoritative statement from the Academy of Sciences or relevant federal authorities once the FDA has been notified and on the basis that the information is known to be true and not deceptive [599].
+Health or nutrient content claims for labeling purposes are approved based on an authoritative statement from the Academy of Sciences or relevant federal authorities once the FDA has been notified and on the basis that the information is known to be true and not deceptive [600].
Therefore, there is often a gap between perceptions by the American public about a nutraceutical or dietary supplement and the actual clinical evidence surrounding its effects.
Despite differences in regulations, similar challenges exist outside of the United States.
-In Europe, where the safety of supplements are monitored by the European Union (EU) under Directive 2002/46/EC [600].
+In Europe, where the safety of supplements are monitored by the European Union (EU) under Directive 2002/46/EC [601].
However, nutraceuticals are not directly mentioned.
-Consequently, nutraceuticals can be generally described as either a medicinal product under Directive 2004/27/EC [601] or as a ‘foodstuff’ under Directive 2002/46/EC of the European council.
+Consequently, nutraceuticals can be generally described as either a medicinal product under Directive 2004/27/EC [602] or as a ‘foodstuff’ under Directive 2002/46/EC of the European council.
In order to synchronize the various existing legislations, Regulation EC 1924/2006 on nutrition and health claims was put into effect to assure customers of safety and efficacy of products and to deliver understandable information to consumers.
However, specific legislation for nutraceuticals is still elusive.
-Health claims are permitted on a product label only following compliance and authorization according to the European Food Safety Authority (EFSA) guidelines on nutrition and health claims [602].
-EFSA does not currently distinguish between food supplements and nutraceuticals for health claim applications of new products, as claim authorization is dependent on the availability of clinical data in order to substantiate efficacy [603].
-These guidelines seem to provide more protection to consumers than the FDA regulations but potentially at the cost of innovation in the sector [604].
-The situation becomes even more complicated when comparing regulations at a global level, as countries such as China and India have existing regulatory frameworks for traditional medicines and phytomedicines not commonly consumed in Western society [605].
-Currently, there is debate among scientists and regulatory authorities surrounding the development of a widespread regulatory framework to deal with the challenges of safety and health claim substantiation for nutraceuticals [599,603], as these products do not necessarily follow the same rigorous clinical trial frameworks used to approve the use of pharmaceuticals.
+Health claims are permitted on a product label only following compliance and authorization according to the European Food Safety Authority (EFSA) guidelines on nutrition and health claims [603].
+EFSA does not currently distinguish between food supplements and nutraceuticals for health claim applications of new products, as claim authorization is dependent on the availability of clinical data in order to substantiate efficacy [604].
+These guidelines seem to provide more protection to consumers than the FDA regulations but potentially at the cost of innovation in the sector [605].
+The situation becomes even more complicated when comparing regulations at a global level, as countries such as China and India have existing regulatory frameworks for traditional medicines and phytomedicines not commonly consumed in Western society [606].
+Currently, there is debate among scientists and regulatory authorities surrounding the development of a widespread regulatory framework to deal with the challenges of safety and health claim substantiation for nutraceuticals [600,604], as these products do not necessarily follow the same rigorous clinical trial frameworks used to approve the use of pharmaceuticals.
Such regulatory disparities have been highlighted by the pandemic, as many individuals and companies have attempted to profit from the vulnerabilities of others by overstating claims in relation to the treatment of COVID-19 using supplements and nutraceuticals.
-The FDA has written several letters to prevent companies marketing or selling products based on false hyperbolic promises about preventing SARS-CoV-2 infection or treating COVID-19 [606,607,608].
-These letters came in response to efforts to market nutraceutical prophylactics against COVID-19, some of which charged the consumer as much as $23,000 [609].
-There have even been some incidents highlighted in the media because of their potentially life threatening consequences; for example, the use of oleandrin was touted as a potential “cure” by individuals close to the former President of the United States despite its high toxicity [610].
+The FDA has written several letters to prevent companies marketing or selling products based on false hyperbolic promises about preventing SARS-CoV-2 infection or treating COVID-19 [607,608,609].
+These letters came in response to efforts to market nutraceutical prophylactics against COVID-19, some of which charged the consumer as much as $23,000 [610].
+There have even been some incidents highlighted in the media because of their potentially life threatening consequences; for example, the use of oleandrin was touted as a potential “cure” by individuals close to the former President of the United States despite its high toxicity [611].
Thus, heterogeneous and at times relaxed regulatory standards have permitted high-profile cases of the sale of nutraceuticals and dietary supplements that are purported to provide protection against COVID-19, despite a lack of research into these compounds.
Notwithstanding the issues of poor safety, efficacy, and regulatory oversight, some dietary supplements and nutraceuticals have exhibited therapeutic and prophylactic potential.
-Some have been linked with reduced immunopathology, antiviral and anti-inflammatory activities, or even the prevention of acute respiratory distress syndrome (ARDS) [592,611,612].
+Some have been linked with reduced immunopathology, antiviral and anti-inflammatory activities, or even the prevention of acute respiratory distress syndrome (ARDS) [593,612,613].
A host of potential candidates have been highlighted in the literature that target various aspects of the COVID-19 viral pathology, while others are thought to prime the host immune system.
-These candidates include vitamins and minerals along with extracts and omega-3 polyunsaturated fatty acids (n-3 PUFA) [613].
-In vitro and in vivo studies suggest that nutraceuticals containing phycocyanobilin, N-acetylcysteine, glucosamine, selenium or phase 2 inductive nutraceuticals (e.g. ferulic acid, lipoic acid, or sulforaphane) can prevent or modulate RNA virus infections via amplification of the signaling activity of mitochondrial antiviral-signaling protein (MAVS) and activation of Toll-like receptor 7 [614].
+These candidates include vitamins and minerals along with extracts and omega-3 polyunsaturated fatty acids (n-3 PUFA) [614].
+In vitro and in vivo studies suggest that nutraceuticals containing phycocyanobilin, N-acetylcysteine, glucosamine, selenium or phase 2 inductive nutraceuticals (e.g. ferulic acid, lipoic acid, or sulforaphane) can prevent or modulate RNA virus infections via amplification of the signaling activity of mitochondrial antiviral-signaling protein (MAVS) and activation of Toll-like receptor 7 [615].
While promising, further animal and human studies are required to assess the therapeutic potential of these various nutrients and nutraceuticals against COVID-19.
For the purpose of this review, we have highlighted some of the main dietary supplements and nutraceuticals that are currently under investigation for their potential prophylactic and therapeutic applications.
These include n-3 PUFA, zinc, vitamins C and D, and probiotics.
6.4 n-3 PUFA
-One category of supplements that has been explored for beneficial effects against various viral infections are the n-3 PUFAs [613], commonly referred to as omega-3 fatty acids, which include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
-EPA and DHA intake can come from a diet high in fish or through dietary supplementation with fish oils or purified oils [615].
-Other, more sustainable sources of EPA and DHA include algae [616,617], which can also be exploited for their rich abundance of other bioactive compounds such as angiotensin converting enzyme inhibitor peptides and antiviral agents including phycobiliproteins, sulfated polysaccharides, and calcium-spirulan [618].
-n-3 PUFAs have been investigated for many years for their therapeutic potential [619].
-Supplementation with fish oils is generally well tolerated [619], and intake of n-3 PUFAs through dietary sources or supplementation is specifically encouraged for vulnerable groups such as pregnant and lactating women [620,621].
+
One category of supplements that has been explored for beneficial effects against various viral infections are the n-3 PUFAs [614], commonly referred to as omega-3 fatty acids, which include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
+EPA and DHA intake can come from a diet high in fish or through dietary supplementation with fish oils or purified oils [616].
+Other, more sustainable sources of EPA and DHA include algae [617,618], which can also be exploited for their rich abundance of other bioactive compounds such as angiotensin converting enzyme inhibitor peptides and antiviral agents including phycobiliproteins, sulfated polysaccharides, and calcium-spirulan [619].
+n-3 PUFAs have been investigated for many years for their therapeutic potential [620].
+Supplementation with fish oils is generally well tolerated [620], and intake of n-3 PUFAs through dietary sources or supplementation is specifically encouraged for vulnerable groups such as pregnant and lactating women [621,622].
As a result, these well-established compounds have drawn significant interest for their potential immune effects and therapeutic potential.
Particular interest has arisen in n-3 PUFAs as potential therapeutics against diseases associated with inflammation.
-n-3 PUFAs have been found to mediate inflammation by influencing processes such as leukocyte chemotaxis, adhesion molecule expression, and the production of eicosanoids [622,623].
-This and other evidence indicates that n-3 PUFAs may have the capacity to modulate the adaptive immune response [595,615,622]; for example, they have been found to influence antigen presentation and the production of CD4(+) Th1 cells, among other relevant effects [624].
-Certainly, preliminary evidence from banked blood samples from 100 COVID-19 patients suggests that patients with a higher omega-3 index, a measure of n-3 and n-6 fatty acids in red blood cells, had a lower risk of death due to COVID-19 [625].
-Interest has also arisen as to whether nutritional status related to n-3 PUFAs can also affect inflammation associated with severe disease, such as ARDS or sepsis [626,627].
-ARDS and sepsis hold particular concern in the treatment of severe COVID-19; an analysis of 82 deceased COVID-19 patients in Wuhan during January to February 2020 reported that respiratory failure (associated with ARDS) was the cause of death in 69.5% of cases, and sepsis or multi-organ failure accounted for 28.0% of deaths [628].
+n-3 PUFAs have been found to mediate inflammation by influencing processes such as leukocyte chemotaxis, adhesion molecule expression, and the production of eicosanoids [623,624].
+This and other evidence indicates that n-3 PUFAs may have the capacity to modulate the adaptive immune response [596,616,623]; for example, they have been found to influence antigen presentation and the production of CD4(+) Th1 cells, among other relevant effects [625].
+Certainly, preliminary evidence from banked blood samples from 100 COVID-19 patients suggests that patients with a higher omega-3 index, a measure of n-3 and n-6 fatty acids in red blood cells, had a lower risk of death due to COVID-19 [626].
+Interest has also arisen as to whether nutritional status related to n-3 PUFAs can also affect inflammation associated with severe disease, such as ARDS or sepsis [627,628].
+ARDS and sepsis hold particular concern in the treatment of severe COVID-19; an analysis of 82 deceased COVID-19 patients in Wuhan during January to February 2020 reported that respiratory failure (associated with ARDS) was the cause of death in 69.5% of cases, and sepsis or multi-organ failure accounted for 28.0% of deaths [629].
Research in ARDS prior to current pandemic suggests that n-3 PUFAs may hold some therapeutic potential.
-One study randomized 16 consecutive ARDS patients to receive either a fish oil-enriched lipid emulsion or a control lipid emulsion (comprised of 100% long-chain triglycerides) under a double-blinded design [629].
+One study randomized 16 consecutive ARDS patients to receive either a fish oil-enriched lipid emulsion or a control lipid emulsion (comprised of 100% long-chain triglycerides) under a double-blinded design [630].
They reported a statistically significant reduction in leukotriene B4 levels in the group receiving the fish oil-enriched emulsion, suggesting that the fish oil supplementation may have reduced inflammation.
However, they also reported that most of their tests were not statistically significant, and therefore it seems that additional research using larger sample sizes is required.
-A recent meta-analysis of 10 randomized controlled trials (RCTs) examining the effects of n-3 PUFAs on ARDS patients did not find evidence of any effect on mortality, although the effect on secondary outcomes could not be determined due to a low quality of evidence [630].
-However, another meta-analysis that examined 24 RCTs studying the effects of n-3 fatty acids on sepsis, including ARDS-induced sepsis, did find support for an effect on mortality when n-3 fatty acids were administered via enteral nutrition, although a paucity of high-quality evidence again limited conclusions [631].
+A recent meta-analysis of 10 randomized controlled trials (RCTs) examining the effects of n-3 PUFAs on ARDS patients did not find evidence of any effect on mortality, although the effect on secondary outcomes could not be determined due to a low quality of evidence [631].
+However, another meta-analysis that examined 24 RCTs studying the effects of n-3 fatty acids on sepsis, including ARDS-induced sepsis, did find support for an effect on mortality when n-3 fatty acids were administered via enteral nutrition, although a paucity of high-quality evidence again limited conclusions [632].
Therefore, despite theoretical support for an immunomodulatory effect of n-3 PUFAs in COVID-19, evidence from existing RCTs is insufficient to determine whether supplementation offers an advantage in a clinical setting that would be relevant to COVID-19.
-Another potential mechanism that has led to interest in n-3 PUFAs as protective against viral infections including COVID-19 is its potential as a precursor molecule for the biosynthesis of endogenous specialized proresolving mediators (SPM), such as protectins and resolvins, that actively resolve inflammation and infection [632].
-SPM have exhibited beneficial effects against a variety of lung infections, including some caused by RNA viruses [633,634].
-Indeed, protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [635].
-Several mechanisms for SPM have been proposed, including preventing the release of pro-inflammatory cytokines and chemokines or increasing phagocytosis of cellular debris by macrophages [636].
-In influenza, SPM promote antiviral B lymphocytic activities [637], and protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [635].
-It has thus been hypothesized that SPM could aid in the resolution of the cytokine storm and pulmonary inflammation associated with COVID-19 [638,639].
-Another theory is that some comorbidities, such as obesity, could lead to deficiencies of SPM, which could in turn be related to the occurrence of adverse outcomes for COVID-19 [640].
-However, not all studies are in agreement that n-3 PUFAs or their resulting SPM are effective against infections [641].
-At a minimum, the effectiveness of n-3 PUFAs against infections would be dependent on the dosage, timing, and the specific pathogens responsible [642].
-On another level, there is still the question of whether fish oils can raise the levels of SPM levels upon ingestion and in response to acute inflammation in humans [643].
-Currently, Karolinska University Hospital is running a trial that will measure the levels of SPM as a secondary outcome following intravenous supplementation of n-3 PUFAs in hospitalized COVID-19 patients to determine whether n-3 PUFAs provides therapeutic value [644,645].
+
Another potential mechanism that has led to interest in n-3 PUFAs as protective against viral infections including COVID-19 is its potential as a precursor molecule for the biosynthesis of endogenous specialized proresolving mediators (SPM), such as protectins and resolvins, that actively resolve inflammation and infection [633].
+SPM have exhibited beneficial effects against a variety of lung infections, including some caused by RNA viruses [634,635].
+Indeed, protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [636].
+Several mechanisms for SPM have been proposed, including preventing the release of pro-inflammatory cytokines and chemokines or increasing phagocytosis of cellular debris by macrophages [637].
+In influenza, SPM promote antiviral B lymphocytic activities [638], and protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [636].
+It has thus been hypothesized that SPM could aid in the resolution of the cytokine storm and pulmonary inflammation associated with COVID-19 [639,640].
+Another theory is that some comorbidities, such as obesity, could lead to deficiencies of SPM, which could in turn be related to the occurrence of adverse outcomes for COVID-19 [641].
+However, not all studies are in agreement that n-3 PUFAs or their resulting SPM are effective against infections [642].
+At a minimum, the effectiveness of n-3 PUFAs against infections would be dependent on the dosage, timing, and the specific pathogens responsible [643].
+On another level, there is still the question of whether fish oils can raise the levels of SPM levels upon ingestion and in response to acute inflammation in humans [644].
+Currently, Karolinska University Hospital is running a trial that will measure the levels of SPM as a secondary outcome following intravenous supplementation of n-3 PUFAs in hospitalized COVID-19 patients to determine whether n-3 PUFAs provides therapeutic value [645,646].
Therefore, while this mechanism provides theoretical support for a role for n-3 PUFAs against COVID-19, experimental support is still needed.
-A third possible mechanism by which n-3 PUFAs could benefit COVID-19 patients arises from the fact that some COVID-19 patients, particularly those with comorbidities, are at a significant risk of thrombotic complications including arterial and venous thrombosis [107,646].
-Therefore, the use of prophylactic and therapeutic anticoagulants and antithrombotic agents is under consideration [647,648].
-Considering that there is significant evidence that n-3 fatty acids and other fish oil-derived lipids possess antithrombotic properties and anti-inflammatory properties [615,649,650], they may have therapeutic value against the prothrombotic complications of COVID-19.
-In particular, concerns have been raised within the medical community about using investigational therapeutics on COVID-19 patients who are already on antiplatelet therapies due to pre-existing comorbidities because the introduction of such therapeutics could lead to issues with dosing and drug choice and/or negative drug-drug interactions [647].
+
A third possible mechanism by which n-3 PUFAs could benefit COVID-19 patients arises from the fact that some COVID-19 patients, particularly those with comorbidities, are at a significant risk of thrombotic complications including arterial and venous thrombosis [109,647].
+Therefore, the use of prophylactic and therapeutic anticoagulants and antithrombotic agents is under consideration [648,649].
+Considering that there is significant evidence that n-3 fatty acids and other fish oil-derived lipids possess antithrombotic properties and anti-inflammatory properties [616,650,651], they may have therapeutic value against the prothrombotic complications of COVID-19.
+In particular, concerns have been raised within the medical community about using investigational therapeutics on COVID-19 patients who are already on antiplatelet therapies due to pre-existing comorbidities because the introduction of such therapeutics could lead to issues with dosing and drug choice and/or negative drug-drug interactions [648].
In such cases, dietary sources of n-3 fatty acids or other nutraceuticals with antiplatelet activities could hold particular value for reducing the risk of thrombotic complications in patients already receiving pharmaceutical antiplatelet therapies.
-A new clinical trial [651] is currently recruiting COVID-19 positive patients to investigate the anti-inflammatory activity of a recently developed, highly purified nutraceutical derivative of EPA known as icosapent ethyl (VascepaTM) [652].
-Other randomized controlled trials that are in the preparatory stages intend to investigate the administration of EPA and other bioactive compounds to COVID-19 positive patients in order to observe whether anti-inflammatory effects or disease state improvements occur [653,654].
-Finally, while there have been studies investigating the therapeutic value of n-3 fatty acids against ARDS in humans, there is still limited evidence of their effectiveness [655].
+A new clinical trial [652] is currently recruiting COVID-19 positive patients to investigate the anti-inflammatory activity of a recently developed, highly purified nutraceutical derivative of EPA known as icosapent ethyl (VascepaTM) [653].
+Other randomized controlled trials that are in the preparatory stages intend to investigate the administration of EPA and other bioactive compounds to COVID-19 positive patients in order to observe whether anti-inflammatory effects or disease state improvements occur [654,655].
+Finally, while there have been studies investigating the therapeutic value of n-3 fatty acids against ARDS in humans, there is still limited evidence of their effectiveness [656].
It should be noted that the overall lack of human studies in this area means there is limited evidence as to whether these supplements could affect COVID-19 infection.
Consequently, the clinical trials that are underway and those that have been proposed will provide valuable insight into whether the anti-inflammatory potential of n-3 PUFAs and their derivatives can be beneficial to the treatment of COVID-19.
All the same, while the evidence is not present to draw conclusions about whether n-3 PUFAs will be useful in treating COVID-19, there is likely little harm associated with a diet rich in fish oils, and interest in n-3 PUFA supplementation by the general public is unlikely to have negative effects.
6.5 Zinc
Zinc is nutrient supplement that may exhibit some benefits against RNA viral infections.
-Zinc is a trace metal obtained from dietary sources or supplementation and is important for the maintenance of immune cells involved in adaptive and innate immunity [656].
+Zinc is a trace metal obtained from dietary sources or supplementation and is important for the maintenance of immune cells involved in adaptive and innate immunity [657].
Supplements can be administered orally as a tablet or as a lozenge and are available in many forms, such as zinc picolinate, zinc acetate, and zinc citrate.
Zinc is also available from dietary sources including meat, seafood, nuts, seeds, legumes, and dairy.
-The role of zinc in immune function has been extensively reviewed [656].
+The role of zinc in immune function has been extensively reviewed [657].
Zinc is an important signaling molecule, and zinc levels can alter host defense systems.
-In inflammatory situations such as an infection, zinc can regulate leukocyte immune responses and activate the nuclear factor kappa-light-chain-enhancer of activated B cells, thus altering cytokine production [657,658].
-In particular, zinc supplementation can increase natural killer cell levels, which are important cells for host defense against viral infections [656,659].
+In inflammatory situations such as an infection, zinc can regulate leukocyte immune responses and activate the nuclear factor kappa-light-chain-enhancer of activated B cells, thus altering cytokine production [658,659].
+In particular, zinc supplementation can increase natural killer cell levels, which are important cells for host defense against viral infections [657,660].
As a result of these immune-related functions, zinc is also under consideration for possible benefits against COVID-19.
-Adequate zinc intake has been associated with reduced incidence of infection [660] and antiviral immunity [661].
-A randomized, double-blind, placebo-controlled trial that administered zinc supplementation to elderly subjects over the course of a year found zinc deficiency to be associated with increased susceptibility to infection and that zinc deficiency could be prevented through supplementation [660].
-Clinical trial data supports the utility of zinc to diminish the duration and severity of symptoms associated with common colds when it is provided within 24 hours of the onset of symptoms [662,663].
-An observational study showed that COVID-19 patients had significantly lower zinc levels in comparison to healthy controls and that zinc-deficient COVID-19 patients (those with levels less than 80 μg/dl) tended to have more complications (70.4% vs 30.0%, p = 0.009) and potentially prolonged hospital stays (7.9 vs 5.7 days, p = 0.048) relative to patients who were not zinc deficient [664].
-In coronaviruses specifically, in vitro evidence has demonstrated that the combination of zinc (Zn2+) and zinc ionophores (pyrithione) can interrupt the replication mechanisms of SARS-CoV-GFP (a fluorescently tagged SARS-CoV-1) and a variety of other RNA viruses [665,666].
+
Adequate zinc intake has been associated with reduced incidence of infection [661] and antiviral immunity [662].
+A randomized, double-blind, placebo-controlled trial that administered zinc supplementation to elderly subjects over the course of a year found zinc deficiency to be associated with increased susceptibility to infection and that zinc deficiency could be prevented through supplementation [661].
+Clinical trial data supports the utility of zinc to diminish the duration and severity of symptoms associated with common colds when it is provided within 24 hours of the onset of symptoms [663,664].
+An observational study showed that COVID-19 patients had significantly lower zinc levels in comparison to healthy controls and that zinc-deficient COVID-19 patients (those with levels less than 80 μg/dl) tended to have more complications (70.4% vs 30.0%, p = 0.009) and potentially prolonged hospital stays (7.9 vs 5.7 days, p = 0.048) relative to patients who were not zinc deficient [665].
+In coronaviruses specifically, in vitro evidence has demonstrated that the combination of zinc (Zn2+) and zinc ionophores (pyrithione) can interrupt the replication mechanisms of SARS-CoV-GFP (a fluorescently tagged SARS-CoV-1) and a variety of other RNA viruses [666,667].
Currently, there are over twenty clinical trials registered with the intention to use zinc in a preventative or therapeutic manner for COVID-19.
-However, many of these trials proposed the use of zinc in conjunction with hydroxychloroquine and azithromycin [667,668,669,670], and it is not known how the lack of evidence supporting the use of hydroxychloroquine will affect investigation of zinc.
+However, many of these trials proposed the use of zinc in conjunction with hydroxychloroquine and azithromycin [668,669,670,671], and it is not known how the lack of evidence supporting the use of hydroxychloroquine will affect investigation of zinc.
One retrospective observational study of New York University Langone hospitals in New York compared outcomes among hospitalized COVID-19 patients administered hydroxychloroquine and azithromycin with zinc sulfate (n = 411) versus hydroxychloroquine and azithromycin alone (n = 521).
-Notably, zinc is the only treatment that was used in this trial that is still under consideration as a therapeutic agent due to the lack of efficacy and potential adverse events associated with hydroxychloroquine and azithromycin against COVID-19 [671,672,673].
-While the addition of zinc sulfate did not affect the duration of hospitalization, the length of ICU stays or patient ventilation duration, univariate analyses indicated that zinc did increase the frequency of patients discharged and decreased the requirement for ventilation, referrals to the ICU, mortality [674].
-However, a smaller retrospective study at Hoboken University Medical Center New Jersey failed to find an association between zinc supplementation and survival of hospitalized patients [675].
+Notably, zinc is the only treatment that was used in this trial that is still under consideration as a therapeutic agent due to the lack of efficacy and potential adverse events associated with hydroxychloroquine and azithromycin against COVID-19 [672,673,674].
+While the addition of zinc sulfate did not affect the duration of hospitalization, the length of ICU stays or patient ventilation duration, univariate analyses indicated that zinc did increase the frequency of patients discharged and decreased the requirement for ventilation, referrals to the ICU, mortality [675].
+However, a smaller retrospective study at Hoboken University Medical Center New Jersey failed to find an association between zinc supplementation and survival of hospitalized patients [676].
Therefore, whether zinc contributes to COVID-19 recovery remains unclear.
-Other trials are now investigating zinc in conjunction with other supplements such as vitamin C or n-3 PUFA [654,676].
+Other trials are now investigating zinc in conjunction with other supplements such as vitamin C or n-3 PUFA [655,677].
Though there is, overall, encouraging data for zinc supplementation against the common cold and viral infections, there is currently limited evidence to suggest zinc supplementation has any beneficial effects against the current novel COVID-19; thus, the clinical trials that are currently underway will provide vital information on the efficacious use of zinc in COVID-19 prevention and/or treatment.
However, given the limited risk and the potential association between zinc deficiency and illness, maintaining a healthy diet to ensure an adequate zinc status may be advisable for individuals seeking to reduce their likelihood of infection.
6.6 Vitamin C
-Vitamins B, C, D, and E have also been suggested as potential nutrient supplement interventions for COVID-19 [613,677].
-In particular vitamin C has been proposed as a potential therapeutic agent against COVID-19 due to its long history of use against the common cold and other respiratory infections [678,679].
+
Vitamins B, C, D, and E have also been suggested as potential nutrient supplement interventions for COVID-19 [614,678].
+In particular vitamin C has been proposed as a potential therapeutic agent against COVID-19 due to its long history of use against the common cold and other respiratory infections [679,680].
Vitamin C can be obtained via dietary sources such as fruits and vegetables or via supplementation.
Vitamin C plays a significant role in promoting immune function due to its effects on various immune cells.
-It affects inflammation by modulating cytokine production, decreasing histamine levels, enhancing the differentiation and proliferation of T- and B-lymphocytes, increasing antibody levels, and protecting against the negative effects of reactive oxygen species, among other effects related to COVID-19 pathology [680,681,682].
+It affects inflammation by modulating cytokine production, decreasing histamine levels, enhancing the differentiation and proliferation of T- and B-lymphocytes, increasing antibody levels, and protecting against the negative effects of reactive oxygen species, among other effects related to COVID-19 pathology [681,682,683].
Vitamin C is utilized by the body during viral infections, as evinced by lower concentrations in leukocytes and lower concentrations of urinary vitamin C.
-Post-infection, these levels return to baseline ranges [683,684,685,686,687].
-It has been shown that as little as 0.1 g/d of vitamin C can maintain normal plasma levels of vitamin C in healthy individuals, but higher doses of at least 1-3 g/d are required for critically ill patients in ICUs [688].
-Indeed, vitamin C deficiency appears to be common among COVID-19 patients [689,690].
-COVID-19 is also associated with the formation of microthrombi and coagulopathy [109] that contribute to its characteristic lung pathology [691], but these symptoms can be ameliorated by early infusions of vitamin C to inhibit endothelial surface P-selectin expression and platelet-endothelial adhesion [692].
-Intravenous vitamin C also reduced D-dimer levels, which are notably elevated in COVID-19 patients [105,106], in a case study of 17 COVID-19 patients [693].
+Post-infection, these levels return to baseline ranges [684,685,686,687,688].
+It has been shown that as little as 0.1 g/d of vitamin C can maintain normal plasma levels of vitamin C in healthy individuals, but higher doses of at least 1-3 g/d are required for critically ill patients in ICUs [689].
+Indeed, vitamin C deficiency appears to be common among COVID-19 patients [690,691].
+COVID-19 is also associated with the formation of microthrombi and coagulopathy [111] that contribute to its characteristic lung pathology [692], but these symptoms can be ameliorated by early infusions of vitamin C to inhibit endothelial surface P-selectin expression and platelet-endothelial adhesion [693].
+Intravenous vitamin C also reduced D-dimer levels, which are notably elevated in COVID-19 patients [107,108], in a case study of 17 COVID-19 patients [694].
There is therefore preliminary evidence suggesting that vitamin C status and vitamin C administration may be relevant to COVID-19 outcomes.
Larger-scale studies of vitamin C, however, have provided mixed results.
-A recent meta-analysis found consistent support for regular vitamin C supplementation reducing the duration of the common cold, but that supplementation with vitamin C (> 200 mg) failed to reduce the incidence of colds [694].
-Individual studies have found Vitamin C to reduce the susceptibility of patients to lower respiratory tract infections, such as pneumonia [695].
+A recent meta-analysis found consistent support for regular vitamin C supplementation reducing the duration of the common cold, but that supplementation with vitamin C (> 200 mg) failed to reduce the incidence of colds [695].
+Individual studies have found Vitamin C to reduce the susceptibility of patients to lower respiratory tract infections, such as pneumonia [696].
Another meta-analysis demonstrated that in twelve trials, vitamin C supplementation reduced the length of stay of patients in intensive care units (ICUs) by 7.8% (95% CI: 4.2% to 11.2%; p = 0.00003).
Furthermore, high doses (1-3 g/day) significantly reduced the length of an ICU stay by 8.6% in six trials (p = 0.003).
-Vitamin C also shortened the duration of mechanical ventilation by 18.2% in three trials in which patients required intervention for over 24 hours (95% CI 7.7% to 27%; p = 0.001) [688].
-Despite these findings, an RCT of 167 patients known as CITRUS ALI failed to show a benefit of a 96-hour infusion of vitamin C to treat ARDS [696].
-Clinical trials specifically investigating vitamin C in the context of COVID-19 have now begun, as highlighted by Carr et al. [679].
+Vitamin C also shortened the duration of mechanical ventilation by 18.2% in three trials in which patients required intervention for over 24 hours (95% CI 7.7% to 27%; p = 0.001) [689].
+Despite these findings, an RCT of 167 patients known as CITRUS ALI failed to show a benefit of a 96-hour infusion of vitamin C to treat ARDS [697].
+Clinical trials specifically investigating vitamin C in the context of COVID-19 have now begun, as highlighted by Carr et al. [680].
These trials intend to investigate the use of intravenous vitamin C in hospitalized COVID-19 patients.
-The first trial to report initial results took place in Wuhan, China [697].
-These initial results indicated that the administration of 12 g/12 hr of intravenous vitamin C for 7 days in 56 critically ill COVID-19 patients resulted in a promising reduction of 28-day mortality (p = 0.06) in univariate survival analysis [698].
-Indeed, the same study reported a significant decrease in IL-6 levels by day 7 of vitamin C infusion (p = 0.04) [699].
+The first trial to report initial results took place in Wuhan, China [698].
+These initial results indicated that the administration of 12 g/12 hr of intravenous vitamin C for 7 days in 56 critically ill COVID-19 patients resulted in a promising reduction of 28-day mortality (p = 0.06) in univariate survival analysis [699].
+Indeed, the same study reported a significant decrease in IL-6 levels by day 7 of vitamin C infusion (p = 0.04) [700].
Additional studies that are being conducted in Canada, China, Iran, and the USA will provide additional insight into whether vitamin C supplementation affects COVID-19 outcomes on a larger scale.
Even though evidence supporting the use of vitamin C is beginning to emerge, we will not know how effective vitamin C is as a therapeutic for quite some time.
Currently (as of January 2021) over fifteen trials are registered with clinicaltrials.gov that are either recruiting, active or are currently in preparation.
@@ -2456,166 +2457,166 @@
6.6[582].
-The recommended dietary allowance according to the FDA is 75-90 mg/d, whereas EFSA recommends 110 mg/d [700].
+To maintain vitamin C status, it would be prudent for individuals to ensure that they consume the recommended dietary allowance of vitamin C to maintain a healthy immune system [583].
+The recommended dietary allowance according to the FDA is 75-90 mg/d, whereas EFSA recommends 110 mg/d [701].
6.7 Vitamin D
Of all of the supplements currently under investigation, vitamin D has become a leading prophylactic and therapeutic candidate against SARS-CoV-2.
-Vitamin D can modulate both the adaptive and innate immune system and is associated with various aspects of immune health and antiviral defense [701,702,703,704,705].
+Vitamin D can modulate both the adaptive and innate immune system and is associated with various aspects of immune health and antiviral defense [702,703,704,705,706].
Vitamin D can be sourced through diet or supplementation, but it is mainly biosynthesized by the body on exposure to ultraviolet light (UVB) from sunlight.
-Vitamin D deficiency is associated with an increased susceptibility to infection [706].
-In particular, vitamin D deficient patients are at risk of developing acute respiratory infections [707] and ARDS [707].
+Vitamin D deficiency is associated with an increased susceptibility to infection [707].
+In particular, vitamin D deficient patients are at risk of developing acute respiratory infections [708] and ARDS [708].
1,25-dihydroxyvitamin D3 is the active form of vitamin D that is involved in adaptive and innate responses; however, due to its low concentration and a short half life of a few hours, vitamin D levels are typically measured by the longer lasting and more abundant precursor 25-hydroxyvitamin D.
-The vitamin D receptor is expressed in various immune cells, and vitamin D is an immunomodulator of antigen presenting cells, dendritic cells, macrophages, monocytes, and T- and B-lymphocytes [706,708].
+The vitamin D receptor is expressed in various immune cells, and vitamin D is an immunomodulator of antigen presenting cells, dendritic cells, macrophages, monocytes, and T- and B-lymphocytes [707,709].
Due to its potential immunomodulating properties, vitamin D supplementation may be advantageous to maintain a healthy immune system.
-Early in the pandemic it was postulated that an individual’s vitamin D status could significantly affect their risk of developing COVID-19 [709].
+
Early in the pandemic it was postulated that an individual’s vitamin D status could significantly affect their risk of developing COVID-19 [710].
This hypothesis was derived from the fact that the current pandemic emerged in Wuhan China during winter, when 25-hydroxyvitamin D concentrations are at their lowest due to a lack of sunlight, whereas in the Southern Hemisphere, where it was nearing the end of the summer and higher 25-hydroxyvitamin D concentrations would be higher, the number of cases was low.
-This led researchers to question whether there was a seasonal component to the SARS-CoV-2 pandemic and whether vitamin D levels might play a role [709,710,711,712].
+This led researchers to question whether there was a seasonal component to the SARS-CoV-2 pandemic and whether vitamin D levels might play a role [710,711,712,713].
Though it is assumed that COVID-19 is seasonal, multiple other factors that can affect vitamin D levels should also be considered.
These factors include an individual’s nutritional status, their age, their occupation, skin pigmentation, potential comorbidities, and the variation of exposure to sunlight due to latitude amongst others.
-Indeed, it has been estimated that each degree of latitude north of 28 degrees corresponded to a 4.4% increase of COVID-19 mortality, indirectly linking a persons vitamin D levels via exposure to UVB light to COVID-19 mortality [710].
-As the pandemic has evolved, additional research of varying quality has investigated some of the potential links identified early in the pandemic [709] between vitamin D and COVID-19.
+Indeed, it has been estimated that each degree of latitude north of 28 degrees corresponded to a 4.4% increase of COVID-19 mortality, indirectly linking a persons vitamin D levels via exposure to UVB light to COVID-19 mortality [711].
+As the pandemic has evolved, additional research of varying quality has investigated some of the potential links identified early in the pandemic [710] between vitamin D and COVID-19.
Indeed, studies are beginning to investigate whether there is any prophylactic and/or therapeutic relationship between vitamin D and COVID-19.
-A study in Switzerland demonstrated that 27 SARS-CoV-2 positive patients exhibited 25-hydroxyvitamin D plasma concentrations that were significantly lower (11.1 ng/ml) than those of SARS-CoV-2 negative patients (24.6 ng/ml; p = 0.004), an association that held when stratifying patients greater than 70 years old [713].
-These findings seem to be supported by a Belgian observational study of 186 SARS-CoV-2 positive patients exhibiting symptoms of pneumonia, where 25-hydroxyvitamin D plasma concentrations were measured and CT scans of the lungs were obtained upon hospitalization [714].
+A study in Switzerland demonstrated that 27 SARS-CoV-2 positive patients exhibited 25-hydroxyvitamin D plasma concentrations that were significantly lower (11.1 ng/ml) than those of SARS-CoV-2 negative patients (24.6 ng/ml; p = 0.004), an association that held when stratifying patients greater than 70 years old [714].
+These findings seem to be supported by a Belgian observational study of 186 SARS-CoV-2 positive patients exhibiting symptoms of pneumonia, where 25-hydroxyvitamin D plasma concentrations were measured and CT scans of the lungs were obtained upon hospitalization [715].
A significant difference in 25-hydroxyvitamin D levels was observed between the SARS-CoV-2 patients and 2,717 season-matched diseased controls.
Both female and male patients possessed lower median 25-hydroxyvitamin D concentrations than the control group as a whole (18.6 ng/ml versus 21.5 ng/ml; p = 0.0016) and a higher rate of vitamin D deficiency (58.6% versus 42.5%).
However, when comparisons were stratified by sex, evidence of sexual dimorphism became apparent, as female patients had equivalent levels of 25-hydroxyvitamin D to females in the control group, whereas male patients were deficient in 25-hydroxyvitamin D relative to male controls (67% versus 49%; p = 0.0006).
Notably, vitamin D deficiency was progressively lower in males with advancing radiological disease stages (p = 0.001).
-These studies are supported by several others that indicate that vitamin D status may be an independent risk factor for the severity of COVID-19 [715,716,717,718] and in COVID-19 patients relative to population-based controls [719].
-Indeed, serum concentrations of 25-hydroxyvitamin D above 30 ng/ml, which indicate vitamin D sufficiency, seems to be associated with a reduction in serum C-reactive protein, an inflammatory marker, along with increased lymphocyte levels, which suggests that vitamin D levels may modulate the immune response by reducing risk for cytokine storm in response to SARS-CoV-2 infection [719].
-A study in India determined that COVID-19 fatality was higher in patients with severe COVID-19 and low serum 25-hydroxyvitamin D (mean level 6.2 ng/ml; 97% vitamin D deficient) levels versus asymptomatic non-severe patients with higher levels of vitamin D (mean level 27.9 ng/ml; 33% vitamin D deficient) [720].
+These studies are supported by several others that indicate that vitamin D status may be an independent risk factor for the severity of COVID-19 [716,717,718,719] and in COVID-19 patients relative to population-based controls [720].
+Indeed, serum concentrations of 25-hydroxyvitamin D above 30 ng/ml, which indicate vitamin D sufficiency, seems to be associated with a reduction in serum C-reactive protein, an inflammatory marker, along with increased lymphocyte levels, which suggests that vitamin D levels may modulate the immune response by reducing risk for cytokine storm in response to SARS-CoV-2 infection [720].
+A study in India determined that COVID-19 fatality was higher in patients with severe COVID-19 and low serum 25-hydroxyvitamin D (mean level 6.2 ng/ml; 97% vitamin D deficient) levels versus asymptomatic non-severe patients with higher levels of vitamin D (mean level 27.9 ng/ml; 33% vitamin D deficient) [721].
In the same study, vitamin D deficiency was associated with higher levels of inflammatory markers including IL-6, ferritin, and tumor necrosis factor α.
-Collectively, these studies add to a multitude of observational studies reporting potential associations between low levels of 25-hydroxyvitamin D and COVID-19 incidence and severity [713,718,719,721,722,723,724,725,726,727].
-Despite the large number of studies establishing a link between vitamin D status and COVID-19 severity, an examination of data from the UK Biobank did not support this thesis [728,729].
+Collectively, these studies add to a multitude of observational studies reporting potential associations between low levels of 25-hydroxyvitamin D and COVID-19 incidence and severity [714,719,720,722,723,724,725,726,727,728].
+Despite the large number of studies establishing a link between vitamin D status and COVID-19 severity, an examination of data from the UK Biobank did not support this thesis [729,730].
These analyses examined 25-hydroxyvitamin D concentrations alongside SARS-CoV-2 positivity and COVID-19 mortality in over 340,000 UK Biobank participants.
-However, these studies have caused considerable debate that will likely be settled following further studies [730,731].
-Overall, while the evidence suggests that there is likely an association between low serum 25-hydroxyvitamin D and COVID-19 incidence, these studies must be interpreted with caution, as there is the potential for reverse causality, bias, and other confounding factors including that vitamin D deficiency is also associated with numerous pre-existing conditions and risk factors that can increase the risk for severe COVID-19 [582,710,732,733].
+However, these studies have caused considerable debate that will likely be settled following further studies [731,732].
+Overall, while the evidence suggests that there is likely an association between low serum 25-hydroxyvitamin D and COVID-19 incidence, these studies must be interpreted with caution, as there is the potential for reverse causality, bias, and other confounding factors including that vitamin D deficiency is also associated with numerous pre-existing conditions and risk factors that can increase the risk for severe COVID-19 [583,711,733,734].
While these studies inform us of the potential importance of vitamin D sufficiency and the risk of SARS-CoV-2 infection and severe COVID-19, they fail to conclusively determine whether vitamin D supplementation can therapeutically affect the clinical course of COVID-19.
In one study, 40 vitamin D deficient asymptomatic or mildly symptomatic participants patients were either randomized to receive 60,000 IU of cholecalciferol daily for at least 7 days (n = 16) or a placebo (n = 24) with a target serum 25-hydroxyvitamin D level >50 ng/ml.
At day 7, 10 patients achieved >50 ng/ml, followed by another 2 by day 14.
-By the end of the study, the treatment group had a greater proportion of vitamin D-deficient participants that tested negative for SARS-CoV-2 RNA, and they had a significantly lower fibrinogen levels, potentially indicating a beneficial effect [734].
-A pilot study in Spain determined that early administration of high dose calcifediol (~21,000 IU days 1-2 and ~11,000 IU days 3-7 of hospital admission) with hydroxychloroquine and azithromycin to 50 hospitalized COVID-19 patients significantly reduced ICU admissions and may have reduced disease severity versus hydroxychloroquine and azithromycin alone [735].
-Although this study received significant criticism from the National Institute for Health and Care Excellence (NICE) in the UK [736], an independent follow-up statistical analysis supported the findings of the study with respect to the results of cholecalciferol treatment [737].
-Another trial of 986 patients hospitalized for COVID-19 in three UK hospitals administered cholecalciferol supplementation (≥ 280,000 IU in a time period of 7 weeks) to 151 patients and found an association with a reduced risk of COVID-19 mortality, regardless of baseline 25-hydroxyvitamin D levels [738].
+By the end of the study, the treatment group had a greater proportion of vitamin D-deficient participants that tested negative for SARS-CoV-2 RNA, and they had a significantly lower fibrinogen levels, potentially indicating a beneficial effect [735].
+A pilot study in Spain determined that early administration of high dose calcifediol (~21,000 IU days 1-2 and ~11,000 IU days 3-7 of hospital admission) with hydroxychloroquine and azithromycin to 50 hospitalized COVID-19 patients significantly reduced ICU admissions and may have reduced disease severity versus hydroxychloroquine and azithromycin alone [736].
+Although this study received significant criticism from the National Institute for Health and Care Excellence (NICE) in the UK [737], an independent follow-up statistical analysis supported the findings of the study with respect to the results of cholecalciferol treatment [738].
+Another trial of 986 patients hospitalized for COVID-19 in three UK hospitals administered cholecalciferol supplementation (≥ 280,000 IU in a time period of 7 weeks) to 151 patients and found an association with a reduced risk of COVID-19 mortality, regardless of baseline 25-hydroxyvitamin D levels [739].
However, a double-blind, randomized, placebo-controlled trial of 240 hospitalized COVID-19 patients in São Paulo, Brazil administered a single 200,000 IU oral dose of vitamin D.
-While levels of 25-hydroxyvitamin D did increase from 21% to ~27% (p = 0.001) and the supplementation was well tolerated, there was no reduction in the length of hospital stay or mortality and no change to any other relevant secondary outcomes [739].
+While levels of 25-hydroxyvitamin D did increase from 21% to ~27% (p = 0.001) and the supplementation was well tolerated, there was no reduction in the length of hospital stay or mortality and no change to any other relevant secondary outcomes [740].
These early findings are thus still inconclusive with regards to the therapeutic value of vitamin D supplementation.
-However, other trials are underway, including one trial that is investigating the utility of vitamin D as an immune-modulating agent by monitoring whether administration of vitamin D precipitates an improvement of health status in non-severe symptomatic COVID-19 patients and whether vitamin D prevents patient deterioration [740].
-Other trials are examining various factors including mortality, symptom recovery, severity of disease, rates of ventilation, inflammatory markers such as C-reactive protein and IL-6, blood cell counts, and the prophylactic capacity of vitamin D administration [740,741,742,743].
-Concomitant administration of vitamin D with pharmaceuticals such as aspirin [744] and bioactive molecules such as resveratrol [745] are also under investigation.
+However, other trials are underway, including one trial that is investigating the utility of vitamin D as an immune-modulating agent by monitoring whether administration of vitamin D precipitates an improvement of health status in non-severe symptomatic COVID-19 patients and whether vitamin D prevents patient deterioration [741].
+Other trials are examining various factors including mortality, symptom recovery, severity of disease, rates of ventilation, inflammatory markers such as C-reactive protein and IL-6, blood cell counts, and the prophylactic capacity of vitamin D administration [741,742,743,744].
+Concomitant administration of vitamin D with pharmaceuticals such as aspirin [745] and bioactive molecules such as resveratrol [746] are also under investigation.
The effectiveness of vitamin D supplementation against COVID-19 remains open for debate.
-All the same, there is no doubt that vitamin D deficiency is a widespread issue and should be addressed not only because of its potential link to SARS-CoV-2 incidence [746], but also due to its importance for overall health.
+All the same, there is no doubt that vitamin D deficiency is a widespread issue and should be addressed not only because of its potential link to SARS-CoV-2 incidence [747], but also due to its importance for overall health.
There is a possibility that safe exposure to sunlight could improve endogenous synthesis of vitamin D, potentially strengthening the immune system.
However, sun exposure is not sufficient on its own, particularly in the winter months.
Indeed, while the possible link between vitamin D status and COVID-19 is further investigated, preemptive supplementation of vitamin D and encouraging people to maintain a healthy diet for optimum vitamin D status is likely to raise serum levels of 25-hydroxyvitamin D while being unlikely to carry major health risks.
These principles seem to be the basis of a number of guidelines issued by some countries and scientific organizations that have advised supplementation of vitamin D during the pandemic.
The Académie Nationale de Médecine in France recommends rapid testing of 25-hydroxyvitamin D for people over 60 years old to identify those most at risk of vitamin D deficiency and advises them to obtain a bolus dose of 50,000 to 100,000 IU vitamin D to limit respiratory complications.
-It has also recommended that those under 60 years old should take 800 to 1,000 IU daily if they receive a SARS-CoV-2 positive test [747].
-In Slovenia, doctors have been advised to provide nursing home patients with vitamin D [748].
-Both Public Health England and Public Health Scotland have advised members of the Black, Asian, and minority ethnic communities to supplement for vitamin D in light of evidence that they may be at higher risk for vitamin D deficiency along with other COVID-19 risk factors, a trend that has also been observed in the United States [749,750].
+It has also recommended that those under 60 years old should take 800 to 1,000 IU daily if they receive a SARS-CoV-2 positive test [748].
+In Slovenia, doctors have been advised to provide nursing home patients with vitamin D [749].
+Both Public Health England and Public Health Scotland have advised members of the Black, Asian, and minority ethnic communities to supplement for vitamin D in light of evidence that they may be at higher risk for vitamin D deficiency along with other COVID-19 risk factors, a trend that has also been observed in the United States [750,751].
However, other UK scientific bodies including the NICE recommend that individuals supplement for vitamin D as per usual UK government advice but warn that people should not supplement for vitamin D solely to prevent COVID-19.
-All the same, the NICE has provided guidelines for research to investigate the supplementation of vitamin D in the context of COVID-19 [751].
-Despite vitamin D deficiency being a widespread issue in the United States [752], the National Institutes of Health have stated that there is “insufficient data to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19” [753].
+All the same, the NICE has provided guidelines for research to investigate the supplementation of vitamin D in the context of COVID-19 [752].
+Despite vitamin D deficiency being a widespread issue in the United States [753], the National Institutes of Health have stated that there is “insufficient data to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19” [754].
These are just some examples of how public health guidance has responded to the emerging evidence regarding vitamin D and COVID-19.
-Outside of official recommendations, there is also evidence that individuals may be paying increased attention to their vitamin D levels, as a survey of Polish consumers showed that 56% of respondents used vitamin D during the pandemic [754].
-However, some companies have used the emerging evidence surrounding vitamin D to sell products that claim to prevent and treat COVID-19, which in one incident required a federal court to intervene and issue an injunction barring the sale of vitamin-D-related products due to the lack of clinical data supporting these claims [755].
+Outside of official recommendations, there is also evidence that individuals may be paying increased attention to their vitamin D levels, as a survey of Polish consumers showed that 56% of respondents used vitamin D during the pandemic [755].
+However, some companies have used the emerging evidence surrounding vitamin D to sell products that claim to prevent and treat COVID-19, which in one incident required a federal court to intervene and issue an injunction barring the sale of vitamin-D-related products due to the lack of clinical data supporting these claims [756].
It is clear that further studies and clinical trials are required to conclusively determine the prophylactic and therapeutic potential of vitamin D supplementation against COVID-19.
Until such time that sufficient evidence emerges, individuals should follow their national guidelines surrounding vitamin D intake to achieve vitamin D sufficiency.
6.8 Probiotics
-Probiotics are “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” [756].
-Some studies suggest that probiotics are beneficial against common viral infections, and there is modest evidence to suggest that they can modulate the immune response [757,758].
-As a result, it has been hypothesized that probiotics may have therapeutic value worthy of investigation against SARS-CoV-2 [759].
-Probiotics and next-generation probiotics, which are more akin to pharmacological-grade supplements, have been associated with multiple potential beneficial effects for allergies, digestive tract disorders, and even metabolic diseases through their anti-inflammatory and immunomodulatory effects [760,761].
-However, the mechanisms by which probiotics affect these various conditions would likely differ among strains, with the ultimate effect of the probiotic depending on the heterogeneous set of bacteria present [761].
-Some of the beneficial effects of probiotics include reducing inflammation by promoting the expression of anti-inflammatory mediators, inhibiting Toll-like receptors 2 and 4, competing directly with pathogens, synthesizing antimicrobial substances or other metabolites, improving intestinal barrier function, and/or favorably altering the gut microbiota and the brain-gut axis [761,762,763].
-It is also thought that lactobacilli such as Lactobacillus paracasei, Lactobacillus plantarum and Lactobacillus rhamnosus have the capacity to bind to and inactivate some viruses via adsorptive and/or trapping mechanisms [764].
-Other probiotic lactobacilli and even non-viable bacterium-like particles have been shown to reduce both viral attachment to host cells and viral titers, along with reducing cytokine synthesis, enhancing the antiviral IFN-α response, and inducing various other antiviral mechanisms [764,765,766,767,768,769,770,771,772].
-These antiviral and immunobiotic mechanisms and others have been reviewed in detail elsewhere [612,759,773].
-However, there is also a bi-directional relationship between the lungs and gut microbiota known as the gut-lung axis [774], whereby gut microbial metabolites and endotoxins may affect the lungs via the circulatory system and the lung microbiota in return may affect the gut [775].
-Therefore, the gut-lung axis may play role in our future understanding of COVID-19 pathogenesis and become a target for probiotic treatments [776].
-Moreover, as microbial dysbiosis of the respiratory tract and gut may play a role in some viral infections, it has been suggested that SARS-CoV-2 may interact with our commensal microbiota [612; 777; 10.3389/fmicb.2020.01840] and that the lung microbiome could play a role in developing immunity to viral infections [778].
+
Probiotics are “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” [757].
+Some studies suggest that probiotics are beneficial against common viral infections, and there is modest evidence to suggest that they can modulate the immune response [758,759].
+As a result, it has been hypothesized that probiotics may have therapeutic value worthy of investigation against SARS-CoV-2 [760].
+Probiotics and next-generation probiotics, which are more akin to pharmacological-grade supplements, have been associated with multiple potential beneficial effects for allergies, digestive tract disorders, and even metabolic diseases through their anti-inflammatory and immunomodulatory effects [761,762].
+However, the mechanisms by which probiotics affect these various conditions would likely differ among strains, with the ultimate effect of the probiotic depending on the heterogeneous set of bacteria present [762].
+Some of the beneficial effects of probiotics include reducing inflammation by promoting the expression of anti-inflammatory mediators, inhibiting Toll-like receptors 2 and 4, competing directly with pathogens, synthesizing antimicrobial substances or other metabolites, improving intestinal barrier function, and/or favorably altering the gut microbiota and the brain-gut axis [762,763,764].
+It is also thought that lactobacilli such as Lactobacillus paracasei, Lactobacillus plantarum and Lactobacillus rhamnosus have the capacity to bind to and inactivate some viruses via adsorptive and/or trapping mechanisms [765].
+Other probiotic lactobacilli and even non-viable bacterium-like particles have been shown to reduce both viral attachment to host cells and viral titers, along with reducing cytokine synthesis, enhancing the antiviral IFN-α response, and inducing various other antiviral mechanisms [765,766,767,768,769,770,771,772,773].
+These antiviral and immunobiotic mechanisms and others have been reviewed in detail elsewhere [613,760,774].
+However, there is also a bi-directional relationship between the lungs and gut microbiota known as the gut-lung axis [775], whereby gut microbial metabolites and endotoxins may affect the lungs via the circulatory system and the lung microbiota in return may affect the gut [776].
+Therefore, the gut-lung axis may play role in our future understanding of COVID-19 pathogenesis and become a target for probiotic treatments [777].
+Moreover, as microbial dysbiosis of the respiratory tract and gut may play a role in some viral infections, it has been suggested that SARS-CoV-2 may interact with our commensal microbiota [613; 778; 10.3389/fmicb.2020.01840] and that the lung microbiome could play a role in developing immunity to viral infections [779].
These postulations, if correct, could lead to the development of novel probiotic and prebiotic treatments.
However, significant research is required to confirm these associations and their relevance to patient care, if any.
Probiotic therapies and prophylactics may also confer some advantages for managing symptoms of COVID-19 or risks associated with its treatment.
-Probiotics have tentatively been associated with the reduction of risk and duration of viral upper respiratory tract infections [779,780,781].
-Some meta-analyses that have assessed the efficacy of probiotics in viral respiratory infections have reported moderate reductions in the incidence and duration of infection [780,782].
-Indeed, randomized controlled trials have shown that administering Bacillus subtilis and Enterococcus faecalis [783], Lactobacillus rhamnosus GG [784], or Lactobacillus casei and Bifidobacterium breve with galactooligosaccharides [785] via the nasogastric tube to ventilated patients reduced the occurrence of ventilator-associated pneumonia in comparison to the respective control groups in studies of viral infections and sepsis.
-These findings were also supported by a recent meta-analysis [786].
-Additionally, COVID-19 patients carry a significant risk of ventilator-associated bacterial pneumonia [787], but it can be challenging for clinicians to diagnose this infection due to the fact that severe COVID-19 infection presents with the symptoms of pneumonia [788].
+Probiotics have tentatively been associated with the reduction of risk and duration of viral upper respiratory tract infections [780,781,782].
+Some meta-analyses that have assessed the efficacy of probiotics in viral respiratory infections have reported moderate reductions in the incidence and duration of infection [781,783].
+Indeed, randomized controlled trials have shown that administering Bacillus subtilis and Enterococcus faecalis [784], Lactobacillus rhamnosus GG [785], or Lactobacillus casei and Bifidobacterium breve with galactooligosaccharides [786] via the nasogastric tube to ventilated patients reduced the occurrence of ventilator-associated pneumonia in comparison to the respective control groups in studies of viral infections and sepsis.
+These findings were also supported by a recent meta-analysis [787].
+Additionally, COVID-19 patients carry a significant risk of ventilator-associated bacterial pneumonia [788], but it can be challenging for clinicians to diagnose this infection due to the fact that severe COVID-19 infection presents with the symptoms of pneumonia [789].
Therefore, an effective prophylactic therapy for ventilator-associated pneumonia in severe COVID-19 patients would carry significant therapeutic value.
-Additionally, in recent years, probiotics have become almost synonymous with the treatment of gastrointestinal issues due to their supposed anti-inflammatory and immunomodulatory effects [789].
-Notably, gastrointestinal symptoms commonly occur in COVID-19 patients [790], and angiotensin-converting enzyme 2, the portal by which SARS-CoV-2 enters human cells, is highly expressed in enterocytes of the ileum and colon, suggesting that these organs may be a potential route of infection [791,792].
-Indeed, SARS-CoV-2 viral RNA has been detected in human feces [89,793], and fecal-oral transmission of the virus has not yet been ruled out [794].
-Rectal swabs of some SARS-CoV-2 positive pediatric patients persistently tested positive for several days despite negative nasopharyngeal tests, indicating the potential for fecal viral shedding [795].
-However, there is conflicting evidence for the therapeutic value of various probiotics against the incidence or severity of gastrointestinal symptoms in viral or bacterial infections such as gastroenteritis [796,797].
-Nevertheless, it has been proposed that the administration of probiotics to COVID-19 patients and healthcare workers may prevent or ameliorate the gastrointestinal symptoms of COVID-19, a hypothesis that several clinical trials are now preparing to investigate [798,799].
-Other studies are investigating whether probiotics may affect patient outcomes following SARS-CoV-2 infection [800].
+Additionally, in recent years, probiotics have become almost synonymous with the treatment of gastrointestinal issues due to their supposed anti-inflammatory and immunomodulatory effects [790].
+Notably, gastrointestinal symptoms commonly occur in COVID-19 patients [791], and angiotensin-converting enzyme 2, the portal by which SARS-CoV-2 enters human cells, is highly expressed in enterocytes of the ileum and colon, suggesting that these organs may be a potential route of infection [792,793].
+Indeed, SARS-CoV-2 viral RNA has been detected in human feces [91,794], and fecal-oral transmission of the virus has not yet been ruled out [795].
+Rectal swabs of some SARS-CoV-2 positive pediatric patients persistently tested positive for several days despite negative nasopharyngeal tests, indicating the potential for fecal viral shedding [796].
+However, there is conflicting evidence for the therapeutic value of various probiotics against the incidence or severity of gastrointestinal symptoms in viral or bacterial infections such as gastroenteritis [797,798].
+Nevertheless, it has been proposed that the administration of probiotics to COVID-19 patients and healthcare workers may prevent or ameliorate the gastrointestinal symptoms of COVID-19, a hypothesis that several clinical trials are now preparing to investigate [799,800].
+Other studies are investigating whether probiotics may affect patient outcomes following SARS-CoV-2 infection [801].
Generally, the efficacy of probiotic use is a controversial topic among scientists.
-In Europe, EFSA has banned the term probiotics on products labels, which has elicited either criticism for EFSA or support for probiotics from researchers in the field [756,801,802].
+In Europe, EFSA has banned the term probiotics on products labels, which has elicited either criticism for EFSA or support for probiotics from researchers in the field [757,802,803].
This regulation is due to the hyperbolic claims placed on the labels of various probiotic products, which lack rigorous scientific data to support their efficacy.
-Overall, the data supporting probiotics in the treatment or prevention of many different disorders and diseases is not conclusive, as the quality of the evidence is generally considered low [779].
+Overall, the data supporting probiotics in the treatment or prevention of many different disorders and diseases is not conclusive, as the quality of the evidence is generally considered low [780].
However, in the case of probiotics and respiratory infections, the evidence seems to be supportive of their potential therapeutic value.
Consequently, several investigations are underway to investigate the prophylactic and therapeutic potential of probiotics for COVID-19.
-The blind use of conventional probiotics for COVID-19 is currently cautioned against until the pathogenesis of SARS-CoV-2 can be further established [803].
+The blind use of conventional probiotics for COVID-19 is currently cautioned against until the pathogenesis of SARS-CoV-2 can be further established [804].
Until clinical trials investigating the prophylactic and therapeutic potential of probiotics for COVID-19 are complete, it is not possible to provide an evidence-based recommendation for their use.
-Despite these concerns, complementary use of probiotics as an adjuvant therapeutic has been proposed by the Chinese National Health Commission and National Administration of Traditional Chinese Medicine [90].
-While supply issues prevented the probiotics market from showing the same rapid response to the COVID-19 as some other supplements, many suppliers are reporting growth during the pandemic [804].
+Despite these concerns, complementary use of probiotics as an adjuvant therapeutic has been proposed by the Chinese National Health Commission and National Administration of Traditional Chinese Medicine [92].
+While supply issues prevented the probiotics market from showing the same rapid response to the COVID-19 as some other supplements, many suppliers are reporting growth during the pandemic [805].
Therefore, the public response once again seems to have adopted supplements promoted as bolstering the immune response despite a lack of evidence suggesting they are beneficial for preventing or mitigating COVID-19.
6.9 Discussion
In this review, we report the findings to date of analyses of several dietary supplements and nutraceuticals.
While existing evidence suggests potential benefits of n-3 PUFA and probiotic supplementation for COVID-19 treatment and prophylaxis, clinical data is still lacking, although trials are underway.
Both zinc and vitamin C supplementation in hospitalized patients seem to be associated with positive outcomes; however, further clinical trials are required.
In any case, both vitamin C and zinc intake are part of a healthy diet and both likely presents minimal risk when supplemented for, though their potential prophylactic or therapeutic effects against COVID-19 are yet to be determined.
-On the other hand, mounting evidence from observational studies indicates that there is an association between vitamin D deficiency and COVID-19 incidence has also been supported by meta-analysis [805].
+On the other hand, mounting evidence from observational studies indicates that there is an association between vitamin D deficiency and COVID-19 incidence has also been supported by meta-analysis [806].
Indeed, scientists are working to confirm these findings and to determine whether a patient’s serum 25-hydroxyvitamin D levels are also associated with COVID-19 severity.
Clinical trials are required to determine whether preemptive vitamin D supplementation may mitigate against severe COVID-19.
-In terms of the therapeutic potential of vitamin D, initial evidence from clinical trials are conflicting, but seem to indicate that vitamin D supplementation may reduce COVID-19 severity [735].
+In terms of the therapeutic potential of vitamin D, initial evidence from clinical trials are conflicting, but seem to indicate that vitamin D supplementation may reduce COVID-19 severity [736].
The various clinical trials currently underway will be imperative to provide information on the efficacious use of vitamin D supplementation for COVID-19 prevention and/or treatment.
The purported prophylactic and therapeutic benefits of dietary supplements and nutraceuticals for multiple disorders, diseases, and infections has been the subject of significant research and debate for the last few decades.
Inevitably, scientists are also investigating the potential for these various products to treat or prevent COVID-19.
This interest also extends to consumers, which led to a remarkable increase of sales of dietary supplements and nutraceuticals throughout the pandemic due to a desire to obtain additional protections from infection and disease.
The nutraceuticals discussed in this review, namely vitamin C, vitamin D, n-3 PUFA, zinc, and probiotics, were selected because of potential biological mechanisms that could beneficially affect viral and respiratory infections and because they are currently under clinical investigation.
Specifically, these compounds have all been found to influence cellular processes related to inflammation.
-Inflammation is particularly relevant to COVID-19 because of the negative outcomes (often death) observed in a large number of patients whose immune response becomes hyperactive in response to SARS-CoV-2, leading to severe outcomes such as ARDS and sepsis [806].
-Additionally, there is a well-established link between diet and inflammation [807], potentially mediated in part by the microbiome [808].
+Inflammation is particularly relevant to COVID-19 because of the negative outcomes (often death) observed in a large number of patients whose immune response becomes hyperactive in response to SARS-CoV-2, leading to severe outcomes such as ARDS and sepsis [807].
+Additionally, there is a well-established link between diet and inflammation [808], potentially mediated in part by the microbiome [809].
Thus, the idea that dietary modifications or supplementation could be used to modify the inflammatory response is tied to a broader view of how diet and the immune system are interconnected.
-The supplements and nutraceuticals discussed here therefore lie in sharp contrast to other alleged nutraceutical or dietary supplements that have attracted during the pandemic, such as colloidal silver [809], which have no known nutritional function and can be harmful.
+The supplements and nutraceuticals discussed here therefore lie in sharp contrast to other alleged nutraceutical or dietary supplements that have attracted during the pandemic, such as colloidal silver [810], which have no known nutritional function and can be harmful.
Importantly, while little clinical evidence is available about the effects of any supplements against COVID-19, the risks associated with those discussed above are likely to be low, and in some cases, they can be obtained from dietary sources alone.
There are various other products and molecules that have garnered scientific interest and could merit further investigation.
-These include polyphenols, lipid extracts, and tomato-based nutraceuticals, all of which have been suggested for the potential prevention of cardiovascular complications of COVID-19 such as thrombosis [612,648].
-Melatonin is another supplement that has been identified as a potential antiviral agent against SARS-CoV-2 using computational methods [810], and it has also been highlighted as a potential therapeutic agent for COVID-19 due to its documented antioxidant, anti-apoptotic, immunomodulatory, and anti-inflammatory effects [648,811,812].
-Notably, melatonin, vitamin D and zinc have attracted public attention because they were included in the treatment plan of the former President of the United States upon his hospitalization due to COVID-19 [813].
+These include polyphenols, lipid extracts, and tomato-based nutraceuticals, all of which have been suggested for the potential prevention of cardiovascular complications of COVID-19 such as thrombosis [613,649].
+Melatonin is another supplement that has been identified as a potential antiviral agent against SARS-CoV-2 using computational methods [811], and it has also been highlighted as a potential therapeutic agent for COVID-19 due to its documented antioxidant, anti-apoptotic, immunomodulatory, and anti-inflammatory effects [649,812,813].
+Notably, melatonin, vitamin D and zinc have attracted public attention because they were included in the treatment plan of the former President of the United States upon his hospitalization due to COVID-19 [814].
These are just some of the many substances and supplements that are currently under investigation but as of yet lack evidence to support their use for the prevention or treatment of COVID-19.
-While there is plenty of skepticism put forward by physicians and scientists surrounding the use of supplements, these statements have not stopped consumers from purchasing these products, with one study reporting that online searches for dietary supplements in Poland began trending with the start of the pandemic [754].
+While there is plenty of skepticism put forward by physicians and scientists surrounding the use of supplements, these statements have not stopped consumers from purchasing these products, with one study reporting that online searches for dietary supplements in Poland began trending with the start of the pandemic [755].
Additionally, supplement usage increased between the first and second wave of the pandemic.
Participants reported various reasons for their use of supplements, including to improve immunity (60%), to improve overall health (57%), and to fill nutrient gaps in their diet (53%).
Other efforts to collect large datasets regarding such behavior have also sought to explore a possible association between vitamin or supplement consumption and COVID-19.
-An observational analysis of survey responses from 327,720 users of the COVID Symptom Study App found that the consumption of n-3 PUFA supplements, probiotics, multivitamins, and vitamin D was associated with a lower risk of SARS-CoV-2 infection in women but not men after adjusting for potential confounders [814].
-According to the authors, the sexual dimorphism observed may in part be because supplements may better support females due to known differences between the male and female immune systems, or it could be due to behavioral and health consciousness differences between the sexes [814].
+An observational analysis of survey responses from 327,720 users of the COVID Symptom Study App found that the consumption of n-3 PUFA supplements, probiotics, multivitamins, and vitamin D was associated with a lower risk of SARS-CoV-2 infection in women but not men after adjusting for potential confounders [815].
+According to the authors, the sexual dimorphism observed may in part be because supplements may better support females due to known differences between the male and female immune systems, or it could be due to behavioral and health consciousness differences between the sexes [815].
Certainly, randomized controlled trials are required to investigate these findings further.
-Finally, it is known that a patient’s nutritional status affects health outcomes in various infectious diseases [586], and COVID-19 is no different [584,815,816].
-Some of the main risk factors for severe COVID-19, which also happen to be linked to poor nutritional status, include obesity, hypertension, cardiovascular diseases, type II diabetes mellitus, and indeed age-related malnutrition [582,584,817].
+
Finally, it is known that a patient’s nutritional status affects health outcomes in various infectious diseases [587], and COVID-19 is no different [585,816,817].
+Some of the main risk factors for severe COVID-19, which also happen to be linked to poor nutritional status, include obesity, hypertension, cardiovascular diseases, type II diabetes mellitus, and indeed age-related malnutrition [583,585,818].
Although not the main focus of this review, it is important to consider the nutritional challenges associated with severe COVID-19 patients.
-Hospitalized COVID-19 patients tend to report an unusually high loss of appetite preceding admission, some suffer diarrhea and gastrointestinal symptoms that result in significantly lower food intake, and patients with poorer nutritional status were more likely to have worse outcomes and require nutrition therapy [818].
-Dysphagia also seems to be a significant problem in pediatric patients that suffered multisystem inflammatory syndrome [819] and rehabilitating COVID-19 patients, potentially contributing to poor nutritional status [820].
-Almost two-thirds of discharged COVID-19 ICU patients exhibit significant weight loss, of which 26% had weight loss greater than 10% [816].
-As investigated in this review, hospitalized patients also tend to exhibit vitamin D deficiency or insufficiency, which may be associated with greater disease severity [805].
+Hospitalized COVID-19 patients tend to report an unusually high loss of appetite preceding admission, some suffer diarrhea and gastrointestinal symptoms that result in significantly lower food intake, and patients with poorer nutritional status were more likely to have worse outcomes and require nutrition therapy [819].
+Dysphagia also seems to be a significant problem in pediatric patients that suffered multisystem inflammatory syndrome [820] and rehabilitating COVID-19 patients, potentially contributing to poor nutritional status [821].
+Almost two-thirds of discharged COVID-19 ICU patients exhibit significant weight loss, of which 26% had weight loss greater than 10% [817].
+As investigated in this review, hospitalized patients also tend to exhibit vitamin D deficiency or insufficiency, which may be associated with greater disease severity [806].
Therefore, further research is required to determine how dietary supplements and nutraceuticals may contribute to the treatment of severely ill and rehabilitating patients, who often rely on enteral nutrition.
-6.10 Conclusions
+6.10 Conclusions
Despite all the potential benefits of nutraceutical and dietary supplement interventions presented, currently there is a paucity of clinical evidence to support their use for the prevention or mitigation of COVID-19 infection.
-Nevertheless, optimal nutritional status can prime an individual’s immune system to protect against the effects of acute respiratory viral infections by supporting normal maintenance of the immune system [582,586].
-Nutritional strategies can also play a role in the treatment of hospitalized patients, as malnutrition is a risk to COVID-19 patients [820].
+Nevertheless, optimal nutritional status can prime an individual’s immune system to protect against the effects of acute respiratory viral infections by supporting normal maintenance of the immune system [583,587].
+Nutritional strategies can also play a role in the treatment of hospitalized patients, as malnutrition is a risk to COVID-19 patients [821].
Overall, supplementation of vitamin C, vitamin D, and zinc may be an effective method of ensuring their adequate intake to maintain optimal immune function, which may also convey beneficial effects against viral infections due to their immunomodulatory effects.
Individuals should pay attention to their nutritional status, particularly their intake of vitamin D, considering that vitamin D deficiency is widespread.
-The prevailing evidence seems to indicate an association between vitamin D deficiency with COVID-19 incidence and, potentially, severity [710].
+The prevailing evidence seems to indicate an association between vitamin D deficiency with COVID-19 incidence and, potentially, severity [711].
As a result, some international authorities have advised the general public, particularly those at high risk of infection, to consider vitamin D supplementation.
However, further well-controlled clinical trials are required to confirm these observations.
-Many supplements and nutraceuticals designed for various ailments that are available in the United States and beyond are not strictly regulated [821].
+
Many supplements and nutraceuticals designed for various ailments that are available in the United States and beyond are not strictly regulated [822].
Consequently, there can be safety and efficacy concerns associated with many of these products.
Often, the vulnerable members of society can be exploited in this regard and, unfortunately, the COVID-19 pandemic has proven no different.
-As mentioned above, the FDA has issued warnings to several companies for advertising falsified claims in relation to the preventative and therapeutic capabilities of their products against COVID-19 [822].
+As mentioned above, the FDA has issued warnings to several companies for advertising falsified claims in relation to the preventative and therapeutic capabilities of their products against COVID-19 [823].
Further intensive investigation is required to establish the effects of these nutraceuticals, if any, against COVID-19.
-Until more effective therapeutics are established, the most effective mitigation strategies consist of encouraging standard public health practices such as regular hand washing with soap, wearing a face mask, and covering a cough with your elbow [823], along with following social distancing measures, “stay at home” guidelines, expansive testing, and contact tracing [824,825].
+Until more effective therapeutics are established, the most effective mitigation strategies consist of encouraging standard public health practices such as regular hand washing with soap, wearing a face mask, and covering a cough with your elbow [824], along with following social distancing measures, “stay at home” guidelines, expansive testing, and contact tracing [825,826].
Indeed, in light of this review, it would also be pertinent to adopt a healthy diet and lifestyle following national guidelines in order to maintain optimal immune health.
Because of the broad public appeal of dietary supplements and nutraceuticals, it is important to evaluate the evidence regarding the use of such products.
We will continue to update this review as more findings become available.
@@ -2624,21 +2625,21 @@ 7.17.2 Importance
7.3 Introduction
For a highly infectious virus like SARS-CoV-2, a vaccine would hold particular value because it could bolster the immune response to the virus of the population broadly, thereby driving a lower rate of infection and likely significantly reducing fatalities.
-However, the vaccine development process has historically been slow, and vaccines fail to provide immediate prophylactic protection or treat ongoing infections [826].
+However, the vaccine development process has historically been slow, and vaccines fail to provide immediate prophylactic protection or treat ongoing infections [827].
Flu-like illnesses caused by viruses are a common target of vaccine development programs, and influenza vaccine technology in particular has made many strides.
During the H1N1 influenza outbreak, vaccine development was accelerated because of the existing infrastructure, along with the fact that regulatory agencies had already decided that vaccines produced using egg- and cell-based platforms could be licensed under the regulations used for a strain change.
Critiques of the production and distribution of the H1N1 vaccine have stressed the need for alternative development-and-manufacturing platforms that can be readily adapted to new pathogens.
-Although a monovalent H1N1 vaccine was not available before the pandemic peaked in the United States and Europe, it was available soon afterward as a stand-alone vaccine that was eventually incorporated into commercially available seasonal influenza vaccines [827].
+Although a monovalent H1N1 vaccine was not available before the pandemic peaked in the United States and Europe, it was available soon afterward as a stand-alone vaccine that was eventually incorporated into commercially available seasonal influenza vaccines [828].
If H1N1 vaccine development provides any indication, considering developing and manufacturing platforms for promising COVID-19 vaccine trials early could hasten the emergence of an effective prophylactic vaccine against SARS-CoV-2.
-The first critical step towards developing a vaccine against SARS-CoV-2 was characterizing the target, which fortunately happened early in the COVID-19 outbreak with the sequencing and dissemination of the viral genome [828].
+
The first critical step towards developing a vaccine against SARS-CoV-2 was characterizing the target, which fortunately happened early in the COVID-19 outbreak with the sequencing and dissemination of the viral genome [829].
The Coalition for Epidemic Preparedness Innovations (CEPI) is coordinating global health agencies and pharmaceutical companies to develop vaccines against SARS-CoV-2.
-As of September 2020, there were over 180 vaccine candidates against SARS-CoV-2 in development [829].
+As of September 2020, there were over 180 vaccine candidates against SARS-CoV-2 in development [830].
Unlike many global vaccine development programs previously, such as with H1N1, the vaccine development landscape for COVID-19 includes vaccines produced by a wide array of technologies.
-Experience in the field of oncology is encouraging COVID-19 vaccine developers to use next-generation approaches to vaccine development, which have led to the great diversity of vaccine development programs [830].
+Experience in the field of oncology is encouraging COVID-19 vaccine developers to use next-generation approaches to vaccine development, which have led to the great diversity of vaccine development programs [831].
These diverse technology platforms include DNA, RNA, virus-like particle, recombinant protein, both replicating and non-replicating viral vectors, live attenuated virus, and inactivated virus approaches (Figure 5).
Given the wide range of vaccines under development, it is possible that some vaccine products may eventually be shown to be more effective in certain subpopulations, such as children, pregnant women, immunocompromised patients, the elderly, etc.
-The requirements for a successful vaccine trial and deployment are complex and may require coordination between government, industry, academia, and philanthropic entities [831].
-While little is currently known about immunity to SARS-CoV-2, vaccine development typically tests for serum neutralizing activity, as this has been established as a biomarker for adaptive immunity in other respiratory illnesses [832].
+The requirements for a successful vaccine trial and deployment are complex and may require coordination between government, industry, academia, and philanthropic entities [832].
+While little is currently known about immunity to SARS-CoV-2, vaccine development typically tests for serum neutralizing activity, as this has been established as a biomarker for adaptive immunity in other respiratory illnesses [833].
Figure 5: Vaccine Development Strategies.
@@ -2647,13 +2648,13 @@ 7.
7.4 DNA Vaccines
-This vaccination method involves the direct introduction of a plasmid containing a DNA sequence encoding the antigen(s) against which an immune response is sought into appropriate tissues [833].
+
This vaccination method involves the direct introduction of a plasmid containing a DNA sequence encoding the antigen(s) against which an immune response is sought into appropriate tissues [834].
This approach may offer several advantages over traditional vaccination approaches, such as the stimulation of both B- as well as T-cell responses and the absence of any infectious agent.
-Currently, a Phase I safety and immunogenicity clinical trial of INO-4800, a prophylactic vaccine against SARS-CoV-2, is underway [834].
+Currently, a Phase I safety and immunogenicity clinical trial of INO-4800, a prophylactic vaccine against SARS-CoV-2, is underway [835].
The vaccine developer Inovio Pharmaceuticals Technology is overseeing administration of INO-4800 by intradermal injection followed by electroporation with the CELLECTRA® device to healthy volunteers.
Electroporation is the application of brief electric pulses to tissues in order to permeabilize cell membranes in a transient and reversible manner.
-It has been shown that electroporation can enhance vaccine efficacy by up to 100-fold, as measured by increases in antigen-specific antibody titers [835].
-The safety of the CELLECTRA® device has been studied for over seven years, and these studies support the further development of electroporation as a safe vaccine delivery method [836].
+It has been shown that electroporation can enhance vaccine efficacy by up to 100-fold, as measured by increases in antigen-specific antibody titers [836].
+The safety of the CELLECTRA® device has been studied for over seven years, and these studies support the further development of electroporation as a safe vaccine delivery method [837].
The temporary formation of pores through electroporation facilitates the successful transportation of macromolecules into cells, allowing cells to robustly take up INO-4800 for the production of an antibody response.
Approved by the U.S. FDA on April 6, 2020, the Phase I study is enrolling up to 40 healthy adult volunteers in Philadelphia, PA at the Perelman School of Medicine and at the Center for Pharmaceutical Research in Kansas City, MO.
The trial has two experimental arms corresponding to the two locations.
@@ -2664,98 +2665,98 @@
7.4<
Although exciting, the cost of vaccine manufacturing and electroporation may make scaling the use of this technology for prophylactic use for the general public difficult.
7.5 RNA Vaccines
RNA vaccines are nucleic-acid based modalities that code for viral antigens against which the human body elicits a humoral and cellular immune response.
-The mRNA technology is transcribed in vitro and delivered to cells via lipid nanoparticles (LNP) [837].
-They are recognized by ribosomes in vivo and then translated and modified into functional proteins [838].
-The resulting intracellular viral proteins are displayed on surface MHC proteins, provoking a strong CD8+ T cell response as well as a CD4+ T cell and B cell-associated antibody responses [838].
+The mRNA technology is transcribed in vitro and delivered to cells via lipid nanoparticles (LNP) [838].
+They are recognized by ribosomes in vivo and then translated and modified into functional proteins [839].
+The resulting intracellular viral proteins are displayed on surface MHC proteins, provoking a strong CD8+ T cell response as well as a CD4+ T cell and B cell-associated antibody responses [839].
Naturally, mRNA is not very stable and can degrade quickly in the extracellular environment or the cytoplasm.
-The LNP covering protects the mRNA from enzymatic degradation outside of the cell [839].
+The LNP covering protects the mRNA from enzymatic degradation outside of the cell [840].
Codon optimization to prevent secondary structure formation and modifications of the poly-A tail as well as the 5’ untranslated region to promote ribosomal complex binding can increase mRNA expression in cells.
-Furthermore, purifying out double-stranded RNA and immature RNA with FPLC (fast performance liquid chromatography) and HPLC (high performance liquid chromatography) technology will improve translation of the mRNA in the cell [838,840].
+Furthermore, purifying out double-stranded RNA and immature RNA with FPLC (fast performance liquid chromatography) and HPLC (high performance liquid chromatography) technology will improve translation of the mRNA in the cell [839,841].
Vaccines based on mRNA delivery confer many advantages over traditional viral vectored vaccines and DNA vaccines.
-In comparison to live attenuated viruses, mRNA vaccines are non-infectious and can be synthetically produced in an egg-free, cell-free environment, thereby reducing the risk of a detrimental immune response in the host [841].
-Unlike DNA vaccines, mRNA technologies are naturally degradable and non-integrating, and they do not need to cross the nuclear membrane in addition to the plasma membrane for their effects to be seen [838].
+In comparison to live attenuated viruses, mRNA vaccines are non-infectious and can be synthetically produced in an egg-free, cell-free environment, thereby reducing the risk of a detrimental immune response in the host [842].
+Unlike DNA vaccines, mRNA technologies are naturally degradable and non-integrating, and they do not need to cross the nuclear membrane in addition to the plasma membrane for their effects to be seen [839].
Furthermore, mRNA vaccines are easily, affordably, and rapidly scalable.
Although mRNA vaccines have been developed for therapeutic and prophylactic purposes, none have previously been licensed or commercialized.
-Nevertheless, they have shown promise in animal models and preliminary clinical trials for several indications, including rabies, coronavirus, influenza, and cytomegalovirus [842].
-Preclinical data previously identified effective antibody generation against full-length FPLC-purified influenza hemagglutinin stalk-encoding mRNA in mice, rabbits, and ferrets [843].
-Similar immunological responses for mRNA vaccines were observed in humans in Phase I and II clinical trials operated by the pharmaceutical-development companies Curevac and Moderna for rabies, flu, and zika [840].
-Positively charged bilayer LNPs carrying the mRNA attract negatively charged cell membranes, endocytose into the cytoplasm [839], and facilitate endosomal escape.
-LNPs can be coated with modalities recognized and engulfed by specific cell types, and LNPs that are 150 nm or less effectively enter into lymphatic vessels [839,844].
+Nevertheless, they have shown promise in animal models and preliminary clinical trials for several indications, including rabies, coronavirus, influenza, and cytomegalovirus [843].
+Preclinical data previously identified effective antibody generation against full-length FPLC-purified influenza hemagglutinin stalk-encoding mRNA in mice, rabbits, and ferrets [844].
+Similar immunological responses for mRNA vaccines were observed in humans in Phase I and II clinical trials operated by the pharmaceutical-development companies Curevac and Moderna for rabies, flu, and zika [841].
+Positively charged bilayer LNPs carrying the mRNA attract negatively charged cell membranes, endocytose into the cytoplasm [840], and facilitate endosomal escape.
+LNPs can be coated with modalities recognized and engulfed by specific cell types, and LNPs that are 150 nm or less effectively enter into lymphatic vessels [840,845].
Therefore, this technology holds great potential for targeted delivery of modified mRNA.
-There are three types of RNA vaccines: non-replicating, in vivo self-replicating, and in vitro dendritic cell non-replicating [845].
+
There are three types of RNA vaccines: non-replicating, in vivo self-replicating, and in vitro dendritic cell non-replicating [846].
Non-replicating mRNA vaccines consist of a simple open reading frame (ORF) for the viral antigen flanked by the 5’ UTR and 3’ poly-A tail.
-In vivo self-replicating vaccines encode a modified viral genome derived from single-stranded, positive sense RNA alphaviruses [838,840].
+In vivo self-replicating vaccines encode a modified viral genome derived from single-stranded, positive sense RNA alphaviruses [839,841].
The RNA genome encodes the viral antigen along with proteins of the genome replication machinery, including an RNA polymerase.
-Structural proteins required for viral assembly are not included in the engineered genome [838].
-Self-replicating vaccines produce more viral antigens over a longer period of time, thereby evoking a more robust immune response [845].
+Structural proteins required for viral assembly are not included in the engineered genome [839].
+Self-replicating vaccines produce more viral antigens over a longer period of time, thereby evoking a more robust immune response [846].
Finally, in vitro dendritic cell non-replicating RNA vaccines limit transfection to dendritic cells.
Dendritic cells are potent antigen-presenting immune cells that easily take up mRNA and present fragments of the translated peptide on their MHC proteins, which can then interact with T cell receptors.
-Ultimately, primed T follicular helper cells can stimulate germinal center B cells that also present the viral antigen to produce antibodies against the virus [846].
-These cells are isolated from the patient, grown and transfected ex vivo, and reintroduced to the patient [847].
+Ultimately, primed T follicular helper cells can stimulate germinal center B cells that also present the viral antigen to produce antibodies against the virus [847].
+These cells are isolated from the patient, grown and transfected ex vivo, and reintroduced to the patient [848].
Given the potential for this technology to be quickly adapted for a new pathogen, it has held significant interest for the treatment of COVID-19.
-In the vaccines developed under this approach, the spike protein, which is immunogenic [39], can be furnished to the immune system in order to train its response.
-The vaccine candidates developed against SARS-CoV-2 using mRNA vectors utilize similar principles and technologies, although there are slight differences in implementation among candidates such as the formulation of the platform and the specific components of the spike protein encapsulated (e.g., the full Spike protein vs. the RBD alone) [848].
+In the vaccines developed under this approach, the spike protein, which is immunogenic [41], can be furnished to the immune system in order to train its response.
+The vaccine candidates developed against SARS-CoV-2 using mRNA vectors utilize similar principles and technologies, although there are slight differences in implementation among candidates such as the formulation of the platform and the specific components of the spike protein encapsulated (e.g., the full Spike protein vs. the RBD alone) [849].
The results of the interim analyses of two mRNA vaccine candidates became available at the end of 2020 and provided strong support for this emerging approach to vaccination.
Below we describe the results available as of February 2021 for two such candidates, mRNA-1273 produced by ModernaTX and BNT162b2 produced by Pfizer, Inc. and BioNTech.
7.5.1 ModernaTX mRNA Vaccine
ModernaTX’s mRNA-1273 vaccine, which is an was the first COVID-19 vaccine to enter a phase I clinical trial in the United States.
-In this trial, Moderna spearheaded an investigation on the immunogenicity and reactogenicity of mRNA-1273, a conventional lipid nanoparticle encapsulated RNA encoding a full-length prefusion stabilized S protein for SARS-CoV-2 [849].
-An initial report described the results of enrolling forty-five participants who were administered intramuscular injections of mRNA-1273 in their deltoid muscle on day 1 and day 29, and then followed for the next twelve months [832].
+In this trial, Moderna spearheaded an investigation on the immunogenicity and reactogenicity of mRNA-1273, a conventional lipid nanoparticle encapsulated RNA encoding a full-length prefusion stabilized S protein for SARS-CoV-2 [850].
+An initial report described the results of enrolling forty-five participants who were administered intramuscular injections of mRNA-1273 in their deltoid muscle on day 1 and day 29, and then followed for the next twelve months [833].
Healthy males and non-pregnant females aged 18-55 years were recruited for this study and divided into three groups receiving 25, 100, or 250 micrograms (μg) of mRNA-1273.
-IgG ELISA assays on patient serology samples were used to examine the immunogenicity of the vaccine [849].
+IgG ELISA assays on patient serology samples were used to examine the immunogenicity of the vaccine [850].
Binding antibodies were observed at two weeks after the first dose at all concentrations.
At the time point one week after the second dose was administered on day 29, the pseudotyped lentivirus reporter single-round-of-infection neutralization assay (PsVNA), which was used to assess neutralizing activity, reached a median level similar to the median observed in convalescent plasma samples.
Participants reported mild and moderate systemic adverse events after the day 1 injection, and one severe local event was observed in each of the two highest dose levels.
The second injection led to severe systemic adverse events for three of the participants at the highest dose levels, with one participant in the group being evaluated at an urgent care center on the day after the second dose.
The reported localized adverse events from the second dose were similar to those from the first.
-Several months later, a press release from ModernaTX described the results of the first interim analysis of the vaccine [850].
-On November 16, 2020, a report was released describing the initial results from Phase III testing, corresponding to the first 95 cases of COVID-19 in the 30,000 enrolled participants [850], with additional data released to the FDA on December 17, 2020 [851].
-These results were subsequently published in a peer-reviewed journal (The New England Journal of Medicine) on December 30, 2020 [852].
-The first group of 30,420 study participants were randomized to receive the vaccine or a placebo at a ratio of 1:1 [852].
-Administration occurred at 99 sites within the United States in two sessions, spaced 28 days apart [852,853].
-Patients reporting COVID-19 symptoms upon follow-up were tested for SARS-CoV-2 using a nasopharyngeal swab that was evaluated with RT-PCR [853].
+
Several months later, a press release from ModernaTX described the results of the first interim analysis of the vaccine [851].
+On November 16, 2020, a report was released describing the initial results from Phase III testing, corresponding to the first 95 cases of COVID-19 in the 30,000 enrolled participants [851], with additional data released to the FDA on December 17, 2020 [852].
+These results were subsequently published in a peer-reviewed journal (The New England Journal of Medicine) on December 30, 2020 [853].
+The first group of 30,420 study participants were randomized to receive the vaccine or a placebo at a ratio of 1:1 [853].
+Administration occurred at 99 sites within the United States in two sessions, spaced 28 days apart [853,854].
+Patients reporting COVID-19 symptoms upon follow-up were tested for SARS-CoV-2 using a nasopharyngeal swab that was evaluated with RT-PCR [854].
The initial preliminary analysis reported the results of the cases observed up until a cut-off date of November 11, 2020.
-Of these first 95 cases reported, 90 occurred in participants receiving the placebo compared to 5 cases in the group receiving the vaccine [850].
+Of these first 95 cases reported, 90 occurred in participants receiving the placebo compared to 5 cases in the group receiving the vaccine [851].
These results suggested the vaccine is 94.5% effective in preventing COVID-19.
Additionally, eleven severe cases of COVID-19 were observed, and all eleven occurred in participants receiving the placebo.
-The publication reported the results through an extended cut-off date of November 21, 2020, corresponding to 196 cases [852].
+The publication reported the results through an extended cut-off date of November 21, 2020, corresponding to 196 cases [853].
Of these, 11 occurred in the vaccine group and 185 in the placebo group, corresponding to an efficacy of 94.1%.
Once again, all of the severe cases of COVID-19 observed (n=30) occurred in the placebo group, including one death.
Thus, as more cases are reported, the efficacy of the vaccine has remained above 90%, and no cases of severe COVID-19 have yet been reported in participants receiving the vaccine.
These findings suggest the possibility that the vaccine might bolster immune defenses even for subjects who do still develop a SARS-CoV-2 infection.
-The study was designed with an explicit goal of including individuals at high risk for COVID-19, including older adults, people with underlying health conditions, and people of color [854].
-The Phase III trial population was comprised by approximately 25.3% adults over age 65 in the initial report and 24.8% in the publication [853].
-Among the cases reported by both interim analyses, 16-17% occurred in older adults [850,852]..
-Additionally, approximately 10% of participants identified a Black or African-American background and 20% identified Hispanic or Latino ethnicity [852,853].
-Among the first 95 cases, 12.6% occurred in participants identifying a Hispanic or Latino background and 4% in participants reporting a Black or African-American background [850]; in the publication, they indicated only that 41 of the cases reported in the placebo group and 1 case in the treatment group occurred in “communities of color”, corresponding to 21.4% of all cases [852].
+The study was designed with an explicit goal of including individuals at high risk for COVID-19, including older adults, people with underlying health conditions, and people of color [855].
+The Phase III trial population was comprised by approximately 25.3% adults over age 65 in the initial report and 24.8% in the publication [854].
+Among the cases reported by both interim analyses, 16-17% occurred in older adults [851,853]..
+Additionally, approximately 10% of participants identified a Black or African-American background and 20% identified Hispanic or Latino ethnicity [853,854].
+Among the first 95 cases, 12.6% occurred in participants identifying a Hispanic or Latino background and 4% in participants reporting a Black or African-American background [851]; in the publication, they indicated only that 41 of the cases reported in the placebo group and 1 case in the treatment group occurred in “communities of color”, corresponding to 21.4% of all cases [853].
While the sample size in both analyses is small relative to the study population of over 30,000, these results suggest that the vaccine is likely to be effective in people from a variety of backgrounds.
By all indications, this vaccine is likely to be highly useful in mitigating the damage of SARS-CoV-2.
-In-depth safety data was released by ModernaTX as part of their application for an EUA from the FDA and summarized in the associated publication [852,853].
+
In-depth safety data was released by ModernaTX as part of their application for an EUA from the FDA and summarized in the associated publication [853,854].
Because the detail provided in the report is greater than that provided in the publication, here we emphasize the results observed at the time of the first analysis.
-Overall, a large percentage of participants reported adverse effects when solicited, and these reports were higher in the vaccine group than in the placebo group (94.5% versus 59.5%, respectively, at the time of the initial analysis) [853].
-Some of these events met the criteria for grade 3 (local or systemic) or grade 4 (systemic only) toxicity [853], but most were grade 1 or grade 2 and lasted 2-3 days [852].
-The most common local adverse reaction was pain at the injection site, reported by 83.7% of participants receiving the first dose of the vaccine and 88.4% upon receiving the second dose, compared to 19.8% and 19.8% and 17.0%, respectively, of patients in the placebo condition [853].
+Overall, a large percentage of participants reported adverse effects when solicited, and these reports were higher in the vaccine group than in the placebo group (94.5% versus 59.5%, respectively, at the time of the initial analysis) [854].
+Some of these events met the criteria for grade 3 (local or systemic) or grade 4 (systemic only) toxicity [854], but most were grade 1 or grade 2 and lasted 2-3 days [853].
+The most common local adverse reaction was pain at the injection site, reported by 83.7% of participants receiving the first dose of the vaccine and 88.4% upon receiving the second dose, compared to 19.8% and 19.8% and 17.0%, respectively, of patients in the placebo condition [854].
Fewer than 5% of vaccine recipients reported grade 3 pain at either administration.
-Other frequent local reactions included erythema, swelling, and lymphadenopathy [853].
-For systemic adverse reactions, fatigue was the most common [853].
-Among participants receiving either dose of the vaccine, 68.5% reported fatigue compared to 36.1% participants receiving the placebo [853].
-The level of fatigue experienced was usually fairly mild, with only 9.6% and 1.3% of participants in the vaccine and placebo conditions, respectively, reporting grade 3 fatigue [853], which corresponds to significant interference with daily activity [855].
-Based on the results of the report, an EUA was issued on December 18, 2020 to allow distribution of this vaccine in the United States [856], and it was shortly followed by an Interim Order authorizing distribution of the vaccine in Canada [857] and a conditional marketing authorization by the European Medicines Agency to facilitate distribution in the European Union [858].
+Other frequent local reactions included erythema, swelling, and lymphadenopathy [854].
+For systemic adverse reactions, fatigue was the most common [854].
+Among participants receiving either dose of the vaccine, 68.5% reported fatigue compared to 36.1% participants receiving the placebo [854].
+The level of fatigue experienced was usually fairly mild, with only 9.6% and 1.3% of participants in the vaccine and placebo conditions, respectively, reporting grade 3 fatigue [854], which corresponds to significant interference with daily activity [856].
+Based on the results of the report, an EUA was issued on December 18, 2020 to allow distribution of this vaccine in the United States [857], and it was shortly followed by an Interim Order authorizing distribution of the vaccine in Canada [858] and a conditional marketing authorization by the European Medicines Agency to facilitate distribution in the European Union [859].
7.5.2 Pfizer/BioNTech BNT162b2
ModernaTX was, in fact, the second company to release news of a successful interim analysis of an mRNA vaccine and receive an EUA.
-The first report came from Pfizer and BioNTech’s mRNA vaccine BNT162b2 on November 9, 2020 [859], and a preliminary report was published in the New England Journal of Medicine one month later [304].
-The vaccine candidate is contains the full prefusion stabilized, membrane-anchored SARS-CoV-2 spike protein in a vaccine formulation based on modified mRNA (modRNA) technology [860,861].
-This vaccine candidate should not be confused with a similar candidate from Pfizer/BioNTech, BNT162b1, that delivered only the RBD of the spike protein [862,863], which was not advanced to a stage III trial because of the improved reactogenicity/immunogenicity profile of BNT162b2 [305].
-During the Phase III trial of BNT162b2, 43,538 participants were enrolled 1:1 in the placebo and the vaccine candidate and received two 30-μg doses 21 days apart [304].
-Of these enrolled participants, 21,720 received BNT162b2 and 21,728 received a placebo [304].
+The first report came from Pfizer and BioNTech’s mRNA vaccine BNT162b2 on November 9, 2020 [860], and a preliminary report was published in the New England Journal of Medicine one month later [306].
+The vaccine candidate is contains the full prefusion stabilized, membrane-anchored SARS-CoV-2 spike protein in a vaccine formulation based on modified mRNA (modRNA) technology [861,862].
+This vaccine candidate should not be confused with a similar candidate from Pfizer/BioNTech, BNT162b1, that delivered only the RBD of the spike protein [863,864], which was not advanced to a stage III trial because of the improved reactogenicity/immunogenicity profile of BNT162b2 [307].
+During the Phase III trial of BNT162b2, 43,538 participants were enrolled 1:1 in the placebo and the vaccine candidate and received two 30-μg doses 21 days apart [306].
+Of these enrolled participants, 21,720 received BNT162b2 and 21,728 received a placebo [306].
Recruitment occurred at 135 sites across six countries: Argentina, Brazil, Germany, South Africa, Turkey, and the United States.
-An initial press release described the first 94 cases, which were consistent with 90% efficacy of the vaccine at 7 days following the second dose [859].
+An initial press release described the first 94 cases, which were consistent with 90% efficacy of the vaccine at 7 days following the second dose [860].
The release of the full trial information covered a longer period and analyzed the first 170 cases occurring at least 7 days after the second dose, 8 of which occurred in patients who had received BNT162b2.
-The press release characterized the study population as diverse, reporting that 42% of the participants worldwide came from non-white backgrounds, including 10% Black and 26% Hispanic or Latino [864].
-Within the United States, 10% and 13% of participants, respectively, identified themselves as having Black or Hispanic/Latino backgrounds [864].
-Additionally, 41% of participants worldwide were 56 years of age or older [864], and they reported that the efficacy of the vaccine in adults over 65 was 94% [865].
-The primary efficacy analysis of the Phase III study was concluded on November 18, 2020 [865], and the final results indicted 94.6% efficacy of the vaccine [304]v.
-The safety profile of the vaccine was also assessed [304].
+The press release characterized the study population as diverse, reporting that 42% of the participants worldwide came from non-white backgrounds, including 10% Black and 26% Hispanic or Latino [865].
+Within the United States, 10% and 13% of participants, respectively, identified themselves as having Black or Hispanic/Latino backgrounds [865].
+Additionally, 41% of participants worldwide were 56 years of age or older [865], and they reported that the efficacy of the vaccine in adults over 65 was 94% [866].
+The primary efficacy analysis of the Phase III study was concluded on November 18, 2020 [866], and the final results indicted 94.6% efficacy of the vaccine [306]v.
+The safety profile of the vaccine was also assessed [306].
A subset of patients were followed for reactogenicity using electronic diaries, with the data collected from these 8,183 participants comprising the solicited safety events analyzed.
Much like those who received the ModernaTX vaccine candidate, a large proportion of participants reported experiencing site injection pain within 7 days of vaccination.
While percentages are broken down by age group in the publication, these proportions correspond to approximately 78% and 73% of all participants after the first and second doses, respectively, overall.
@@ -2764,8 +2765,8 @@
[866,867].
-As of December 11, 2020, the United States FDA approved this vaccine under an emergency use authorization [868].
+Based on the efficacy and safety information released, the vaccine was approved in early December by the United Kingdom’s Medicines and Healthcare Products Regulatory Agency with administration outside of a clinical trial beginning on December 8, 2020 [867,868].
+As of December 11, 2020, the United States FDA approved this vaccine under an emergency use authorization [869].
7.6 Viral Vector Vaccines
7.6.1 COVID-19 Vaccine AstraZeneca
7.6.2 Sputnik-V
@@ -2784,121 +2785,121 @@ also included a brief summary of the potential of adjuvants for these vaccines, including a brief description of some already commonly used adjuvants.
+A review on the development of SARS-CoV-2 vaccines [870] also included a brief summary of the potential of adjuvants for these vaccines, including a brief description of some already commonly used adjuvants.
Different adjuvants can regulate different types of immune responses, so the type or combination of adjuvants used in a vaccine will depend on both the type of vaccine and concern related to efficacy and safety.
-A variety of possible mechanisms for adjuvants have been researched [870,871,872], including the following: induction of DAMPs that can be recognized by certain PRRs of the innate immune system; functioning as PAMP that can also be recognized by certain PRRs; and more generally enhancing the humoral or cellular immune responses.
+A variety of possible mechanisms for adjuvants have been researched [871,872,873], including the following: induction of DAMPs that can be recognized by certain PRRs of the innate immune system; functioning as PAMP that can also be recognized by certain PRRs; and more generally enhancing the humoral or cellular immune responses.
Selection of one or more adjuvants requires considering how to promote the advantageous effects of the components and/or immune response and, likewise, to inhibit possible deleterious effects.
There are also considerations related to the method of delivering (or co-delivering) the adjuvant and antigen components of a vaccine.
7.10.2 Trained Immunity
Another approach that is being investigated explores the potential for vaccines that are not made from the SARS-CoV-2 virus to confer what has been termed trained immunity.
-In a recent review [873], trained immunity was defined as forms of memory that are temporary (e.g., months or years) and reversible.
+In a recent review [874], trained immunity was defined as forms of memory that are temporary (e.g., months or years) and reversible.
It is induced by exposure to whole-microorganism vaccines or other microbial stimuli that generates heterologous protective effects.
Trained immunity can be displayed by innate immune cells or innate immune features of other cells, and it is characterized by alterations to immune responsiveness to future immune challenges due to epigenetic and metabolic mechanisms.
These alterations can take the form of either an increased or decreased response to immune challenge by a pathogen.
-Trained immunity elicited by non-SARS-CoV-2 whole-microorganism vaccines could potentially improve SARS-CoV-2 susceptibility or severity [874].
+Trained immunity elicited by non-SARS-CoV-2 whole-microorganism vaccines could potentially improve SARS-CoV-2 susceptibility or severity [875].
One type of stimulus which research indicates can induce trained immunity is bacillus Calmette-Guerin (BCG) vaccination.
BCG is an attenuated form of bacteria Mycobacterium bovis.
The vaccine is most commonly administered for the prevention of tuberculosis in humans.
Clinical trials in non-SARS-CoV-2-infected adults have been designed to assess whether BCG vaccination could have prophylactic effects against SARS-CoV-2 by reducing susceptibility, preventing infection, or reducing disease severity.
-A number of trials are now evaluating the effects of the BCG vaccine or the related vaccine VPM1002 [874,875,876,877,878,879,880,881,882,883,884,885,886,887,888].
+A number of trials are now evaluating the effects of the BCG vaccine or the related vaccine VPM1002 [875,876,877,878,879,880,881,882,883,884,885,886,887,888,889].
The ongoing trials are using a number of different approaches.
Some trials enroll healthcare workers, other trials hospitalized elderly adults without immunosuppression who get vaccinated with placebo or BCG at hospital discharge, and yet another set of trials older adults (>50 years) under chronic care for conditions like hypertension and diabetes.
One set of trials, for example, uses time until first infection as the primary study endpoint; more generally, outcomes measured in some of these trials are related to incidence of disease and disease severity or symptoms.
-Some analyses have suggested a possible correlation at the country level between the frequency of BCG vaccination (or BCG vaccination policies) and the severity of COVID-19 [874].
+Some analyses have suggested a possible correlation at the country level between the frequency of BCG vaccination (or BCG vaccination policies) and the severity of COVID-19 [875].
Currently it is unclear whether this correlation has any connection to trained immunity.
Many possible confounding factors are also likely to vary among countries, such as age distribution, detection efficiency, stochastic epidemic dynamic effects, differences in healthcare capacity over time in relation to epidemic dynamics, and these have not been adequately accounted for in current analyses.
It is unclear whether there is an effect of the timing of BCG vaccination, both during an individual’s life cycle and relative to the COVID-19 pandemic.
-Additionally, given that severe SARS-CoV-2 may be associated with a dysregulated immune response, it is unclear what alterations to the immune response would be most likely to be protective versus pathogenic (e.g., [112,874,889,890]).
-The article [874] proposes that trained immunity might lead to an earlier and stronger response, which could in turn reduce viremia and the risk of later, detrimental immunopathology.
+Additionally, given that severe SARS-CoV-2 may be associated with a dysregulated immune response, it is unclear what alterations to the immune response would be most likely to be protective versus pathogenic (e.g., [114,875,890,891]).
+The article [875] proposes that trained immunity might lead to an earlier and stronger response, which could in turn reduce viremia and the risk of later, detrimental immunopathology.
While trained immunity is an interesting possible avenue to complement vaccine development efforts through the use of an existing vaccine, additional research is required to assess whether the BCG vaccine is likely to confer trained immunity in the case of SARS-CoV-2.
7.11 Discussion
Additionally, major advances in vaccines using mRNA and adenoviruses that have led to three vaccines becoming available or close to becoming available in late 2020 (Figure 4).
Though some concerns remain about the duration of sustained immunity for convalescents, vaccine development efforts are ongoing and show initial promising results.
The Moderna trial, for example, reported that the neutralizing activity in participants who received two doses of the vaccine was similar to that observed in convalescent plasma.
-One of the two mRNA vaccines, Pfizer and BioNTech’s BNT162b2, has been issued an EUA for patients as young as 16 [891], while ModernaTX has begun a clinical trial to assess its mRNA vaccine in adolescents ages 12 to 18 [892].
+One of the two mRNA vaccines, Pfizer and BioNTech’s BNT162b2, has been issued an EUA for patients as young as 16 [892], while ModernaTX has begun a clinical trial to assess its mRNA vaccine in adolescents ages 12 to 18 [893].
8 Social Factors Influencing COVID-19 Exposure and Outcomes
8.1 Social Factors Influencing COVID-19 Outcomes
In addition to understanding the fundamental biology of the SARS-CoV-2 virus and COVID-19, it is critical to consider how the broader environment can influence both COVID-19 outcomes and efforts to develop and implement treatments for the disease.
The evidence clearly indicates that social environmental factors are critical determinants of individuals’ and communities’ risks related to COVID-19.
There are distinct components to COVID-19 susceptibility, and an individual’s risk can be elevated at one or all stages from exposure to recovery/mortality: an individual may be more likely to be exposed to the virus, more likely to get infected once exposed, more likely to have serious complications once infected, and be less likely to receive adequate care once they are seriously ill.
-The fact that differences in survival between Black and white patients were no longer significant after controlling for comorbidities and socioeconomic status (type of insurance, neighborhood deprivation score, and hospital where treatment was received) in addition to sex and age [893] underscores the relevance of social factors to understanding mortality differences between racial and ethnic groups.
-Moreover, the Black patients were younger and more likely to be female than white patients, yet still had a higher mortality rate without correction for the other variables [893].
+The fact that differences in survival between Black and white patients were no longer significant after controlling for comorbidities and socioeconomic status (type of insurance, neighborhood deprivation score, and hospital where treatment was received) in addition to sex and age [894] underscores the relevance of social factors to understanding mortality differences between racial and ethnic groups.
+Moreover, the Black patients were younger and more likely to be female than white patients, yet still had a higher mortality rate without correction for the other variables [894].
Here, we outline a few systemic reasons that may exacerbate the COVID-19 pandemic in communities of color.
8.2 Factors Observed to be Associated with Susceptibility
As COVID-19 has spread into communities around the globe, it has become clear that the risks associated with this disease are not equally shared by all individuals or all communities.
Significant disparities in outcomes have led to interest in the demographic, biomedical, and social factors that influence COVID-19 severity.
Untangling the factors influencing COVID-19 susceptibility is a complex undertaking.
-Among patients who are admitted to the hospital, outcomes have generally been poor, with rates of admission to the intensive care unit (ICU) upwards of 15% in both Wuhan, China and Italy [34,894,895].
-However, hospitalization rates vary by location [896].
+Among patients who are admitted to the hospital, outcomes have generally been poor, with rates of admission to the intensive care unit (ICU) upwards of 15% in both Wuhan, China and Italy [36,895,896].
+However, hospitalization rates vary by location [897].
This variation may be influenced by demographic (e.g., average age in the area), medical (e.g., the prevalence of comorbid conditions such as diabetes), and social (e.g., income or healthcare availability) factors that vary geographically.
Additionally, some of the same factors may influence an individual’s probability of exposure to SARS-CoV-2, their risk of developing a more serious case of COVID-19 that would require hospitalization, and their access to medical support.
As a result, quantifying or comparing susceptibility among individuals, communities, or other groups requires consideration of a number of complex phenomena that intersect across many disciplines of research.
In this section, the term “risk factor” is used to refer to variables that are statistically associated with more severe COVID-19 outcomes.
Some are intrinsic characteristics that have been observed to carry an association with variation in outcomes, whereas others may be more functionally linked to the pathophysiology of COVID-19.
8.2.1 Patient Traits Associated with Increased Risk
-Two traits that have been consistently associated with more severe COVID-19 outcomes are male sex and advanced age (typically defined as 60 or older, with the greatest risk among those 85 and older [897]).
-In the United States, males and older individuals diagnosed with COVID-19 were found to be more likely to require hospitalization [898,899].
-A retrospective study of hospitalized Chinese patients [35] found that a higher probability of mortality was associated with older age, and world-wide, population age structure has been found to be an important variable for explaining differences in outbreak severity [900].
-The CFR for adults over 80 has been estimated upwards of 14% or even 20% [901].
-Male sex has also been identified as a risk factor for severe COVID-19 outcomes, including death [902,903,904].
-Early reports from China and Europe indicated that even though the case rates were similar across males and females, males were at elevated risk for hospital admission, ICU admission, and death [903], although data from some US states indicates more cases among females, potentially due to gender representation in care-taking professions [905].
-In older age groups (e.g., age 60 and older), comparable absolute numbers of male and female cases actually suggests a higher rate of occurrence in males, due to increased skew in the sex ratio [903].
-Current estimates based on worldwide data suggest that, compared to females, males may be 30% more likely to be hospitalized, 80% more likely to be admitted to the ICU, and 40% more likely to die as a result of COVID-19 [904].
-There also may be a compounding effect of advanced age and male sex, with differences time to recovery worst for males over 60 years old relative to female members of their age cohort [906].
+Two traits that have been consistently associated with more severe COVID-19 outcomes are male sex and advanced age (typically defined as 60 or older, with the greatest risk among those 85 and older [898]).
+In the United States, males and older individuals diagnosed with COVID-19 were found to be more likely to require hospitalization [899,900].
+A retrospective study of hospitalized Chinese patients [37] found that a higher probability of mortality was associated with older age, and world-wide, population age structure has been found to be an important variable for explaining differences in outbreak severity [901].
+The CFR for adults over 80 has been estimated upwards of 14% or even 20% [902].
+Male sex has also been identified as a risk factor for severe COVID-19 outcomes, including death [903,904,905].
+Early reports from China and Europe indicated that even though the case rates were similar across males and females, males were at elevated risk for hospital admission, ICU admission, and death [904], although data from some US states indicates more cases among females, potentially due to gender representation in care-taking professions [906].
+In older age groups (e.g., age 60 and older), comparable absolute numbers of male and female cases actually suggests a higher rate of occurrence in males, due to increased skew in the sex ratio [904].
+Current estimates based on worldwide data suggest that, compared to females, males may be 30% more likely to be hospitalized, 80% more likely to be admitted to the ICU, and 40% more likely to die as a result of COVID-19 [905].
+There also may be a compounding effect of advanced age and male sex, with differences time to recovery worst for males over 60 years old relative to female members of their age cohort [907].
Both of these risk factors can be approached through the lens of biology.
-The biological basis for greater susceptibility with age is likely linked to the prevalence of extenuating health conditions such as heart failure or diabetes [901].
+The biological basis for greater susceptibility with age is likely linked to the prevalence of extenuating health conditions such as heart failure or diabetes [902].
Several hypotheses have been proposed to account for differences in severity between males and females.
-For example, some evidence suggests that female sex hormones may be protective [903,905].
-ACE2 expression in the kidneys of male mice was observed to be twice as high as that of females, and a regulatory effect of estradiol on ACE2 expression was demonstrated by removing the gonads and then supplementing with estradiol [905,907].
-Other work in mice has shown an inverse association between mortality due to SARS-CoV-1 and estradiol, suggesting a protective role for the sex hormone [905].
+For example, some evidence suggests that female sex hormones may be protective [904,906].
+ACE2 expression in the kidneys of male mice was observed to be twice as high as that of females, and a regulatory effect of estradiol on ACE2 expression was demonstrated by removing the gonads and then supplementing with estradiol [906,908].
+Other work in mice has shown an inverse association between mortality due to SARS-CoV-1 and estradiol, suggesting a protective role for the sex hormone [906].
Similarly, evidence suggests that similar patterns might be found in other tissues.
-A preliminary analysis identified higher levels of ACE2 expression in the myocardium of male patients with aortic valve stenosis showed than female patients, although this pattern was not found in controls [903].
-Additionally, research has indicated that females respond to lower doses than males of heart medications that act on the Renin angiotensin aldosterone system (RAAS) pathway, which is shared with ACE2 [903].
-Additionally, several components of the immune response, including the inflammatory response, may differ in intensity and timing between males and females [905,907].
-This hypothesis is supported by some preliminary evidence showing that female patients who recovered from severe COVID-19 had higher antibody titers than males [905].
-Sex steroids can also bind to immune cell receptors to influence cytokine production [903].
-Additionally, social factors may influence risks related to both age and sex: for example, older adults are more likely to live in care facilities, which have been a source for a large number of outbreaks [908], and gender roles may also influence exposure and/or susceptibility due to differences in care-taking and/or risky behaviors (e.g., caring for elder relatives and smoking, respectively) [903] among men and women (however, it should be noted that both transgender men and women are suspected to be at heightened risk [909].)
+A preliminary analysis identified higher levels of ACE2 expression in the myocardium of male patients with aortic valve stenosis showed than female patients, although this pattern was not found in controls [904].
+Additionally, research has indicated that females respond to lower doses than males of heart medications that act on the Renin angiotensin aldosterone system (RAAS) pathway, which is shared with ACE2 [904].
+Additionally, several components of the immune response, including the inflammatory response, may differ in intensity and timing between males and females [906,908].
+This hypothesis is supported by some preliminary evidence showing that female patients who recovered from severe COVID-19 had higher antibody titers than males [906].
+Sex steroids can also bind to immune cell receptors to influence cytokine production [904].
+Additionally, social factors may influence risks related to both age and sex: for example, older adults are more likely to live in care facilities, which have been a source for a large number of outbreaks [909], and gender roles may also influence exposure and/or susceptibility due to differences in care-taking and/or risky behaviors (e.g., caring for elder relatives and smoking, respectively) [904] among men and women (however, it should be noted that both transgender men and women are suspected to be at heightened risk [910].)
8.2.2 Comorbid Health Conditions
A number of pre-existing or comorbid conditions have repeatedly been identified as risk factors for more severe COVID-19 outcomes.
-Several underlying health conditions were identified at high prevalence among hospitalized patients, including obesity, diabetes, hypertension, lung disease, and cardiovascular disease [896].
-Higher Sequential Organ Failure Assessment (SOFA) scores have been associated with a higher probability of mortality [35], and comorbid conditions such as cardiovascular and lung disease as well as obesity were also associated with an increased risk of hospitalization and death, even when correcting for age and sex [902].
-Diabetes may increase the risk of lengthy hospitalization [910] or of death [910,911].
-[912] and [913] discuss possible ways in which COVID-19 and diabetes may interact.
-Obesity also appears to be associated with higher risk of severe outcomes from SARS-CoV-2 [914,915].
-Obesity is considered an underlying risk factor for other health problems, and the mechanism for its contributions to COVID-19 hospitalization or mortality is not yet clear [916].
-Dementia and cancer were also associated with the risk of death in an analysis of a large number (more than 20,000) COVID-19 patients in the United Kingdom [902].
-It should be noted that comorbid conditions are inextricably tied to age, as conditions tend to be accumulated over time, but that the prevalence of individual comorbidities or of population health overall can vary regionally [917].
-Several comorbidities that are highly prevalent in older adults, such as COPD, hypertension, cardiovascular disease, and diabetes, have been associated with CFRs upwards of 8% compared to an estimate of 1.4% in people without comorbidities [901,918].
-Therefore, both age and health are important considerations when predicting the impact of COVID-19 on a population [917].
-However, other associations may exist, such as patients with sepsis having higher SOFA scores – in fact, SOFA was developed for the assessment of organ failure in the context of sepsis, and the acronym originally stood for Sepsis-Related Organ Failure Assessment [919,920].
+Several underlying health conditions were identified at high prevalence among hospitalized patients, including obesity, diabetes, hypertension, lung disease, and cardiovascular disease [897].
+Higher Sequential Organ Failure Assessment (SOFA) scores have been associated with a higher probability of mortality [37], and comorbid conditions such as cardiovascular and lung disease as well as obesity were also associated with an increased risk of hospitalization and death, even when correcting for age and sex [903].
+Diabetes may increase the risk of lengthy hospitalization [911] or of death [911,912].
+[913] and [914] discuss possible ways in which COVID-19 and diabetes may interact.
+Obesity also appears to be associated with higher risk of severe outcomes from SARS-CoV-2 [915,916].
+Obesity is considered an underlying risk factor for other health problems, and the mechanism for its contributions to COVID-19 hospitalization or mortality is not yet clear [917].
+Dementia and cancer were also associated with the risk of death in an analysis of a large number (more than 20,000) COVID-19 patients in the United Kingdom [903].
+It should be noted that comorbid conditions are inextricably tied to age, as conditions tend to be accumulated over time, but that the prevalence of individual comorbidities or of population health overall can vary regionally [918].
+Several comorbidities that are highly prevalent in older adults, such as COPD, hypertension, cardiovascular disease, and diabetes, have been associated with CFRs upwards of 8% compared to an estimate of 1.4% in people without comorbidities [902,919].
+Therefore, both age and health are important considerations when predicting the impact of COVID-19 on a population [918].
+However, other associations may exist, such as patients with sepsis having higher SOFA scores – in fact, SOFA was developed for the assessment of organ failure in the context of sepsis, and the acronym originally stood for Sepsis-Related Organ Failure Assessment [920,921].
Additionally, certain conditions are likely to be more prevalent under or exacerbated by social conditions, especially poverty, as is discussed further below.
8.2.3 Ancestry
A number of studies have suggested associations between individuals’ racial and ethnic backgrounds and their COVID-19 risk.
-In particular, Black Americans are consistently identified as carrying a higher burden of COVID-19 than white Americans [898,899], with differences in the rates of kidney complications from COVID-19 particularly pronounced [94].
-Statistics from a number of cities indicate significant discrepancies between the proportion of COVID-19 cases and deaths in Black Americans relative to their representation in the general population [921].
-In addition to Black Americans, disproportionate harm and mortality from COVID-19 has also been noted in Latino/Hispanic Americans and in Native American and Alaskan Native communities, including the Navajo nation [922,923,924,925,926,927].
-In Brazil, indigenous communities likewise carry an increased burden of COVID-19 [928].
-In the United Kingdom, nonwhite ethnicity (principally Black or South Asian) was one of several factors found to be associated with a higher risk of death from COVID-19 [929].
+In particular, Black Americans are consistently identified as carrying a higher burden of COVID-19 than white Americans [899,900], with differences in the rates of kidney complications from COVID-19 particularly pronounced [96].
+Statistics from a number of cities indicate significant discrepancies between the proportion of COVID-19 cases and deaths in Black Americans relative to their representation in the general population [922].
+In addition to Black Americans, disproportionate harm and mortality from COVID-19 has also been noted in Latino/Hispanic Americans and in Native American and Alaskan Native communities, including the Navajo nation [923,924,925,926,927,928].
+In Brazil, indigenous communities likewise carry an increased burden of COVID-19 [929].
+In the United Kingdom, nonwhite ethnicity (principally Black or South Asian) was one of several factors found to be associated with a higher risk of death from COVID-19 [930].
From a genetic standpoint, it is highly unlikely that ancestry itself predisposes individuals to contracting COVID-19 or to experiencing severe COVID-19 outcomes.
-Examining human genetic diversity indicates variation over a geographic continuum, and that most human genetic variation is associated with the African continent [930].
-African-Americans are also a more genetically diverse group relative to European-Americans, with a large number of rare alleles and a much smaller fraction of common alleles identified in African-Americans [931].
-Therefore, the idea that African ancestry (at the continent level) might convey some sort of genetic risk for severe COVID-19 contrasts with what is known about worldwide human genetic diversity [932].
+Examining human genetic diversity indicates variation over a geographic continuum, and that most human genetic variation is associated with the African continent [931].
+African-Americans are also a more genetically diverse group relative to European-Americans, with a large number of rare alleles and a much smaller fraction of common alleles identified in African-Americans [932].
+Therefore, the idea that African ancestry (at the continent level) might convey some sort of genetic risk for severe COVID-19 contrasts with what is known about worldwide human genetic diversity [933].
The possibility for genetic variants that confer some risk or some protection remains possible, but has not been widely explored, especially at a global level.
-Research in Beijing of a small number (n=80) hospitalized COVID-19 patients revealed an association between severe COVID-19 outcomes and homozygosity for an allele in the interferon-induced transmembrane protein 3 (IFITM3) gene, which was selected as a candidate because it was previously found to be associated with influenza outcomes in Chinese patients [933].
-Genetic factors may also play a role in the risk of respiratory failure for COVID-19 [934,935,936].
+Research in Beijing of a small number (n=80) hospitalized COVID-19 patients revealed an association between severe COVID-19 outcomes and homozygosity for an allele in the interferon-induced transmembrane protein 3 (IFITM3) gene, which was selected as a candidate because it was previously found to be associated with influenza outcomes in Chinese patients [934].
+Genetic factors may also play a role in the risk of respiratory failure for COVID-19 [935,936,937].
However, genetic variants associated with outcomes within ancestral groups are far less surprising than genetic variants explaining outcomes between groups.
-Alleles in ACE2 and TMPRSS2 have been identified that vary in frequency among ancestral groups [937], but whether these variants are associated with COVID-19 susceptibility has not been explored.
+Alleles in ACE2 and TMPRSS2 have been identified that vary in frequency among ancestral groups [938], but whether these variants are associated with COVID-19 susceptibility has not been explored.
Instead, examining patterns of COVID-19 susceptibility on a global scale that suggest that social factors are of primary importance in predicting mortality.
Reports from several sub-Saharan African countries have indicated that the effects of the COVID-19 pandemic have been less severe than expected based on the outbreaks in China and Italy.
-In Kenya, for example, estimates of national prevalence based on testing blood donors for SARS-CoV-2 antibodies were consistent with 5% of Kenyan adults having recovered from COVID-19 [938].
-This high seroprevalence of antibodies lies in sharp contrast to the low number of COVID-19 fatalities in Kenya, which at the time was 71 out of 2093 known cases [938].
-Likewise, a serosurvey of health care workers in Blantyre City, Malawi reported an adjusted antibody prevalence of 12.3%, suggesting that the virus had been circulating more widely than thought and that the death rate was up eight times lower than models had predicted [939].
-While several possible hypotheses for the apparent reduced impact of COVID-19 on the African continent are being explored, such as young demographics in many places [940], these reports present a stark contrast to the severity of COVID-19 in Americans and Europeans of African descent.
-Additionally, ethnic minorities in the United Kingdom also tend to be younger than white British living in the same areas, yet the burden of COVID-19 is still more serious for minorities, especially people of Black Caribbean ancestry, both in absolute numbers and when controlling for age and location [941].
+In Kenya, for example, estimates of national prevalence based on testing blood donors for SARS-CoV-2 antibodies were consistent with 5% of Kenyan adults having recovered from COVID-19 [939].
+This high seroprevalence of antibodies lies in sharp contrast to the low number of COVID-19 fatalities in Kenya, which at the time was 71 out of 2093 known cases [939].
+Likewise, a serosurvey of health care workers in Blantyre City, Malawi reported an adjusted antibody prevalence of 12.3%, suggesting that the virus had been circulating more widely than thought and that the death rate was up eight times lower than models had predicted [940].
+While several possible hypotheses for the apparent reduced impact of COVID-19 on the African continent are being explored, such as young demographics in many places [941], these reports present a stark contrast to the severity of COVID-19 in Americans and Europeans of African descent.
+Additionally, ethnic minorities in the United Kingdom also tend to be younger than white British living in the same areas, yet the burden of COVID-19 is still more serious for minorities, especially people of Black Caribbean ancestry, both in absolute numbers and when controlling for age and location [942].
Furthermore, the groups in the United States and United Kingdom that have been identified as carrying elevated COVID-19 burden, namely Black American, indigenous American, and Black and South Asian British, are quite distinct in their position on the human ancestral tree.
What is shared across these groups is instead a history of disenfranchisement under colonialism and ongoing systematic racism.
-A large analysis of over 11,000 COVID-19 patients hospitalized in 92 hospitals across U.S. states revealed that Black patients were younger, more often female, more likely to be on Medicaid, more likely to have comorbidities, and came from neighborhoods identified as more economically deprived than white patients [893].
+A large analysis of over 11,000 COVID-19 patients hospitalized in 92 hospitals across U.S. states revealed that Black patients were younger, more often female, more likely to be on Medicaid, more likely to have comorbidities, and came from neighborhoods identified as more economically deprived than white patients [894].
This study reported that when these factors were accounted for, the differences in mortality between Black and white patients were no longer significant.
Thus, the current evidence suggests that the apparent correlations between ancestry and health outcomes must be examined in the appropriate social context.
8.3 Environmental Influences on Susceptibility
@@ -2906,83 +2907,83 @@ .
-A linear relationship was observed between counties’ reduction in mobility and their wealth and health, as measured by access to health care, food security, income, space, and other factors [942].
-Counties with greater reductions in mobility were also found to have much lower child poverty and household crowding and to be more racially segregated, and to have fewer youth and more elderly residents [942].
-Similar associations between wealth and decreased mobility were observed in cellphone GPS data from Colombia, Indonesia, and Mexico collected between January and May 2020 [943], as well as in a very large data set from several US cities [944].
+In U.S. counties with and without stay-at-home orders, smartphone tracking indicated a significant decrease in the general population’s mobility in April relative to February through March of 2020 (-52.3% and -60.8%, respectively) [943].
+A linear relationship was observed between counties’ reduction in mobility and their wealth and health, as measured by access to health care, food security, income, space, and other factors [943].
+Counties with greater reductions in mobility were also found to have much lower child poverty and household crowding and to be more racially segregated, and to have fewer youth and more elderly residents [943].
+Similar associations between wealth and decreased mobility were observed in cellphone GPS data from Colombia, Indonesia, and Mexico collected between January and May 2020 [944], as well as in a very large data set from several US cities [945].
These disparities in mobility are likely to be related to the role that essential workers have played during the pandemic.
-Essential workers are disproportionately likely to be female, people of color, immigrants, and to have an income below 200% of the poverty line [945].
-Black Americans in particular are over-represented among front-line workers and in professions where social distancing is infeasible [946].
-Health care work in particular presents an increased risk of exposure to SARS-CoV-2 [946,947,948,949,950].
-In the United Kingdom, (South) Asians are more likely than their white counterparts to be medical professionals [941], although BAME medical professionals are still disproportionately represented in the proportion of National Health Service staff deaths [951].
-Similar trends have been reported for nurses, especially nurses of color, in the United States [952].
-Furthermore, beyond the risks associated with work itself, use of public transportation may also impact COVID-19 risk [953].
+Essential workers are disproportionately likely to be female, people of color, immigrants, and to have an income below 200% of the poverty line [946].
+Black Americans in particular are over-represented among front-line workers and in professions where social distancing is infeasible [947].
+Health care work in particular presents an increased risk of exposure to SARS-CoV-2 [947,948,949,950,951].
+In the United Kingdom, (South) Asians are more likely than their white counterparts to be medical professionals [942], although BAME medical professionals are still disproportionately represented in the proportion of National Health Service staff deaths [952].
+Similar trends have been reported for nurses, especially nurses of color, in the United States [953].
+Furthermore, beyond the risks associated with work itself, use of public transportation may also impact COVID-19 risk [954].
The socioeconomic and racial/ethnic gaps in who is working on the front lines of the pandemic make it clear that socioeconomic privilege is likely to decrease the probability of exposure to SARS-CoV-2.
Increased risk of exposure can also arise outside the workplace.
-Nursing homes and skilled nursing facilities received attention early on as high-risk locations for COVID-19 outbreaks [954].
-Prisons and detention centers also confer a high risk of exposure or infection [955,956].
-Populations in care facilities are largely older adults, and in the United States, incarcerated people are more likely to be male and persons of color, especially Black [957].
-Additionally, multi-generational households are less common among non-Hispanic white Americans than people of other racial and ethnic backgrounds [958], increasing the risk of exposure for more susceptible family members.
-Analysis suggests that household crowding may also be associated with increased risk of COVID-19 exposure [942], and household crowding is associated with poverty [959].
-Forms of economic insecurity like housing insecurity, which is associated with poverty and more pronounced in communities subjected to racism [960,961], would be likely to increase household crowding and other possible sources of exposure.
+Nursing homes and skilled nursing facilities received attention early on as high-risk locations for COVID-19 outbreaks [955].
+Prisons and detention centers also confer a high risk of exposure or infection [956,957].
+Populations in care facilities are largely older adults, and in the United States, incarcerated people are more likely to be male and persons of color, especially Black [958].
+Additionally, multi-generational households are less common among non-Hispanic white Americans than people of other racial and ethnic backgrounds [959], increasing the risk of exposure for more susceptible family members.
+Analysis suggests that household crowding may also be associated with increased risk of COVID-19 exposure [943], and household crowding is associated with poverty [960].
+Forms of economic insecurity like housing insecurity, which is associated with poverty and more pronounced in communities subjected to racism [961,962], would be likely to increase household crowding and other possible sources of exposure.
As a result, facets of systemic inequality such as mass incarceration of Black Americans and poverty are likely to increase the risk of exposure outside of the workplace.
8.3.2 Severity of COVID-19 Following Exposure
Following exposure to SARS-CoV-2, the likelihood that an individual develops COVID-19 and the severity of the disease presentation can be influenced by a number of social factors.
As discussed above, a number of patient characteristics are associated with the likelihood of severe COVID-19 symptoms.
-In some cases, these trends run counter to those expected given rates of exposure: for example, although women are more likely to be exposed, men are more likely to be diagnosed with, hospitalized from, or die from COVID-19 [905].
+In some cases, these trends run counter to those expected given rates of exposure: for example, although women are more likely to be exposed, men are more likely to be diagnosed with, hospitalized from, or die from COVID-19 [906].
In the case of comorbid conditions and racial/ethnic demographics, however, social factors are highly likely to modulate or at least influence the apparent association between these traits and the increased risk from COVID-19.
In particular, the comorbidities and racial/ethnic correlates of severe COVID-19 outcomes suggest that poverty confers additional risk for COVID-19.
In order to explore the relationship between poverty and COVID-19 outcomes, it is necessary to consider how poverty impacts biology.
In particular, we focus on the United States and the United Kingdom.
-Comorbidities that increase risk for COVID-19, including obesity, type II diabetes, hypertension, and cardiovascular disease, are known to be intercorrelated [962].
-Metabolic conditions related to heightened inflammation, like obesity, type II diabetes, and hypertension, are more strongly associated with negative COVID-19 outcomes than other comorbid conditions, such as chronic heart disease [963].
+Comorbidities that increase risk for COVID-19, including obesity, type II diabetes, hypertension, and cardiovascular disease, are known to be intercorrelated [963].
+Metabolic conditions related to heightened inflammation, like obesity, type II diabetes, and hypertension, are more strongly associated with negative COVID-19 outcomes than other comorbid conditions, such as chronic heart disease [964].
As discussed above, dysregulated inflammation characteristic of cytokine release syndrome is one of the greatest concerns for COVID-19-related death.
-Therefore, it is possible that chronic inflammation characteristic of these metabolic conditions predisposes patients to COVID-19-related death [963].
-The association between these diseases and severe COVID-19 outcomes is a concern from a health equity perspective because poverty exposes people to “obesogenic” conditions [964] and is therefore unsurprisingly associated with higher incidence of obesity and associated disorders [965].
-Furthermore, cell phone GPS data suggests that lower socioeconomic status may also be associated with decreased access to healthy food choices during the COVID-19 pandemic [966,967], suggesting that health-related risk factors for COVID-19 may be exacerbated as the pandemic continues [968].
-Chronic inflammation is a known outcome of chronic stress (e.g., [969,970,971,972]).
-Therefore, the chronic stress of poverty is likely to influence health broadly (as summarized in [973]) and especially during the stress of the ongoing pandemic.
-A preprint [974] provided observational evidence that geographical areas in the United States that suffer from worse air pollution by fine particulate matter have also suffered more COVID-19 deaths per capita, after adjusting for demographic covariates.
-Although lack of individual-level exposure data and the impossibility of randomization make it difficult to elucidate the exact causal mechanism, this finding would be consistent with similar findings for all-cause mortality (e.g., [975]).
-Exposure to air pollution is associated with both poverty (e.g., [976]) and chronic inflammation [977].
-Other outcomes of environmental racism, such as the proximity of abandoned uranium mines to Navajo land, can also cause respiratory illnesses and other health issues [927].
-Similarly, preliminary findings indicate that nutritional status (e.g., vitamin D deficiency [719]) may be associated with COVID-19 outcomes, and reduced access to grocery stores and fresh food often co-occurs with environmental racism [927,978].
+Therefore, it is possible that chronic inflammation characteristic of these metabolic conditions predisposes patients to COVID-19-related death [964].
+The association between these diseases and severe COVID-19 outcomes is a concern from a health equity perspective because poverty exposes people to “obesogenic” conditions [965] and is therefore unsurprisingly associated with higher incidence of obesity and associated disorders [966].
+Furthermore, cell phone GPS data suggests that lower socioeconomic status may also be associated with decreased access to healthy food choices during the COVID-19 pandemic [967,968], suggesting that health-related risk factors for COVID-19 may be exacerbated as the pandemic continues [969].
+Chronic inflammation is a known outcome of chronic stress (e.g., [970,971,972,973]).
+Therefore, the chronic stress of poverty is likely to influence health broadly (as summarized in [974]) and especially during the stress of the ongoing pandemic.
+A preprint [975] provided observational evidence that geographical areas in the United States that suffer from worse air pollution by fine particulate matter have also suffered more COVID-19 deaths per capita, after adjusting for demographic covariates.
+Although lack of individual-level exposure data and the impossibility of randomization make it difficult to elucidate the exact causal mechanism, this finding would be consistent with similar findings for all-cause mortality (e.g., [976]).
+Exposure to air pollution is associated with both poverty (e.g., [977]) and chronic inflammation [978].
+Other outcomes of environmental racism, such as the proximity of abandoned uranium mines to Navajo land, can also cause respiratory illnesses and other health issues [928].
+Similarly, preliminary findings indicate that nutritional status (e.g., vitamin D deficiency [720]) may be associated with COVID-19 outcomes, and reduced access to grocery stores and fresh food often co-occurs with environmental racism [928,979].
Taken together, the evidence suggests that low-income workers who face greater exposure to SARS-CoV-2 due to their home or work conditions are also more likely to face environmental and social stressors associated with increased inflammation, and therefore with increased risk from COVID-19.
In particular, structural racism can play an important role on disease severity after SARS-CoV-2 exposure, due to consequences of racism which include an increased likelihood of poverty and its associated food and housing instability.
-COVID-19 can thus be considered a “syndemic”, or a synergistic interaction between several epidemics [979].
+COVID-19 can thus be considered a “syndemic”, or a synergistic interaction between several epidemics [980].
As a result, it is not surprising that people from minoritized backgrounds and/or with certain pre-existing conditions are more likely to suffer severe effects of COVID-19, but these “risk factors” are likely to be causally linked to poverty.
8.3.3 Access to Treatment
Finally, COVID-19 outcomes can be influenced by access to healthcare.
Receiving care for COVID-19 can, but does not always, include receiving a positive test for the SARS-CoV-2 virus.
-For example, it is common to see treatment guidelines for suspected cases regardless of whether the presence of SARS-CoV-2 has been confirmed (e.g., [980]).
+For example, it is common to see treatment guidelines for suspected cases regardless of whether the presence of SARS-CoV-2 has been confirmed (e.g., [981]).
Whether and where a patient is diagnosed can depend on their access to testing, which can vary both between and within countries.
-In the United States, it is not always clear whether an individual will have access to free testing [981,982].
-The concern has been raised that more economic privilege is likely to correspond to increased access to testing, at least within the United States [983].
-This is supported by the fact that African Americans seem to be more likely to be diagnosed in the hospital, while individuals from other groups were more likely to have been diagnosed in ambulatory settings in the community [898].
-Any delays in treatment are a cause for concern [983], which could potentially be increased by an inability to acquire testing because in the United States, insurance coverage for care received can depend on a positive test [984].
+In the United States, it is not always clear whether an individual will have access to free testing [982,983].
+The concern has been raised that more economic privilege is likely to correspond to increased access to testing, at least within the United States [984].
+This is supported by the fact that African Americans seem to be more likely to be diagnosed in the hospital, while individuals from other groups were more likely to have been diagnosed in ambulatory settings in the community [899].
+Any delays in treatment are a cause for concern [984], which could potentially be increased by an inability to acquire testing because in the United States, insurance coverage for care received can depend on a positive test [985].
Another important question is whether patients with moderate to severe cases are able to access hospital facilities and treatments, to the extent that they have been identified.
-Early findings from China as of February 2020 suggested the COVID-19 mortality rate to be much lower in the most developed regions of the country [985], although reported mortality is generally an estimate of CFR, which is dependent on rates of testing.
-Efforts to make treatment accessible for all confirmed and suspected cases of COVID-19 in China are credited with expanding care to people with fewer economic resources [986].
-In the United States, access to healthcare varies widely, with certain sectors of the workforce less likely to have health insurance; many essential workers in transportation, food service, and other frontline fields are among those likely to be uninsured or underinsured [983].
-As of 2018, Hispanic Americans of all races were much less likely to have health insurance than people from non-Hispanic backgrounds [987].
+Early findings from China as of February 2020 suggested the COVID-19 mortality rate to be much lower in the most developed regions of the country [986], although reported mortality is generally an estimate of CFR, which is dependent on rates of testing.
+Efforts to make treatment accessible for all confirmed and suspected cases of COVID-19 in China are credited with expanding care to people with fewer economic resources [987].
+In the United States, access to healthcare varies widely, with certain sectors of the workforce less likely to have health insurance; many essential workers in transportation, food service, and other frontline fields are among those likely to be uninsured or underinsured [984].
+As of 2018, Hispanic Americans of all races were much less likely to have health insurance than people from non-Hispanic backgrounds [988].
Therefore, access to diagnostics and care prior to the development of severe COVID-19 is likely to vary depending on socioeconomic and social factors, many of which overlap with the risks of exposure and of developing more severe COVID-19 symptoms.
This discrepancy ties into concerns about broad infrastructural challenges imposed by COVID-19.
-A major concern in many countries has been the saturation of healthcare systems due to the volume of COVID-19 hospitalizations (e.g., [240]).
-Similarly, there have been shortages of supplies such as ventilators that are critical to the survival of many COVID-19 patients, leading to extensive ethical discussions about how to allocate limited resources among patients [988,989,990,991].
-Although it is generally considered unethical to consider demographic factors such as age, sex, race, or ethnicity while making such decisions, and ideally this information would not be shared with triage teams tasked with allocating limited resources among patients [992], there are substantial concerns about implicit and explicit biases against older adults [993], premature infants [994], and people with disabilities or comorbidities [992,995,996].
-Because of the greater burden of chronic disease in populations subjected to systemic racism, algorithms intended to be blind to race and ethnicity could, in fact, reinforce systemic inequalities caused by structural racism [997,998,999].
-Because of this inequality, it has been argued that groups facing health disparities should be prioritized by these algorithms [1000].
-This approach would carry its own ethical concerns, including the fact that many resources that need to be distributed do not have well-established risks and benefits [1000].
-As the pandemic has progressed, it has become clear that ICU beds and ventilators are not the only limited resources that needs to be allocated, and, in fact, the survival rate for patients who receive mechanical ventilation is lower than these discussions would suggest [1001].
-Allocation of interventions that may reduce suffering, including palliative care, has become critically important [1001,1002].
-The ambiguities surrounding the risks and benefits associated with therapeutics that have been approved under emergency use authorizations also present ethical concerns related to the distribution of resources [1000].
-For example, remdesivir, discussed above, is currently available for the treatment of COVID-19 under compassionate use guidelines and through expanded access programs, and in many cases has been donated to hospitals by Gilead [1003,1004].
-Regulations guiding the distribution of drugs in situations like these typically do not address how to determine which patients receive them [1004].
-Prioritizing marginalized groups for treatment with a drug like remdesivir would also be unethical because it would entail disproportionately exposing these groups to a therapeutic that may or not be beneficial [1000].
+A major concern in many countries has been the saturation of healthcare systems due to the volume of COVID-19 hospitalizations (e.g., [242]).
+Similarly, there have been shortages of supplies such as ventilators that are critical to the survival of many COVID-19 patients, leading to extensive ethical discussions about how to allocate limited resources among patients [989,990,991,992].
+Although it is generally considered unethical to consider demographic factors such as age, sex, race, or ethnicity while making such decisions, and ideally this information would not be shared with triage teams tasked with allocating limited resources among patients [993], there are substantial concerns about implicit and explicit biases against older adults [994], premature infants [995], and people with disabilities or comorbidities [993,996,997].
+Because of the greater burden of chronic disease in populations subjected to systemic racism, algorithms intended to be blind to race and ethnicity could, in fact, reinforce systemic inequalities caused by structural racism [998,999,1000].
+Because of this inequality, it has been argued that groups facing health disparities should be prioritized by these algorithms [1001].
+This approach would carry its own ethical concerns, including the fact that many resources that need to be distributed do not have well-established risks and benefits [1001].
+As the pandemic has progressed, it has become clear that ICU beds and ventilators are not the only limited resources that needs to be allocated, and, in fact, the survival rate for patients who receive mechanical ventilation is lower than these discussions would suggest [1002].
+Allocation of interventions that may reduce suffering, including palliative care, has become critically important [1002,1003].
+The ambiguities surrounding the risks and benefits associated with therapeutics that have been approved under emergency use authorizations also present ethical concerns related to the distribution of resources [1001].
+For example, remdesivir, discussed above, is currently available for the treatment of COVID-19 under compassionate use guidelines and through expanded access programs, and in many cases has been donated to hospitals by Gilead [1004,1005].
+Regulations guiding the distribution of drugs in situations like these typically do not address how to determine which patients receive them [1005].
+Prioritizing marginalized groups for treatment with a drug like remdesivir would also be unethical because it would entail disproportionately exposing these groups to a therapeutic that may or not be beneficial [1001].
On the other hand, given that the drug is one of the most promising treatments available for many patients, using a framework that tacitly feeds into structural biases would also be unethical.
-At present, the report prepared for the Director of the CDC by Ethics Subcommittee of the CDC fails to address the complexity of this ethical question given the state of structural racism in the United States, instead stating that “prioritizing individuals according to their chances for short-term survival also avoids ethically irrelevant considerations, such as race or socioeconomic status” [1005].
-In many cases, experimental therapeutics are made available only through participation in clinical trials [1006].
-However, given the history of medical trials abusing minority communities, especially Black Americans, there is a history of unequal representation in clinical trial enrollment [1006].
+At present, the report prepared for the Director of the CDC by Ethics Subcommittee of the CDC fails to address the complexity of this ethical question given the state of structural racism in the United States, instead stating that “prioritizing individuals according to their chances for short-term survival also avoids ethically irrelevant considerations, such as race or socioeconomic status” [1006].
+In many cases, experimental therapeutics are made available only through participation in clinical trials [1007].
+However, given the history of medical trials abusing minority communities, especially Black Americans, there is a history of unequal representation in clinical trial enrollment [1007].
As a result, the standard practice of requiring enrollment in a clinical trial in order to receive experimental treatment may also reinforce patterns established by systemic racism.
8.3.4 Access to and Representation in Clinical Trials
@@ -2999,7 +3000,7 @@ [1007]
.
+The WHO Director‐General Tedros Adhanom Ghebreyesus stated his condemnation of utilizing low and middle income countries as test subjects for clinical trials, yet having highly developed countries as the majority of clinical trial representation is also not the answer [1008].
Figure 6 showcases two choropleths detailing COVID-19 clinical trial recruitment by country.
China, the United States, and France are among the countries with the most clinical trial recruiting for trials with single-country enrollment.
Many countries have little to no clinical trial recruiting, with the continents of Africa and South America much less represented than Asia, Europe, and North America.
@@ -3008,46 +3009,46 @@
Figure 6: Geographic distribution of COVID-19 clinical trials.
The density of clinical trials is reported at the country level.
-As of November 9, 2020, there are 6,417 trials in the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [371].
+As of November 9, 2020, there are 6,417 trials in the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [372].
The top figure demonstrates the density of trials recruiting only from a singular country, while the bottom shows the distribution of recruitment for trials that involve more than one country.
A few different concerns arise from this skewed geographic representation in clinical trial recruitment.
First, treatments such as remdesivir that are promising but primarily available to clinical trial participants are unlikely to be accessible by people in many countries.
Second, it raises the concern that the findings of clinical trials will be based on participants from many of the wealthiest countries, which may lead to ambiguity in whether the findings can be extrapolated to COVID-19 patients elsewhere.
-Especially with the global nature of COVID-19, equitable access to therapeutics and vaccines has been a concern at the forefront of many discussions about policy (e.g., [1008], yet data like that shown in Figure 6 demonstrates that accessibility is likely to be a significant issue.
-Another concern with the heterogeneous international distribution of clinical trials is that the governments of countries leading these clinical trials might prioritize their own populations once vaccines are developed, causing unequal health outcomes [1009].
-Additionally, even within a single state in the United States (Maryland), geography was found to influence the likelihood of being recruited into or enrolled in a clinical trial, with patients in under-served rural areas less likely to enroll [1010].
+Especially with the global nature of COVID-19, equitable access to therapeutics and vaccines has been a concern at the forefront of many discussions about policy (e.g., [1009], yet data like that shown in Figure 6 demonstrates that accessibility is likely to be a significant issue.
+Another concern with the heterogeneous international distribution of clinical trials is that the governments of countries leading these clinical trials might prioritize their own populations once vaccines are developed, causing unequal health outcomes [1010].
+Additionally, even within a single state in the United States (Maryland), geography was found to influence the likelihood of being recruited into or enrolled in a clinical trial, with patients in under-served rural areas less likely to enroll [1011].
Thus, geography both on the global and local levels may influence when treatments and vaccines are available and who is able to access them.
-Efforts such as the African Union’s efforts to coordinate and promote vaccine development [1011] are therefore critical to promoting equity in the COVID-19 response.
+Efforts such as the African Union’s efforts to coordinate and promote vaccine development [1012] are therefore critical to promoting equity in the COVID-19 response.
Even when patients are located within the geographic recruitment area of clinical trials, however, there can still be demographic inequalities in enrollment.
-When efforts are made to ensure equal opportunity to participate in clinical trials, there is no significant difference in participation among racial/ethnic groups [1012].
-However, within the United States, real clinical trial recruitment numbers have indicated for many years that racial minorities, especially African-Americans, tend to be under-represented (e.g., [1013,1014,1015,1016]).
+When efforts are made to ensure equal opportunity to participate in clinical trials, there is no significant difference in participation among racial/ethnic groups [1013].
+However, within the United States, real clinical trial recruitment numbers have indicated for many years that racial minorities, especially African-Americans, tend to be under-represented (e.g., [1014,1015,1016,1017]).
This trend is especially concerning given the disproportionate impact of COVID-19 on African-Americans.
-Early evidence suggests that the proportion of Black, Latinx, and Native American participants in clinical trials for drugs such as remdesivir is much lower than the representation of these groups among COVID-19 patients [1017].
+Early evidence suggests that the proportion of Black, Latinx, and Native American participants in clinical trials for drugs such as remdesivir is much lower than the representation of these groups among COVID-19 patients [1018].
One proposed explanation for differences among racial and ethnic groups in clinical trial enrollment refers to different experiences in healthcare settings.
-While some plausible reasons for the disparity in communication between physicians and patients could be a lack of awareness and education, mistrust in healthcare professionals, and a lack of health insurance [1012], a major concern is that patients from certain racial and ethnic groups are marginalized even while seeking healthcare.
-In the United States, many patients experience “othering” from physicians and other medical professionals due to their race or other external characteristics such as gender (e.g., [1018]).
+While some plausible reasons for the disparity in communication between physicians and patients could be a lack of awareness and education, mistrust in healthcare professionals, and a lack of health insurance [1013], a major concern is that patients from certain racial and ethnic groups are marginalized even while seeking healthcare.
+In the United States, many patients experience “othering” from physicians and other medical professionals due to their race or other external characteristics such as gender (e.g., [1019]).
Many studies have sought to characterize implicit biases in healthcare providers and whether they affect their perceptions or treatment of patients.
-A systematic review that examined 37 such studies reported that most (31) identified racial and/or ethnic biases in healthcare providers in many different roles, although the evidence about whether these biases translated to different attitudes towards patients was mixed [1019], with similar findings reported by a second systematic review [1020].
-However, data about real-world patient outcomes are very limited, with most studies relying on clinical vignette-based exercises [1019], and other analyses suggest that physician implicit bias could impact the patient’s perception of the negativity/positivity of the interaction regardless of the physician’s explicit behavior towards the patient [1021].
-Because racism is a common factor in both, negative patient experiences with medical professionals are likely to compound other issues of systemic inequality, such as a lack of access to adequate care, a lack of insurance, or increased exposure to SARS-CoV-2 [1022].
+A systematic review that examined 37 such studies reported that most (31) identified racial and/or ethnic biases in healthcare providers in many different roles, although the evidence about whether these biases translated to different attitudes towards patients was mixed [1020], with similar findings reported by a second systematic review [1021].
+However, data about real-world patient outcomes are very limited, with most studies relying on clinical vignette-based exercises [1020], and other analyses suggest that physician implicit bias could impact the patient’s perception of the negativity/positivity of the interaction regardless of the physician’s explicit behavior towards the patient [1022].
+Because racism is a common factor in both, negative patient experiences with medical professionals are likely to compound other issues of systemic inequality, such as a lack of access to adequate care, a lack of insurance, or increased exposure to SARS-CoV-2 [1023].
Furthermore, the experience of being othered is not only expected to impact patients’ trust in and comfort with their provider, but also may directly impact whether or not the patient is offered the opportunity to participate in a clinical trial at all.
Some studies suggest communication between physicians and patients impacts whether or not a physician offers a patient participation in a clinical trial.
-For example, researchers utilized a linguistic analysis to assess mean word count of phrases related to clinical trial enrollment, such as voluntary participation, clinical trial, etc. [1012].
+For example, researchers utilized a linguistic analysis to assess mean word count of phrases related to clinical trial enrollment, such as voluntary participation, clinical trial, etc. [1013].
The data indicated that the mean word count of the entire visit was 1.5 times more for white patients in comparison to Black patients.
-In addition, the greatest disparity between white and Black patients’ experience was the discussion of risks, with over 2 times as many risk-related words spoken with white patients than Black patients [1012].
+In addition, the greatest disparity between white and Black patients’ experience was the discussion of risks, with over 2 times as many risk-related words spoken with white patients than Black patients [1013].
The trends observed for other clinical trials raise the concern that COVID-19 clinical trial information may not be discussed as thoroughly or as often with Black patients compared to white patients.
These discrepancies are especially concerning given that many COVID-19 treatments are being or are considered being made available to patients prior to FDA approval through Emergency Use Authorizations.
-In the past, African-Americans have been over-represented relative to national demographics in use of the FDA’s Exception From Informed Consent (EFIC) pathway [1023].
+In the past, African-Americans have been over-represented relative to national demographics in use of the FDA’s Exception From Informed Consent (EFIC) pathway [1024].
Through this pathway, people who are incapacitated can receive an experimental treatment even if they are not able to consent and there is not sufficient time to seek approval from an authorized representative.
-This pathway presents concerns, however, when it is considered in the context of a long history of systematic abuses in medical experimentation where informed consent was not obtained from people of color, such as the Tuskegee syphilis experiments [1024].
+This pathway presents concerns, however, when it is considered in the context of a long history of systematic abuses in medical experimentation where informed consent was not obtained from people of color, such as the Tuskegee syphilis experiments [1025].
While the goal of EFIC approval is to provide treatment to patients who urgently need it, the combination of the ongoing legacy of racism in medicine renders this trend concerning.
-With COVID-19, efforts to prioritize people who suffer from systemic racism are often designed with the goal of righting some of these inequalities (e.g., [1025]), but particular attention to informed consent will be imperative in ensuring these trials are ethical given that the benefits and risks of emerging treatments are still poorly characterized.
+With COVID-19, efforts to prioritize people who suffer from systemic racism are often designed with the goal of righting some of these inequalities (e.g., [1026]), but particular attention to informed consent will be imperative in ensuring these trials are ethical given that the benefits and risks of emerging treatments are still poorly characterized.
Making a substantial effort to run inclusive clinical trials is also important because of the possibility that racism could impact how a patient responds to a treatment.
For example, as discussed above, dexamethasone has been identified as a promising treatment for patients experiencing cytokine release syndrome, but the mechanism of action is tied to the stress response.
-A study from 2005 reported that Black asthma patients showed reduced responsiveness to dexamethasone in comparison to white patients and suggested Black patients might therefore require higher doses of the drug [1026].
-In the context of chronic stress caused by systemic racism, this result is not surprising: chronic stress is associated with dysregulated production of glucocorticoids [1027] and glucocorticoid receptor resistance [1028].
+A study from 2005 reported that Black asthma patients showed reduced responsiveness to dexamethasone in comparison to white patients and suggested Black patients might therefore require higher doses of the drug [1027].
+In the context of chronic stress caused by systemic racism, this result is not surprising: chronic stress is associated with dysregulated production of glucocorticoids [1028] and glucocorticoid receptor resistance [1029].
However, it underscores the critical need for treatment guidelines to take into account differences in life experience, which would be facilitated by the recruitment of patients from a wide range of backgrounds.
Attention to the social aspects of clinical trial enrollment must therefore be an essential component of the medical research community’s response to COVID-19.
-Our primary goal is to sort and distill informative content out of the overwhelming flood of information [5] and help the broader scientific community become more conversant on this critical subject.
+Our primary goal is to sort and distill informative content out of the overwhelming flood of information [7] and help the broader scientific community become more conversant on this critical subject.
Thus, our approach has been to develop a real-time, collaborative effort that welcomes submissions from scientists worldwide into this ongoing effort.
This document represents the first snapshot, which aims to reflect the state of the field as of October, 2020.
We plan to refine and expand this document until technologies to mitigate the pandemic are widely available.
-In an effort to keep pace as new information about COVID-19 and SARS-CoV-2 becomes available, this project is an open, collaborative effort that invited contributions from the scientific community broadly, similar to previous efforts to develop collaborative reviews [1029,1030].
+
In an effort to keep pace as new information about COVID-19 and SARS-CoV-2 becomes available, this project is an open, collaborative effort that invited contributions from the scientific community broadly, similar to previous efforts to develop collaborative reviews [1030,1031].
Contributors were recruited by word of mouth and on Twitter.
-Existing efforts to train early-career scientists were also integrated: Appendix A contains summaries written by the students, post-docs, and faculty of the Immunology Institute at the Mount Sinai School of Medicine [1031,1032], and two of the authors were recruited through the American Physician Scientist Association’s Virtual Summer Research Program [1033].
-The project was managed through GitHub [1034] using Manubot [6] to continuously generate a version of the manuscript online [1035].
+Existing efforts to train early-career scientists were also integrated: Appendix A contains summaries written by the students, post-docs, and faculty of the Immunology Institute at the Mount Sinai School of Medicine [1032,1033], and two of the authors were recruited through the American Physician Scientist Association’s Virtual Summer Research Program [1034].
+The project was managed through GitHub [1035] using Manubot [8] to continuously generate a version of the manuscript online [1036].
Contributors developed text that was proposed through GitHub’s pull request system and then reviewed and approved by at least one other author.
While this document reflects the current version of record, the online version will continue to be developed as information about the pandemic emerges.
Below, we will describe the processes used to synthesize the literature.
10.3 Technical Infrastructure
10.3.1 Collaborative Writing and Manuscript Generation
-Manubot [6] is a collaborative framework developed to adapt open-source software development techniques and version control for manuscript writing.
+
Manubot [8] is a collaborative framework developed to adapt open-source software development techniques and version control for manuscript writing.
Here, Manubot was used to generate a manuscript from text maintained using GitHub, a popular, online version control interface.
The GitHub implementation allowed users to contribute either using git on the command line or using the GitHub user interface, and we developed documentation for users with less experience with this platform.
Manubot also provides a functionality to create a bibliography using digital object identifiers (DOIs), website URLs, or other identifiers such as PubMed identifiers and arXiv IDs.
Due to the needs of this project, project contributors also implemented new features in Manubot and Zotero, which Manubot uses to extract metadata for some types of citations.
-These features support directly citing clinical trial identifiers such as clinicaltrials:NCT04292899 [399] and generating the complete review manuscript along with the individual manuscripts reviewing specific topics.
+These features support directly citing clinical trial identifiers such as clinicaltrials:NCT04292899 [400] and generating the complete review manuscript along with the individual manuscripts reviewing specific topics.
Finally, Manubot and GitHub Actions continuous integration allowed for scripted updates to be run each time the manuscript was generated.
These scripts were used to check that the manuscript was built correctly, run spellchecking, and cross-reference the manuscripts cited in this review, summarized in Appendix A, and discussed in the project’s issues and pull requests.
10.3.2 Data Analysis and Visualization
The combination of Manubot and GitHub Actions also made it possible to dynamically update information such as statistics and visualizations in the manuscript.
-Data about worldwide cases and deaths from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [368] were read using a Python script.
-Similarly, the clinical trials statistics and figure were generated based on data from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [371].
-In both cases, frequency data were plotted using Matplotlib [1036] in Python.
+Data about worldwide cases and deaths from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [369] were read using a Python script.
+Similarly, the clinical trials statistics and figure were generated based on data from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [372].
+In both cases, frequency data were plotted using Matplotlib [1037] in Python.
The figure showing the geographic distribution of COVID-19 clinical trials was generated using the countries associated with the trials listed in the COVID-19 TrialsTracker, converting the country names to 3-letter ISO codes using pycountry or manual adjustment when necessary, and visualizing the geographic distribution of trial recruitment using geopandas.
GitHub Actions runs a nightly workflow to update these external data and regenerate the statistics and figures for the manuscript.
The workflow uses the GitHub API to detect and save the latest commit of the external data sources, which are both GitHub repositories.
@@ -3202,7 +3203,7 @@
10.4 Article Selection and Evaluation
Relevant articles were identified and submitted as issues on GitHub for review.
Articles were classified as diagnostic, therapeutic, or other, and a template was developed to guide the review of papers and preprints in each category.
-Following a framework often used for assessing medical literature, the review consisted of examining methods used in each relevant article, assignment (whether the study was observational or randomized), assessment, results, interpretation, and how well the study extrapolates [1037].
+Following a framework often used for assessing medical literature, the review consisted of examining methods used in each relevant article, assignment (whether the study was observational or randomized), assessment, results, interpretation, and how well the study extrapolates [1038].
For examples of each template, please see Appendices B-D.
10.4.1 Diagnostic Papers
10.4.1.1 Methods
@@ -3245,15 +3246,15 @@ 10.4.2.6 Extrapolation
Reviewers describe how the study may extrapolate to a different species or population.
-10.5 Conclusions
+10.5 Conclusions
Figure 7: Summary of the relationships among topics covered in this review.
Several review articles on aspects of COVID-19 have already been published.
-These have included reviews on the disease epidemiology [38], immunological response [39], diagnostics [40], and pharmacological treatments [39,41].
-Others [42,43] provide narrative reviews of progress on some important ongoing COVID-19 research questions.
+These have included reviews on the disease epidemiology [40], immunological response [41], diagnostics [42], and pharmacological treatments [41,43].
+Others [44,45] provide narrative reviews of progress on some important ongoing COVID-19 research questions.
With the worldwide scientific community uniting during 2020 to investigate SARS-CoV-2 and COVID-19 from a wide range of perspectives, findings from many disciplines are relevant on a rapid timescale to a broad scientific audience.
Additionally, many findings are published as preprints, which are available prior to going through the peer review process.
As a result, centralizing, summarizing, and critiquing new literature broadly relevant to COVID-19 can help to expedite the interdisciplinary scientific process that is currently happening at an advanced pace.
@@ -3724,6631 +3725,6636 @@
12 References
+
+1. Pathogenesis, Symptomatology, and Transmission of SARS-CoV-2 through analysis of Viral Genomics and Structure
+Halie M. Rando, Adam L. MacLean, Alexandra J. Lee, Sandipan Ray, Vikas Bansal, Ashwin N. Skelly, Elizabeth Sell, John J. Dziak, Lamonica Shinholster, Lucy D’Agostino McGowan, … Casey S. Greene
+arXiv (2021-02-03) https://arxiv.org/abs/2102.01521
+
+
+2. Dietary Supplements and Nutraceuticals Under Investigation for COVID-19 Prevention and Treatment
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Serina Chang, Emma Pierson, Pang Wei Koh, Jaline Gerardin, Beth Redbird, David Grusky, Jure Leskovec
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978. Early life stress, air pollution, inflammation, and disease: An integrative review and immunologic model of social-environmental adversity and lifespan health
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Matthew J. Belanger, Michael A. Hill, Angeliki M. Angelidi, Maria Dalamaga, James R. Sowers, Christos S. Mantzoros
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980. Systemic racism, chronic health inequities, and ‐19: A syndemic in the making?
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Yunpeng Ji, Zhongren Ma, Maikel P Peppelenbosch, Qiuwei Pan
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987. Combating COVID-19: health equity matters
Zhicheng Wang, Kun Tang
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Dumache Raluca, Ciocan Veronica, Muresan Camelia Oana, Enache Alexandra
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John Raffensperger, Marygail Brauner, R. Briggs
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Quyen Chu, Ricardo Correa, Tracey L. Henry, Kyle A. McGregor, Hanni Stoklosa, Loren Robinson, Sachin Jha, Alagappan Annamalai, Benson S. Hsu, Rohit Gupta, … SreyRam Kuy
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Maya Sabatello, Teresa Blankmeyer Burke, Katherine E. McDonald, Paul S. Appelbaum
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Leonard E. Egede, Rebekah J. Walker
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1001. Allocating Remdesivir Under Scarcity: Social Justice or More Systemic Racism
Eli Weber, Mark J. Bliton
The American Journal of Bioethics (2020-08-25) https://doi.org/ghfprf
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Angela Ballantyne, Wendy A Rogers, Vikki Entwistle, Cindy Towns
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Aisha T. Langford, Ken Resnicow, Eileen P. Dimond, Andrea M. Denicoff, Diane St. Germain, Worta McCaskill-Stevens, Rebecca A. Enos, Angela Carrigan, Kathy Wilkinson, Ronald S. Go
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John H. Stewart, Alain G. Bertoni, Jennifer L. Staten, Edward A. Levine, Cary P. Gross
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Stacie E. Geller, Abby Koch, Beth Pellettieri, Molly Carnes
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Titilola Falasinnu, Yashaar Chaichian, Michelle B. Bass, Julia F. Simard
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Daniel B. Chastain, Sharmon P. Osae, Andrés F. Henao-Martínez, Carlos Franco-Paredes, Joeanna S. Chastain, Henry N. Young
New England Journal of Medicine (2020-08-27) https://doi.org/gg7vcf
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Joy L. Johnson, Joan L. Bottorff, Annette J. Browne, Sukhdev Grewal, B. Ann Hilton, Heather Clarke
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Ivy W. Maina, Tanisha D. Belton, Sara Ginzberg, Ajit Singh, Tiffani J. Johnson
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Erin Dehon, Nicole Weiss, Jonathan Jones, Whitney Faulconer, Elizabeth Hinton, Sarah Sterling
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Louis A. Penner, John F. Dovidio, Tessa V. West, Samuel L. Gaertner, Terrance L. Albrecht, Rhonda K. Dailey, Tsveti Markova
Journal of Experimental Social Psychology (2010-03) https://doi.org/dc5342
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Tiffani J. Johnson
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1024. A Systematic Review Of The Food And Drug Administration’s “Exception From Informed Consent” Pathway
William B. Feldman, Spencer Phillips Hey, Aaron S. Kesselheim
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Terri A. Schmidt
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Sarah Al-Arshani
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Monica J. Federico, Ronina A. Covar, Eleanor E. Brown, Donald Y. M. Leung, Joseph D. Spahn
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Evangelia Charmandari, Constantine Tsigos, George Chrousos
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S. Cohen, D. Janicki-Deverts, W. J. Doyle, G. E. Miller, E. Frank, B. S. Rabin, R. B. Turner
Proceedings of the National Academy of Sciences (2012-04-02) https://doi.org/f4n6r8
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-1029. Opportunities and obstacles for deep learning in biology and medicine
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1030. Opportunities and obstacles for deep learning in biology and medicine
Travers Ching, Daniel S. Himmelstein, Brett K. Beaulieu-Jones, Alexandr A. Kalinin, Brian T. Do, Gregory P. Way, Enrico Ferrero, Paul-Michael Agapow, Michael Zietz, Michael M. Hoffman, … Casey S. Greene
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Casey S. Greene, Daniel S. Himmelstein, Daniel C. Elton, Brock C. Christensen, Anthony Gitter, Alexander J. Titus, Joshua J. Levy
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Human Immune Monitoring Center at Mount Sinai
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1033. Advancing scientific knowledge in times of pandemics
Nicolas Vabret, Robert Samstein, Nicolas Fernandez, Miriam Merad, The Sinai Immunology Review Project, Trainees, Faculty
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1036. SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics
Halie M. Rando, Casey S. Greene, Michael P. Robson, Simina M. Boca, Nils Wellhausen, Ronan Lordan, Christian Brueffer, Sandipan Ray, Lucy D\’Agostino McGowan, Anthony Gitter, … Rishi Raj Goel
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John D. Hunter
Computing in Science & Engineering (2007) https://doi.org/drbjhg
DOI: 10.1109/mcse.2007.55
-1037. Using the MAARIE Framework To Read the Research Literature
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1038. Using the MAARIE Framework To Read the Research Literature
M. Corcoran
American Journal of Occupational Therapy (2006-07-01) https://doi.org/bqh97x
DOI: 10.5014/ajot.60.4.367 · PMID: 16915865
-1038. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody
+
1039. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody
Xiaolong Tian, Cheng Li, Ailing Huang, Shuai Xia, Sicong Lu, Zhengli Shi, Lu Lu, Shibo Jiang, Zhenlin Yang, Yanling Wu, Tianlei Ying
Cold Spring Harbor Laboratory (2020-01-28) https://doi.org/ggjqfd
DOI: 10.1101/2020.01.28.923011
-1039. Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of 2019-nCoV
+
1040. Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of 2019-nCoV
Xiang He, Lei Zhang, Qin Ran, Junyi Wang, Anying Xiong, Dehong Wu, Feng Chen, Guoping Li
Cold Spring Harbor Laboratory (2020-02-05) https://doi.org/ggrbd8
DOI: 10.1101/2020.02.03.20020206
-1040. Diarrhea may be underestimated: a missing link in 2019 novel coronavirus
+
1041. Diarrhea may be underestimated: a missing link in 2019 novel coronavirus
Weicheng Liang, Zhijie Feng, Shitao Rao, Cuicui Xiao, Ze-Xiao Lin, Qi Zhang, Qi Wei
Cold Spring Harbor Laboratory (2020-02-17) https://doi.org/ggrbdw
DOI: 10.1101/2020.02.03.20020289
-1041. Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection
+
1042. Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection
Xiaoqiang Chai, Longfei Hu, Yan Zhang, Weiyu Han, Zhou Lu, Aiwu Ke, Jian Zhou, Guoming Shi, Nan Fang, Jia Fan, … Fei Lan
Cold Spring Harbor Laboratory (2020-02-04) https://doi.org/ggq626
DOI: 10.1101/2020.02.03.931766
-1042. Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids
+
1043. Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids
Bing Zhao, Chao Ni, Ran Gao, Yuyan Wang, Li Yang, Jinsong Wei, Ting Lv, Jianqing Liang, Qisheng Zhang, Wei Xu, … Xinhua Lin
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq648
DOI: 10.1101/2020.03.16.990317
-1043. ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism
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1044. ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism
Jun Wang, Shanmeizi Zhao, Ming Liu, Zhiyao Zhao, Yiping Xu, Ping Wang, Meng Lin, Yanhui Xu, Bing Huang, Xiaoyu Zuo, … Yuxia Zhang
Cold Spring Harbor Laboratory (2020-02-07) https://doi.org/ggrfbx
DOI: 10.1101/2020.02.05.20020545
-1044. The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice
+
1045. The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice
Linlin Bao, Wei Deng, Baoying Huang, Hong Gao, Jiangning Liu, Lili Ren, Qiang Wei, Pin Yu, Yanfeng Xu, Feifei Qi, … Chuan Qin
Cold Spring Harbor Laboratory (2020-02-28) https://doi.org/dph2
DOI: 10.1101/2020.02.07.939389
-1045. Caution on Kidney Dysfunctions of COVID-19 Patients
+
1046. Caution on Kidney Dysfunctions of COVID-19 Patients
Zhen Li, Ming Wu, Jiwei Yao, Jie Guo, Xiang Liao, Siji Song, Jiali Li, Guangjie Duan, Yuanxiu Zhou, Xiaojun Wu, … Junan Yan
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq627
DOI: 10.1101/2020.02.08.20021212
-1046. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome
+
1047. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome
Kwok Hong Chu, Wai Kay Tsang, Colin S. Tang, Man Fai Lam, Fernand M. Lai, Ka Fai To, Ka Shun Fung, Hon Lok Tang, Wing Wa Yan, Hilda W. H. Chan, … Kar Neng Lai
Kidney International (2005-02) https://doi.org/b7tgtx
DOI: 10.1111/j.1523-1755.2005.67130.x · PMID: 15673319 · PMCID: PMC7112337
-1047. Single-cell Analysis of ACE2 Expression in Human Kidneys and Bladders Reveals a Potential Route of 2019-nCoV Infection
+
1048. Single-cell Analysis of ACE2 Expression in Human Kidneys and Bladders Reveals a Potential Route of 2019-nCoV Infection
Wei Lin, Longfei Hu, Yan Zhang, Joshua D. Ooi, Ting Meng, Peng Jin, Xiang Ding, Longkai Peng, Lei Song, Zhou Xiao, … Yong Zhong
Cold Spring Harbor Laboratory (2020-02-18) https://doi.org/ggq629
DOI: 10.1101/2020.02.08.939892
-1048. The immune vulnerability landscape of the 2019 Novel Coronavirus, SARS-CoV-2
+
1049. The immune vulnerability landscape of the 2019 Novel Coronavirus, SARS-CoV-2
James Zhu, Jiwoong Kim, Xue Xiao, Yunguan Wang, Danni Luo, Shuang Jiang, Ran Chen, Lin Xu, He Zhang, Lenny Moise, … Yang Xie
Cold Spring Harbor Laboratory (2020-09-04) https://doi.org/ggq628
DOI: 10.1101/2020.02.08.939553 · PMID: 32908981
-1049. Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection
+
1050. Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection
Yaseen M. Arabi, Ahmed A. Arifi, Hanan H. Balkhy, Hani Najm, Abdulaziz S. Aldawood, Alaa Ghabashi, Hassan Hawa, Adel Alothman, Abdulaziz Khaldi, Basel Al Raiy
Annals of Internal Medicine (2014-03-18) https://doi.org/ggptxw
DOI: 10.7326/m13-2486 · PMID: 24474051
-1050. Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage
+
1051. Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage
Jingyuan Liu, Yao Liu, Pan Xiang, Lin Pu, Haofeng Xiong, Chuansheng Li, Ming Zhang, Jianbo Tan, Yanli Xu, Rui Song, … Xianbo Wang
Cold Spring Harbor Laboratory (2020-02-12) https://doi.org/ggrbdx
DOI: 10.1101/2020.02.10.20021584
-1051. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China
+
1052. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China
Chuan Qin, Luoqi Zhou, Ziwei Hu, Shuoqi Zhang, Sheng Yang, Yu Tao, Cuihong Xie, Ke Ma, Ke Shang, Wei Wang, Dai-Shi Tian
Clinical Infectious Diseases (2020-08-01) https://doi.org/ggpxcf
DOI: 10.1093/cid/ciaa248 · PMID: 32161940 · PMCID: PMC7108125
-1052. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)
+
1053. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)
Suxin Wan, Qingjie Yi, Shibing Fan, Jinglong Lv, Xianxiang Zhang, Lian Guo, Chunhui Lang, Qing Xiao, Kaihu Xiao, Zhengjun Yi, … Yongping Chen
Cold Spring Harbor Laboratory (2020-02-12) https://doi.org/ggq63b
DOI: 10.1101/2020.02.10.20021832
-1053. Longitudinal Characteristics of Lymphocyte Responses and Cytokine Profiles in the Peripheral Blood of SARS-CoV-2 Infected Patients
+
1054. Longitudinal Characteristics of Lymphocyte Responses and Cytokine Profiles in the Peripheral Blood of SARS-CoV-2 Infected Patients
Jing Liu, Sumeng Li, Jia Liu, Boyun Liang, Xiaobei Wang, Wei Li, Hua Wang, Qiaoxia Tong, Jianhua Yi, Lei Zhao, … Xin Zheng
SSRN Electronic Journal (2020) https://doi.org/ggq655
DOI: 10.2139/ssrn.3539682
-1054. Epidemiological and Clinical Characteristics of 17 Hospitalized Patients with 2019 Novel Coronavirus Infections Outside Wuhan, China
+
1055. Epidemiological and Clinical Characteristics of 17 Hospitalized Patients with 2019 Novel Coronavirus Infections Outside Wuhan, China
Jie Li, Shilin Li, Yurui Cai, Qin Liu, Xue Li, Zhaoping Zeng, Yanpeng Chu, Fangcheng Zhu, Fanxin Zeng
Cold Spring Harbor Laboratory (2020-02-12) https://doi.org/ggq63c
DOI: 10.1101/2020.02.11.20022053
-1055. ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection
+
1056. ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection
Caibin Fan, Kai Li, Yanhong Ding, Wei Lu, Jianqing Wang
Cold Spring Harbor Laboratory (2020-02-13) https://doi.org/ggq63d
DOI: 10.1101/2020.02.12.20022418
-1056. Aberrant pathogenic GM-CSF + T cells and inflammatory CD14 + CD16 + monocytes in severe pulmonary syndrome patients of a new coronavirus
+
1057. Aberrant pathogenic GM-CSF + T cells and inflammatory CD14 + CD16 + monocytes in severe pulmonary syndrome patients of a new coronavirus
Yonggang Zhou, Binqing Fu, Xiaohu Zheng, Dongsheng Wang, Changcheng Zhao, Yingjie qi, Rui Sun, Zhigang Tian, Xiaoling Xu, Haiming Wei
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggq63f
DOI: 10.1101/2020.02.12.945576
-1057. Clinical Characteristics of 2019 Novel Infected Coronavirus Pneumonia: A Systemic Review and Meta-analysis
+
1058. Clinical Characteristics of 2019 Novel Infected Coronavirus Pneumonia: A Systemic Review and Meta-analysis
Kai Qian, Yi Deng, Yong-Hang Tai, Jun Peng, Hao Peng, Li-Hong Jiang
Cold Spring Harbor Laboratory (2020-02-17) https://doi.org/ggrgbq
DOI: 10.1101/2020.02.14.20021535
-1058. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients
+
1059. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients
Jing Liu, Sumeng Li, Jia Liu, Boyun Liang, Xiaobei Wang, Hua Wang, Wei Li, Qiaoxia Tong, Jianhua Yi, Lei Zhao, … Xin Zheng
Cold Spring Harbor Laboratory (2020-02-22) https://doi.org/ggq63g
DOI: 10.1101/2020.02.16.20023671
-1059. Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019
+
1060. Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019
Guang Chen, Di Wu, Wei Guo, Yong Cao, Da Huang, Hongwu Wang, Tao Wang, Xiaoyun Zhang, Huilong Chen, Haijing Yu, … Qin Ning
Cold Spring Harbor Laboratory (2020-02-19) https://doi.org/ggq63h
DOI: 10.1101/2020.02.16.20023903
-1060. SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development
+
1061. SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development
Chunyun Sun, Long Chen, Ji Yang, Chunxia Luo, Yanjing Zhang, Jing Li, Jiahui Yang, Jie Zhang, Liangzhi Xie
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggq63j
DOI: 10.1101/2020.02.16.951723
-1061. Protection of Rhesus Macaque from SARS-Coronavirus challenge by recombinant adenovirus vaccine
+
1062. Protection of Rhesus Macaque from SARS-Coronavirus challenge by recombinant adenovirus vaccine
Yiyou Chen, Qiang Wei, Ruobing Li, Hong Gao, Hua Zhu, Wei Deng, Linlin Bao, Wei Tong, Zhe Cong, Hong Jiang, Chuan Qin
Cold Spring Harbor Laboratory (2020-02-21) https://doi.org/ggq63k
DOI: 10.1101/2020.02.17.951939
-1062. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)
+
1063. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)
Bo Diao, Chenhui Wang, Yingjun Tan, Xiewan Chen, Ying Liu, Lifen Ning, Li Chen, Min Li, Yueping Liu, Gang Wang, … Yongwen Chen
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggq63m
DOI: 10.1101/2020.02.18.20024364
-1063. Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China
+
1064. Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China
Xun Li, Luwen Wang, Shaonan Yan, Fan Yang, Longkui Xiang, Jiling Zhu, Bo Shen, Zuojiong Gong
Cold Spring Harbor Laboratory (2020-02-25) https://doi.org/ggq63n
DOI: 10.1101/2020.02.19.20025239
-1064. SARS-CoV-2 infection does not significantly cause acute renal injury: an analysis of 116 hospitalized patients with COVID-19 in a single hospital, Wuhan, China
+
1065. SARS-CoV-2 infection does not significantly cause acute renal injury: an analysis of 116 hospitalized patients with COVID-19 in a single hospital, Wuhan, China
Luwen Wang, Xun Li, Hui Chen, Shaonan Yan, Yan Li, Dong Li, Zuojiong Gong
Cold Spring Harbor Laboratory (2020-02-23) https://doi.org/ggq63p
DOI: 10.1101/2020.02.19.20025288
-1065. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China
+
1066. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China
Dawei Wang, Bo Hu, Chang Hu, Fangfang Zhu, Xing Liu, Jing Zhang, Binbin Wang, Hui Xiang, Zhenshun Cheng, Yong Xiong, … Zhiyong Peng
JAMA (2020-03-17) https://doi.org/ggkh48
DOI: 10.1001/jama.2020.1585 · PMID: 32031570 · PMCID: PMC7042881
-1066. Clinical characteristics of 2019 novel coronavirus infection in China
+
1067. Clinical characteristics of 2019 novel coronavirus infection in China
Wei-jie Guan, Zheng-yi Ni, Yu Hu, Wen-hua Liang, Chun-quan Ou, Jian-xing He, Lei Liu, Hong Shan, Chun-liang Lei, David S. C. Hui, … Nan-shan Zhong
Cold Spring Harbor Laboratory (2020-02-09) https://doi.org/ggkj9s
DOI: 10.1101/2020.02.06.20020974
-1067. Potential T-cell and B-cell Epitopes of 2019-nCoV
+
1068. Potential T-cell and B-cell Epitopes of 2019-nCoV
Ethan Fast, Russ B. Altman, Binbin Chen
Cold Spring Harbor Laboratory (2020-03-18) https://doi.org/ggq63q
DOI: 10.1101/2020.02.19.955484
-1068. Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein
+
1069. Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein
Alexandra C. Walls, Young-Jun Park, M. Alexandra Tortorici, Abigail Wall, Andrew T. McGuire, David Veesler
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggrgbr
DOI: 10.1101/2020.02.19.956581
-1069. Breadth of concomitant immune responses underpinning viral clearance and patient recovery in a non-severe case of COVID-19
+
1070. Breadth of concomitant immune responses underpinning viral clearance and patient recovery in a non-severe case of COVID-19
Irani Thevarajan, Thi HO Nguyen, Marios Koutsakos, Julian Druce, Leon Caly, Carolien E van de Sandt, Xiaoxiao Jia, Suellen Nicholson, Mike Catton, Benjamin Cowie, … Katherine Kedzierska
Cold Spring Harbor Laboratory (2020-02-23) https://doi.org/ggq63r
DOI: 10.1101/2020.02.20.20025841
-1070. The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing
+
1071. The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing
Minfeng Liao, Yang Liu, Jin Yuan, Yanling Wen, Gang Xu, Juanjuan Zhao, Lin Chen, Jinxiu Li, Xin Wang, Fuxiang Wang, … Zheng Zhang
Cold Spring Harbor Laboratory (2020-02-26) https://doi.org/ggq63s
DOI: 10.1101/2020.02.23.20026690
-1071. Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells
+
1072. Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells
Marlena Scharenberg, Sindhu Vangeti, Eliisa Kekäläinen, Per Bergman, Mamdoh Al-Ameri, Niclas Johansson, Klara Sondén, Sara Falck-Jones, Anna Färnert, Hans-Gustaf Ljunggren, … Nicole Marquardt
Frontiers in Immunology (2019-05-17) https://doi.org/ggq656
DOI: 10.3389/fimmu.2019.01116 · PMID: 31156653 · PMCID: PMC6534051
-1072. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
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1073. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
Chaolin Huang, Yeming Wang, Xingwang Li, Lili Ren, Jianping Zhao, Yi Hu, Li Zhang, Guohui Fan, Jiuyang Xu, Xiaoying Gu, … Bin Cao
The Lancet (2020-02) https://doi.org/ggjfnn
DOI: 10.1016/s0140-6736(20)30183-5
-1073. Alveolar Macrophages in the Resolution of Inflammation, Tissue Repair, and Tolerance to Infection
+
1074. Alveolar Macrophages in the Resolution of Inflammation, Tissue Repair, and Tolerance to Infection
Benoit Allard, Alice Panariti, James G. Martin
Frontiers in Immunology (2018-07-31) https://doi.org/gd3bnz
DOI: 10.3389/fimmu.2018.01777 · PMID: 30108592 · PMCID: PMC6079255
-1074. PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery following Respiratory Viral Infection
+
1075. PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery following Respiratory Viral Infection
Su Huang, Bibo Zhu, In Su Cheon, Nick P. Goplen, Li Jiang, Ruixuan Zhang, R. Stokes Peebles, Matthias Mack, Mark H. Kaplan, Andrew H. Limper, Jie Sun
Journal of Virology (2019-04-17) https://doi.org/ggq652
DOI: 10.1128/jvi.00030-19 · PMID: 30787149 · PMCID: PMC6475778
-1075. Can routine laboratory tests discriminate 2019 novel coronavirus infected pneumonia from other community-acquired pneumonia?
+
1076. Can routine laboratory tests discriminate 2019 novel coronavirus infected pneumonia from other community-acquired pneumonia?
Yunbao Pan, Guangming Ye, Xiantao Zeng, Guohong Liu, Xiaojiao Zeng, Xianghu Jiang, Jin Zhao, Liangjun Chen, Shuang Guo, Qiaoling Deng, … Xinghuan Wang
Cold Spring Harbor Laboratory (2020-02-25) https://doi.org/ggq63t
DOI: 10.1101/2020.02.25.20024711
-1076. Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia
+
1077. Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia
Jing Gong, Hui Dong, Qingsong Xia, Zhaoyi Huang, Dingkun Wang, Yan Zhao, Wenhua Liu, Shenghao Tu, Mingmin Zhang, Qi Wang, Fuer Lu
Cold Spring Harbor Laboratory (2020-02-26) https://doi.org/ggq63v
DOI: 10.1101/2020.02.25.20025643
-1077. An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors’ CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design
+
1078. An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors’ CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design
CV Herst, S Burkholz, J Sidney, A Sette, PE Harris, S Massey, T Brasel, E Cunha-Neto, DS Rosa, WCH Chao, … R Rubsamen
Cold Spring Harbor Laboratory (2020-04-06) https://doi.org/ggq63x
DOI: 10.1101/2020.02.25.963546
-1078. Epitope-based peptide vaccine design and target site characterization against novel coronavirus disease caused by SARS-CoV-2
+
1079. Epitope-based peptide vaccine design and target site characterization against novel coronavirus disease caused by SARS-CoV-2
Lin Li, Ting Sun, Yufei He, Wendong Li, Yubo Fan, Jing Zhang
Cold Spring Harbor Laboratory (2020-02-27) https://doi.org/ggnqwt
DOI: 10.1101/2020.02.25.965434
-1079. The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and Retrospective Analysis
+
1080. The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and Retrospective Analysis
Wang Wenjun, Liu Xiaoqing, Wu Sipei, Lie Puyi, Huang Liyan, Li Yimin, Cheng Linling, Chen Sibei, Nong Lingbo, Lin Yongping, He Jianxing
Cold Spring Harbor Laboratory (2020-02-27) https://doi.org/ggrgbs
DOI: 10.1101/2020.02.26.20026989
-1080. Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China
+
1081. Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China
Ying Huang, Rui Yang, Ying Xu, Ping Gong
Cold Spring Harbor Laboratory (2020-03-05) https://doi.org/ggq63z
DOI: 10.1101/2020.02.27.20029009
-1081. Risk factors related to hepatic injury in patients with corona virus disease 2019
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1082. Risk factors related to hepatic injury in patients with corona virus disease 2019
Lu Li, Shuang Li, Manman Xu, Pengfei Yu, Sujun Zheng, Zhongping Duan, Jing Liu, Yu Chen, Junfeng Li
Cold Spring Harbor Laboratory (2020-03-10) https://doi.org/ggq632
DOI: 10.1101/2020.02.28.20028514
-1082. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients
+
1083. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients
Xiaohua Chen, Binghong Zhao, Yueming Qu, Yurou Chen, Jie Xiong, Yong Feng, Dong Men, Qianchuan Huang, Ying Liu, Bo Yang, … Feng Li
Cold Spring Harbor Laboratory (2020-03-03) https://doi.org/ggq633
DOI: 10.1101/2020.02.29.20029520
-1083. Prognostic factors in the acute respiratory distress syndrome
+
1084. Prognostic factors in the acute respiratory distress syndrome
Wei Chen, Lorraine B Ware
Clinical and Translational Medicine (2015-07-02) https://doi.org/ggq653
DOI: 10.1186/s40169-015-0065-2 · PMID: 26162279 · PMCID: PMC4534483
-1084. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study
+
1085. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study
Li Tan, Qi Wang, Duanyang Zhang, Jinya Ding, Qianchuan Huang, Yi-Quan Tang, Qiongshu Wang, Hongming Miao
Cold Spring Harbor Laboratory (2020-03-03) https://doi.org/ggq634
DOI: 10.1101/2020.03.01.20029074
-1085. The potential role of IL-6 in monitoring severe case of coronavirus disease 2019
+
1086. The potential role of IL-6 in monitoring severe case of coronavirus disease 2019
Tao Liu, Jieying Zhang, Yuhui Yang, Hong Ma, Zhengyu Li, Jiaoyu Zhang, Ji Cheng, Xiaoyun Zhang, Yanxia Zhao, Zihan Xia, … Jianhua Yi
Cold Spring Harbor Laboratory (2020-03-10) https://doi.org/ggq635
DOI: 10.1101/2020.03.01.20029769
-1086. Clinical and Laboratory Profiles of 75 Hospitalized Patients with Novel Coronavirus Disease 2019 in Hefei, China
+
1087. Clinical and Laboratory Profiles of 75 Hospitalized Patients with Novel Coronavirus Disease 2019 in Hefei, China
Zonghao Zhao, Jiajia Xie, Ming Yin, Yun Yang, Hongliang He, Tengchuan Jin, Wenting Li, Xiaowu Zhu, Jing Xu, Changcheng Zhao, … Xiaoling Ma
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq636
DOI: 10.1101/2020.03.01.20029785
-1087. Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome
+
1088. Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome
Yang Yang, Chenguang Shen, Jinxiu Li, Jing Yuan, Minghui Yang, Fuxiang Wang, Guobao Li, Yanjie Li, Li Xing, Ling Peng, … Yingxia Liu
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq637
DOI: 10.1101/2020.03.02.20029975
-1088. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019
+
1089. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019
Juanjuan Zhao, Quan Yuan, Haiyan Wang, Wei Liu, Xuejiao Liao, Yingying Su, Xin Wang, Jing Yuan, Tingdong Li, Jinxiu Li, … Zheng Zhang
Cold Spring Harbor Laboratory (2020-03-02) https://doi.org/ggrbj6
DOI: 10.1101/2020.03.02.20030189
-1089. Restoration of leukomonocyte counts is associated with viral clearance in COVID-19 hospitalized patients
+
1090. Restoration of leukomonocyte counts is associated with viral clearance in COVID-19 hospitalized patients
Xiaoping Chen, Jiaxin Ling, Pingzheng Mo, Yongxi Zhang, Qunqun Jiang, Zhiyong Ma, Qian Cao, Wenjia Hu, Shi Zou, Liangjun Chen, … Yong Xiong
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq639
DOI: 10.1101/2020.03.03.20030437
-1090. Effects of Systemically Administered Hydrocortisone on the Human Immunome
+
1091. Effects of Systemically Administered Hydrocortisone on the Human Immunome
Matthew J. Olnes, Yuri Kotliarov, Angélique Biancotto, Foo Cheung, Jinguo Chen, Rongye Shi, Huizhi Zhou, Ena Wang, John S. Tsang, Robert Nussenblatt, The CHI Consortium
Scientific Reports (2016-03-14) https://doi.org/f8dmvw
DOI: 10.1038/srep23002 · PMID: 26972611 · PMCID: PMC4789739
-1091. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis
+
1092. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis
Giuseppe Lippi, Mario Plebani
Clinica Chimica Acta (2020-06) https://doi.org/ggpxp7
DOI: 10.1016/j.cca.2020.03.004 · PMID: 32145275 · PMCID: PMC7094472
-1092. Clinical findings in critically ill patients infected with SARS-CoV-2 in Guangdong Province, China: a multi-center, retrospective, observational study
+
1093. Clinical findings in critically ill patients infected with SARS-CoV-2 in Guangdong Province, China: a multi-center, retrospective, observational study
Yonghao Xu, Zhiheng Xu, Xuesong Liu, Lihua Cai, Haichong Zheng, Yongbo Huang, Lixin Zhou, Linxi Huang, Yun Lin, Liehua Deng, … Yimin Li
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq64b
DOI: 10.1101/2020.03.03.20030668
-1093. Multi-epitope vaccine design using an immunoinformatics approach for 2019 novel coronavirus (SARS-CoV-2)
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1094. Multi-epitope vaccine design using an immunoinformatics approach for 2019 novel coronavirus (SARS-CoV-2)
Ye Feng, Min Qiu, Liang Liu, Shengmei Zou, Yun Li, Kai Luo, Qianpeng Guo, Ning Han, Yingqiang Sun, Kui Wang, … Fan Mo
Cold Spring Harbor Laboratory (2020-06-30) https://doi.org/ggq64c
DOI: 10.1101/2020.03.03.962332
-1094. Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19) in Shanghai, China
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1095. Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19) in Shanghai, China
Min Cao, Dandan Zhang, Youhua Wang, Yunfei Lu, Xiangdong Zhu, Ying Li, Honghao Xue, Yunxiao Lin, Min Zhang, Yiguo Sun, … Hongzhou Lu
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq64d
DOI: 10.1101/2020.03.04.20030395 · PMID: 32511465
-1095. Serological detection of 2019-nCoV respond to the epidemic: A useful complement to nucleic acid testing
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1096. Serological detection of 2019-nCoV respond to the epidemic: A useful complement to nucleic acid testing
Jin Zhang, Jianhua Liu, Na Li, Yong Liu, Rui Ye, Xiaosong Qin, Rui Zheng
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq64f
DOI: 10.1101/2020.03.04.20030916
-1096. Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection
+
1097. Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection
Bo Diao, Chenhui Wang, Rongshuai Wang, Zeqing Feng, Yingjun Tan, Huiming Wang, Changsong Wang, Liang Liu, Ying Liu, Yueping Liu, … Yongwen Chen
Cold Spring Harbor Laboratory (2020-04-10) https://doi.org/ggq64g
DOI: 10.1101/2020.03.04.20031120
-1097. COVID-19 early warning score: a multi-parameter screening tool to identify highly suspected patients
+
1098. COVID-19 early warning score: a multi-parameter screening tool to identify highly suspected patients
Cong-Ying Song, Jia Xu, Jian-Qin He, Yuan-Qiang Lu
Cold Spring Harbor Laboratory (2020-03-08) https://doi.org/ggq64h
DOI: 10.1101/2020.03.05.20031906
-1098. LY6E impairs coronavirus fusion and confers immune control of viral disease
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1099. LY6E impairs coronavirus fusion and confers immune control of viral disease
Stephanie Pfaender, Katrina B. Mar, Eleftherios Michailidis, Annika Kratzel, Dagny Hirt, Philip V’kovski, Wenchun Fan, Nadine Ebert, Hanspeter Stalder, Hannah Kleine-Weber, … Volker Thiel
Cold Spring Harbor Laboratory (2020-03-07) https://doi.org/dpvn
DOI: 10.1101/2020.03.05.979260 · PMID: 32511345
-1099. A preliminary study on serological assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 238 admitted hospital patients
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1100. A preliminary study on serological assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 238 admitted hospital patients
Lei Liu, Wanbing Liu, Yaqiong Zheng, Xiaojing Jiang, Guomei Kou, Jinya Ding, Qiongshu Wang, Qianchuan Huang, Yinjuan Ding, Wenxu Ni, … Shangen Zheng
Cold Spring Harbor Laboratory (2020-03-08) https://doi.org/ggq64j
DOI: 10.1101/2020.03.06.20031856
-1100. Monoclonal antibodies for the S2 subunit of spike of SARS-CoV cross-react with the newly-emerged SARS-CoV-2
+
1101. Monoclonal antibodies for the S2 subunit of spike of SARS-CoV cross-react with the newly-emerged SARS-CoV-2
Zhiqiang Zheng, Vanessa M. Monteil, Sebastian Maurer-Stroh, Chow Wenn Yew, Carol Leong, Nur Khairiah Mohd-Ismail, Suganya Cheyyatraivendran Arularasu, Vincent Tak Kwong Chow, Raymond Lin Tzer Pin, Ali Mirazimi, … Yee-Joo Tan
Cold Spring Harbor Laboratory (2020-03-07) https://doi.org/ggrbj7
DOI: 10.1101/2020.03.06.980037
-1101. Mortality of COVID-19 is Associated with Cellular Immune Function Compared to Immune Function in Chinese Han Population
+
1102. Mortality of COVID-19 is Associated with Cellular Immune Function Compared to Immune Function in Chinese Han Population
Qiang Zeng, Yong-zhe Li, Gang Huang, Wei Wu, Sheng-yong Dong, Yang Xu
Cold Spring Harbor Laboratory (2020-03-13) https://doi.org/ggq64k
DOI: 10.1101/2020.03.08.20031229
-1102. Retrospective Analysis of Clinical Features in 101 Death Cases with COVID-19
+
1103. Retrospective Analysis of Clinical Features in 101 Death Cases with COVID-19
Hua Fan, Lin Zhang, Bin Huang, Muxin Zhu, Yong Zhou, Huan Zhang, Xiaogen Tao, Shaohui Cheng, Wenhu Yu, Liping Zhu, Jian Chen
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq64n
DOI: 10.1101/2020.03.09.20033068
-1103. Relationship between the ABO Blood Group and the COVID-19 Susceptibility
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1104. Relationship between the ABO Blood Group and the COVID-19 Susceptibility
Jiao Zhao, Yan Yang, Hanping Huang, Dong Li, Dongfeng Gu, Xiangfeng Lu, Zheng Zhang, Lei Liu, Ting Liu, Yukun Liu, … Peng George Wang
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggpn3d
DOI: 10.1101/2020.03.11.20031096
-1104. The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15
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1105. The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15
Shutoku Matsuyama, Miyuki Kawase, Naganori Nao, Kazuya Shirato, Makoto Ujike, Wataru Kamitani, Masayuki Shimojima, Shuetsu Fukushi
Cold Spring Harbor Laboratory (2020-03-12) https://doi.org/ggq64p
DOI: 10.1101/2020.03.11.987016
-1105. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19
+
1106. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19
Bicheng Zhang, Xiaoyang Zhou, Chengliang Zhu, Fan Feng, Yanru Qiu, Jia Feng, Qingzhu Jia, Qibin Song, Bo Zhu, Jun Wang
Cold Spring Harbor Laboratory (2020-03-16) https://doi.org/ggq64q
DOI: 10.1101/2020.03.12.20035048
-1106. Lack of Reinfection in Rhesus Macaques Infected with SARS-CoV-2
+
1107. Lack of Reinfection in Rhesus Macaques Infected with SARS-CoV-2
Linlin Bao, Wei Deng, Hong Gao, Chong Xiao, Jiayi Liu, Jing Xue, Qi Lv, Jiangning Liu, Pin Yu, Yanfeng Xu, … Chuan Qin
Cold Spring Harbor Laboratory (2020-05-01) https://doi.org/ggn8r8
DOI: 10.1101/2020.03.13.990226
-1107. A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV
+
1108. A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV
Meng Yuan, Nicholas C. Wu, Xueyong Zhu, Chang-Chun D. Lee, Ray T. Y. So, Huibin Lv, Chris K. P. Mok, Ian A. Wilson
Cold Spring Harbor Laboratory (2020-03-14) https://doi.org/ggq64s
DOI: 10.1101/2020.03.13.991570
-1108. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein
+
1109. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein
Ke Wang, Wei Chen, Yu-Sen Zhou, Jian-Qi Lian, Zheng Zhang, Peng Du, Li Gong, Yang Zhang, Hong-Yong Cui, Jie-Jie Geng, … Zhi-Nan Chen
Cold Spring Harbor Laboratory (2020-03-14) https://doi.org/ggq64t
DOI: 10.1101/2020.03.14.988345
-1109. CD147 (EMMPRIN/Basigin) in kidney diseases: from an inflammation and immune system viewpoint
+
1110. CD147 (EMMPRIN/Basigin) in kidney diseases: from an inflammation and immune system viewpoint
Tomoki Kosugi, Kayaho Maeda, Waichi Sato, Shoichi Maruyama, Kenji Kadomatsu
Nephrology Dialysis Transplantation (2015-07) https://doi.org/ggq624
DOI: 10.1093/ndt/gfu302 · PMID: 25248362
-1110. The roles of CyPA and CD147 in cardiac remodelling
+
1111. The roles of CyPA and CD147 in cardiac remodelling
Hongyan Su, Yi Yang
Experimental and Molecular Pathology (2018-06) https://doi.org/ggq622
DOI: 10.1016/j.yexmp.2018.05.001 · PMID: 29772453
-1111. Cancer-related issues of CD147.
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1112. Cancer-related issues of CD147.
Ulrich H Weidle, Werner Scheuer, Daniela Eggle, Stefan Klostermann, Hannes Stockinger
Cancer genomics & proteomics https://www.ncbi.nlm.nih.gov/pubmed/20551248
PMID: 20551248
-1112. Blood single cell immune profiling reveals the interferon-MAPK pathway mediated adaptive immune response for COVID-19
+
1113. Blood single cell immune profiling reveals the interferon-MAPK pathway mediated adaptive immune response for COVID-19
Lulin Huang, Yi Shi, Bo Gong, Li Jiang, Xiaoqi Liu, Jialiang Yang, Juan Tang, Chunfang You, Qi Jiang, Bo Long, … Zhenglin Yang
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq64v
DOI: 10.1101/2020.03.15.20033472
-1113. Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections
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1114. Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections
Huibin Lv, Nicholas C. Wu, Owen Tak-Yin Tsang, Meng Yuan, Ranawaka A. P. M. Perera, Wai Shing Leung, Ray T. Y. So, Jacky Man Chun Chan, Garrick K. Yip, Thomas Shiu Hong Chik, … Chris K. P. Mok
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq64w
DOI: 10.1101/2020.03.15.993097 · PMID: 32511317
-1114. The feasibility of convalescent plasma therapy in severe COVID- 19 patients: a pilot study
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1115. The feasibility of convalescent plasma therapy in severe COVID- 19 patients: a pilot study
Kai Duan, Bende Liu, Cesheng Li, Huajun Zhang, Ting Yu, Jieming Qu, Min Zhou, Li Chen, Shengli Meng, Yong Hu, … Xiaoming Yang
Cold Spring Harbor Laboratory (2020-03-23) https://doi.org/dqrs
DOI: 10.1101/2020.03.16.20036145
-1115. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial
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1116. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial
Philippe Gautret, Jean-Christophe Lagier, Philippe Parola, Van Thuan Hoang, Line Meddeb, Morgane Mailhe, Barbara Doudier, Johan Courjon, Valérie Giordanengo, Vera Esteves Vieira, … Didier Raoult
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/dqbv
DOI: 10.1101/2020.03.16.20037135
-1116. Chloroquine: Modes of action of an undervalued drug
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1117. Chloroquine: Modes of action of an undervalued drug
Rodolfo Thomé, Stefanie Costa Pinto Lopes, Fabio Trindade Maranhão Costa, Liana Verinaud
Immunology Letters (2013-06) https://doi.org/f5b5cr
DOI: 10.1016/j.imlet.2013.07.004 · PMID: 23891850
-1117. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy
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1118. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy
B. Lo, K. Zhang, W. Lu, L. Zheng, Q. Zhang, C. Kanellopoulou, Y. Zhang, Z. Liu, J. M. Fritz, R. Marsh, … M. B. Jordan
Science (2015-07-23) https://doi.org/f7kc8d
DOI: 10.1126/science.aaa1663 · PMID: 26206937
-1118. The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2
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1119. The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2
Erik Procko
Cold Spring Harbor Laboratory (2020-05-11) https://doi.org/ggrbj8
DOI: 10.1101/2020.03.16.994236 · PMID: 32511321
-1119. Comparative Pathogenesis Of COVID-19, MERS And SARS In A Non-Human Primate Model
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1120. Comparative Pathogenesis Of COVID-19, MERS And SARS In A Non-Human Primate Model
Barry Rockx, Thijs Kuiken, Sander Herfst, Theo Bestebroer, Mart M. Lamers, Dennis de Meulder, Geert van Amerongen, Judith van den Brand, Nisreen M. A. Okba, Debby Schipper, … Bart L. Haagmans
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq649
DOI: 10.1101/2020.03.17.995639
-1120. Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus
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1121. Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus
Paul B. McCray, Lecia Pewe, Christine Wohlford-Lenane, Melissa Hickey, Lori Manzel, Lei Shi, Jason Netland, Hong Peng Jia, Carmen Halabi, Curt D. Sigmund, … Stanley Perlman
Journal of Virology (2007-01-15) https://doi.org/b2dr3s
DOI: 10.1128/jvi.02012-06 · PMID: 17079315 · PMCID: PMC1797474
-1121. Modeling the Impact of Asymptomatic Carriers on COVID-19 Transmission Dynamics During Lockdown
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1122. Modeling the Impact of Asymptomatic Carriers on COVID-19 Transmission Dynamics During Lockdown
Jacob B. Aguilar, Jeremy Samuel Faust, Lauren M. Westafer, Juan B. Gutierrez
Cold Spring Harbor Laboratory (2020-08-11) https://doi.org/ggqnvp
DOI: 10.1101/2020.03.18.20037994
-1122. Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice
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1123. Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice
Quan-xin Long, Hai-jun Deng, Juan Chen, Jie-li Hu, Bei-zhong Liu, Pu Liao, Yong Lin, Li-hua Yu, Zhan Mo, Yin-yin Xu, … Ai-long Huang
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggpvz3
DOI: 10.1101/2020.03.18.20038018
-1123. Heat inactivation of serum interferes with the immunoanalysis of antibodies to SARS-CoV-2
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1124. Heat inactivation of serum interferes with the immunoanalysis of antibodies to SARS-CoV-2
Xiumei Hu, Taixue An, Bo Situ, Yuhai Hu, Zihao Ou, Qiang Li, Xiaojing He, Ye Zhang, Peifu Tian, Dehua Sun, … Lei Zheng
Cold Spring Harbor Laboratory (2020-03-16) https://doi.org/ggq646
DOI: 10.1101/2020.03.12.20034231
-1124. SARS-CoV-2 specific antibody responses in COVID-19 patients
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1125. SARS-CoV-2 specific antibody responses in COVID-19 patients
Nisreen M. A. Okba, Marcel A. Müller, Wentao Li, Chunyan Wang, Corine H. GeurtsvanKessel, Victor M. Corman, Mart M. Lamers, Reina S. Sikkema, Erwin de Bruin, Felicity D. Chandler, … Bart L. Haagmans
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggpvz2
DOI: 10.1101/2020.03.18.20038059
-1125. A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19
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1126. A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19
Drifa Belhadi, Nathan Peiffer-Smadja, François-Xavier Lescure, Yazdan Yazdanpanah, France Mentré, Cédric Laouénan
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65b
DOI: 10.1101/2020.03.18.20038190
-1126. ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19
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1127. ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19
Janice M. Leung, Chen X. Yang, Anthony Tam, Tawimas Shaipanich, Tillie-Louise Hackett, Gurpreet K. Singhera, Delbert R. Dorscheid, Don D. Sin
Cold Spring Harbor Laboratory (2020-03-23) https://doi.org/dqx2
DOI: 10.1101/2020.03.18.20038455
-1127. Dynamic profile of severe or critical COVID-19 cases
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1128. Dynamic profile of severe or critical COVID-19 cases
Yang Xu
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggrbj9
DOI: 10.1101/2020.03.18.20038513
-1128. Association between Clinical, Laboratory and CT Characteristics and RT-PCR Results in the Follow-up of COVID-19 patients
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1129. Association between Clinical, Laboratory and CT Characteristics and RT-PCR Results in the Follow-up of COVID-19 patients
Hang Fu, Huayan Xu, Na Zhang, Hong Xu, Zhenlin Li, Huizhu Chen, Rong Xu, Ran Sun, Lingyi Wen, Linjun Xie, … Yingkun Guo
Cold Spring Harbor Laboratory (2020-03-23) https://doi.org/ggq65c
DOI: 10.1101/2020.03.19.20038315
-1129. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus
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1130. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus
Timothy P. Sheahan, Amy C. Sims, Shuntai Zhou, Rachel L. Graham, Collin S. Hill, Sarah R. Leist, Alexandra Schäfer, Kenneth H. Dinnon, Stephanie A. Montgomery, Maria L. Agostini, … Ralph S. Baric
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggrbkb
DOI: 10.1101/2020.03.19.997890
-1130. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs
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1131. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs
Sangeun Jeon, Meehyun Ko, Jihye Lee, Inhee Choi, Soo Young Byun, Soonju Park, David Shum, Seungtaek Kim
Cold Spring Harbor Laboratory (2020-03-28) https://doi.org/ggq65h
DOI: 10.1101/2020.03.20.999730
-1131. Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2
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1132. Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2
Vincent J. Munster, Friederike Feldmann, Brandi N. Williamson, Neeltje van Doremalen, Lizzette Pérez-Pérez, Jonathan Schulz, Kimberly Meade-White, Atsushi Okumura, Julie Callison, Beniah Brumbaugh, … Emmie de Wit
Cold Spring Harbor Laboratory (2020-03-21) https://doi.org/ggq65j
DOI: 10.1101/2020.03.21.001628 · PMID: 32511299
-1132. Ocular conjunctival inoculation of SARS-CoV-2 can cause mild COVID-19 in Rhesus macaques
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1133. Ocular conjunctival inoculation of SARS-CoV-2 can cause mild COVID-19 in Rhesus macaques
Wei Deng, Linlin Bao, Hong Gao, Zhiguang Xiang, Yajin Qu, Zhiqi Song, Shunran Gong, Jiayi Liu, Jiangning Liu, Pin Yu, … Chuan Qin
Cold Spring Harbor Laboratory (2020-03-30) https://doi.org/ggq64r
DOI: 10.1101/2020.03.13.990036
-1133. ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19
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1134. ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19
Bruna G. G. Pinto, Antonio E. R. Oliveira, Youvika Singh, Leandro Jimenez, Andre N A. Gonçalves, Rodrigo L. T. Ogava, Rachel Creighton, Jean Pierre Schatzmann Peron, Helder I. Nakaya
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65k
DOI: 10.1101/2020.03.21.20040261 · PMID: 32511627
-1134. Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial
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1135. Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial
Huijie Bian, Zhao-Hui Zheng, Ding Wei, Zheng Zhang, Wen-Zhen Kang, Chun-Qiu Hao, Ke Dong, Wen Kang, Jie-Lai Xia, Jin-Lin Miao, … Ping Zhu
Cold Spring Harbor Laboratory (2020-07-15) https://doi.org/ggq65m
DOI: 10.1101/2020.03.21.20040691
-1135. CD147 facilitates HIV-1 infection by interacting with virus-associated cyclophilin A
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1136. CD147 facilitates HIV-1 infection by interacting with virus-associated cyclophilin A
T. Pushkarsky, G. Zybarth, L. Dubrovsky, V. Yurchenko, H. Tang, H. Guo, B. Toole, B. Sherry, M. Bukrinsky
Proceedings of the National Academy of Sciences (2001-05-15) https://doi.org/cc4c7p
DOI: 10.1073/pnas.111583198 · PMID: 11353871 · PMCID: PMC33473
-1136. CD147/EMMPRIN Acts as a Functional Entry Receptor for Measles Virus on Epithelial Cells
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1137. CD147/EMMPRIN Acts as a Functional Entry Receptor for Measles Virus on Epithelial Cells
Akira Watanabe, Misako Yoneda, Fusako Ikeda, Yuri Terao-Muto, Hiroki Sato, Chieko Kai
Journal of Virology (2010-05-01) https://doi.org/dpcsqg
DOI: 10.1128/jvi.02168-09 · PMID: 20147391 · PMCID: PMC2863760
-1137. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum
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1138. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum
Cécile Crosnier, Leyla Y. Bustamante, S. Josefin Bartholdson, Amy K. Bei, Michel Theron, Makoto Uchikawa, Souleymane Mboup, Omar Ndir, Dominic P. Kwiatkowski, Manoj T. Duraisingh, … Gavin J. Wright
Nature (2011-11-09) https://doi.org/dm59hf
DOI: 10.1038/nature10606 · PMID: 22080952 · PMCID: PMC3245779
-1138. Function of HAb18G/CD147 in Invasion of Host Cells by Severe Acute Respiratory Syndrome Coronavirus
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1139. Function of HAb18G/CD147 in Invasion of Host Cells by Severe Acute Respiratory Syndrome Coronavirus
Zhinan Chen, Li Mi, Jing Xu, Jiyun Yu, Xianhui Wang, Jianli Jiang, Jinliang Xing, Peng Shang, Airong Qian, Yu Li, … Ping Zhu
The Journal of Infectious Diseases (2005-03) https://doi.org/cd8snd
DOI: 10.1086/427811 · PMID: 15688292 · PMCID: PMC7110046
-1139. CD147 mediates intrahepatic leukocyte aggregation and determines the extent of liver injury
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1140. CD147 mediates intrahepatic leukocyte aggregation and determines the extent of liver injury
Christine Yee, Nathan M. Main, Alexandra Terry, Igor Stevanovski, Annette Maczurek, Alison J. Morgan, Sarah Calabro, Alison J. Potter, Tina L. Iemma, David G. Bowen, … Nicholas A. Shackel
PLOS ONE (2019-07-10) https://doi.org/ggq654
DOI: 10.1371/journal.pone.0215557 · PMID: 31291257 · PMCID: PMC6619953
-1140. Characterisation of the transcriptome and proteome of SARS-CoV-2 using direct RNA sequencing and tandem mass spectrometry reveals evidence for a cell passage induced in-frame deletion in the spike glycoprotein that removes the furin-like cleavage site
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1141. Characterisation of the transcriptome and proteome of SARS-CoV-2 using direct RNA sequencing and tandem mass spectrometry reveals evidence for a cell passage induced in-frame deletion in the spike glycoprotein that removes the furin-like cleavage site
Andrew D. Davidson, Maia Kavanagh Williamson, Sebastian Lewis, Deborah Shoemark, Miles W. Carroll, Kate Heesom, Maria Zambon, Joanna Ellis, Phillip A. Lewis, Julian A. Hiscox, David A. Matthews
Cold Spring Harbor Laboratory (2020-03-24) https://doi.org/ggq65n
DOI: 10.1101/2020.03.22.002204
-1141. Modifications to the Hemagglutinin Cleavage Site Control the Virulence of a Neurotropic H1N1 Influenza Virus
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1142. Modifications to the Hemagglutinin Cleavage Site Control the Virulence of a Neurotropic H1N1 Influenza Virus
Xiangjie Sun, Longping V. Tse, A Damon Ferguson, Gary R. Whittaker
Journal of Virology (2010-09-01) https://doi.org/drs2zt
DOI: 10.1128/jvi.00797-10 · PMID: 20554779 · PMCID: PMC2919019
-1142. The architecture of SARS-CoV-2 transcriptome
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1143. The architecture of SARS-CoV-2 transcriptome
Dongwan Kim, Joo-Yeon Lee, Jeong-Sun Yang, Jun Won Kim, V. Narry Kim, Hyeshik Chang
Cold Spring Harbor Laboratory (2020-03-14) https://doi.org/ggpx9q
DOI: 10.1101/2020.03.12.988865
-1143. First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naïve and Experienced COVID-19 Patients
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1144. First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naïve and Experienced COVID-19 Patients
Hongyi Chen, Zhicheng Zhang, Li Wang, Zhihua Huang, Fanghua Gong, Xiaodong Li, Yahong Chen, Jinzi J. Wu
Cold Spring Harbor Laboratory (2020-03-24) https://doi.org/ggrgbt
DOI: 10.1101/2020.03.22.20034041
-1144. Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)
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1145. Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)
Scott D. Seiwert, Steven W. Andrews, Yutong Jiang, Vladimir Serebryany, Hua Tan, Karl Kossen, P. T. Ravi Rajagopalan, Shawn Misialek, Sarah K. Stevens, Antitsa Stoycheva, … Lawrence M. Blatt
Antimicrobial Agents and Chemotherapy (2008-12) https://doi.org/btpg52
DOI: 10.1128/aac.00699-08 · PMID: 18824605 · PMCID: PMC2592891
-1145. Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China
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1146. Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China
Xiaoyuan Xu, Bo Feng, Yujuan Guan, Sujun Zheng, Jifang Sheng, Xingxiang Yang, Yuanji Ma, Yan Huang, Yi Kang, Xiaofeng Wen, … Lai Wei
Journal of Clinical and Translational Hepatology (2019-09-30) https://doi.org/ggrbkd
DOI: 10.14218/jcth.2019.00033 · PMID: 31608212 · PMCID: PMC6783683
-1146. Potentially highly potent drugs for 2019-nCoV
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1147. Potentially highly potent drugs for 2019-nCoV
Duc Duy Nguyen, Kaifu Gao, Jiahui Chen, Rui Wang, Guo-Wei Wei
Cold Spring Harbor Laboratory (2020-02-13) https://doi.org/ggrbj5
DOI: 10.1101/2020.02.05.936013 · PMID: 32511344
-1147. Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset
+
1148. Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset
Bin Lou, Ting-Dong Li, Shu-Fa Zheng, Ying-Ying Su, Zhi-Yong Li, Wei Liu, Fei Yu, Sheng-Xiang Ge, Qian-Da Zou, Quan Yuan, … Yu Chen
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggrbkc
DOI: 10.1101/2020.03.23.20041707
-1148. SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems
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1149. SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems
Daniel Blanco-Melo, Benjamin E. Nilsson-Payant, Wen-Chun Liu, Rasmus Møller, Maryline Panis, David Sachs, Randy A. Albrecht, Benjamin R. tenOever
Cold Spring Harbor Laboratory (2020-03-24) https://doi.org/ggq65q
DOI: 10.1101/2020.03.24.004655
-1149. A New Predictor of Disease Severity in Patients with COVID-19 in Wuhan, China
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1150. A New Predictor of Disease Severity in Patients with COVID-19 in Wuhan, China
Ying Zhou, Zhen Yang, Yanan Guo, Shuang Geng, Shan Gao, Shenglan Ye, Yi Hu, Yafei Wang
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65r
DOI: 10.1101/2020.03.24.20042119
-1150. Metabolic disturbances and inflammatory dysfunction predict severity of coronavirus disease 2019 (COVID-19): a retrospective study
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1151. Metabolic disturbances and inflammatory dysfunction predict severity of coronavirus disease 2019 (COVID-19): a retrospective study
Shuke Nie, Xueqing Zhao, Kang Zhao, Zhaohui Zhang, Zhentao Zhang, Zhan Zhang
Cold Spring Harbor Laboratory (2020-03-26) https://doi.org/ggq65s
DOI: 10.1101/2020.03.24.20042283
-1151. Viral Kinetics and Antibody Responses in Patients with COVID-19
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1152. Viral Kinetics and Antibody Responses in Patients with COVID-19
Wenting Tan, Yanqiu Lu, Juan Zhang, Jing Wang, Yunjie Dan, Zhaoxia Tan, Xiaoqing He, Chunfang Qian, Qiangzhong Sun, Qingli Hu, … Guohong Deng
Cold Spring Harbor Laboratory (2020-03-26) https://doi.org/ggq65t
DOI: 10.1101/2020.03.24.20042382
-1152. Global profiling of SARS-CoV-2 specific IgG/ IgM responses of convalescents using a proteome microarray
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1153. Global profiling of SARS-CoV-2 specific IgG/ IgM responses of convalescents using a proteome microarray
He-wei Jiang, Yang Li, Hai-nan Zhang, Wei Wang, Dong Men, Xiao Yang, Huan Qi, Jie Zhou, Sheng-ce Tao
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65g
DOI: 10.1101/2020.03.20.20039495
-1153. COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome
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1154. COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome
Dan Zhang, Rui Guo, Lei Lei, Hongjuan Liu, Yawen Wang, Yili Wang, Hongbo Qian, Tongxin Dai, Tianxiao Zhang, Yanjun Lai, … Jinsong Hu
Cold Spring Harbor Laboratory (2020-03-26) https://doi.org/ggq65v
DOI: 10.1101/2020.03.24.20042655
-1154. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study
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1155. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study
Aaron Miller, Mac Josh Reandelar, Kimberly Fasciglione, Violeta Roumenova, Yan Li, Gonzalo H. Otazu
Cold Spring Harbor Laboratory (2020-03-28) https://doi.org/ggq65w
DOI: 10.1101/2020.03.24.20042937
-1155. Non-specific effects of BCG vaccine on viral infections
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1156. Non-specific effects of BCG vaccine on viral infections
S. J. C. F. M. Moorlag, R. J. W. Arts, R. van Crevel, M. G. Netea
Clinical Microbiology and Infection (2019-12) https://doi.org/ggq62z
DOI: 10.1016/j.cmi.2019.04.020 · PMID: 31055165
-1156. BCG vaccination to reduce the impact of COVID-19 in healthcare workers (The BRACE Trial)
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1157. BCG vaccination to reduce the impact of COVID-19 in healthcare workers (The BRACE Trial)
Murdoch Children’s Research Institute
https://www.mcri.edu.au/BRACE
-1157. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia
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1158. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia
David H. Brann, Tatsuya Tsukahara, Caleb Weinreb, Marcela Lipovsek, Koen Van den Berge, Boying Gong, Rebecca Chance, Iain C. Macaulay, Hsin-jung Chou, Russell Fletcher, … Sandeep Robert Datta
Cold Spring Harbor Laboratory (2020-05-18) https://doi.org/ggqr4m
DOI: 10.1101/2020.03.25.009084
-1158. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract
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1159. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract
Joan C. Smith, Erin L. Sausville, Vishruth Girish, Monet Lou Yuan, Kristen M. John, Jason M. Sheltzer
Cold Spring Harbor Laboratory (2020-04-26) https://doi.org/ggq65x
DOI: 10.1101/2020.03.28.013672
-1159. The comparative superiority of IgM-IgG antibody test to real-time reverse transcriptase PCR detection for SARS-CoV-2 infection diagnosis
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1160. The comparative superiority of IgM-IgG antibody test to real-time reverse transcriptase PCR detection for SARS-CoV-2 infection diagnosis
Rui Liu, Xinghui Liu, Huan Han, Muhammad Adnan Shereen, Zhili Niu, Dong Li, Fang Liu, Kailang Wu, Zhen Luo, Chengliang Zhu
Cold Spring Harbor Laboratory (2020-03-30) https://doi.org/ggqtp5
DOI: 10.1101/2020.03.28.20045765
@@ -10360,7 +10366,7 @@
While the SARS-CoV-2 virus is very similar to other HCoV in several ways, including in its genomic structure and the structure of the virus itself, there are also some differences that may account for differences in the COVID-19 pandemic compared to the SARS and MERS epidemics of the past two decades. -The R0 of SARS-CoV-2 has been estimated to be similar to SARS-CoV-1 but much higher than that of MERS-CoV [30,30]. +The R0 of SARS-CoV-2 has been estimated to be similar to SARS-CoV-1 but much higher than that of MERS-CoV [32,32]. While the structures of the viruses are very similar, evolution among these species may account for differences in their transmissibility and virulence. For example, the acquisition of a furin cleavage site the S1/S2 boundary within the SARS-CoV-2 S protein may be associated with increased virulence. Additionally, concerns have been raised about the accumulation of mutations within the SARS-CoV-2 species itself, and whether these could influence virulence. The coming of age of genomic technologies has made these types of analyses feasible, and genomics research characterizing changes in SARS-CoV-2 along with temporal and spatial movement is likely to provide additional insights into whether within-species evolution influences the effect of the virus on the human host. Additionally, the rapid development of sequencing technologies over the past decade has made it possible to rapidly characterize the host response to the virus. -For example, proteomics analysis of patient-derived cells revealed candidate genes whose regulation is altered by SARS-CoV-2 infection, suggesting possible approaches for pharmaceutical invention and providing insight into which systems are likely to be disrupted in COVID-19 [163]. +For example, proteomics analysis of patient-derived cells revealed candidate genes whose regulation is altered by SARS-CoV-2 infection, suggesting possible approaches for pharmaceutical invention and providing insight into which systems are likely to be disrupted in COVID-19 [165]. As more patient data becomes available, the biotechnological advances of the 2000s are expected to allow for more rapid identification of potential drug targets than was feasible during the SARS, or even MERS, pandemic.
Thus, though the COVID-19 crisis is still evolving, the insights acquired over the past 20 years of HCoV research have provided a solid foundation for understanding the SARS-CoV-2 virus and the disease it causes. As the scientific community continues to respond to COVID-19 and to elucidate more of the relationships between viral pathogenesis, transmission, and symptomatology, and as more data about the regulatory shifts associated with COVID-19 become available, this understanding will no doubt continue to evolve and to reveal additional connections among virology, pathogenesis, and health. @@ -1182,52 +1183,52 @@
3.13.2 Introduction
3.3 Initial Characterization of SARS-CoV-2
The first genome sequence of the virus was released on January 3, 2020. -It revealed that the cluster of pneumonia cases seen in Wuhan were caused by a novel coronavirus [10]. -Multiple research groups have drafted the genome sequence of SARS-CoV-2 based on sequences developed from clinical samples collected from the lower respiratory tract, namely bronchoalveolar lavage fluid (BALF), and the upper respiratory tract, in the form of throat and nasopharyngeal swabs [11,12,13]. -Analysis of the SARS-CoV-2 genome revealed significant sequence homology with two coronaviruses known to infect humans, with about 79% identity to SARS-CoV-1 and 50% to MERS-CoV [13]. -However, in this analysis, the highest degree of similarity was observed between SARS-CoV-2 and bat-derived SARS-like coronaviruses (bat-SL-CoVZC45 and bat-SL-CoVZXC21) [13]. -Other analyses have reported even greater similarity between SARS-CoV-2 and the bat coronavirus BatCoV-RaTG13, with identity as high as 96.2% [12,14], and the closely related pangolin coronavirus [15]. +It revealed that the cluster of pneumonia cases seen in Wuhan were caused by a novel coronavirus [12]. +Multiple research groups have drafted the genome sequence of SARS-CoV-2 based on sequences developed from clinical samples collected from the lower respiratory tract, namely bronchoalveolar lavage fluid (BALF), and the upper respiratory tract, in the form of throat and nasopharyngeal swabs [13,14,15]. +Analysis of the SARS-CoV-2 genome revealed significant sequence homology with two coronaviruses known to infect humans, with about 79% identity to SARS-CoV-1 and 50% to MERS-CoV [15]. +However, in this analysis, the highest degree of similarity was observed between SARS-CoV-2 and bat-derived SARS-like coronaviruses (bat-SL-CoVZC45 and bat-SL-CoVZXC21) [15]. +Other analyses have reported even greater similarity between SARS-CoV-2 and the bat coronavirus BatCoV-RaTG13, with identity as high as 96.2% [14,16], and the closely related pangolin coronavirus [17]. This evidence therefore suggests the SARS-CoV-2 virus is the result of zoonotic transfer of a virus from bats to humans. Nevertheless, some fragments between SARS-CoV-2 and RATG13 differ by up to 17%, suggesting a complex natural selection process during zoonotic transfer. -While the S region is highly similar to that of viruses found in pangolins [15], there is no consensus about the origin of S in SARS-CoV-2, as it could potentially be the result either of recombination or coevolution [14,16]. +While the S region is highly similar to that of viruses found in pangolins [17], there is no consensus about the origin of S in SARS-CoV-2, as it could potentially be the result either of recombination or coevolution [16,18]. Though the intermediate host serving as the source for the zoonotic introduction of SARS-CoV-2 to human populations has not yet been identified, the SARS-CoV-2 virus has been placed within the coronavirus phylogeny through comparative genomic analyses. -Genomic analyses and comparisons to other known coronaviruses suggest that SARS-CoV-2 is unlikely to have originated in a laboratory – either purposely engineered and released, or escaped – and instead evolved naturally in an animal host [17]. -Indeed, the World Health Organization (WHO) have published their intentions to thoroughly investigate the origins of SARS-CoV-2 [255]. -While the position of the SARS-CoV-2 virus within the coronavirus phylogeny has been largely resolved, the functional consequences of molecular variation between this virus and other viruses, such as its bat and pangolin sister taxa or SARS-CoV-1, remain unknown [17]. +Genomic analyses and comparisons to other known coronaviruses suggest that SARS-CoV-2 is unlikely to have originated in a laboratory – either purposely engineered and released, or escaped – and instead evolved naturally in an animal host [19]. +Indeed, the World Health Organization (WHO) have published their intentions to thoroughly investigate the origins of SARS-CoV-2 [257]. +While the position of the SARS-CoV-2 virus within the coronavirus phylogeny has been largely resolved, the functional consequences of molecular variation between this virus and other viruses, such as its bat and pangolin sister taxa or SARS-CoV-1, remain unknown [19]. Fortunately, the basic genome structure of coronaviruses is highly conserved, and insight into the mechanisms the virus uses to enter cells, replicate, and spread is available from prior research on coronaviruses, which has been instrumental in the mobilization of global research to understand the biology of SARS-CoV-2.
Additionally, worldwide sequencing of viral samples has provided some preliminary insights into possible mechanisms of adaptation in the virus and the detection of novel variants, and omics-based analysis of patient samples has elucidated some of the biological changes the virus induces in its human hosts.
3.4 Coronaviruses and Animal Hosts
-Coronaviruses have long been known to infect animals and have been the subject of veterinary medical investigations and vaccine development efforts due to their effect on the health of companion and agricultural animals [18]. +
Coronaviruses have long been known to infect animals and have been the subject of veterinary medical investigations and vaccine development efforts due to their effect on the health of companion and agricultural animals [20].
Most coronaviruses show little to no transmission in humans. -However, it is thought that approximately one-third of common cold infections are caused by four seasonal human coronaviruses (HCoV): Human coronavirus 229E (HCoV-229E), Human coronavirus NL63 (HCoV-NL63), Human coronavirus OC43 (HCoV-OC43), and Human coronavirus HKU1 (HCoV-HKU1) [19,20,256]. -The first HCoV were identified in the 1960s: HCoV-229E in 1965 [21] and HCoV-OC43 in 1967 [22]. -Both of these viruses typically cause cold-like symptoms, including upper and lower respiratory infections [23,24,257], but they have also been associated with gastrointestinal symptoms [258]. -Two additional HCoV were subsequently identified [25,26]. -In 2003, HCoV-NL63 [25] was first identified in a 7-month-old infant and then in clinical specimens collected from seven additional patients, five of whom were infants younger than 1 year old and the remainder of whom were adults. -CoV-HKU1 was identified in samples collected from a 71-year-old pneumonia patient in 2004 and then found in samples collected from a second adult patient [26]. -These viruses are associated with respiratory diseases of varying severity, ranging from common cold to severe pneumonia, with severe symptoms mostly observed in immunocompromised individuals [27], and also have gastrointestinal involvement in some cases [258]. -In addition to these relatively mild HCoV, however, highly pathogenic human coronaviruses have been identified, including Severe acute respiratory syndrome-related coronavirus (SARS-CoV or SARS-CoV-1) and Middle East respiratory syndrome-related coronavirus (MERS-CoV) [19,28,29].
-At the time that SARS-CoV-1 emerged in the early 2000s, no HCoV had been identified in almost 40 years [28]. -The first case of SARS was reported in November 2002 in the Guangdong Province of China, and over the following month, the disease spread more widely within China and then into several countries across multiple continents [28,30]. -Unlike previously identified HCoV, SARS was much more severe, with an estimated death rate of 9.5% [30]. -It was also highly contagious via droplet transmission, with a basic reproduction number (R0) of 4 (i.e., each person infected was estimated to infect four other people) [30]. -However, the identity of the virus behind the infection remained unknown until April of 2003, when the SARS-CoV-1 virus was identified through a worldwide scientific effort spearheaded by the WHO [28]. -SARS-CoV-1 belonged to a distinct lineage from the two other HCoV known at the time [30]. -By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices [28]. +However, it is thought that approximately one-third of common cold infections are caused by four seasonal human coronaviruses (HCoV): Human coronavirus 229E (HCoV-229E), Human coronavirus NL63 (HCoV-NL63), Human coronavirus OC43 (HCoV-OC43), and Human coronavirus HKU1 (HCoV-HKU1) [21,22,258]. +The first HCoV were identified in the 1960s: HCoV-229E in 1965 [23] and HCoV-OC43 in 1967 [24]. +Both of these viruses typically cause cold-like symptoms, including upper and lower respiratory infections [25,26,259], but they have also been associated with gastrointestinal symptoms [260]. +Two additional HCoV were subsequently identified [27,28]. +In 2003, HCoV-NL63 [27] was first identified in a 7-month-old infant and then in clinical specimens collected from seven additional patients, five of whom were infants younger than 1 year old and the remainder of whom were adults. +CoV-HKU1 was identified in samples collected from a 71-year-old pneumonia patient in 2004 and then found in samples collected from a second adult patient [28]. +These viruses are associated with respiratory diseases of varying severity, ranging from common cold to severe pneumonia, with severe symptoms mostly observed in immunocompromised individuals [29], and also have gastrointestinal involvement in some cases [260]. +In addition to these relatively mild HCoV, however, highly pathogenic human coronaviruses have been identified, including Severe acute respiratory syndrome-related coronavirus (SARS-CoV or SARS-CoV-1) and Middle East respiratory syndrome-related coronavirus (MERS-CoV) [21,30,31].
+At the time that SARS-CoV-1 emerged in the early 2000s, no HCoV had been identified in almost 40 years [30]. +The first case of SARS was reported in November 2002 in the Guangdong Province of China, and over the following month, the disease spread more widely within China and then into several countries across multiple continents [30,32]. +Unlike previously identified HCoV, SARS was much more severe, with an estimated death rate of 9.5% [32]. +It was also highly contagious via droplet transmission, with a basic reproduction number (R0) of 4 (i.e., each person infected was estimated to infect four other people) [32]. +However, the identity of the virus behind the infection remained unknown until April of 2003, when the SARS-CoV-1 virus was identified through a worldwide scientific effort spearheaded by the WHO [30]. +SARS-CoV-1 belonged to a distinct lineage from the two other HCoV known at the time [32]. +By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices [30]. A decade later, a second outbreak of severe respiratory illness associated with a coronavirus emerged, this time in the Arabian Peninsula. This disease, known as Middle East respiratory syndrome (MERS), was linked to another novel coronavirus, MERS-CoV. -The fatality rate associated with MERS is much higher than that of SARS, at almost 35%, but the disease is much less easily transmitted, with an R0 of 1 [30]. -Although MERS is still circulating, its low reproduction number has allowed for its spread to be contained [30]. +The fatality rate associated with MERS is much higher than that of SARS, at almost 35%, but the disease is much less easily transmitted, with an R0 of 1 [32]. +Although MERS is still circulating, its low reproduction number has allowed for its spread to be contained [32]. The COVID-19 pandemic is thus associated with the seventh HCoV to be identified and the fifth since the turn of the millennium, though additional HCoVs may be in circulation but remain undetected.
-SARS-CoV-1 and MERS-CoV were ultimately managed largely through infection management practices (e.g., mask wearing) and properties of the virus itself (i.e., low rate of transmission), respectively [28,30]. -Vaccines were not used to control either outbreak, although vaccine development programs were established for SARS-CoV-1 [31]. -In general, care for SARS and MERS patients focuses on supportive care and symptom management [30]. +
SARS-CoV-1 and MERS-CoV were ultimately managed largely through infection management practices (e.g., mask wearing) and properties of the virus itself (i.e., low rate of transmission), respectively [30,32]. +Vaccines were not used to control either outbreak, although vaccine development programs were established for SARS-CoV-1 [33]. +In general, care for SARS and MERS patients focuses on supportive care and symptom management [32]. Clinical treatments for SARS and MERS developed during the outbreaks generally do not have strong evidence supporting their use. -Common treatments included Ribavirin, an antiviral, often in combination with corticosteroids or sometimes interferon (IFN) medications, which would both be expected to have immunomodulatory effects [28]. -However, retrospective and in vitro analyses have reported inconclusive results of these treatments on SARS and the SARS-CoV-1 virus, respectively [28]. -IFNs and Ribavirin have shown promise in in vitro analyses of MERS, but their clinical effectiveness remains unknown [28]. +Common treatments included Ribavirin, an antiviral, often in combination with corticosteroids or sometimes interferon (IFN) medications, which would both be expected to have immunomodulatory effects [30]. +However, retrospective and in vitro analyses have reported inconclusive results of these treatments on SARS and the SARS-CoV-1 virus, respectively [30]. +IFNs and Ribavirin have shown promise in in vitro analyses of MERS, but their clinical effectiveness remains unknown [30]. Therefore, only limited strategies can be adopted for the pharmaceutical management of COVID-19 from previous severe HCoV infections. Research in response to prior outbreaks of HCoV-borne infections, such as SARS and MERS, have, however, provided a strong foundation for hypotheses about the pathogenesis of SARS-CoV-2 as well as potential diagnostic and therapeutic approaches.
3.5 Zoonotic Transfer of Coronaviruses
@@ -1237,90 +1238,90 @@Evolution in SARS-CoV-2 has also been observed over a short timescale. -After zoonotic transfer, SARS-CoV-2 continued evolving in the human population [245]. -The SARS-CoV-2 mutation rate is moderate compared to other RNA viruses [246], which likely restricts the pace of evolution in SARS-CoV-2. +After zoonotic transfer, SARS-CoV-2 continued evolving in the human population [247]. +The SARS-CoV-2 mutation rate is moderate compared to other RNA viruses [248], which likely restricts the pace of evolution in SARS-CoV-2. Nevertheless, genomic analyses have yielded statistical evidence of ongoing evolution. -Initially, two known variants of the spike protein emerged that differed by a single amino acid at position 614 (G614 and D614), and there is evidence that G614 had become more prevalent than D614 by June 2020 [174]. -While there is a hypothesis that this genomic change increased the SARS-CoV-2 infectivity and virulence, this hypothesis has not yet been tested due to a lack of data [259]. -Another study [246] identified 198 recurrent mutations in a dataset of 7,666 curated sequences. +Initially, two known variants of the spike protein emerged that differed by a single amino acid at position 614 (G614 and D614), and there is evidence that G614 had become more prevalent than D614 by June 2020 [176]. +While there is a hypothesis that this genomic change increased the SARS-CoV-2 infectivity and virulence, this hypothesis has not yet been tested due to a lack of data [261]. +Another study [248] identified 198 recurrent mutations in a dataset of 7,666 curated sequences. This pattern of convergent evolution at some sites could indicate that certain mutations confer an adaptive advantage. While it is evident that SARS-CoV-2 exhibits moderate potential for ongoing and future evolution, the relationship between mutations and pathogenicity is not yet known. Additional data is needed in order to understand patterns of evolutionary change and whether they are likely to affect virulence.
Several factors could promote the evolution of SARS-CoV-2, including host immunodeficiency and transient exposure to antibodies directed against SARS-CoV-2 proteins. -A single case study of SARS-CoV-2 infection in an immunocompromised female with chronic lymphocytic leukemia and hypogammaglobulinemia [260] suggested that an accelerated evolution of the virus could occur in conditions of immunodeficiency. +A single case study of SARS-CoV-2 infection in an immunocompromised female with chronic lymphocytic leukemia and hypogammaglobulinemia [262] suggested that an accelerated evolution of the virus could occur in conditions of immunodeficiency. A first administration of convalescent plasma did not clear the virus, and an ensuing increase in the genomic diversity in the samples was observed, suggesting an accelerated evolution due to selection pressure. A second administration of convalescent plasma cleared the virus from the host 105 days after the initial diagnosis. However, throughout the duration of infection, the patient was asymptomatic but contagious. -A second single case study in a 45-year old male with antiphospholipid syndrome [261] confirmed the earlier results, providing evidence of persistent COVID-19 symptoms in an immunocompromised patient for 154 days following diagnosis, ultimately leading to the death of patient. +A second single case study in a 45-year old male with antiphospholipid syndrome [263] confirmed the earlier results, providing evidence of persistent COVID-19 symptoms in an immunocompromised patient for 154 days following diagnosis, ultimately leading to the death of patient. The treatments administered included remdesivir and the Regeneron anti-spike protein antibody cocktail. Genomic analyses of the patient’s nasopharyngeal swabs confirmed an accelerated evolution of the virus through mutations in the spike gene and the receptor-binding domain. In summary, these two case studies suggested an accelerated evolution and persistent shedding of the virus in conditions of immunodeficiency. In particular, the first case highlighted the role of convalescent plasma in creating escape variants. -In fact, one study [262] exposed the SARS-CoV-2 virus to convalescent plasma in vitro repeatedly to see how much plasma was required to neutralize the virus. +In fact, one study [264] exposed the SARS-CoV-2 virus to convalescent plasma in vitro repeatedly to see how much plasma was required to neutralize the virus. The results of the first six exposures were similar, but they reported that after the seventh exposure (on day 45), the amount of plasma required began to increase. In analyzing the viral variants present, they found that this viral escape was promoted by the sudden accumulation of mutations, especially in the receptor-binding domain (RBD) and N-terminal domain (NTD), that quickly rose in frequency. By the thirteenth exposure (day 85), the virus had evolved three mutations and could not longer be neutralized by the plasma used. Taken together, these observations suggest that evolutionary analyses of SARS-CoV-2 can provide crucial information about the conditions that promote resistance in SARS-CoV-2 and the kinetics of how resistance develops, information which will be important for understanding the implications of how vaccine regimens are designed and whether/when next-generation vaccines will be needed.
When variants occur, they can rise in frequency by chance or through an adaptive process that confers a competitive advantage to the virus. Variants that had the D614G mutation in the spike glycoprotein seemed to spread faster. -However, it has been suggested that the mutation rose in frequency due to early chance events rather than by adaptive events [263]. +However, it has been suggested that the mutation rose in frequency due to early chance events rather than by adaptive events [265]. Another mutation, Y453F, that occurred in the receptor binding domain of S, was first detected in mink; however, the transmission to humans has been established. -In mink, this mutation conferred an advantage by increasing the affinity towards ACE2 [264]. -Similarly, N501Y mutation induces an increased affinity towards human ACE2 and has been involved in the dominance of B.1.1.7 by outcompeting other variants [265]. -Therefore, genomic surveillance is essential to prevent the emergence of super-spreaders [266].
+In mink, this mutation conferred an advantage by increasing the affinity towards ACE2 [266]. +Similarly, N501Y mutation induces an increased affinity towards human ACE2 and has been involved in the dominance of B.1.1.7 by outcompeting other variants [267]. +Therefore, genomic surveillance is essential to prevent the emergence of super-spreaders [268].Emerging methods are being applied to this problem in an effort to understand which mutations are most likely to be of significant concern. Novel machine learning methods were developed to predict the mutations in the sequence that promote viral escape. While they preserve the pathogenicity of the virus, escape mutations change the virus’s sequence to evade detection by the immune system. -By using tools from natural language processing (NLP), viral escape was modeled as an NLP problem [267] where a modification makes a sentence grammatically correct but semantically different. +By using tools from natural language processing (NLP), viral escape was modeled as an NLP problem [269] where a modification makes a sentence grammatically correct but semantically different. Therefore, language models of viruses could predict mutations that change the presentation of the virus to the immune system but preserve its infectivity.
3.6.3 Variants of concern and variants under surveillance
-Viral replication naturally leads to the occurrence of mutations, and thus to genetic variation [268]. +
Viral replication naturally leads to the occurrence of mutations, and thus to genetic variation [270]. The emergence of new genetic variants of SARS-CoV-2 has attracted significant media attention since the detection of a variant of concern (VOC), a distinct phylogenetic cluster referred to as B.1.1.7/VOC 202012/01. While the B.1.1.7 lineage garnered attention in November 2020, two genomes of the lineage were detected as early as September 20th, 2020 from routine genomic data sampled in Kent (U.K.) by the COVID-19 Genomics UK Consortium (COG-UK). -The following day, a second B.1.1.7 genome was reported in greater London [263,269,270,271] -Since then, B.1.1.7 has spread across the UK and internationally, and it has now been detected in at least 62 countries [272], despite several countries imposing travel restrictions on travelers from the UK. -Of the twenty-three mutations that define B.1.1.7 from the original strain isolated in Wuhan (lineage A), fourteen are lineage-specific and three appear to be biologically consequential mutations associated with the spike protein, namely N501Y, P681H, and 69-70del [269,270]. -The latter is a 6-bp deletion that leads to the loss of two amino acids and has consequences for immune recognition; it may, in conjunction with N501Y, be responsible for the increased transmissibility of the B.1.1.7 VOC due to changes in the RBD that increase binding affinity with ACE2 [269,273]. +The following day, a second B.1.1.7 genome was reported in greater London [265,271,272,273] +Since then, B.1.1.7 has spread across the UK and internationally, and it has now been detected in at least 62 countries [274], despite several countries imposing travel restrictions on travelers from the UK. +Of the twenty-three mutations that define B.1.1.7 from the original strain isolated in Wuhan (lineage A), fourteen are lineage-specific and three appear to be biologically consequential mutations associated with the spike protein, namely N501Y, P681H, and 69-70del [271,272]. +The latter is a 6-bp deletion that leads to the loss of two amino acids and has consequences for immune recognition; it may, in conjunction with N501Y, be responsible for the increased transmissibility of the B.1.1.7 VOC due to changes in the RBD that increase binding affinity with ACE2 [271,275]. B.1.1.7 has increased transmissibility by up to 56%, leading to an R0 of approximately 1.4. -While there is also the possibility that this VOC may be associated with increased disease severity, there is currently insufficient evidence to draw any conclusions [265,271,274,275]. -Other variants also express the 69-70del mutation [276,277], and public health officials in the United States and the UK have been able to use RT-PCR-based assays (ThermoFisher TaqPath COVID-19 assay) to identify sequences with this deletion because it occurs where the qPCR probe binds [271]. -In the UK, B.1.1.7 is present in more than 97% of diagnostic tests that return negative for S-gene targets and positive for the other targets; thus, the frequency of S-gene target failure can be used as a proxy for the detection of B.1.1.7 [269; https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/950823/Variant_of_Concern_VOC_202012_01_Technical_Briefing_3_-England.pdf]. -The FDA has highlighted that the performance of three diagnostic tests may be affected by the B.1.1.7 lineage because it could cause false negative tests [278].
-While B.1.1.7 is currently the main VOC, other genetic variants not designated VOCs have been detected, including B.1.351 (20H/501Y.V2) and P.1 (20J/501Y.V3), both of which emerged independently [279]. -B.1.351 was first detected in October 2020 in South Africa, was later detected in the EU on December 28th, 2020 and has now spread to at least 26 countries [280,281,282]. +While there is also the possibility that this VOC may be associated with increased disease severity, there is currently insufficient evidence to draw any conclusions [267,273,276,277]. +Other variants also express the 69-70del mutation [278,279], and public health officials in the United States and the UK have been able to use RT-PCR-based assays (ThermoFisher TaqPath COVID-19 assay) to identify sequences with this deletion because it occurs where the qPCR probe binds [273]. +In the UK, B.1.1.7 is present in more than 97% of diagnostic tests that return negative for S-gene targets and positive for the other targets; thus, the frequency of S-gene target failure can be used as a proxy for the detection of B.1.1.7 [271; https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/950823/Variant_of_Concern_VOC_202012_01_Technical_Briefing_3_-England.pdf]. +The FDA has highlighted that the performance of three diagnostic tests may be affected by the B.1.1.7 lineage because it could cause false negative tests [280].
+While B.1.1.7 is currently the main VOC, other genetic variants not designated VOCs have been detected, including B.1.351 (20H/501Y.V2) and P.1 (20J/501Y.V3), both of which emerged independently [281].
+B.1.351 was first detected in October 2020 in South Africa, was later detected in the EU on December 28th, 2020 and has now spread to at least 26 countries [282,283,284].
B.1.351 contains several mutations at the RBD including K417N, E484K, and N501Y.
-While the biological significance of these mutations are still under investigation, it does appear that this lineage may be associated with increased transmissibility [283] due to the N501Y mutation [270,273].
-The P.1 variant is a branch of the B.1.1.28 lineage that was first detected in Japan in samples obtained from four travelers from Brazil during a screening at a Tokyo airport on January 10, 2021 [284].
+While the biological significance of these mutations are still under investigation, it does appear that this lineage may be associated with increased transmissibility [285] due to the N501Y mutation [272,275].
+The P.1 variant is a branch of the B.1.1.28 lineage that was first detected in Japan in samples obtained from four travelers from Brazil during a screening at a Tokyo airport on January 10, 2021 [286].
Shortly thereafter, it was established that there was a concentration of cases of the P.1 variant in Manaus, in the Amazonas State, Brazil.
-In a small number of samples (n=31) sequenced in Manaus, 42% were identified as the P.1 variant as early as mid-December, but the variant seemed to be absent in genome surveillance testing prior to December [285].
-To date, at least eight countries have detected the P.1 lineage [286].
-While the majority of P.1 cases detected internationally have been linked to travel originating from Brazil, the UK has also reported evidence of community transmission detected via routine community sequencing [286,287].
-P.1 has eight lineage-specific mutations along with three concerning spike protein mutations in the RBD, including K417T, E484K, and N501Y [283].
There have been multiple different SARS-CoV-2 lineages detected that have mostly been of no more clinical concern than the original devastating lineage originating in Wuhan [288].
+In a small number of samples (n=31) sequenced in Manaus, 42% were identified as the P.1 variant as early as mid-December, but the variant seemed to be absent in genome surveillance testing prior to December [287].
+To date, at least eight countries have detected the P.1 lineage [288].
+While the majority of P.1 cases detected internationally have been linked to travel originating from Brazil, the UK has also reported evidence of community transmission detected via routine community sequencing [288,289].
+P.1 has eight lineage-specific mutations along with three concerning spike protein mutations in the RBD, including K417T, E484K, and N501Y [285].
There have been multiple different SARS-CoV-2 lineages detected that have mostly been of no more clinical concern than the original devastating lineage originating in Wuhan [290].
However, the spotlight has been cast on other variants of unknown clinical relevance due to the increase of cases observed that have been associated with B.1.1.7 in particular.
-Although early in its ascendency, CAL.20C (B.1.429) is a SARS-CoV-2 variant that was detected in California, USA [289].
+Although early in its ascendency, CAL.20C (B.1.429) is a SARS-CoV-2 variant that was detected in California, USA [291].
It was first detected in July 2020 but was not detected again until October 2020.
In December 2020, CAL.20C accounted for ~24% of the total cases in Southern California and ~36% of total cases in the Los Angeles area.
-CAL.20C has now been detected in New York and Washington, D.C., and some cases have been reported outside the USA in Oceania [289].
+CAL.20C has now been detected in New York and Washington, D.C., and some cases have been reported outside the USA in Oceania [291].
This variant is characterized by five lineage-specific mutations (ORF1a: I4205V, ORF1b:D1183Y, S: S13I;W152C;L452R).
-The latter spike mutation, L452R, is found in an area of the RBD known to resist monoclonal antibodies to the spike protein [290], and it is hypothesized that this mutation may resist polyclonal sera in convalescent patients or in individuals post-vaccination [289,291].
+The latter spike mutation, L452R, is found in an area of the RBD known to resist monoclonal antibodies to the spike protein [292], and it is hypothesized that this mutation may resist polyclonal sera in convalescent patients or in individuals post-vaccination [291,293].
CAL.20C is not a designated VOC; however, further research is required to determine the implications of the mutations encoded in this genetic variant.
-Another notable variant has recently been discovered in 35 patients in a Bavarian hospital in Germany; however, the sequencing data has not been published to date and it remains to be determined whether this variant is of any further concern [292].
There are several shared mutations and deletions between the three lineages, P.1, B.1.1.7, and B.1.315 and indeed other variants of SARS-CoV-2 that are under investigation [285]. +Another notable variant has recently been discovered in 35 patients in a Bavarian hospital in Germany; however, the sequencing data has not been published to date and it remains to be determined whether this variant is of any further concern [294].
+There are several shared mutations and deletions between the three lineages, P.1, B.1.1.7, and B.1.315 and indeed other variants of SARS-CoV-2 that are under investigation [287].
For example, N501Y, which appears to have occurred independently in each of the three lineages.
-E484K is present in both B.1.351 and P.1 [293].
-The mutations N501Y and E484K are found in the RBD within the receptor-binding motif responsible for forming an interface with the ACE2 receptor, which seems to be consequential for ACE2 binding affinity [294].
-Indeed, N501Y is associated with increased virulence and infectivity in mouse models [295].
-E484K has also been associated with evasion from neutralizing antibodies [262,291,296].
+E484K is present in both B.1.351 and P.1 [295].
+The mutations N501Y and E484K are found in the RBD within the receptor-binding motif responsible for forming an interface with the ACE2 receptor, which seems to be consequential for ACE2 binding affinity [296].
+Indeed, N501Y is associated with increased virulence and infectivity in mouse models [297].
+E484K has also been associated with evasion from neutralizing antibodies [264,293,298].
The del69-70 (del:11288:9) is also shared between P.1 and B.1.1.7 and happens to be a common deletion found in the N terminal mutation of the spike protein.
-This deletion has also been associated with several RBD mutations [270,273,297].
-There is concern that mutations in the spike protein of variants may lead to clinical consequences for transmissibility, disease severity, re-infection, therapeutics, and vaccinations [262,291,298,299,300,301,302].
Vaccine producers are working to determine whether the vaccines are still effective against the novel genetic variants. Moderna recently published data for their mRNA-1273 vaccine that showed no significant impact of neutralization against the B.1.1.7 variant upon vaccination in humans and non-human primates. -On the other hand, Moderna reported a reduced but significant neutralization against the B.1.351 variant upon vaccination [303]. -Indeed, Pfizer–BioNTech reported that sera from twenty participants vaccinated with the BNT162b COVID-19 vaccine in previous clinical trials [304,305] elicited equivalent neutralizing titers against isogenic Y501 SARS-CoV-2 on an N501Y genetic background in vitro [306]. -Another study has reported that the plasma neutralizing activity against SARS-CoV-2 variants encoding the combination of K417N:E484K:N501Y or E484K or N501Y was variably and significantly reduced in the sera of twenty participants who received either the Pfizer–BioNTech BNT162b (n = 6) vaccine or the Moderna’s mRNA-1273 vaccine (n =14) [307]. -For now, the consensus appears to be that the FDA approved vaccines still seem to be effective against the genetic variants of SARS-CoV-2 and their accompanying mutations, albeit with a slightly lower neutralizing capacity [303,306,307,308]. +On the other hand, Moderna reported a reduced but significant neutralization against the B.1.351 variant upon vaccination [305]. +Indeed, Pfizer–BioNTech reported that sera from twenty participants vaccinated with the BNT162b COVID-19 vaccine in previous clinical trials [306,307] elicited equivalent neutralizing titers against isogenic Y501 SARS-CoV-2 on an N501Y genetic background in vitro [308]. +Another study has reported that the plasma neutralizing activity against SARS-CoV-2 variants encoding the combination of K417N:E484K:N501Y or E484K or N501Y was variably and significantly reduced in the sera of twenty participants who received either the Pfizer–BioNTech BNT162b (n = 6) vaccine or the Moderna’s mRNA-1273 vaccine (n =14) [309]. +For now, the consensus appears to be that the FDA approved vaccines still seem to be effective against the genetic variants of SARS-CoV-2 and their accompanying mutations, albeit with a slightly lower neutralizing capacity [305,308,309,310]. Further research is required to discern the clinical, prophylactic, and therapeutic consequences of these genetic SARS-CoV-2 variants as the pandemic evolves.
3.7 Conclusions
As of October 2020 the SARS-CoV-2 virus remains a serious worldwide threat. @@ -1334,7 +1335,7 @@
4.
Identifying individuals who have contracted COVID-19 is crucial to slowing down the global pandemic.
Given the high transmissibility of SARS-CoV-2, the development of reliable assays to detect SARS-CoV-2 infection even in asymptomatic carriers is vitally important.
For instance, the deployment of wide-scale diagnostic testing followed by the isolation of infected people has been a key factor in South Korea’s successful strategy for controlling the spread of the virus.
-Following the first release of the genetic sequence of the virus by Chinese officials on January 10, 2020, the first test was released about 13 days later [309].
+Following the first release of the genetic sequence of the virus by Chinese officials on January 10, 2020, the first test was released about 13 days later [311].
Diagnostic approaches utilizing a variety of methods are currently or have been developed.
There are two main classes of diagnostic tests: molecular tests, which can diagnose an active infection by identifying the presence of SARS-CoV-2, and serological tests, which can assess whether an individual was infected in the past via the presence or absence of antibodies against SARS-CoV-2.
Molecular tests are essential for identifying individuals for treatment and alerting their contacts to quarantine and be alert for possible symptoms.
@@ -1346,37 +1347,37 @@
4.
The innate immune system consists of barriers, such as the skin, mucous secretions, neutrophils, macrophages, and dendritic cells.
It also includes cell-surface receptors that can recognize the molecular patterns of pathogens.
The adaptive immune system utilizes antigen-specific receptors that are expressed on B and T lymphocytes.
-These components of the immune system typically act together; the innate response acts first, and the adaptive response begins to act several days after initial infection following the clonal expansion of T and B cells [32].
+These components of the immune system typically act together; the innate response acts first, and the adaptive response begins to act several days after initial infection following the clonal expansion of T and B cells [34].
After a virus enters into a host cell, its antigen is presented by major histocompatibility complex 1 (MHC 1) molecules and is then recognized by cytotoxic T lymphocytes.
In the case of COVID-19, there is also concern about the immune system becoming over-active.
One of the main immune responses contributing to the onset of acute respiratory distress syndrome (ARDS) in COVID-19 patients is cytokine storm syndrome (CSS), which causes an extreme inflammatory response due to a release of pro-inflammatory cytokines and chemokines by immune effector cells.
-In addition to respiratory distress, this mechanism can lead to organ failure and death in severe COVID-19 cases [33].
+In addition to respiratory distress, this mechanism can lead to organ failure and death in severe COVID-19 cases [35].
4.3 Molecular Tests
Molecular tests are used to identify distinct genomic subsequences of a viral molecule in a sample and thus to diagnose an active viral infection.
This first requires identifying which biospecimens are likely to contain the virus during infection and then acquiring these samples from the patient(s) to be tested.
-Common sampling sources for molecular tests include nasopharyngeal cavity samples, such as throat wash and saliva [310], and stool samples [311].
+Common sampling sources for molecular tests include nasopharyngeal cavity samples, such as throat wash and saliva [312], and stool samples [313].
Once a sample is acquired from a patient, molecular testing will utilize a number of steps, described below, to analyze a sample and identify whether evidence of SARS-CoV-2 is present.
When testing for RNA viruses like SARS-CoV-2, pre-processing is necessary in order to create DNA from the RNA sample.
The DNA can then be amplified with PCR.
Some tests use the results of the PCR itself to determine whether the pathogen is present, but in other cases, it may be necessary to sequence the amplified DNA.
Sequencing requires an additional pre-processing step: library preparation.
-Library preparation is the process of preparing the sample for sequencing, typically by fragmenting the sequences and adding adapters [312].
+Library preparation is the process of preparing the sample for sequencing, typically by fragmenting the sequences and adding adapters [314].
In some cases, library preparation can involve other modifications of the sample, such as adding “barcoding” to identify a particular sample in the sequence data, which is useful for pooling samples from multiple sources.
-There are different reagents used for library preparation that are specific to identifying one or more target sections with PCR [313].
+There are different reagents used for library preparation that are specific to identifying one or more target sections with PCR [315].
Sequential pattern matching is then used to identify unique subsequences of the virus that identify it in specific.
If sufficient subsequences are found, the test is considered positive.
4.3.1 RT-PCR
Real-Time Polymerase Chain Reaction (RT-PCR) tests determine whether a target is present by measuring the rate of amplification during PCR compared to a standard.
When the target is RNA, such as in the case of RNA viruses, the RNA must be converted into complementary DNA during pre-processing.
The Drosten Lab, from Germany, was the first lab to establish and validate a diagnostic test to detect SARS-CoV-2.
-This test uses RT-PCR with reverse transcription [309] to detect several regions of the viral genome: the ORF1b of the RNA-dependent RNA polymerase (RdRP), the Envelope protein gene (E), and the Nucleocapsid protein gene (N).
+This test uses RT-PCR with reverse transcription [311] to detect several regions of the viral genome: the ORF1b of the RNA-dependent RNA polymerase (RdRP), the Envelope protein gene (E), and the Nucleocapsid protein gene (N).
In collaboration with several other labs in Europe and in China, the researchers confirmed the specificity of this test with respect to other coronaviruses against specimens from 297 patients infected with a broad range of respiratory agents.
-Specifically this test utilizes two probes against RdRP, one of which is specific to SARS-CoV-2 [309].
+Specifically this test utilizes two probes against RdRP, one of which is specific to SARS-CoV-2 [311].
Importantly, this assay was not found to return false positive results.
4.3.2 qRT-PCR
-Chinese researchers developed a quantitative real-time reverse transcription PCR (qRT-PCR) test to identify two gene regions of the viral genome, ORF1b and N [314].
+
Chinese researchers developed a quantitative real-time reverse transcription PCR (qRT-PCR) test to identify two gene regions of the viral genome, ORF1b and N [316].
This assay was tested on samples coming two COVID-19 patients and a panel of positive and negative controls consisting of RNA extracted from several cultured viruses.
-The assay uses the N gene to screen patients, while the ORF1b gene region is used to confirm the infection [314].
+The assay uses the N gene to screen patients, while the ORF1b gene region is used to confirm the infection [316].
In this case the test was designed to detect sequences conserved across sarbecoviruses, or viruses within the same subgenus as SARS-CoV-2.
Considering that SARS-CoV-1 and SARS-CoV-2 are the only sarbecoviruses currently known to infect humans, a positive test can be assumed to indicate that the patient is infected with SARS-CoV-2.
However, this test is not able to discriminate the genetics of viruses within the sarbecovirus clade.
@@ -1384,15 +1385,15 @@ 4.3.2.1<
Digital PCR (dPCR) is a new generation of PCR technologies offering an alternative to traditional real-time quantitative PCR.
In dPCR, a sample is partitioned into thousands of compartments, such as nanodroplets (droplet dPCR or ddPCR) or nanowells, and a PCR reaction takes place in each compartment.
This design allows for a digital read-out where each partition is either positive or negative for the nucleic acid sequence being tested for, allowing for much higher throughput.
-While dPCR equipment is not yet as common as that for RT-PCR, dPCR for DNA targets generally achieves higher sensitivity than other PCR technologies while maintaining high specificity, though sensitivity is slightly lower for RNA targets [315].
+While dPCR equipment is not yet as common as that for RT-PCR, dPCR for DNA targets generally achieves higher sensitivity than other PCR technologies while maintaining high specificity, though sensitivity is slightly lower for RNA targets [317].
High sensitivity is particularly relevant for SARS-CoV-2 detection, since low viral load in clinical samples can lead to false negatives.
-Suo et al. [316] performed a double-blind evaluation of ddPCR for SARS-CoV-2 detection on 57 samples, comprised by 43 samples from suspected positive patients and 14 from supposed convalescents, that had all tested negative for SARS-CoV-2 using RT-PCR.
+Suo et al. [318] performed a double-blind evaluation of ddPCR for SARS-CoV-2 detection on 57 samples, comprised by 43 samples from suspected positive patients and 14 from supposed convalescents, that had all tested negative for SARS-CoV-2 using RT-PCR.
Despite the initial negative results, 33 out of 35 (94.3%) patients were later clinically confirmed positive.
All of these individuals tested positive using ddPCR.
Additionally, of 14 supposed convalescents who had received two consecutive negative RT-PCR tests, nine (64.2%) tested positive for SARS-CoV-2 using ddPCR.
Two symptomatic patients tested negative with both RT-PCR and ddPCR, but were later clinically diagnosed positive, and 5 of the 14 suspected convalescents tested negative by ddPCR.
While this study did not provide a complete head-to-head comparison to RT-PCR in all aspects, e.g., no samples testing positive using RT-PCR were evaluated by ddPCR, the study shows the potential of dPCR for viral detection even in highly diluted samples.
-In a second study, Dong et al. [317] compared the results of qRT-PCR and ddPCR testing for SARS-CoV-2 in 194 samples, including 103 samples from suspected patients, 75 from contacts and close contacts, and 16 from suspected convalescents.
+In a second study, Dong et al. [319] compared the results of qRT-PCR and ddPCR testing for SARS-CoV-2 in 194 samples, including 103 samples from suspected patients, 75 from contacts and close contacts, and 16 from suspected convalescents.
Of the 103 suspected patient samples, 29 were reported as positive, 25 as negative, and 49 as suspected by qRT-PCR; all patients were later confirmed to be SARS-CoV-2 positive.
Of the qRT-PCR negative or suspected samples, a total of 61 (17 negative and 44 suspected) were later confirmed to be positive by ddPCR, improving the overall detection rate among these patients from 28.2% to 87.4%.
Of 75 patient samples from contacts and close contacts, 48 tested negative with both methods, and these patients were observed to remain healthy.
@@ -1404,43 +1405,43 @@
4.3.2.1<
Overall, these studies suggest that dPCR is a promising tool for overcoming the problem of false-negative SARS-CoV-2 testing.
4.3.3 Pooled and Automated PCR Testing
Due to limited supplies and the need for more tests, several labs have found ways to pool or otherwise strategically design tests to increase throughput.
-The first such result came from Yelin et al. [318], who found they could pool up to 32 samples in a single qPCR run.
-This was followed by larger-scale pooling with slightly different methods [319].
+The first such result came from Yelin et al. [320], who found they could pool up to 32 samples in a single qPCR run.
+This was followed by larger-scale pooling with slightly different methods [321].
Although these approaches are also PCR based, they allow for more rapid scaling and higher efficiency for testing than the initial PCR-based methods developed.
4.3.3.1 CRISPR-based Detection
Two CRISPR-associated nucleases, Cas12 and Cas13, have been used for nucleic acid detection.
Multiple assays exploiting these nucleases have emerged as potential diagnostic tools for the rapid detection of SARS-CoV-2 genetic material and therefore SARS-CoV-2 infection.
-The SHERLOCK method (Specific High-sensitivity Enzymatic Reporter unLOCKing) from Sherlock Biosciences relies on Cas13a to discriminate between inputs that differ by a single nucleotide at very low concentrations [320].
+The SHERLOCK method (Specific High-sensitivity Enzymatic Reporter unLOCKing) from Sherlock Biosciences relies on Cas13a to discriminate between inputs that differ by a single nucleotide at very low concentrations [322].
The target RNA is amplified by RT-RPA and T7 transcription, and the amplified product activates Cas13a.
The nuclease then cleaves a reporter RNA, which liberates a fluorescent dye from a quencher.
Several groups have used the SHERLOCK method to detect SARS-CoV-2 viral RNA.
-An early study reported that the method could detect 7.5 copies of viral RNA in all 10 replicates, 2.5 copies in 6 out of 10, and 1.25 copies in 2 out of 10 runs [321].
+An early study reported that the method could detect 7.5 copies of viral RNA in all 10 replicates, 2.5 copies in 6 out of 10, and 1.25 copies in 2 out of 10 runs [323].
It also reported 100% specificity and sensitivity on 114 RNA samples from clinical respiratory samples (61 suspected cases, among which 52 were confirmed and nine were ruled out by metagenomic next-generation sequencing, 17 nCoV-/HCoV+ cases and 36 samples from healthy subjects), and a reaction turnaround time of 40 minutes.
A separate study screened four designs of SHERLOCK and extensively tested the best-performing assay.
-They determined the limit of detection to be 10 copies/μl using both fluorescent and lateral flow detection [322].
+They determined the limit of detection to be 10 copies/μl using both fluorescent and lateral flow detection [324].
Lateral flow test strips are simple to use and read, but there are limitations in terms of availability and cost per test.
-Another group therefore proposed the CREST protocol (Cas13-based, Rugged, Equitable, Scalable Testing), which uses a P51 cardboard fluorescence visualizer, powered by a 9V battery, for the detection of Cas13 activity instead of immunochromatography [323].
+Another group therefore proposed the CREST protocol (Cas13-based, Rugged, Equitable, Scalable Testing), which uses a P51 cardboard fluorescence visualizer, powered by a 9V battery, for the detection of Cas13 activity instead of immunochromatography [325].
CREST can be run, from RNA sample to result, with no need for AC power or a dedicated facility, with minimal handling in approximately 2 hours.
Testing was performed on 14 nasopharyngeal swabs.
CREST picked up the same positives as the CDC-recommended TaqMan assay with the exception of one borderline sample that displayed low-quality RNA.
The DETECTR method (DNA Endonuclease-Targeted CRISPR Trans Reporter) from Mammoth Biosciences involves purification of RNA extracted from patient specimens, amplification of extracted RNAs by loop-mediated amplification, which is a rapid, isothermal nucleic acid amplification technique, and application of their Cas12-based technology.
-In their assay, guide RNAs were designed to recognize portions of sequences corresponding to the SARS-CoV-2 genome, specifically the N2 and E regions [324].
+In their assay, guide RNAs were designed to recognize portions of sequences corresponding to the SARS-CoV-2 genome, specifically the N2 and E regions [326].
In the presence of SARS-CoV-2 genetic material, sequence recognition by the guide RNAs results in double-stranded DNA cleavage by Cas12, as well as cleavage of a single-stranded DNA molecular beacon.
The cleavage of this molecular beacon acts as a colorimetric reporter that is subsequently read out in a lateral flow assay and indicates the positive presence of SARS-CoV-2 genetic material and therefore SARS-CoV-2 infection.
The 40-minute assay is considered positive if there is detection of both the E and N genes or presumptive positive if there is detection of either of them.
The assay had 95% positive predictive agreement and 100% negative predictive agreement with the US Centers for Disease Control and Prevention SARS-CoV-2 real-time RT–PCR assay.
The estimated limit of detection was 10 copies per μl reaction, versus 1 copy per μl reaction for the CDC assay.
These results have been confirmed by other DETECTR approaches.
-Using RTRPA for amplification, another group detected 10 copies of synthetic SARS-CoV-2 RNA per μl of input within 60 minutes of RNA sample preparation in a proof-of-principle evaluation [325].
+Using RTRPA for amplification, another group detected 10 copies of synthetic SARS-CoV-2 RNA per μl of input within 60 minutes of RNA sample preparation in a proof-of-principle evaluation [327].
The DETECTR protocol was improved by combining RT-RPA and CRISPR-based detection in a one-pot reaction that incubates at a single temperature, and by using dual crRNAs (which increases sensitivity).
-This new assay, known as All-In-One Dual CRISPR-Cas12a (AIOD-CRISPR), detected 4.6 copies of SARS-CoV-2 RNA per μl of input in 40 minutes [326].
-Another single-tube, constant-temperature approach using Cas12b instead of Cas12a achieved a detection limit of 5 copies/μl in 40-60 minutes [327].
-It was also reported that electric field gradients can be used to control and accelerate CRISPR assays by co-focusing Cas12-gRNA, reporters, and target [328].
+This new assay, known as All-In-One Dual CRISPR-Cas12a (AIOD-CRISPR), detected 4.6 copies of SARS-CoV-2 RNA per μl of input in 40 minutes [328].
+Another single-tube, constant-temperature approach using Cas12b instead of Cas12a achieved a detection limit of 5 copies/μl in 40-60 minutes [329].
+It was also reported that electric field gradients can be used to control and accelerate CRISPR assays by co-focusing Cas12-gRNA, reporters, and target [330].
The authors generated an appropriate electric field gradient using a selective ionic focusing technique known as isotachophoresis (ITP) implemented on a microfluidic chip.
They also used ITP for automated purification of target RNA from raw nasopharyngeal swab samples.
Combining this ITP purification with loop-mediated isothermal amplification, their ITP-enhanced assay to achieved detection of SARS-CoV-2 RNA (from raw sample to result) in 30 minutes.
There is an increasing body of evidence that CRISPR-based assays offer a practical solution for rapid, low-barrier testing in areas that are at greater risk of infection, such as airports and local community hospitals.
-In the largest study to date, DETECTR was compared to qRT-PCR on 378 patient samples [329].
+In the largest study to date, DETECTR was compared to qRT-PCR on 378 patient samples [331].
The authors reported a 95% reproducibility.
Both techniques were equally sensitive in detecting SARS-CoV-2.
Lateral flow strips showed a 100% correlation to the high-throughput DETECTR assay.
@@ -1451,26 +1452,26 @@
False-negative responses, which can present a significant problem to large-scale testing.
-To reduce occurrence of false negatives, correct execution of the analysis is crucial [330].
-Uncertainty surrounding the SARS-CoV-2 viral shedding kinetics, which could affect the result of a test depending on when it was taken [330].
-Type of specimen, as it is not clear which clinical samples are best for detecting the virus [330].
-Expensive machinery, which might be present in major hospitals and/or diagnostic centers but is often not available to smaller facilities [331].
-Timing of the test, which might take up to 4 days to return results [331].
-The availability of supplies for testing, including swabs and testing media, has been limited [332].
+To reduce occurrence of false negatives, correct execution of the analysis is crucial [332].
+Uncertainty surrounding the SARS-CoV-2 viral shedding kinetics, which could affect the result of a test depending on when it was taken [332].
+Type of specimen, as it is not clear which clinical samples are best for detecting the virus [332].
+Expensive machinery, which might be present in major hospitals and/or diagnostic centers but is often not available to smaller facilities [333].
+Timing of the test, which might take up to 4 days to return results [333].
+The availability of supplies for testing, including swabs and testing media, has been limited [334].
Because the guide RNA can recognize other interspersed sequences on the patient’s genome, false positives and a loss of specificity can occur.
Similarly, in tests that use CRISPR, false positives can occur due to the specificity of the technique, as the guide RNA can recognize other interspersed sequences on the patient’s genome.
As noted above, false negatives are a significant concern for several reason.
-Importantly, clinical reports indicate that it is imperative to exercise caution when interpreting the results of molecular tests for SARS-CoV-2 because negative results do not necessarily mean a patient is virus-free [333].
+Importantly, clinical reports indicate that it is imperative to exercise caution when interpreting the results of molecular tests for SARS-CoV-2 because negative results do not necessarily mean a patient is virus-free [335].
4.4 Serological Tests
Although diagnostic tests based on the detection of genetic material can be quite sensitive, they cannot provide information about the extent of the disease over time.
Most importantly, they would not work on a patient who has fully recovered from the virus at the time of sample collection.
In this context, serological tests, which use serum to test for the presence of antibodies against SARS-CoV-2, are significantly more informative.
Additionally, serological tests can help scientists to understand why the disease has a different course among patients, as well as which strategies might work to manage the spread of the infection.
Furthermore, serological tests hold significant interest because of the possibility that they could provide information relevant to advancing economic recovery and allowing reopenings.
-For instance, people that had developed antibodies might be able to return to work, assuming (still-unproven) protective immunity [334].
+For instance, people that had developed antibodies might be able to return to work, assuming (still-unproven) protective immunity [336].
Some infectious agents can be controlled through “herd immunity”, which is when a critical mass within the population acquires immunity through vaccination and/or infection, preventing an infectious agent from spreading widely.
-A simple SIR model predicts that to achieve the required level of exposure for herd immunity to be effective, at least (1-(1/R0)) fraction of the population must be immune or, equivalently, less than (1/R0) fraction of the population susceptible [223].
+A simple SIR model predicts that to achieve the required level of exposure for herd immunity to be effective, at least (1-(1/R0)) fraction of the population must be immune or, equivalently, less than (1/R0) fraction of the population susceptible [225].
However, for SARS-CoV-2 and COVID-19, the R0 and mortality rates that have been observed suggest that relying on herd immunity without some combination of vaccines, proven treatment options, and strong non-pharmaceutical measures of prevention and control would likely result in a significant loss of life.
4.4.1 Sustained Immunity to COVID-19
In the process of mounting a response to a pathogen, the immune system produces antibodies specific to the pathogen.
@@ -1478,19 +1479,19 @@
[335].
-A two-year longitudinal study following convalesced SARS patients with a mean age of 29 found that IgG antibodies were detectable in all 56 patients surveyed for at least 16 months, and remained detectable in all but 4 (11.8%) of patients through the full two-year study period [336].
+IgG titers peaked by day 60, and persisted in all donors through the two-year duration of study [337].
+A two-year longitudinal study following convalesced SARS patients with a mean age of 29 found that IgG antibodies were detectable in all 56 patients surveyed for at least 16 months, and remained detectable in all but 4 (11.8%) of patients through the full two-year study period [338].
These results suggest that immunity to SARS-CoV-1 is sustained for at least a year.
The persistence of antibodies to SARS-CoV-2 remains under investigation.
-Circulating antibody titers to other coronaviruses have been reported to decline significantly after 1 year [337].
-Autopsies of lymph nodes and spleens from severe acute COVID-19 patients showed a loss of T follicular helper cells and germinal centers that may explain some of the impaired development of antibody responses [338].
-An early study (initially released on medRxiv on February 25, 2020) presented a chemiluminescence immunoassay to a synthetic peptide derived from the amino acid sequence of the SARS-CoV-2 S protein [339].
+Circulating antibody titers to other coronaviruses have been reported to decline significantly after 1 year [339].
+Autopsies of lymph nodes and spleens from severe acute COVID-19 patients showed a loss of T follicular helper cells and germinal centers that may explain some of the impaired development of antibody responses [340].
+An early study (initially released on medRxiv on February 25, 2020) presented a chemiluminescence immunoassay to a synthetic peptide derived from the amino acid sequence of the SARS-CoV-2 S protein [341].
This method was highly specific to SARS-CoV-2 and detected IgM in 57.2% and IgG in 71.4% and 57.2% of sera samples from 276 confirmed COVID-19 patients.
They reported that they could detect IgG within two days of the onset of fever and were not able to detect IgM any earlier, a pattern they compared to findings in MERS.
-Since then, several trials have reported the potential protective effect of antibodies in convalescent plasma obtained from recovered COVID-19 patients to treat critically ill COVID-19 patients [340,341,342].
+Since then, several trials have reported the potential protective effect of antibodies in convalescent plasma obtained from recovered COVID-19 patients to treat critically ill COVID-19 patients [342,343,344].
-Evidence to date suggests that sustained immunity to SARS-CoV-2 occurs for a period of at least 6-8 months [343,344,345].
-One study assessed sustained immunity using 245 blood samples from 188 COVID-19 positive patients [344].
+
Evidence to date suggests that sustained immunity to SARS-CoV-2 occurs for a period of at least 6-8 months [345,346,347].
+One study assessed sustained immunity using 245 blood samples from 188 COVID-19 positive patients [346].
The samples were collected at various time points between 6 and 240 days post-symptom onset, meaning some patients were assessed longitudinally.
Of the samples, 43 were collected at least 6 months after symptom onset.
After 1 month, 98% of patients were seropositive for Spike IgG.
@@ -1498,54 +1499,54 @@
[345,346], and this study confirms these finding and shows that these cells steadily increase over the 4-5 months post-symptom onset [344].
-Likewise, nucleocapsid-specific memory B cells seem to follow a similar pattern [344].
-SARS-CoV-2 memory CD8+ T cells were also detected in 70% of 169 COVID-19 patients after 1 month [344], which is consistent with previous research [347].
+RBD-specific memory B cells had been detected in COVID-19 patients 90 days post-symptom onset in previous studies [347,348], and this study confirms these finding and shows that these cells steadily increase over the 4-5 months post-symptom onset [346].
+Likewise, nucleocapsid-specific memory B cells seem to follow a similar pattern [346].
+SARS-CoV-2 memory CD8+ T cells were also detected in 70% of 169 COVID-19 patients after 1 month [346], which is consistent with previous research [349].
However, SARS-CoV-2 memory CD8+ T cells were slightly decreased (50%) 6 months post-symptom onset.
In this same subset of COVID-19 patients, 93% of subjects had detectable levels of SARS-CoV-2 memory CD4+ T cells, of which 42% had > 1% SARS-CoV-2-specific CD4+ T cells.
At 6 months, 92% of patients were positive for SARS-CoV-2 memory CD4+ T cells.
-Indeed, the spike-specific memory CD4+ T cells abundance over time were similar to the overall SARS-CoV-2-specific CD4+ T cells [344].
-T cell immunity to SARS-CoV-2 at 6-8 months post-symptom onset has also been confirmed by others [348,349].
+Indeed, the spike-specific memory CD4+ T cells abundance over time were similar to the overall SARS-CoV-2-specific CD4+ T cells [346].
+T cell immunity to SARS-CoV-2 at 6-8 months post-symptom onset has also been confirmed by others [350,351].
In another study, T cell reactivity to SARS-CoV-2 epitopes was also detected in some individuals never before exposed to SARS-CoV-2.
-This indicates that there is potential for cross-reactive T cell recognition between SARS-CoV-2 and pre-existing circulating coronaviruses that are responsible for the “common cold” [347], but further research is required.
-There is concern that immunity may wane over time, as there several reported cases of reinfection have been confirmed via genomic analysis that revealed distinct variants of SARS-CoV-2 within a single patient [350,351,352].
+This indicates that there is potential for cross-reactive T cell recognition between SARS-CoV-2 and pre-existing circulating coronaviruses that are responsible for the “common cold” [349], but further research is required.
+There is concern that immunity may wane over time, as there several reported cases of reinfection have been confirmed via genomic analysis that revealed distinct variants of SARS-CoV-2 within a single patient [352,353,354].
Further research is required to determine the full extent to which sustained immunity can be and is typically achieved following SARS-CoV-2 infection
-Furthermore, it is unclear whether previous infection may carry repercussions in terms of disease severity for patients [353] and what implications the possibility of reinfection holds for vaccine development and the long-term efficacy of vaccines [354,355].
+Furthermore, it is unclear whether previous infection may carry repercussions in terms of disease severity for patients [355] and what implications the possibility of reinfection holds for vaccine development and the long-term efficacy of vaccines [356,357].
4.4.2 Current Approaches
-
Several countries are now focused on implementing antibody tests, and in the United States, the FDA recently approved a serological test by Cellex for use under emergency conditions [356].
-Specifically, the Cellex qSARS-CoV-2 IgG/IgM Rapid Test is a chromatographic immunoassay designed to qualitatively detect IgM and IgG antibodies against SARS-CoV-2 in the plasma (from a blood sample) of patients suspected to have developed the SARS-CoV-2 infection [356].
+
Several countries are now focused on implementing antibody tests, and in the United States, the FDA recently approved a serological test by Cellex for use under emergency conditions [358].
+Specifically, the Cellex qSARS-CoV-2 IgG/IgM Rapid Test is a chromatographic immunoassay designed to qualitatively detect IgM and IgG antibodies against SARS-CoV-2 in the plasma (from a blood sample) of patients suspected to have developed the SARS-CoV-2 infection [358].
Such tests illuminate the progression of viral disease, as IgM are the first antibodies produced by the body and indicate that the infection is active.
-Once the body has responded to the infection, IgG are produced and gradually replace IgM, indicating that the body has developed immunogenic memory [357].
-The test cassette contains a pad of SARS-CoV-2 antigens and a nitrocellulose strip with lines for each of IgG and IgM, as well as a control (goat IgG) [356].
-In a specimen that contains antibodies against the SARS-CoV-2 antigen, the antibodies will bind to the strip and be captured by the IgM and/or IgG line(s), resulting in a change of color [356].
-With this particular assay, results can be read within 15-20 minutes [356].
-Other research groups, such as the Krammer lab of the Icahn School of Medicine at Mount Sinai, proposed an ELISA test that detects IgG and IgM that react against the receptor binding domain (RBD) of the spike proteins (S) of the virus [358].
-The authors are now working to get the assay into clinical use [359].
+Once the body has responded to the infection, IgG are produced and gradually replace IgM, indicating that the body has developed immunogenic memory [359].
+The test cassette contains a pad of SARS-CoV-2 antigens and a nitrocellulose strip with lines for each of IgG and IgM, as well as a control (goat IgG) [358].
+In a specimen that contains antibodies against the SARS-CoV-2 antigen, the antibodies will bind to the strip and be captured by the IgM and/or IgG line(s), resulting in a change of color [358].
+With this particular assay, results can be read within 15-20 minutes [358].
+Other research groups, such as the Krammer lab of the Icahn School of Medicine at Mount Sinai, proposed an ELISA test that detects IgG and IgM that react against the receptor binding domain (RBD) of the spike proteins (S) of the virus [360].
+The authors are now working to get the assay into clinical use [361].
4.4.3 Limitations of Serological Tests
-Importantly, false-positives can occur due to the cross-reactivity with other antibodies according to the clinical condition of the patient [356].
-Therefore, this test should be used in combination with RNA detection tests [356].
+
Importantly, false-positives can occur due to the cross-reactivity with other antibodies according to the clinical condition of the patient [358].
+Therefore, this test should be used in combination with RNA detection tests [358].
Due to the long incubation times and delayed immune responses of infected patients, serological tests are insufficiently sensitive for a diagnosis in the early stages of an infection.
The limitations due to timing make serological tests far less useful for enabling test-and-trace strategies.
4.5 Possible Alternatives to Current Practices for Identifying Active Cases
Clinical symptoms are too similar to other types of pneumonia to be sufficient as a sole diagnostics criterion.
In addition, as noted above, identifying asymptomatic cases is critical.
-Even among mildly symptomatic patients, a predictive model based on clinical symptoms had a sensitivity of only 56% and a specificity of 91% [360].
+Even among mildly symptomatic patients, a predictive model based on clinical symptoms had a sensitivity of only 56% and a specificity of 91% [362].
More problematic is that clinical symptom-based tests are only able to identify already symptomatic cases, not presymptomatic or asymptomatic cases.
They may still be important for clinical practice, and for reducing tests needed for patients deemed unlikely to have COVID-19.
-X-ray diagnostics have been reported to have high sensitivity but low specificity in some studies [361].
-Other studies have shown that specificity varies between radiologists [362], though the sensitivity reported here was lower than that published in the previous paper.
-However, preliminary machine-learning results have shown far higher sensitivity and specificity from analyzing chest X-rays than was possible with clinical examination [363].
+
X-ray diagnostics have been reported to have high sensitivity but low specificity in some studies [363].
+Other studies have shown that specificity varies between radiologists [364], though the sensitivity reported here was lower than that published in the previous paper.
+However, preliminary machine-learning results have shown far higher sensitivity and specificity from analyzing chest X-rays than was possible with clinical examination [365].
X-ray tests with machine learning can potentially detect asymptomatic or presymptomatic infections that show lung manifestations.
This approach would still not recognize entirely asymptomatic cases.
Given the above, the widespread use of X-ray tests on otherwise healthy adults is likely inadvisable.
4.6 Strategies and Considerations for Determining Whom to Test
-Early in the COVID-19 pandemic, testing was typically limited to individuals considered high risk for developing serious illness [364].
+
Early in the COVID-19 pandemic, testing was typically limited to individuals considered high risk for developing serious illness [366].
This approach often involved limiting testing to people with severe symptoms and people showing mild symptoms that had been in contact with a person who had tested positive.
Individuals who are asymptomatic (i.e., potential spreaders) and individuals who are able to recover at home are therefore often unaware of their status.
However, this method of testing administration misses a high proportion of infections and does not allow for test-and-trace methods to be used.
-For instance, a recent study from Imperial College estimates that in Italy, the true number of infections was around 5.9 million in a total population ~60 million, compared to the 70,000 detected as of March 28th [239].
-Another analysis, which examined New York state, indicated that as of May, 2020, approximately 300,000 cases had been reported in a total population of approximately 20 million [365].
-This corresponded to ~1.5% of the population, but ~12% of individuals sampled statewide were estimated as positive through antibody tests (along with indications of spatial heterogeneity at higher resolution) [365].
+For instance, a recent study from Imperial College estimates that in Italy, the true number of infections was around 5.9 million in a total population ~60 million, compared to the 70,000 detected as of March 28th [241].
+Another analysis, which examined New York state, indicated that as of May, 2020, approximately 300,000 cases had been reported in a total population of approximately 20 million [367].
+This corresponded to ~1.5% of the population, but ~12% of individuals sampled statewide were estimated as positive through antibody tests (along with indications of spatial heterogeneity at higher resolution) [367].
Technological advancements that facilitate widespread, rapid testing will therefore improve the potential to accurately assess the rate of infection and aid in controlling the virus’ spread.
4.7 Conclusions
Major advancements have been made in identifying diagnostic approaches.
@@ -1553,11 +1554,11 @@
4.7
As of October 2020, a range of diagnostic tests have become available.
One class of tests uses PCR (RT-PCR or qRT-PCR) to assess the presence of SARS-CoV-2 RNA, while another typically uses ELISA to test for the presence of antibodies to SARS-CoV-2.
The former approach is useful for identifying active infections, while the latter measures hallmarks of the immune response and therefore can detect either active infections or immunity gained from prior infection.
-Combining these tests leads to extremely accurate detection of SARS-CoV-2 infection (98.6%), but when used alone, PCR-based tests are recommended before 5.5 days after the onset of the illness and antibody tests after 5.5 days [366].
-Other strategies for testing can also influence the tests’ accuracy, such as the use of nasopharyngeal swabs versus BALF [366], which allow for trade-offs between patient’s comfort and test sensitivity.
+Combining these tests leads to extremely accurate detection of SARS-CoV-2 infection (98.6%), but when used alone, PCR-based tests are recommended before 5.5 days after the onset of the illness and antibody tests after 5.5 days [368].
+Other strategies for testing can also influence the tests’ accuracy, such as the use of nasopharyngeal swabs versus BALF [368], which allow for trade-offs between patient’s comfort and test sensitivity.
Additionally, technologies such as digital PCR may allow for scale-up in the throughput of diagnostic testing, facilitating widespread testing.
One major question that remains is whether people who recover from SARS-CoV-2 develop sustained immunity, and over what period this immunity is expected to last.
-Some reports have suggested that some patients may develop COVID-19 reinfections (e.g., [350]), but the rates of reinfection are currently unknown.
+Some reports have suggested that some patients may develop COVID-19 reinfections (e.g., [352]), but the rates of reinfection are currently unknown.
Serologic testing combined with PCR testing will be critical to confirming purported cases of reinfection and to identifying the duration over which immunity is retained and to understanding reinfection risks.
5 Identification and Development of Prophylactics and Therapeutics for COVID-19
5.1 Abstract
@@ -1566,7 +1567,7 @@ 5.1
5.2 Importance
@@ -1578,54 +1579,54 @@ 5.2<
This rapidly changing area of research provides important insight into how the ongoing pandemic can be managed and also demonstrates the power of interdisciplinary collaboration to rapidly understand a virus and match its characteristics with existing or novel pharmaceuticals.
5.3 Introduction
The novel coronavirus Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) emerged in late 2019 and quickly precipitated the worldwide spread of novel coronavirus disease 2019 (COVID-19).
-COVID-19 is associated with symptoms ranging from none (asymptomatic) to mild to severe, with approximately 2% of patients dying from COVID-19-related complications, such as acute respiratory disease syndrome (ARDS) [367].
-The virus is likely spread between people primarily by droplets, with the role of contact and aerosol transmission still in question [194,195].
+COVID-19 is associated with symptoms ranging from none (asymptomatic) to mild to severe, with approximately 2% of patients dying from COVID-19-related complications, such as acute respiratory disease syndrome (ARDS) [1].
+The virus is likely spread between people primarily by droplets, with the role of contact and aerosol transmission still in question [196,197].
As a result, public health guidelines have been critical to efforts to control the spread of the virus.
However, as of early 2021, COVID-19 remains a significant worldwide concern (Figure 2), with cases in some places surging far above the numbers reported during the initial outbreak in early 2020.
Due to the continued threat of the virus and the severity of the disease, the identification and development of prophylactic and therapeutic interventions have emerged as significant international priorities.
Both approaches hold valuable potential for controlling the impact of the disease.
Prophylactics bolster immunity to prevent an individual from contracting a disease, whereas therapeutics treat a disease in individuals who have already been infected.
While vaccine development programs have attracted significant attention and produced a number of promising candidates, there is also an immediate need for treatments that palliate symptoms and prevent the most severe outcomes from infection.
-Fortunately, prior developments during other recent pandemics, especially those caused by human coronaviruses (HCoV), has provided a number of hypotheses guiding a biomedical approach to the novel coronavirus infection.
+Fortunately, prior developments during other recent pandemics, especially those caused by human coronaviruses (HCoV), have provided a number of hypotheses guiding a biomedical approach to the novel coronavirus infection.
2,354,561 COVID-19 deaths had been reported worldwide as of February 10, 2021 (Figure 2).
Figure 2: Cumulative global COVID-19 deaths since January 22, 2020.
-Data are from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [368].
+Data are from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [369].
5.3.1 Lessons from Prior HCoV Outbreaks
SARS-CoV-2’s rapid shift from an unknown virus to a significant worldwide threat closely parallels the emergence of Severe acute respiratory syndrome-related coronavirus (SARS-CoV-1).
The first documented case of COVID-19 was reported in Wuhan, China in November 2019, and the disease quickly spread worldwide during the early months of 2020.
-Similarly, the first case of SARS was reported in November 2002 in the Guangdong Province of China, and it spread within China and then into several countries across continents over the following months [28,30].
-In fact, genome sequencing quickly revealed the virus causing COVID-19 to be a novel betacoronavirus closely related to SARS-CoV-1 [10].
+Similarly, the first case of SARS was reported in November 2002 in the Guangdong Province of China, and it spread within China and then into several countries across continents over the following months [30,32].
+In fact, genome sequencing quickly revealed the virus causing COVID-19 to be a novel betacoronavirus closely related to SARS-CoV-1 [12].
There are many similarities but also some differences in the characteristics of the two viruses that determine how they spread.
-SARS infection is severe, with an estimated death rate of 9.5% [30], while estimates of the death rate associated with COVID-19 are much lower, at approximately 2% [367].
-SARS-CoV-1 is highly contagious via droplet transmission and has a basic reproduction number (R0) of 4 (i.e., each person infected was estimated to infect four other people) [30].
-SARS-CoV-2 also appears to be spread primarily by droplet transmission [194,195], and most estimates of its R0 fall between 2.5 and 3 [367].
+SARS infection is severe, with an estimated death rate of 9.5% [32], while estimates of the death rate associated with COVID-19 are much lower, at approximately 2% [1].
+SARS-CoV-1 is highly contagious via droplet transmission and has a basic reproduction number (R0) of 4 (i.e., each person infected was estimated to infect four other people) [32].
+SARS-CoV-2 also appears to be spread primarily by droplet transmission [196,197], and most estimates of its R0 fall between 2.5 and 3 [1].
Furthermore, the 17-year difference in the timing of these two outbreaks has led to some major differences in the tools available for the international community’s response.
-At the time that SARS-CoV-1 emerged, no new HCoV had been identified in almost 40 years [28].
-The identity of the virus underlying the SARS disease remained unknown until April of 2003, when the SARS-CoV-1 virus was characterized through a worldwide scientific effort spearheaded by the WHO [28].
-In contrast, the SARS-CoV-2 genomic sequence was released on January 3, 2020 [10], only days after the international community became aware of the novel pneumonia-like illness now known as COVID-19.
-While SARS-CoV-1 belonged to a distinct lineage from the two other HCoV known at the time of its discovery [30], SARS-CoV-2 is closely related to SARS-CoV-1 and a more distant relative of another HCoV characterized in 2012, Middle East respiratory syndrome-related coronavirus [13,369].
-Thus, despite their phylogenetic similarity, SARS-CoV-2 emerged under very different circumstances than SARS-CoV-1 in terms of scientific knowledge about HCoV.
+At the time that SARS-CoV-1 emerged, no new HCoV had been identified in almost 40 years [30].
+The identity of the virus underlying the SARS disease remained unknown until April of 2003, when the SARS-CoV-1 virus was characterized through a worldwide scientific effort spearheaded by the World Health Organization (WHO) [30].
+In contrast, the SARS-CoV-2 genomic sequence was released on January 3, 2020 [12], only days after the international community became aware of the novel pneumonia-like illness now known as COVID-19.
+While SARS-CoV-1 belonged to a distinct lineage from the two other HCoV known at the time of its discovery [32], SARS-CoV-2 is closely related to SARS-CoV-1 and a more distant relative of another HCoV characterized in 2012, Middle East respiratory syndrome-related coronavirus [15,370].
+Despite their phylogenetic similarity, SARS-CoV-2 emerged under very different circumstances than SARS-CoV-1 in terms of scientific knowledge about HCoV.
The trajectories of the pandemics associated with each of the viruses have also diverged significantly.
-By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices such as mask wearing [28].
-In contrast, MERS is still circulating and remains a concern; although the fatality rate is very high at almost 35%, the disease is much less easily transmitted, as its R0 has been estimated to be 1 [30].
-The low R0 in combination with public health practices allowed for its spread to be contained [30].
+By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices such as mask wearing [30].
+In contrast, MERS is still circulating and remains a concern; although the fatality rate is very high at almost 35%, the disease is much less easily transmitted, as its R0 has been estimated to be 1 [32].
+The low R0 in combination with public health practices allowed for its spread to be contained [32].
Neither of these trajectories are comparable to that of SARS-CoV-2, which remains a serious threat worldwide more than a year after the first cases of COVID-19 emerged.
Early results suggest that pharmaceutical interventions for COVID-19 may be more successful than efforts to develop prophylactics and therapeutics for SARS and MERS were.
-Care for SARS and MERS patients prioritized supportive care and symptom management [30].
+Care for SARS and MERS patients prioritized supportive care and symptom management [32].
To the extent that clinical treatments for SARS and MERS were explored, there is generally a lack of evidence supporting their efficacy.
-For example, Ribavirin is an antiviral that was often used in combination with corticosteroids and sometimes interferon (IFN) medications to treat SARS and MERS [28], but its effects have been found to be inconclusive in retrospective and in vitro analyses of SARS and the SARS-CoV-1 virus, respectively [28].
-IFNs and Ribavirin have shown promise in in vitro analyses of MERS, but their clinical effectiveness remains unknown [28].
+For example, Ribavirin is an antiviral that was often used in combination with corticosteroids and sometimes interferon (IFN) medications to treat SARS and MERS [30], but its effects have been found to be inconclusive in retrospective and in vitro analyses of SARS and the SARS-CoV-1 virus, respectively [30].
+IFNs and Ribavirin have shown promise in in vitro analyses of MERS, but their clinical effectiveness remains unknown [30].
Therefore, only limited pharmaceutical advances from prior HCoV outbreaks can be adopted to COVID-19.
Importantly, though, prior analyses of the virological and pathogenic properties of SARS-CoV-1 and MERS-CoV provide a strong foundation for the development of hypotheses about SARS-CoV-2 that have served to accelerated the development and identification of potential prophylactic and therapeutic approaches.
5.3.2 Therapeutic Approaches
Therapeutic approaches to the current pandemic can utilize two potential avenues: they can reduce the symptoms that are harmful to COVID-19 patients, or they can directly target the virus to hinder the spread of infection.
The goal of the former is to reduce the severity and risks of an active infection, while for the latter, it is to inhibit the replication of the virus once an individual is infected.
A variety of symptom profiles with a range of severity are associated with COVID-19, many of which are not life-threatening.
-A study of COVID-19 patients in a hospital in Berlin, Germany found that the symptoms associated with the highest risk of death included infection-related symptoms, such as sepsis, respiratory symptoms such as ARDS, and cardiovascular failure or pulmonary embolism [370].
+A study of COVID-19 patients in a hospital in Berlin, Germany found that the symptoms associated with the highest risk of death included infection-related symptoms, such as sepsis, respiratory symptoms such as ARDS, and cardiovascular failure or pulmonary embolism [371].
Therapeutics that reduce the risks associated with these severe outcomes hold particular potential to reduce the pandemic death toll.
On the other hand, therapeutics that directly target the virus itself would hold the potential to prevent people infected with SARS-CoV-2 from developing potentially damaging symptoms.
These treatments typically fall into the broad category of antivirals.
@@ -1644,44 +1645,44 @@
[371].
+Trials data are from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [372].
5.4 Small Molecule Drugs
-
Small molecules are synthesized compounds of low molecular weight, typically less than 1 kilodalton (kDa) [372].
-Small-molecule pharmaceutical agents have been a backbone of drug development since the discovery of penicillin in the early twentieth century [373].
-It and other antibiotics have long been among the best known applications of small molecules to therapeutics, but biotechnological developments such as the prediction of protein-protein interactions have facilitated advances in precise targeting of specific structures using small molecules [373].
+
Small molecules are synthesized compounds of low molecular weight, typically less than 1 kilodalton (kDa) [373].
+Small-molecule pharmaceutical agents have been a backbone of drug development since the discovery of penicillin in the early twentieth century [374].
+It and other antibiotics have long been among the best known applications of small molecules to therapeutics, but biotechnological developments such as the prediction of protein-protein interactions have facilitated advances in precise targeting of specific structures using small molecules [374].
Small molecule drugs today encompass a wide range of therapeutics beyond antibiotics, including antivirals, protein inhibitors, and many broad-spectrum pharmaceuticals.
5.4.1 Small Molecule Antivirals
Antiviral drugs against SARS-CoV-2 are designed to inhibit replication of a virus within an epithelial host cell.
-This process requires inhibiting the replication cycle of a virus by disrupting one of six fundamental steps [374].
+This process requires inhibiting the replication cycle of a virus by disrupting one of six fundamental steps [375].
In the first of these steps, the virus attaches to and enters the host cell through endocytosis.
Then the virus undergoes uncoating, which is classically defined as the release of viral contents into the host cell.
Next, the viral genetic material enters the nucleus where it gets replicated during the biosynthesis stage.
During the assembly stage, viral proteins are translated, allowing new viral particles to be assembled.
In the final step new viruses are released into the extracellular environment.
Many antiviral drugs are designed to inhibit the replication of viral genetic material during the biosynthesis step.
-Unlike DNA viruses, which can use the host enzymes to propagate themselves, RNA viruses like SARS-CoV-2 depend on their own polymerase, the RNA-dependent RNA polymerase (RdRP), for replication [375,376].
-Targeting RdRP is therefore an effective strategy for antivirals against RNA viruses and is the proposed mechanism underlying the treatment of SARS and MERS with Ribavirin [377].
+Unlike DNA viruses, which can use the host enzymes to propagate themselves, RNA viruses like SARS-CoV-2 depend on their own polymerase, the RNA-dependent RNA polymerase (RdRP), for replication [376,377].
+Targeting RdRP is therefore an effective strategy for antivirals against RNA viruses and is the proposed mechanism underlying the treatment of SARS and MERS with Ribavirin [378].
However, although antivirals are designed to target a virus, they can also impact other processes in the host and may have unintended effects.
Therefore, these therapeutics must be evaluated for both efficacy and safety.
5.4.1.1 Nucleoside and Nucleotide Analogs
5.4.1.1.1 Favipiravir
-Favipiravir (Avigan), also known as T-705, was discovered by Toyama Chemical Co., Ltd. [378].
-The drug was found to be effective at blocking viral amplification in several influenza subtypes as well as other RNA viruses, such as Flaviviridae and Picornaviridae, through a reduction in plaque formation [379] and viral replication in Madin-Darby canine kidney cells [380].
-Furthermore, inoculation of mice with favipiravir was shown to increase survival of influenza infections [379,380].
-In 2014, the drug was approved in Japan for the treatment of influenza that was resistant to conventional treatments like neuraminidase inhibitors [381].
-Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) acts as a purine and purine nucleoside analogue that inhibits viral RNA polymerase in a dose-dependent manner across a range of RNA viruses, including influenza viruses [382,383,384,385,386].
+
Favipiravir (Avigan), also known as T-705, was discovered by Toyama Chemical Co., Ltd. [379].
+The drug was found to be effective at blocking viral amplification in several influenza subtypes as well as other RNA viruses, such as Flaviviridae and Picornaviridae, through a reduction in plaque formation [380] and viral replication in Madin-Darby canine kidney cells [381].
+Furthermore, inoculation of mice with favipiravir was shown to increase survival of influenza infections [380,381].
+In 2014, the drug was approved in Japan for the treatment of influenza that was resistant to conventional treatments like neuraminidase inhibitors [382].
+Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) acts as a purine and purine nucleoside analogue that inhibits viral RNA polymerase in a dose-dependent manner across a range of RNA viruses, including influenza viruses [383,384,385,386,387].
Nucleotides and nucleosides are the natural building blocks for RNA synthesis.
-Because of this, modifications to nucleotides and nucleosides can disrupt key processes including replication [387].
+Because of this, modifications to nucleotides and nucleosides can disrupt key processes including replication [388].
Biochemical experiments showed that favipiravir was recognized as a purine nucleoside analogue and incorporated into the viral RNA template.
-A single incorporation does not influence RNA transcription; however, multiple events of incorporation lead to the arrest of RNA synthesis [388].
-Evidence for T-705 inhibiting viral RNA polymerase are based on time-of-drug addition studies that found that viral loads were reduced with the addition of favipiravir in early times post-infection [382,385,386].
+A single incorporation does not influence RNA transcription; however, multiple events of incorporation lead to the arrest of RNA synthesis [389].
+Evidence for T-705 inhibiting viral RNA polymerase are based on time-of-drug addition studies that found that viral loads were reduced with the addition of favipiravir in early times post-infection [383,386,387].
The effectiveness of favipiravir for treating patients with COVID-19 is currently under investigation.
-An open-label, nonrandomized, before-after controlled study was recently conducted [389].
+An open-label, nonrandomized, before-after controlled study was recently conducted [390].
The study included 80 COVID-19 patients (35 treated with favipiravir, 45 control) from the isolation ward of the National Clinical Research Center for Infectious Diseases (The Third People’s Hospital of Shenzhen), Shenzhen, China.
The patients in the control group were treated with other antivirals, such as lopinavir and ritonavir.
-It should be noted that although the control patients received antivirals, two subsequent large-scale analyses, the WHO Solidarity trial and the RECOVERY trial, identified no effect of lopinavir or of a lopinavir-ritonavir combination, respectively, on the metrics of COVID-19-related mortality that each assessed [390,391,392].
+It should be noted that although the control patients received antivirals, two subsequent large-scale analyses, the WHO Solidarity trial and the RECOVERY trial, identified no effect of lopinavir or of a lopinavir-ritonavir combination, respectively, on the metrics of COVID-19-related mortality that each assessed [391,392,393].
Treatment was applied on days 2-14; treatment stopped either when viral clearance was confirmed or at day 14.
The efficacy of the treatment was measured by, first, the time until viral clearance using Kaplan-Meier survival curves, and, second, the improvement rate of chest computed tomography (CT) scans on day 14 after treatment.
The study found that favipiravir increased the speed of recovery, measured as viral clearance from the patient by RT-PCR, with patients receiving favipiravir recovering in four days compared to 11 days for patients receiving antivirals such as lopinavir and ritonavir.
@@ -1692,33 +1693,32 @@
[393].
-
In late 2020 and early 2021, the first randomized controlled trials of favipiravir for the treatment of COVID-19 released results [394,395,396].
-The first [394] used a randomized, controlled, open-label design to compare two drugs, favipiravir and baloxavir marboxil, to SOC alone.
+Additionally, it should be noted that this study was temporarily retracted and then restored without an explanation [394].
+In late 2020 and early 2021, the first randomized controlled trials of favipiravir for the treatment of COVID-19 released results [395,396,397].
+The first [395] used a randomized, controlled, open-label design to compare two drugs, favipiravir and baloxavir marboxil, to standard of care (SOC) alone.
Here, SOC included antivirals such as lopinavir/ritonavir and was administered to all patients.
The primary endpoint analyzed was viral clearance at day 14.
The sample size for this study was very small, with 29 total patients enrolled, and no significant effect of the treatments was found for the primary or any of the secondary outcomes analyzed, which included mortality.
The second study was larger, with 96 patients enrolled, and also utilized a randomized design.
-This study enrolled only patients with mild to moderate symptoms and randomized them into two groups: one receiving CQ in addition to SOC, and the other receiving favipiravir in addition to SOC.
+This study enrolled only patients with mild to moderate symptoms and randomized them into two groups: one receiving chloroquine (CQ) in addition to SOC, and the other receiving favipiravir in addition to SOC.
This study reported a non-significant trend for patients receiving favipiravir to have a shorter hospital stay and less likelihood of progressing to mechanical ventilation or to an oxygen saturation < 90%.
However, given the fact that favipiravir was being compared to CQ, which is now widely understood to be ineffective for treating COVID-19, these results do not suggest that favipiravir was likely to have had a strong effect on these outcomes.
-On the other hand, another trial of 60 patients reported a significant effect of favipiravir on viral clearance at four days (a secondary endpoint), but not at 10 days (the primary endpoint) [396].
-This study, as well as a prior study of favipiravir [397], also reported that the drug was generally well-tolerated.
+On the other hand, another trial of 60 patients reported a significant effect of favipiravir on viral clearance at four days (a secondary endpoint), but not at 10 days (the primary endpoint) [397].
+This study, as well as a prior study of favipiravir [398], also reported that the drug was generally well-tolerated.
Thus, in combination, these small studies suggest that the effects of favipiravir as a treatment for COVID-19 cannot be determined based on the available evidence, but additionally, none raise major concerns about the safety profile of the drug.
5.4.1.1.2 Remdesivir
Remdesivir (GS-5734) is an intravenous antiviral that was developed by Gilead Sciences to treat Ebola Virus Disease (EVD).
At the outset of the COVID-19 pandemic, it did not have any have any FDA-approved use.
-However, on May 1, 2020, the FDA issued an Emergency Use Authorization (EUA) for remdesivir for the treatment of hospitalized COVID-19 patients [398].
-The EUA was based on information from two clinical trials, NCT04280705 and NCT04292899 [399,400,401,402].
-Remdesivir is metabolized to GS-441524, an adenosine analog that inhibits a broad range of polymerases and then evades exonuclease repair, causing chain termination [403,404,405].
-A clinical trial in the Democratic Republic of Congo found some evidence of effectiveness against EVD, but two antibody preparations were found to be more effective, and remdesivir was not pursued [406].
-Although it was developed against EVD, remdesivir also inhibits polymerase and replication of the coronaviruses MERS-CoV and SARS-CoV-1 in cell culture assays with submicromolar IC50s [407].
-It has also been found to inhibit SARS-CoV-2, showing synergy with chloroquine in vitro [405].
-The effectiveness of remdesivir for treating patients with COVID-19 is currently under investigation.
-Remdesivir was first used on some COVID-19 patients under compassionate use guidelines [408,409].
+However, on May 1, 2020, the FDA issued an Emergency Use Authorization (EUA) for remdesivir for the treatment of hospitalized COVID-19 patients [399].
+The EUA was based on information from two clinical trials, NCT04280705 and NCT04292899 [400,401,402,403].
+Remdesivir is metabolized to GS-441524, an adenosine analog that inhibits a broad range of polymerases and then evades exonuclease repair, causing chain termination [404,405,406].
+A clinical trial in the Democratic Republic of Congo found some evidence of effectiveness against EVD, but two antibody preparations were found to be more effective, and remdesivir was not pursued [407].
+Although it was developed against EVD, remdesivir also inhibits polymerase and replication of the coronaviruses MERS-CoV and SARS-CoV-1 in cell culture assays with submicromolar IC50s [408].
+It has also been found to inhibit SARS-CoV-2, showing synergy with CQ in vitro [406].
+Remdesivir was first used on some COVID-19 patients under compassionate use guidelines [409,410].
All were in late stages of COVID-19 infection, and initial reports were inconclusive about the drug’s efficacy.
Gilead Sciences, the maker of remdesivir, led a recent publication that reported outcomes for compassionate use of the drug in 61 patients hospitalized with confirmed COVID-19.
-Here, 200 mg of remdesivir was administered intravenously on day 1, followed by a further 100 mg/day for 9 days [402].
+Here, 200 mg of remdesivir was administered intravenously on day 1, followed by a further 100 mg/day for 9 days [403].
There were significant issues with the study design, or lack thereof.
There was no randomized control group.
The inclusion criteria were variable: some patients only required low doses of oxygen, while others required ventilation.
@@ -1727,49 +1727,48 @@
There was a short follow-up period of investigation.
Some patients worsened, some patients died, and eight were excluded from the analysis mainly due to missing post-baseline information; thus, their health was unaccounted for.
Therefore, even though the study reported clinical improvement in 68% of the 53 patients ultimately evaluated, due to the significant issues with study design, it could not be determined whether treatment with remdesivir had an effect or whether these patients would have recovered regardless of treatment.
-Another study comparing 5- and 10-day treatment regimens reported similar results but was also limited because of the lack of a placebo control [411].
+Another study comparing 5- and 10-day treatment regimens reported similar results but was also limited because of the lack of a placebo control [412].
These studies did not alter the understanding of the efficacy of remdesivir in treating COVID-19, but the encouraging results provided motivation for placebo-controlled studies.
-Remdesivir was later tested in a double-blind placebo-controlled phase 3 clinical trial performed at 60 trial sites, 45 of which were in the United States [400,401].
+
Remdesivir was later tested in a double-blind placebo-controlled phase 3 clinical trial performed at 60 trial sites, 45 of which were in the United States [401,402].
The trial recruited 1,062 patients and randomly assigned them to placebo treatment or treatment with remdesivir.
-Patients were stratified for randomization based on site and the severity of disease presentation at baseline [401].
+Patients were stratified for randomization based on site and the severity of disease presentation at baseline [402].
The treatment was 200 mg on day 1, followed by 100 mg on days 2 through 10.
-Data was analyzed from a total of 1,059 patients who completed the 29-day course of the trial, with 517 assigned to remdesivir and 508 to placebo [401].
+Data was analyzed from a total of 1,059 patients who completed the 29-day course of the trial, with 517 assigned to remdesivir and 508 to placebo [402].
The two groups were well matched demographically and clinically at baseline.
Those who received remdesivir had a median recovery time of 10 days, as compared with 15 days in those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; p < 0.001).
The Kaplan-Meier estimates of mortality by 14 days were 6.7% with remdesivir and 11.9% with placebo, with a hazard ratio (HR) for death of 0.55 and a 95% CI of 0.36 to 0.83, and at day 29, remdesivir corresponded to 11.4% and the placebo to 15.2% (HR: 0.73; 95% CI: 0.52 to 1.03).
Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients in the placebo group (31.6%).
-This study also reported an association between remdesivir administration and both clinical improvement and a lack of progression to more invasive respiratory intervention in patients receiving non-invasive and invasive ventilation at randomization [401].
-Largely on the results of this trial, the FDA reissued and expanded the EUA for remdesivir for the treatment of hospitalized COVID-19 patients ages twelve and older [398].
-Additional clinical trials are currently underway to evaluate the use of remdesivir to treat COVID-19 patients at both early and late stages of infection and in combination with other drugs (Figure 3).
-These trials include [405,412,413,414,415].
-As of October 22, 2020, remdesivir received FDA approval based on three clinical trials [416].
-However, results suggesting no effect of remdesivir on survival were reported by the WHO Solidarity trial [390].
-This large-scale, open-label trial enrolled 11,330 adult in-patients at 405 hospitals in 30 countries around the world [390].
+This study also reported an association between remdesivir administration and both clinical improvement and a lack of progression to more invasive respiratory intervention in patients receiving non-invasive and invasive ventilation at randomization [402].
+Largely on the results of this trial, the FDA reissued and expanded the EUA for remdesivir for the treatment of hospitalized COVID-19 patients ages twelve and older [399].
+Additional clinical trials [406,413,414,415,416] are currently underway to evaluate the use of remdesivir to treat COVID-19 patients at both early and late stages of infection and in combination with other drugs (Figure 3).
+As of October 22, 2020, remdesivir received FDA approval based on three clinical trials [417].
+However, results suggesting no effect of remdesivir on survival were reported by the WHO Solidarity trial [391].
+This large-scale, open-label trial enrolled 11,330 adult in-patients at 405 hospitals in 30 countries around the world [391].
Patients were randomized in equal proportions into four experimental and a control conditions, corresponding to four candidate treatments for COVID-19 and SOC, respectively; no placebo was administered.
The 2,750 patients in the remdesivir group were administered 200 mg intravenously on the first day and 100 mg on each subsequent day until day 10 and assessed for in-hospital death (primary endpoint), duration of hospitalization, and progression to mechanical ventilation.
There were also 2,708 control patients who would have been eligible and able to receive remdesivir were they not assigned to the control group.
A total of 604 patients among these two cohorts deceased during initial hospitalization, with 301 in the remdesivir group and 303 in the control group.
The rate ratio of death between these two groups was therefore not significant (p = 0.50), suggesting that the administration of remdesivir did not affect survival.
The two secondary analyses similarly did not find any effect of remdesivir.
-Additionally, the authors compared data from their study with data from three other studies of remdesivir (including [401]) stratified by supplemental oxygen status.
+Additionally, the authors compared data from their study with data from three other studies of remdesivir (including [402]) stratified by supplemental oxygen status.
The adjusted rate ratio for death based on this meta-analysis was 0.91.
These results thus do not support the previous findings that remdesivir reduced median recovery time and mortality risk in COVID-19 patients.
-In response to the results of the Solidarity trial, Gilead, which manufactures remdesivir, released a statement pointing to the fact that the Solidarity trial was not placebo-controlled or double-blind and at the time of the statement had not been peer reviewed [417]; these sentiments have been echoed elsewhere [418].
-Other critiques of this study have noted that antivirals are not typically targeted at patients with severe illness, and therefore remdesivir could be more beneficial for patients with mild rather than severe cases [392,419].
-However, the publication associated with the trial sponsored by Gilead did purport an effect of remdesivir on patients with severe disease, identifying an 11 versus 18 day recovery period (rate ratio for recovery: 1.31, 95% CI 1.12 to 1.52), although the results of a significance test were not provided [401].
-Additionally, a smaller analysis of 598 patients, of whom two-thirds were randomized to receive remdesivir for either 5 or 10 days, reported a small effect of treatment with remdesivir for five days relative to standard of care in patients with moderate COVID-19 [420].
+
In response to the results of the Solidarity trial, Gilead, which manufactures remdesivir, released a statement pointing to the fact that the Solidarity trial was not placebo-controlled or double-blind and at the time of the statement had not been peer reviewed [418]; these sentiments have been echoed elsewhere [419].
+Other critiques of this study have noted that antivirals are not typically targeted at patients with severe illness, and therefore remdesivir could be more beneficial for patients with mild rather than severe cases [393,420].
+However, the publication associated with the trial sponsored by Gilead did purport an effect of remdesivir on patients with severe disease, identifying an 11 versus 18 day recovery period (rate ratio for recovery: 1.31, 95% CI 1.12 to 1.52), although the results of a significance test were not provided [402].
+Additionally, a smaller analysis of 598 patients, of whom two-thirds were randomized to receive remdesivir for either 5 or 10 days, reported a small effect of treatment with remdesivir for five days relative to standard of care in patients with moderate COVID-19 [421].
These results suggest that remdesivir could improve outcomes for patients with moderate COVID-19, but that additional information would be needed to understand the effects of different durations of treatment.
-Therefore, the arguments put forward in defense of remdesivir do not necessarily seem robust in light of the large sample size used in the Solidarity trial, especially since the broad international nature of the Solidarity clinical trial, which included countries with a wide range of economic profiles and a variety of healthcare systems, provides a much-needed global perspective in a pandemic [392].
-On the other hand, only 62% of patients in the Solidarity trial were randomized on the day of admission or one day afterwards [390], and concerns have been raised that differences in disease progression could influence the effectiveness of remdesivir [392].
+Therefore, the arguments put forward in defense of remdesivir do not necessarily seem robust in light of the large sample size used in the Solidarity trial, especially since the broad international nature of the Solidarity clinical trial, which included countries with a wide range of economic profiles and a variety of healthcare systems, provides a much-needed global perspective in a pandemic [393].
+On the other hand, only 62% of patients in the Solidarity trial were randomized on the day of admission or one day afterwards [391], and concerns have been raised that differences in disease progression could influence the effectiveness of remdesivir [393].
Despite the findings of the Solidarity trial, remdesivir remains available for the treatment of COVID-19 in many places.
-Follow-up studies are needed and, in many cases, are underway to further investigate remdesivir-related outcomes, with possibilities including combinations of remdesivir with other drugs such as baricitinib, which is an inhibitor of Janus kinase 1 and 2 [421].
+Follow-up studies are needed and, in many cases, are underway to further investigate remdesivir-related outcomes, with possibilities including combinations of remdesivir with other drugs such as baricitinib, which is an inhibitor of Janus kinase 1 and 2 [422].
Similarly, the extent to which the remdesivir dosing regimen could influence outcomes continues to be under consideration.
-In complement to the study that found that a 5-day course of remdesivir improved outcomes for patients with moderate COVID-19 but a 10-day course did not [420], a randomized, open-label trial compared the effect of remdesivir on 397 patients with severe COVID-19 over 5 versus 10 days [399,411].
+A randomized, open-label trial compared the effect of remdesivir on 397 patients with severe COVID-19 over 5 versus 10 days [400,412], complementing the study that found that a 5-day course of remdesivir improved outcomes for patients with moderate COVID-19 but a 10-day course did not [421].
Patients in the two groups were administered 200 mg of remdesivir intravenously on the first day, followed by 100 mg on the subsequent four or nine days, respectively.
The two groups differed significantly in their clinical status, with patients assigned to the 10-day group having more severe illness.
This study also differed from most because it included not only adults, but also pediatric patients as young as 12 years old.
It reported no significant differences across several outcomes for patients receiving a 5-day or 10-day course, when correcting for baseline clinical status.
-The data did suggest that the 10-day course might reduce mortality in the most severe patients at day 14, but the representation of this group in the study population was too low to justify any conclusions [411].
+The data did suggest that the 10-day course might reduce mortality in the most severe patients at day 14, but the representation of this group in the study population was too low to justify any conclusions [412].
Thus, additional research is also required to determine whether the dosage and duration of remdesivir administration influences outcomes.
In summary, remdesivir is a first in class drug due to its FDA approval.
Early investigations of this drug established proof of principle that drugs targeting the virus can benefit COVID-19 patients.
@@ -1781,43 +1780,43 @@
They are typically combined with protease inhibitors, integrase inhibitors, and even other polymerase inhibitors.
Additional clinical trials of remdesivir in different patient pools and in combination with other therapies will refine its use in the clinic.
5.4.1.2 Protease Inhibitors
-Several studies showed that viral proteases play an important role in the life cycle of viruses, including coronaviruses, by modulating the cleavage of viral polyprotein precursors [422].
+
Several studies showed that viral proteases play an important role in the life cycle of viruses, including coronaviruses, by modulating the cleavage of viral polyprotein precursors [423].
Several FDA-approved drugs target proteases, including lopinavir and ritonavir for HIV infection and simeprevir for hepatitis C virus infection.
-In particular, serine protease inhibitors were suggested for the treatment of SARS and MERS viruses [423].
-Recently, a study [67] suggested that camostat mesylate, an FDA-approved protease inhibitor (PI) could block the entry of SARS-CoV-2 into lung cells in vitro.
+In particular, serine protease inhibitors were suggested for the treatment of SARS and MERS viruses [424].
+Recently, a study [69] suggested that camostat mesylate, an FDA-approved protease inhibitor (PI) could block the entry of SARS-CoV-2 into lung cells in vitro.
Thus far, investigation of possible PIs that could work against SARS-CoV-2 has been driven by computational predictions.
Computer-aided design allowed for the development of a Michael acceptor inhibitor, now known as N3, to target a protease critical to SARS-CoV-2 replication.
-Discovery of the N3 mechanism arose from interest in the two polyproteins encoded by the SARS-CoV-2 replicase gene, pp1a and pp1ab, that are critical for viral replication and transcription [424].
+Discovery of the N3 mechanism arose from interest in the two polyproteins encoded by the SARS-CoV-2 replicase gene, pp1a and pp1ab, that are critical for viral replication and transcription [425].
These polyproteins must undergo proteolytic processing.
This processing is usually conducted by Mpro, a 33.8-kDa SARS-CoV-2 protease that is therefore fundamental to viral replication and transcription.
-N3 was designed computationally [425] to bind in the substrate binding pocket of the Mpro protease of SARS-like coronaviruses [426], therefore inhibiting proteolytic processing.
-Subsequently, the structure of N3-bound SARS-CoV-2 Mpro was solved [424], confirming the computational prediction.
-N3 was tested in vitro on SARS-CoV-2-infected Vero cells, which belong to a line of cells established from the kidney epithelial cells of an African green monkey, and was found to inhibit SARS-CoV-2 [424].
+N3 was designed computationally [426] to bind in the substrate binding pocket of the Mpro protease of SARS-like coronaviruses [427], therefore inhibiting proteolytic processing.
+Subsequently, the structure of N3-bound SARS-CoV-2 Mpro was solved [425], confirming the computational prediction.
+N3 was tested in vitro on SARS-CoV-2-infected Vero cells, which belong to a line of cells established from the kidney epithelial cells of an African green monkey, and was found to inhibit SARS-CoV-2 [425].
Although N3 is a strong inhibitor of SARS-CoV-2 in vitro, its safety and efficacy still need to be tested in healthy volunteers and patients.
-After the design and confirmation of N3 as a highly potent Michael acceptor inhibitor and the identification of Mpro’s structure [424,427], 10,000 compounds were screened for their in vitro anti-Mpro activity.
+After the design and confirmation of N3 as a highly potent Michael acceptor inhibitor and the identification of Mpro’s structure [425,428], 10,000 compounds were screened for their in vitro anti-Mpro activity.
The six leads that were identified were ebselen, disulfiram, tideglusib, carmofur, and PX-12.
-In vitro analysis revealed that Ebselen had the strongest potency in reducing the viral load in SARS-CoV-2-infected Vero cells [424].
-Ebselen is an organoselenium compound with anti-inflammatory and antioxidant properties [428].
-It has been proposed as a possible treatment for conditions ranging from bipolar disorder to diabetes to heart disease [428], and a preliminary investigation of ebselen as a treatment for noise-induced hearing loss provided promising reports of its safety [429].
-For COVID-19, the NSP5 in SARS-CoV-2 contains a cysteine at the active site of Mpro, and ebselen is able to inactivate the protease by bonding covalently with this cysteine to form a selenosulfide [428,430].
-Interestingly there has been some argument that selenium deficiency may be associated with more severe COVID-19 outcomes [431,432,433], possibly indicating that its antioxidative properties are protective [430].
-On the other hand, ebselen and the other compounds identified are likely to be promiscuous binders, which could diminish their therapeutic potential [424].
+In vitro analysis revealed that ebselen had the strongest potency in reducing the viral load in SARS-CoV-2-infected Vero cells [425].
+Ebselen is an organoselenium compound with anti-inflammatory and antioxidant properties [429].
+It has been proposed as a possible treatment for conditions ranging from bipolar disorder to diabetes to heart disease [429], and a preliminary investigation of ebselen as a treatment for noise-induced hearing loss provided promising reports of its safety [430].
+For COVID-19, the NSP5 in SARS-CoV-2 contains a cysteine at the active site of Mpro, and ebselen is able to inactivate the protease by bonding covalently with this cysteine to form a selenosulfide [429,431].
+Interestingly there has been some argument that selenium deficiency may be associated with more severe COVID-19 outcomes [432,433,434], possibly indicating that its antioxidative properties are protective [431].
+On the other hand, ebselen and the other compounds identified are likely to be promiscuous binders, which could diminish their therapeutic potential [425].
While there is clear computational and in vitro support for ebselen’s potential as a COVID-19 therapeutic, results from clinical trials are not yet available for this compound.
-However, as of July 2020, phase II clinical trials commenced to assess the effects of SPI-1005, an investigational drug from Sound Pharmaceuticals that contains ebselen [434], on 60 adults presenting with each of moderate [435] and severe [436] COVID-19.
+However, as of July 2020, phase II clinical trials commenced to assess the effects of SPI-1005, an investigational drug from Sound Pharmaceuticals that contains ebselen [435], on 60 adults presenting with each of moderate [436] and severe [437] COVID-19.
In summary, N3 is a computationally designed molecule that inhibits the viral transcription through inhibiting Mpro.
Ebselen is both a strong Mpro inhibitor and strong inhibitor of viral replication in vitro that was found to reduce SARS-CoV-2 viral load even more effectively than N3.
-Ebselen is a very promising compound since its safety has been demonstrated in other indications.
-However, ebselen may be a false positive, since it is a promiscuous compound that can have many targets [437].
+Ebselen is a promising compound since its safety has been demonstrated in other indications.
+However, ebselen may be a false positive, since it is a promiscuous compound that can have many targets [438].
Therefore, the results of ongoing clinical trials are expected to help establish whether compounds with higher specificity are required.
5.4.2 Broad-Spectrum Pharmaceuticals
-When a virus enters a host, the host becomes the virus’ environment.
+
When a virus enters a host, the host becomes the virus’s environment.
Therefore, the state of the host can also influence the virus’s ability to replicate and spread.
-Traditionally, viral targets have been favored for pharmaceutical interventions because altering host processes is likely to be less specific than targeting the virus directly [438].
-On the other hand, targeting the host offers potential for a complementary strategy to antivirals that could broadly limit the ability of viruses to replicate [438].
+Traditionally, viral targets have been favored for pharmaceutical interventions because altering host processes is likely to be less specific than targeting the virus directly [439].
+On the other hand, targeting the host offers potential for a complementary strategy to antivirals that could broadly limit the ability of viruses to replicate [439].
As a result, therapeutic approaches that target host proteins have become an area of interest for SARS-CoV-2.
Viral entry receptors in particular have been identified as a potential target.
-Entry of SARS-CoV-2 into the cell depends on binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which is catalyzed by the enzyme encoded by TMPRSS2 [67].
+Entry of SARS-CoV-2 into the cell depends on binding to angiotensin-converting enzyme 2 (ACE2), which is catalyzed by the enzyme encoded by TMPRSS2 [69].
In principle, drugs that reduce the expression of these proteins or sterically hinder viral interactions with them might reduce viral entry into cells.
Due to the urgent nature of the COVID-19 pandemic, many of the pharmaceutical agents that have been widely publicized as having possible therapeutic or prophylactic effects are broad-spectrum pharmaceuticals that pre-date the COVID-19 pandemic.
These treatments are not specifically targeted at the virus itself or at the host receptors it relies on, but rather induce broad shifts in host biology that are hypothesized to be potential inhibitors of the virus.
@@ -1825,56 +1824,56 @@
5.4.2.1 ACEi and ARB
-Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are among today’s most commonly prescribed medications [439,440].
+
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are among today’s most commonly prescribed medications [440,441].
In the United States, for example, they are prescribed well over 100,000,000 times annually.
-Data from some animal models suggest that several, but not all, ACE inhibitors and several ARBs increase ACE2 expression in the cells of some organs [441].
-Clinical studies have not established whether plasma ACE2 expression is increased in humans treated with these medications [442].
+Data from some animal models suggest that several, but not all, ACE inhibitors and several ARBs increase ACE2 expression in the cells of some organs [442].
+Clinical studies have not established whether plasma ACE2 expression is increased in humans treated with these medications [443].
While randomized clinical trials are ongoing, a variety of observational studies have examined the relationship between exposure to ACE inhibitors or ARBs and outcomes in patients with COVID-19.
-An observational study of the association of exposure to ACE inhibitors or ARB with outcomes in COVID-19 was retracted from the New England Journal of Medicine [443].
-Moreover, because observational studies are subject to confounding, randomized controlled trials are the standard means of assessing the effects of medications, and the findings of the various observational studies bearing on this topic cannot be interpreted as indicating a protective effect of the drug [444,445].
-Several clinical trials testing the effects of ACE inhibitors or ARBs on COVID-19 outcomes are ongoing [446,447,448,449,450,451].
+An observational study of the association of exposure to ACE inhibitors or ARB with outcomes in COVID-19 was retracted from the New England Journal of Medicine [444].
+Moreover, because observational studies are subject to confounding, randomized controlled trials are the standard means of assessing the effects of medications, and the findings of the various observational studies bearing on this topic cannot be interpreted as indicating a protective effect of the drug [445,446].
+Several clinical trials testing the effects of ACE inhibitors or ARBs on COVID-19 outcomes are ongoing [447,448,449,450,451,452].
These studies of randomized intervention will provide important data for understanding whether exposure to ACEis or ARBs is associated with COVID-19 outcomes.
-Additional information about ACE2, observational studies of ACE inhibitors and ARBs in COVID-19, and clinical trials on this topic have been summarized [452].
+Additional information about ACE2, observational studies of ACE inhibitors and ARBs in COVID-19, and clinical trials on this topic have been summarized [453].
5.4.2.2 Hydroxychloroquine and Chloroquine
-Chloroquine (CQ) and hydroxychloroquine (HCQ) are lysosomotropic agents, meaning they are weak bases that can pass through the plasma membrane.
-Both drugs increase cellular pH by accumulating in their protonated form inside lysosomes [453,454].
-This shift in pH inhibits the breakdown of proteins and peptides by the lysosomes during the process of proteolysis [454].
+
CQ and hydroxychloroquine (HCQ) are lysosomotropic agents, meaning they are weak bases that can pass through the plasma membrane.
+Both drugs increase cellular pH by accumulating in their protonated form inside lysosomes [454,455].
+This shift in pH inhibits the breakdown of proteins and peptides by the lysosomes during the process of proteolysis [455].
A number of mechanisms have been proposed through which these drugs could influence the immune response to pathogen challenge.
-For example, CQ/HCQ can interfere with digestion of antigens within the lysosome and inhibit CD4 T-cell stimulation while promoting the stimulation of CD8 T-cells [454].
-CQ/HCQ can also decrease the production of certain key cytokines involved in the immune response, including interleukin-6 (IL-6), and inhibit the stimulation of Toll-like receptors (TLR) and TLR signaling [454].
-The drugs also have anti-inflammatory and photoprotective effects and may also affect rates of cell death, blood clotting, glucose tolerance, and cholesterol levels [454].
+For example, CQ/HCQ can interfere with digestion of antigens within the lysosome and inhibit CD4 T-cell stimulation while promoting the stimulation of CD8 T-cells [455].
+CQ/HCQ can also decrease the production of certain key cytokines involved in the immune response, including interleukin-6 (IL-6), and inhibit the stimulation of Toll-like receptors (TLR) and TLR signaling [455].
+The drugs also have anti-inflammatory and photoprotective effects and may also affect rates of cell death, blood clotting, glucose tolerance, and cholesterol levels [455].
Interest in CQ and HCQ for treating COVID-19 was catalyzed by a mechanism observed in in vitro studies of both SARS-CoV-1 and SARS-CoV-2.
-In one study, CQ inhibited viral entry of SARS-CoV-1 into Vero E6 cells, a cell line that was derived from Vero cells in 1968, through the elevation of endosomal pH and the terminal glycosylation of the cellular entry receptor, ACE2 [455].
+In one study, CQ inhibited viral entry of SARS-CoV-1 into Vero E6 cells, a cell line that was derived from Vero cells in 1968, through the elevation of endosomal pH and the terminal glycosylation of ACE2 [456].
Increased pH within the cell, as discussed above, inhibits proteolysis, and terminal glycosylation of ACE2 is thought to interfere with virus-receptor binding.
-An in vitro study of SARS-CoV-2 infection of Vero cells found both HCQ and CQ to be effective in inhibiting viral replication, with HCQ being more potent [456].
-Additionally, an early case study of three COVID-19 patients reported the presence of antiphospholipid antibodies in all three patients [102].
-Antiphospholipid antibodies are central to the diagnosis of the antiphospholipid syndrome, a disorder that HCQ has often been used to treat [457,458,459].
-Because the 90% effective concentration (EC90) of CQ in Vero E6 cells (6.90 μM) can be achieved in and tolerated by rheumatoid arthritis (RA) patients, it was hypothesized that it might also be possible to achieve the effective concentration in COVID-19 patients [460].
-Additionally, HCQ has been found to be effective in treating HIV [461] and chronic Hepatitis C [462].
+An in vitro study of SARS-CoV-2 infection of Vero cells found both HCQ and CQ to be effective in inhibiting viral replication, with HCQ being more potent [457].
+Additionally, an early case study of three COVID-19 patients reported the presence of antiphospholipid antibodies in all three patients [104].
+Antiphospholipid antibodies are central to the diagnosis of the antiphospholipid syndrome, a disorder that HCQ has often been used to treat [458,459,460].
+Because the 90% effective concentration (EC90) of CQ in Vero E6 cells (6.90 μM) can be achieved in and tolerated by rheumatoid arthritis (RA) patients, it was hypothesized that it might also be possible to achieve the effective concentration in COVID-19 patients [461].
+Additionally, HCQ has been found to be effective in treating HIV [462] and chronic Hepatitis C [463].
Together, these studies triggered initial enthusiasm about the therapeutic potential for HCQ and CQ against COVID-19.
HCQ/CQ has been proposed both as a treatment for COVID-19 and a prophylaxis against SARS-CoV-2 exposure, and trials often investigated these drugs in combination with azithromycin (AZ) and/or zinc supplementation.
However, as more evidence has emerged, it has become clear that HCQ/CQ offer no benefits against SARS-CoV-2 or COVID-19.
5.4.2.2.1 Trials Assessing Therapeutic Administration of HCQ/CQ
-The initial study evaluating HCQ as a treatment for COVID-19 patients was published on March 20, 2020 by Gautret et al. [463].
-This non-randomized, non-blinded, non-placebo clinical trial compared HCQ to standard of care (SOC) in 42 hospitalized patients in southern France.
+
The initial study evaluating HCQ as a treatment for COVID-19 patients was published on March 20, 2020 by Gautret et al. [464].
+This non-randomized, non-blinded, non-placebo clinical trial compared HCQ to SOC in 42 hospitalized patients in southern France.
It reported that patients who received HCQ showed higher rates of virological clearance by nasopharyngeal swab on days 3-6 when compared to SOC.
This study also treated six patients with both HCQ + AZ and found this combination therapy to be more effective than HCQ alone.
However, the design and analyses used showed weaknesses that severely limit interpretability of results, including the lack of randomization, lack of blinding, lack of placebo, lack of Intention-To-Treat analysis, lack of correction for sequential multiple comparisons, trial arms entirely confounded by hospital, false negatives in outcome measurements, lack of trial pre-registration, and small sample size.
Two of these weaknesses are due to inappropriate data analysis and can therefore be corrected post hoc by recalculating the p-values (lack of Intention-To-Treat analysis and multiple comparisons).
However, all other weaknesses are fundamental design flaws and cannot be corrected for.
-Thus, conclusions cannot be generalized outside of the study.
-The International Society of Antimicrobial Chemotherapy, the scientific organization that publishes the journal where the article appeared, subsequently announced that the article did not meet its expected standard for publications [464], although it has not been officially retracted.
+Thus, the conclusions cannot be generalized outside of the study.
+The International Society of Antimicrobial Chemotherapy, the scientific organization that publishes the journal where the article appeared, subsequently announced that the article did not meet its expected standard for publications [465], although it has not been officially retracted.
Because of the preliminary data presented in this study, HCQ treatment was subsequently explored by other researchers.
-About one week later, a follow-up case study reported that 11 consecutive patients were treated with HCQ + AZ using the same dosing regimen [465].
+About one week later, a follow-up case study reported that 11 consecutive patients were treated with HCQ + AZ using the same dosing regimen [466].
One patient died, two were transferred to the intensive care unit (ICU), and one developed a prolonged QT interval, leading to discontinuation of HCQ + AZ administration.
As in the Gautret et al. study, the outcome assessed was virological clearance at day 6 post-treatment, as measured from nasopharyngeal swabs.
Of the ten living patients on day 6, eight remained positive for SARS-CoV-2 RNA.
Like in the original study, interpretability was severely limited by the lack of a comparison group and the small sample size.
However, these results stand in contrast to the claims by Gautret et al. that all six patients treated with HCQ + AZ tested negative for SARS-CoV-2 RNA by day 6 post-treatment.
This case study illustrated the need for further investigation using robust study design to evaluate the efficacy of HCQ and/or CQ.
-On April 10, 2020, a randomized, non-placebo trial of 62 COVID-19 patients at the Renmin Hospital of Wuhan University was released [466].
-This study investigated whether HCQ decreased time to fever break or time to cough relief when compared to SOC [466].
+
On April 10, 2020, a randomized, non-placebo trial of 62 COVID-19 patients at the Renmin Hospital of Wuhan University was released [467].
+This study investigated whether HCQ decreased time to fever break or time to cough relief when compared to SOC [467].
This trial found HCQ decreased both average time to fever break and average time to cough relief, defined as mild or no cough.
While this study improved on some of the methodological flaws in Gautret et al. by randomizing patients, it also had several flaws in trial design and data analysis that prevent generalization of the results.
These weaknesses include the lack of placebo, lack of correction for multiple primary outcomes, inappropriate choice of outcomes, lack of sufficient detail to understand analysis, drastic disparities between pre-registration and published protocol, and small sample size.
@@ -1883,67 +1882,67 @@
[467]
.
-The design limitations mean that the conclusions cannot be generalized outside of the study.
-A second randomized trial, conducted by the Shanghai Public Health Clinical Center, analyzed whether HCQ increased rates of virological clearance at day 7 in respiratory pharyngeal swabs compared to SOC [468].
+Additionally, the observation of drastic disparities between pre-registration and published protocol could indicate p-hacking [468].
+The design limitations mean that the conclusions cannot be generalized outside of the study.
+
A second randomized trial, conducted by the Shanghai Public Health Clinical Center, analyzed whether HCQ increased rates of virological clearance at day 7 in respiratory pharyngeal swabs compared to SOC [469].
This trial was published in Chinese along with an abstract in English, and only the English abstract was read and interpreted for this review.
The trial found comparable outcomes in virological clearance rate, time to virological clearance, and time to body temperature normalization between the treatment and control groups.
-A known weakness is small sample size, with only 30 patients enrolled and 15 in each arm.
+The small sample size is one weakness, with only 30 patients enrolled and 15 in each arm.
This problem suggests the study is underpowered to detect potentially useful differences and precludes interpretation of results.
Additionally, because only the abstract could be read, other design and analysis issues could be present.
Thus, though these studies added randomization to their assessment of HCQ, their conclusions should be interpreted very cautiously.
These two studies assessed different outcomes and reached differing conclusions about the efficacy of HCQ for treating COVID-19; the designs of both studies, especially with respect to sample size, meant that no general conclusions can be made about the efficacy of the drug.
Several widely reported studies on HCQ also have issues with data integrity and/or provenance.
-A Letter to the Editor published in BioScience Trends on March 16, 2020 claimed that numerous clinical trials have shown that HCQ is superior to control treatment in inhibiting the exacerbation of COVID-19 pneumonia [469].
-This letter has been cited by numerous primary literature, review articles, and media alike [470,471].
+A Letter to the Editor published in BioScience Trends on March 16, 2020 claimed that numerous clinical trials have shown that HCQ is superior to control treatment in inhibiting the exacerbation of COVID-19 pneumonia [470].
+This letter has been cited by numerous primary literature, review articles, and media alike [471,472].
However, the letter referred to 15 pre-registration identifiers from the Chinese Clinical Trial Registry.
When these identifiers are followed back to the registry, most trials claim they are not yet recruiting patients or are currently recruiting patients.
For all of these 15 identifiers, no data uploads or links to publications could be located on the pre-registrations.
At the very least, the lack of availability of the primary data means the claim that HCQ is efficacious against COVID-19 pneumonia cannot be verified.
-Similarly, a recent multinational registry analysis [472] analyzed the efficacy of CQ and HCQ with and without a macrolide, which is a class of antibiotics that includes Azithromycin, for the treatment of COVID-19.
+Similarly, a recent multinational registry analysis [473] analyzed the efficacy of CQ and HCQ with and without a macrolide, which is a class of antibiotics that includes Azithromycin, for the treatment of COVID-19.
The study observed 96,032 patients split into a control and four treatment conditions (CQ with and without a macrolide; HCQ with and without a macrolide).
They concluded that treatment with CQ and HCQ was associated with increased risk of de novo ventricular arrhythmia during hospitalization.
-However, this study has since been retracted by The Lancet due to an inability to validate the data used [473].
-These studies demonstrate that increased skepticism in evaluation of the HCQ/CQ and COVID-19 literature may be warranted, possible because of the significant attention HCQ and CQ have received as possible treatments for COVID-19 and the politicization of these drugs.
+However, this study has since been retracted by The Lancet due to an inability to validate the data used [474].
+These studies demonstrate that increased skepticism in evaluation of the HCQ/CQ and COVID-19 literature may be warranted, possibly because of the significant attention HCQ and CQ have received as possible treatments for COVID-19 and the politicization of these drugs.
Despite the fact that the study suggesting that CQ/HCQ increased risk of ventricular arrhythmia in COVID-19 patients has now been retracted, previous studies have identified risks associated with HCQ/CQ.
-A patient with systemic lupus erythematosus developed a prolonged QT interval that was likely exacerbated by use of HCQ in combination with renal failure [474].
-A prolonged QT interval is associated with ventricular arrhythmia [475].
-Furthermore, a separate study [476] investigated the safety associated with the use of HCQ with and without macrolides between 2000 and 2020.
+A patient with systemic lupus erythematosus developed a prolonged QT interval that was likely exacerbated by use of HCQ in combination with renal failure [475].
+A prolonged QT interval is associated with ventricular arrhythmia [476].
+Furthermore, a separate study [477] investigated the safety associated with the use of HCQ with and without macrolides between 2000 and 2020.
The study involved 900,000 cases treated with HCQ and 300,000 cases treated with HCQ + AZ.
The results indicated that short-term use of HCQ was not associated with additional risk, but that HCQ + AZ was associated with an enhanced risk of cardiovascular complications (15-20% increased risk of chest pain) and a two-fold increased risk of mortality.
Therefore, whether studies utilize HCQ alone or HCQ in combination with a macrolide may be an important consideration in assessing risk.
-As results from initial investigations of these drug combinations have emerged, concerns about the efficacy and risks of treating COVID-19 with HCQ and CQ has led to the removal of CQ/HCQ from SOC practices in several countries [477,478].
-As of May 25, 2020, WHO had suspended administration of HCQ as part of the worldwide Solidarity Trial [479], and later the final results of this large-scale trial that compared 947 patients administered HCQ to 906 controls revealed no effect on the primary outcome, mortality during hospitalization (rate ratio: 1.19; p = 0.23)
+As results from initial investigations of these drug combinations have emerged, concerns about the efficacy and risks of treating COVID-19 with HCQ and CQ has led to the removal of CQ/HCQ from SOC practices in several countries [478,479].
+As of May 25, 2020, WHO had suspended administration of HCQ as part of the worldwide Solidarity Trial [480], and later the final results of this large-scale trial that compared 947 patients administered HCQ to 906 controls revealed no effect on the primary outcome, mortality during hospitalization (rate ratio: 1.19; p = 0.23)
Additional research has emerged largely identifying HCQ/CQ to be ineffective against COVID-19 while simultaneously revealing a number of significant side effects.
-A randomized, open-label, non-placebo trial of 150 COVID-19 patients was conducted in parallel at 16 government-designated COVID-19 centers in China to assess the safety and efficacy of HCQ [480].
+A randomized, open-label, non-placebo trial of 150 COVID-19 patients was conducted in parallel at 16 government-designated COVID-19 centers in China to assess the safety and efficacy of HCQ [481].
The trial compared treatment with HCQ in conjunction with SOC to SOC alone in 150 infected patients who were assigned randomly to the two groups (75 per group).
The primary endpoint of the study was the negative conversion rate of SARS-CoV-2 in 28 days, and the investigators found no difference in this parameter between the groups.
The secondary endpoints were an amelioration of the symptoms of the disease such as axillary temperature ≤36.6°C, SpO2 >94% on room air, and disappearance of symptoms like shortness of breath, cough, and sore throat.
-The median time to symptom alleviation was similar across different conditions (19 days in HCQ+SOC vs. 21 days in SOC).
-Additionally, 30% of the patients receiving SOC+HCQ reported adverse outcomes compared to 8.8% of patients receiving only SOC, with the most common adverse outcome in the SOC+HCQ group being diarrhea (10% vs. 0% in the SOC group, p=0.004).
+The median time to symptom alleviation was similar across different conditions (19 days in HCQ + SOC versus 21 days in SOC).
+Additionally, 30% of the patients receiving SOC+HCQ reported adverse outcomes compared to 8.8% of patients receiving only SOC, with the most common adverse outcome in the SOC+HCQ group being diarrhea (10% versus 0% in the SOC group, p = 0.004).
However, there are several factors that limit the interpretability of this study.
Most of the enrolled patients had mild-to-moderate symptoms (98%), and the average age was 46.
SOC in this study included the use of antivirals (Lopinavir-Ritonavir, Arbidol, Oseltamivir, Virazole, Entecavir, Ganciclovir, and Interferon alfa), which appeared to introduce confounding effects.
Thus, to isolate the effect of HCQ, SOC would need to exclude the use of antivirals.
-In this trial, the samples used to test for the presence of the SARS-CoV-2 virus were collected from the upper respiratory tract, and the authors indicated that the use of upper respiratory samples may have introduced false negatives (e.g., [81]).
+In this trial, the samples used to test for the presence of the SARS-CoV-2 virus were collected from the upper respiratory tract, and the authors indicated that the use of upper respiratory samples may have introduced false negatives (e.g., [83]).
Another limitation of the study that the authors acknowledge was that the HCQ treatment began, on average, at a 16-day delay from the symptom onset.
The fact that this study was open-label and lacked a placebo limits interpretation, and additional analysis is required to determine whether HCQ reduces inflammatory response.
Therefore, despite some potential areas of investigation identified in post hoc analysis, this study cannot be interpreted as providing support for HCQ as a therapeutic against COVID-19.
-Additional evidence comes from a retrospective analysis [481] that examined data from 368 COVID-19 patients across all United States Veteran Health Administration medical centers.
+
Additional evidence comes from a retrospective analysis [482] that examined data from 368 COVID-19 patients across all United States Veteran Health Administration medical centers.
The study retrospectively investigated the effect of the administration of HCQ (n=97), HCQ + AZ (n=113), and no HCQ (n=158) on 368 patients.
The primary outcomes assessed were death and the need for mechanical ventilation.
Standard supportive care was rendered to all patients.
Due to the low representation of women (N=17) in the available data, the analysis included only men, and the median age was 65 years.
The rate of death in the HCQ-only treatment condition was 27.8% and in the HCQ + AZ treatment condition, it was 22.1%.
-In comparison to the 14.1% rate of death in the no-HCQ cohort, these data indicated a statistically significant elevation in the risk of death for the HCQ-only group compared to the no-HCQ group (adjusted HR: 2.61, p=0.03), but not for the HCQ + AZ group compared to the no-HCQ group (adjusted HR: 1.14; p=0.72).
+In comparison to the 14.1% rate of death in the no-HCQ cohort, these data indicated a statistically significant elevation in the risk of death for the HCQ-only group compared to the no-HCQ group (adjusted HR: 2.61, p = 0.03), but not for the HCQ + AZ group compared to the no-HCQ group (adjusted HR: 1.14; p = 0.72).
Further, the risk of ventilation was similar across all three groups (adjusted HR: 1.43, p = 0.48 (HCQ) and 0.43, p = 0.09 (HCQ + AZ) compared to no HCQ).
The study thus showed evidence of an association between increased mortality and HCQ in this cohort of COVID-19 patients but no change in rates of mechanical ventilation among the treatment conditions.
The study had a few limitations: it was not randomized, and the baseline vital signs, laboratory tests, and prescription drug use were significantly different among the three groups.
All of these factors could potentially influence treatment outcome.
Furthermore, the authors acknowledge that the effect of the drugs might be different in females and pediatric subjects, since these subjects were not part of the study.
-The reported result that HCQ + AZ is safer than HCQ contradicts the findings of the previous large-scale analysis of twenty years of records that found HCQ + AZ to be more frequently associated with cardiac arrhythmia than HCQ alone [476]; whether this discrepancy is caused by the pathology of COVID-19, is influenced by age or sex, or is a statistical artifact is not presently known.
+The reported result that HCQ + AZ is safer than HCQ contradicts the findings of the previous large-scale analysis of twenty years of records that found HCQ + AZ to be more frequently associated with cardiac arrhythmia than HCQ alone [477]; whether this discrepancy is caused by the pathology of COVID-19, is influenced by age or sex, or is a statistical artifact is not presently known.
Finally, findings from the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial were released on October 8, 2020.
-This study used a randomized, open-label design to study the effects of HCQ compared to SOC at 176 hospitals in the United Kingdom [482].
+This study used a randomized, open-label design to study the effects of HCQ compared to SOC at 176 hospitals in the United Kingdom [483].
This large study enrolled 11,197 hospitalized patients whose physicians believed it would not harm them to participate.
Patients were randomized into either the control group or one of the treatment arms, with twice as many patients enrolled in the control group as any treatment group.
Of the patients eligible to receive HCQ, 1,561 were randomized into the HCQ arm, and 3,155 were randomized into the control arm.
@@ -1958,14 +1957,14 @@
5.4.2.2.2 HCQ for the Treatment of Mild Cases
One additional possible therapeutic application of HCQ considered was the treatment of mild COVID-19 cases in otherwise healthy individuals.
-This possibility was assessed in a randomized, open-label, multi-center analysis conducted in Catalonia (Spain) [483].
+This possibility was assessed in a randomized, open-label, multi-center analysis conducted in Catalonia (Spain) [484].
This analysis enrolled adults 18 and older who had been experiencing mild symptoms of COVID-19 for fewer than five days.
Participants were randomized into an HCQ arm (N=136) and a control arm (N=157), and those in the treatment arm were administered 800 mg of HCQ on the first day of treatment followed by 400 mg on each of the subsequent six days.
The primary outcome assessed was viral clearance at days 3 and 7 following the onset of treatment, and secondary outcomes were clinical progression and time to complete resolution of symptoms.
They found no significant differences between the two groups.
This study thus suggests that HCQ does not improve recovery from COVID-19, even in otherwise healthy adult patients with mild symptoms.
5.4.2.2.3 Prophylactic Administration of HCQ
-An initial study of the possible prophylactic application of HCQ utilized a randomized, double-blind, placebo-controlled design to analyze the administration of HCQ prophylactically [484].
+
An initial study of the possible prophylactic application of HCQ utilized a randomized, double-blind, placebo-controlled design to analyze the administration of HCQ prophylactically [485].
Asymptomatic adults in the United States and Canada who had been exposed to SARS-CoV-2 within the past four days were enrolled in an online study to evaluate whether administration of HCQ over five days influenced the probability of developing COVID-19 symptoms over a 14-day period.
Of the participants, 414 received HCQ and 407 received a placebo.
No significant difference in the rate of symptomatic illness was observed between the two groups (11.8% HCQ, 14.3% placebo, p = 0.35).
@@ -1979,7 +1978,7 @@
-A second study [485] examined the effect of administering HCQ to healthcare workers as a pre-exposure prophylactic.
+
A second study [486] examined the effect of administering HCQ to healthcare workers as a pre-exposure prophylactic.
The primary outcome assessed was the conversion from SARS-CoV-2 negative to SARS-CoV-2 positive status over the 8 week study period.
This study was also randomized, double-blind, and placebo-controlled, and it sought to address some of the limitations of the first prophylactic study.
They aimed to enroll 200 healthcare workers, preferentially those working with COVID-19 patients, at two hospitals within the University of Pennsylvania hospital system in Philadelphia, PA.
@@ -1990,117 +1989,117 @@
5.4.2.2.4 Summary of HCQ/CQ Research Findings
Early in vitro evidence indicated that HCQ could be an effective therapeutic against SARS-CoV-2 and COVID-19, leading to significant media attention and public interest in its potential as both a therapeutic and prophylactic.
-Initially it was hypothesized that CQ/HCQ might be effective against SARS-CoV-2 in part because CQ and HCQ have both been found to inhibit the expression of CD154 in T-cells and to reduce TLR signaling that leads to the production of pro-inflammatory cytokines [486].
+Initially it was hypothesized that CQ/HCQ might be effective against SARS-CoV-2 in part because CQ and HCQ have both been found to inhibit the expression of CD154 in T-cells and to reduce TLR signaling that leads to the production of pro-inflammatory cytokines [487].
Clinical trials for COVID-19 have more often used HCQ rather than CQ because it offers the advantages of being cheaper and having fewer side effects than CQ.
However, research has not found support for a positive effect of HCQ on COVID-19 patients.
Multiple clinical studies have already been carried out to assess HCQ as a therapeutic agent for COVID-19, and many more are in progress.
To date, none of these studies have used randomized, double-blind, placebo-controlled designs with a large sample size, which would be the gold standard.
Despite the design limitations (which would be more likely to produce false positives than false negatives), initial optimism about HCQ has largely dissipated.
-The most methodologically rigorous analysis of HCQ as a prophylactic [484] found no significant differences between the treatment and control groups, and the WHO’s global Solidarity trial similarly reported no effect of HCQ on mortality [390].
+The most methodologically rigorous analysis of HCQ as a prophylactic [485] found no significant differences between the treatment and control groups, and the WHO’s global Solidarity trial similarly reported no effect of HCQ on mortality [391].
Thus, HCQ/CQ are not likely to be effective therapeutic or prophylactic agents against COVID-19.
-Additionally, one study identified an increased risk of mortality in older men receiving HCQ, and administration of HCQ and HCQ+AZ did not decrease the use of mechanical ventilation in these patients [481].
+Additionally, one study identified an increased risk of mortality in older men receiving HCQ, and administration of HCQ and HCQ + AZ did not decrease the use of mechanical ventilation in these patients [482].
HCQ use for COVID-19 could also lead to shortages for anti-malarial or anti-rheumatic use, where it has documented efficacy.
Despite significant early attention, these drugs appear to be ineffective against COVID-19.
Several countries have now removed CQ/HCQ from their SOC for COVID-19 due to the lack of evidence of efficacy and the frequency of adverse effects.
5.4.2.3 Dexamethasone
-Dexamethasone (9α-fluoro-16α-methylprednisolone) is a synthetic corticosteroid that binds to glucocorticoid receptors [487,488].
-It was first synthesized in the late 1950s as an anti-inflammatory and has been used to treat RA and other inflammatory conditions [489,490].
-Steroids such as dexamethasone are widely available and affordable, and they are often used to treat community-acquired pneumonia [491].
-A clinical trial that began in 2012 recently reported that dexamethasone may improve outcomes for patients with ARDS [492].
-However, a meta-analysis of a small amount of available data about dexamethasone as a treatment for SARS suggested that it may, in fact, be associated with patient harm [493]; however, these findings may have been biased by the fact that all of the studies examined were observational and a large number of inconclusive studies were not included [494].
-Dexamethasone works as an anti-inflammatory agent by binding to glucocorticoid receptors with higher affinity than endogenous cortisol [495].
+
Dexamethasone (9α-fluoro-16α-methylprednisolone) is a synthetic corticosteroid that binds to glucocorticoid receptors [488,489].
+It was first synthesized in the late 1950s as an anti-inflammatory and has been used to treat RA and other inflammatory conditions [490,491].
+Steroids such as dexamethasone are widely available and affordable, and they are often used to treat community-acquired pneumonia [492].
+A clinical trial that began in 2012 recently reported that dexamethasone may improve outcomes for patients with ARDS [493].
+However, a meta-analysis of a small amount of available data about dexamethasone as a treatment for SARS suggested that it may, in fact, be associated with patient harm [494]; however, these findings may have been biased by the fact that all of the studies examined were observational and a large number of inconclusive studies were not included [495].
+Dexamethasone works as an anti-inflammatory agent by binding to glucocorticoid receptors with higher affinity than endogenous cortisol [496].
In order to understand how dexamethasone reduces inflammation, it is necessary to consider the stress response broadly.
-In response to stress, corticotropin‐releasing hormone stimulates the release of neurotransmitters known as catecholamines, such as epinephrine, and steroid hormones known as glucocorticoids, such as cortisol [496,497].
-While catecholamines are often associated with the fight-or-flight response, the specific role that glucocorticoids play is less clear, although they are thought to be important to restoring homeostasis [498].
+In response to stress, corticotropin‐releasing hormone stimulates the release of neurotransmitters known as catecholamines, such as epinephrine, and steroid hormones known as glucocorticoids, such as cortisol [497,498].
+While catecholamines are often associated with the fight-or-flight response, the specific role that glucocorticoids play is less clear, although they are thought to be important to restoring homeostasis [499].
Immune challenge is a stressor that is known to interact closely with the stress response.
-The immune system can therefore interact with the central nervous system; for example, macrophages can both respond to and produce catecholamines [496].
-Additionally, the production of both catecholamines and glucocorticoids is associated with inhibition of proinflammatory cytokines such as IL-6, IL-12, and tumor necrosis factor-α (TNF‐α) and the stimulation of anti-inflammatory cytokines such as IL-10, meaning that the stress response can regulate inflammatory immune activity [497].
-Administration of dexamethasone has been found to correspond to dose-dependent inhibition of IL-12 production, but not to affect IL-10 [499]; the fact that this relationship could be disrupted by administration of a glucocorticoid-receptor antagonist suggests that it is regulated by the receptor itself [499].
+The immune system can therefore interact with the central nervous system; for example, macrophages can both respond to and produce catecholamines [497].
+Additionally, the production of both catecholamines and glucocorticoids is associated with inhibition of proinflammatory cytokines such as IL-6, IL-12, and tumor necrosis factor-α (TNF‐α) and the stimulation of anti-inflammatory cytokines such as IL-10, meaning that the stress response can regulate inflammatory immune activity [498].
+Administration of dexamethasone has been found to correspond to dose-dependent inhibition of IL-12 production, but not to affect IL-10 [500]; the fact that this relationship could be disrupted by administration of a glucocorticoid-receptor antagonist suggests that it is regulated by the receptor itself [500].
Thus, the administration of dexamethasone for COVID-19 is likely to simulate the release of glucocorticoids endogenously during stress, resulting in binding of the synthetic steroid to the glucocorticoid receptor and the associated inhibition of the production of proinflammatory cytokines.
-In this model, dexamethasone reduces inflammation by stimulating the biological mechanism that reduces inflammation following a threat such as immune challenge.
-Immunosuppressive drugs such as steroids are typically contraindicated in the setting of infection [500], but because COVID-19 results in hyperinflammation that appears to contribute to mortality via lung damage, immunosuppression may be a helpful approach to treatment [127].
-The decision of whether and/or when to counter hyperinflammation with immunosuppression in the setting of COVID-19 was an area of intense debate, as the risks of inhibiting antiviral immunity needed to be weighed against the beneficial anti-inflammatory effects [501].
-As a result, guidelines early in the pandemic typically recommended avoiding treating COVID-19 patients with corticosteroids such as dexamethasone [493].
-The application of dexamethasone for the treatment of COVID-19 was evaluated as part of the multi-site RECOVERY trial in the United Kingdom [502].
+In this model, dexamethasone reduces inflammation by stimulating the biological mechanism that reduces inflammation following a threat such as immune challenge.
+Immunosuppressive drugs such as steroids are typically contraindicated in the setting of infection [501], but because COVID-19 results in hyperinflammation that appears to contribute to mortality via lung damage, immunosuppression may be a helpful approach to treatment [129].
+The decision of whether and/or when to counter hyperinflammation with immunosuppression in the setting of COVID-19 was an area of intense debate, as the risks of inhibiting antiviral immunity needed to be weighed against the beneficial anti-inflammatory effects [502].
+As a result, guidelines early in the pandemic typically recommended avoiding treating COVID-19 patients with corticosteroids such as dexamethasone [494].
+The application of dexamethasone for the treatment of COVID-19 was evaluated as part of the multi-site RECOVERY trial in the United Kingdom [503].
Over 6,000 hospitalized COVID-19 patients were assigned into the SOC or treatment (dexamethasone) arms of the trial with a 2:1 ratio.
At the time of randomization, some patients were ventilated (16%), others were on non-invasive oxygen (60%), and others were breathing independently (24%).
Patients in the treatment arm were administered dexamethasone either orally or intravenously at 6 mg per day for up to 10 days.
The primary end-point was the patient’s status at 28-days post-randomization (mortality, discharge, or continued hospitalization), and secondary outcomes analyzed included the progression to invasive mechanical ventilation over the same period.
The 28-day mortality rate was found to be lower in the treatment group than in the SOC group (21.6% vs 24.6%, p < 0.001).
However, this finding was driven by differences in mortality among patients who were receiving mechanical ventilation or supplementary oxygen at the start of the study.
-The report indicated that dexamethasone reduced 28-day mortality relative to SOC in patients who were ventilated (29.3% vs. 41.4%) and among those who were receiving oxygen supplementation (23.3% vs. 26.2%) at randomization, but not in patients who were breathing independently (17.8% vs. 14.0%).
+The report indicated that dexamethasone reduced 28-day mortality relative to SOC in patients who were ventilated (29.3% versus 41.4%) and among those who were receiving oxygen supplementation (23.3% versus 26.2%) at randomization, but not in patients who were breathing independently (17.8% versus 14.0%).
One possible confounder is that patients receiving mechanical ventilation tended to be younger than patients who were not receiving respiratory support (by 10 years on average) and to have had symptoms for a longer period.
However, adjusting for age did not change the conclusions, although the duration of symptoms was found to be significantly associated with the effect of dexamethasone administration.
These findings also suggested that dexamethasone may have reduced progression to mechanical ventilation, especially among patients who were receiving oxygen support at randomization.
Thus, this large, randomized, and multi-site, albeit not placebo-controlled, study suggests that administration of dexamethasone to patients who are unable to breathe independently may significantly improve survival outcomes.
Additionally, dexamethasone is a widely available and affordable medication, raising the hope that it could be made available to COVID-19 patients globally.
-The results of the RECOVERY trial’s analysis of dexamethasone suggest that this therapeutic is effective primarily in patients who had been experiencing symptoms for at least seven days and patients who were not breathing independently [503].
-A meta-analysis that evaluated the results of the RECOVERY trial alongside trials of other corticosteroids, such as hydrocortisone, similarly concluded that corticosteroids may be beneficial to patients with severe COVID-19 who are receiving oxygen supplementation [504].
-Thus, it seems likely that dexamethasone is useful for treating inflammation associated with immunopathy or cytokine release syndrome.
-In fact, corticosteroids such as dexamethasone are sometimes used to treat cytokine release syndrome (CRS) [505].
+
The results of the RECOVERY trial’s analysis of dexamethasone suggest that this therapeutic is effective primarily in patients who had been experiencing symptoms for at least seven days and patients who were not breathing independently [504].
+A meta-analysis that evaluated the results of the RECOVERY trial alongside trials of other corticosteroids, such as hydrocortisone, similarly concluded that corticosteroids may be beneficial to patients with severe COVID-19 who are receiving oxygen supplementation [505].
+Thus, it seems likely that dexamethasone is useful for treating inflammation associated with immunopathy or cytokine release syndrome (CRS).
+In fact, corticosteroids such as dexamethasone are sometimes used to treat CRS [506].
It is not surprising that administration of an immunosuppressant would be most beneficial when the immune system was dysregulated towards inflammation.
However, it is also unsurprising that care must be taken in administering an immunosuppressant to patients fighting a viral infection.
-In particular, the concern has been raised that treatment with dexamethasone might increase patient susceptibility to concurrent (e.g., nosocomial) infections [506].
-Additionally, the drug could potentially slow viral clearance and inhibit patients’ ability to develop antibodies to SARS-CoV-2 [493,506], and the lack of data about viral clearance has been put forward as a major limitation of the RECOVERY trial [507].
-Furthermore, dexamethasone has been associated with side effects that include psychosis, glucocorticoid-induced diabetes, and avascular necrosis [493], and the RECOVERY trial did not report outcomes with enough detail to be able to determine whether they observed similar complications.
-The effects of dexamethasone have also been found to differ among populations, especially in high-income versus middle- or low-income countries [508].
-However, since the RECOVERY trial’s results were released, strategies have been proposed for administering dexamethasone alongside more targeted treatments to minimize the likelihood of negative side effects [506].
+In particular, the concern has been raised that treatment with dexamethasone might increase patient susceptibility to concurrent (e.g., nosocomial) infections [507].
+Additionally, the drug could potentially slow viral clearance and inhibit patients’ ability to develop antibodies to SARS-CoV-2 [494,507], and the lack of data about viral clearance has been put forward as a major limitation of the RECOVERY trial [508].
+Furthermore, dexamethasone has been associated with side effects that include psychosis, glucocorticoid-induced diabetes, and avascular necrosis [494], and the RECOVERY trial did not report outcomes with enough detail to be able to determine whether they observed similar complications.
+The effects of dexamethasone have also been found to differ among populations, especially in high-income versus middle- or low-income countries [509].
+However, since the RECOVERY trial’s results were released, strategies have been proposed for administering dexamethasone alongside more targeted treatments to minimize the likelihood of negative side effects [507].
Given the available evidence, dexamethasone is currently the most promising treatment for severe COVID-19.
5.5 Biologics
Biologics are produced from components of living organisms or viruses.
-They include treatments such as humanized monoclonal antibodies (mAb) tocilizumab (TCZ), and neutralizing antibodies (nAbs), and can also include prophylactics such as vaccines.
-Historically produced from animal tissue, biologics have become increasingly feasible to produce as recombinant DNA technologies have advanced [509].
-Often, they are glycoproteins or peptides [510], but whole viruses can also be used therapeutically or prophylactically, not only for vaccines but also as vectors for gene therapy or therapeutic proteins or for oncolytic virotherapy [511].
-They are typically catabolized by the body to their amino acid components [510].
+They include treatments such as humanized monoclonal antibodies (mAb), tocilizumab (TCZ), and neutralizing antibodies (nAbs), and can also include prophylactics such as vaccines.
+Historically produced from animal tissue, biologics have become increasingly feasible to produce as recombinant DNA technologies have advanced [510].
+Often, they are glycoproteins or peptides [511], but whole viruses can also be used therapeutically or prophylactically, not only for vaccines but also as vectors for gene therapy or therapeutic proteins or for oncolytic virotherapy [512].
+They are typically catabolized by the body to their amino acid components [511].
There are many differences on the development side between biologics and synthesized pharmaceuticals, such as small molecule drugs.
-Biologics are typically orders of magnitude larger than small molecule drugs, and their physiochemical properties are often much less understood [510].
-They are often heat sensitive, and their toxicity can vary, as it is not directly associated with the primary effects of the drug [510].
+Biologics are typically orders of magnitude larger than small molecule drugs, and their physiochemical properties are often much less understood [511].
+They are often heat sensitive, and their toxicity can vary, as it is not directly associated with the primary effects of the drug [511].
However, this class includes some extremely significant medical breakthroughs, including insulin for the management of diabetes and the smallpox vaccine.
As a result, biologics are another possible avenue through which the pharmacological management of SARS-CoV-2 infection can be approached.
5.5.1 Tocilizumab
-TCZ is a receptor antibody that was developed to manage chronic inflammation caused by the continuous synthesis of the cytokine IL-6 [512].
+
TCZ is a receptor antibody that was developed to manage chronic inflammation caused by the continuous synthesis of the cytokine IL-6 [513].
IL-6 is a pro-inflammatory cytokine belonging to the interleukin family, which is comprised by immune system regulators that are primarily responsible for immune cell differentiation.
-Often used to treat conditions such as RA [512], TCZ has become a pharmaceutical of interest for the treatment of COVID-19 because of the role IL-6 plays in this disease.
-While secretion of IL-6 can be associated with chronic conditions, it is a key player in the innate immune response and is secreted by macrophages in response to the detection of pathogen-associated molecular patterns and damage-associated molecular patterns [512].
+Often used to treat conditions such as RA [513], TCZ has become a pharmaceutical of interest for the treatment of COVID-19 because of the role IL-6 plays in this disease.
+While secretion of IL-6 can be associated with chronic conditions, it is a key player in the innate immune response and is secreted by macrophages in response to the detection of pathogen-associated molecular patterns and damage-associated molecular patterns [513].
An analysis of 191 in-patients at two Wuhan hospitals revealed that blood concentrations of IL-6 differed between patients who did and did not recover from COVID-19.
-Patients who ultimately deceased had higher IL-6 levels at admission than those who recovered [35].
-Additionally, IL-6 levels remained higher throughout the course of hospitalization in the patients who ultimately deceased [35].
-This finding provided some early evidence that COVID-19 deaths may be induced by the hyperactive immune response, often referred to as CRS or cytokine storm syndrome (CSS), as IL-6 plays a key role in this response [114].
+Patients who ultimately deceased had higher IL-6 levels at admission than those who recovered [37].
+Additionally, IL-6 levels remained higher throughout the course of hospitalization in the patients who ultimately deceased [37].
+This finding provided some early evidence that COVID-19 deaths may be induced by the hyperactive immune response, often referred to as CRS or cytokine storm syndrome (CSS), as IL-6 plays a key role in this response [116].
In this context, the observation of elevated IL-6 in patients who died may reflect an over-production of proinflammatory interleukins, suggesting that TCZ could potentially palliate some of the most severe symptoms of COVID-19 associated with increased cytokine production.
Human IL-6 is a 26-kDa glycoprotein that consists of 184 amino acids and contains two potential N-glycosylation sites and four cysteine residues.
-It binds to a type I cytokine receptor (IL-6Rα or glycoprotein 80) that exists in both membrane-bound (IL-6Rα) and soluble (sIL-6Rα) forms [513].
-It is not the binding of IL-6 to the receptor that initiates pro- and/or anti-inflammatory signaling, but rather the binding of the complex to another subunit, known as IL-6Rβ or glycoprotein 130 (gp13) [513,514].
-Unlike membrane-bound IL-6Rα, which is only found on hepatocytes and some types of leukocytes, gp130 is found on most cells [515].
-When IL-6 binds to sIL-6Rα, the complex can then bind to a gp130 protein on any cell [515].
-The binding of IL-6 to IL-6Rα is termed classical signaling, while its binding to sIL-6Rα is termed trans-signaling [515,516,517].
+It binds to a type I cytokine receptor (IL-6Rα or glycoprotein 80) that exists in both membrane-bound (IL-6Rα) and soluble (sIL-6Rα) forms [514].
+It is not the binding of IL-6 to the receptor that initiates pro- and/or anti-inflammatory signaling, but rather the binding of the complex to another subunit, known as IL-6Rβ or glycoprotein 130 (gp13) [514,515].
+Unlike membrane-bound IL-6Rα, which is only found on hepatocytes and some types of leukocytes, gp130 is found on most cells [516].
+When IL-6 binds to sIL-6Rα, the complex can then bind to a gp130 protein on any cell [516].
+The binding of IL-6 to IL-6Rα is termed classical signaling, while its binding to sIL-6Rα is termed trans-signaling [516,517,518].
These two signaling processes are thought to play different roles in health and illness.
-For example, trans-signaling may play a role in the proliferation of mucosal T-helper TH2 cells associated with asthma, while an earlier step in this proliferation process may be regulated by classical signaling [515].
-Similarly, IL-6 is known to play a role in Crohn’s Disease via trans-, but not classical, signaling [515].
-Both classical and trans-signaling can occur through three independent pathways: the Janus-activated kinase-STAT3 pathway, the Ras/Mitogen-Activated Protein Kinases (MAPK) pathway and the Phosphoinositol-3 Kinase/Akt pathway [513].
-These signaling pathways are involved in a variety of different functions, including cell type differentiation, immunoglobulin synthesis, and cellular survival signaling pathways, respectively [513].
-The ultimate result of the IL-6 cascade is to direct transcriptional activity of various promoters of pro-inflammatory cytokines, such as IL-1, TFN, and even IL-6 itself, through the activity of NF-κB [513].
-IL-6 synthesis is tightly regulated both transcriptionally and post-transcriptionally, and it has been shown that viral proteins can enhance transcription of the IL-6 gene by strengthening the DNA-binding activity between several transcription factors and IL-6 gene-cis-regulatory elements [518].
+For example, trans-signaling may play a role in the proliferation of mucosal T-helper TH2 cells associated with asthma, while an earlier step in this proliferation process may be regulated by classical signaling [516].
+Similarly, IL-6 is known to play a role in Crohn’s Disease via trans-, but not classical, signaling [516].
+Both classical and trans-signaling can occur through three independent pathways: the Janus-activated kinase-STAT3 pathway, the Ras/Mitogen-Activated Protein Kinases (MAPK) pathway and the Phosphoinositol-3 Kinase/Akt pathway [514].
+These signaling pathways are involved in a variety of different functions, including cell type differentiation, immunoglobulin synthesis, and cellular survival signaling pathways, respectively [514].
+The ultimate result of the IL-6 cascade is to direct transcriptional activity of various promoters of pro-inflammatory cytokines, such as IL-1, TFN, and even IL-6 itself, through the activity of NF-κB [514].
+IL-6 synthesis is tightly regulated both transcriptionally and post-transcriptionally, and it has been shown that viral proteins can enhance transcription of the IL-6 gene by strengthening the DNA-binding activity between several transcription factors and IL-6 gene-cis-regulatory elements [519].
Therefore, drugs inhibiting the binding of IL-6 to IL-6Rα or sIL-6Rα are of interest for combating the hyperactive inflammatory response characteristic of CRS and CSS.
TCZ is a humanized monoclonal antibody that binds both to the insoluble and soluble receptor of IL-6, providing de facto inhibition of the IL-6 immune cascade.
Tocilizumab is being administered either as an intervention or as concomitant medication in 84 COVID-19 clinical trials (Figure 3).
No randomized, placebo-controlled studies of TCZ have currently released results.
Therefore, no conclusions can be drawn about its efficacy for the treatment of COVID-19.
-However, early interest in TCZ as a possible treatment for COVID-19 emerged from a very small retrospective study in China that examined 20 patients with severe symptoms in early February 2020 and reported rapid improvement in symptoms following treatment with TCZ [519].
+However, early interest in TCZ as a possible treatment for COVID-19 emerged from a very small retrospective study in China that examined 20 patients with severe symptoms in early February 2020 and reported rapid improvement in symptoms following treatment with TCZ [520].
Subsequently, a number of retrospective studies have been conducted in several countries.
Many studies use a retrospective, observational design, where they compare outcomes for COVID-19 patients who received TCZ to those who did not over a set period of time.
-For example, one of the largest retrospective, observational analysis released to date [520] compared the rates at which patients who received TCZ deceased or progressed to invasive medical ventilation over a 14-day period compared to patients receiving only SOC.
+For example, one of the largest retrospective, observational analysis released to date [521] compared the rates at which patients who received TCZ deceased or progressed to invasive medical ventilation over a 14-day period compared to patients receiving only SOC.
Under this definition, SOC could include other drugs such as HCQ, azithromycin, lopinavir-ritonavir or darunavir-cobicistat, or heparin.
While this study was not randomized, a subset of patients who were eligible to receive TCZ were unable to obtain it due to shortages; however, these groups were not directly compared in the analysis.
After adjusting for variables such as age, sex, and SOFA (sequential organ failure assessment) score, they found that patients treated with TCZ were less likely to progress to invasive medical ventilation and/or death (adjusted HR = 0.61, CI 0.40-0.92, p = 0.020), although analysis of death and ventilation separately suggests that this effect may have been driven by differences in the death rate (20% of control versus 7% of TCZ-treated patients).
They reported particular benefits for patients whose PaO2/FiO2 ratio, also known as the Horowitz Index for Lung Function, fell below a 150 mm Hg threshold.
They found no differences between groups administered subcutaneous versus intravenous TCZ.
-Another retrospective observational analysis of interest examined the charts of patients at a hospital in Connecticut, USA where 64% of all 239 COVID-19 patients in the study period were administered TCZ based on assignment by a standardized algorithm [521].
+
Another retrospective observational analysis of interest examined the charts of patients at a hospital in Connecticut, USA where 64% of all 239 COVID-19 patients in the study period were administered TCZ based on assignment by a standardized algorithm [522].
They found that TCZ administration was associated with more similar rates of survivorship in patients with severe versus nonsevere COVID-19 at intake, defined based on the amount of supplemental oxygen needed.
They therefore proposed that their algorithm was able to identify patients presenting with or likely to develop CRS as good candidates for TCZ.
This study also reported higher survivorship in Black and Hispanic patients compared to white patients when adjusted for age.
The major limitation with interpretation for these studies is that there may be clinical characteristics that influenced medical practitioners decisions to administer TCZ to some patients and not others.
-One interesting example therefore comes from an analysis of patients at a single hospital in Brescia, Italy, where TCZ was not available for a period of time [522].
+One interesting example therefore comes from an analysis of patients at a single hospital in Brescia, Italy, where TCZ was not available for a period of time [523].
This study compared COVID-19 patients admitted to the hospital before and after March 13, 2020, when the hospital received TCZ.
Therefore, patients who would have been eligible for TCZ prior to this arbitrary date did not receive it as treatment, making this retrospective analysis something of a natural experiment.
Despite this design, demographic factors did not appear to be consistent between the two groups, and the average age of the control group was older than the TCZ group.
@@ -2111,113 +2110,114 @@
5.5
However, this study also holds a significant limitation: the time delay between the two groups means that knowledge about how to treat the disease likely improved over this timeframe as well.
All the same, the results of these observational retrospective studies provide support for TCZ as a pharmaceutical of interest for follow-up in clinical trials.
In addition to the retrospective observational studies, other analysis have utilized a retrospective case-control design to match pairs of patients with similar baseline characteristics, only one of whom received TCZ for COVID-19.
-In one such study, TCZ was significantly associated with a reduced risk of progression to ICU admission or death [523].
+In one such study, TCZ was significantly associated with a reduced risk of progression to ICU admission or death [524].
This study examined only 20 patients treated with TCZ (all but one of the patients treated with TCZ in the hospital during the study period) and compared them to 25 patients receiving SOC.
For the combined primary endpoint of death and/or ICU admission, only 25% of patients receiving TCZ progressed to an endpoint compared to 72% in the SOC group (p = 0.002, presumably based on a chi-square test based on the information provided in the text).
When the two endpoints were examined separately, progression to invasive medical ventilation remained significant (32% SOC compared to 0% TCZ, p = 0.006) but not for mortality (48% SOC compared to 25% TCZ, p = 0.066).
-In contrast, a study that compared 96 patients treated with TCZ to 97 patients treated with SOC only in New York City found that differences in mortality did not differ between the two groups, but that this difference did become significant when intubated patients were excluded from the analysis [524].
+In contrast, a study that compared 96 patients treated with TCZ to 97 patients treated with SOC only in New York City found that differences in mortality did not differ between the two groups, but that this difference did become significant when intubated patients were excluded from the analysis [525].
Taken together, these findings suggest that future clinical trials of TCZ may want to include intubation as an endpoint.
However, these studies should be approached with caution, not only because of the small number of patients enrolled and the retrospective design, but also because they performed a large number of statistical tests and did not account for multiple hypothesis testing.
These last findings highlight the need to search for a balance between impairing a harmful immune response, such as the one generated during CRS and CSS, and preventing the worsening of the clinical picture of the patients by potential new viral infections.
Though data about TCZ for COVID-19 is still only just emerging, some meta-analyses and systematic reviews have investigated the available data.
-One meta-analysis [525] evaluated 19 studies published or released as preprints prior to July 1, 2020 and found that the overall trends were supportive of the frequent conclusion that TCZ does improve survivorship, with a significant HR of 0.41 (p < 0.001).
+One meta-analysis [526] evaluated 19 studies published or released as preprints prior to July 1, 2020 and found that the overall trends were supportive of the frequent conclusion that TCZ does improve survivorship, with a significant HR of 0.41 (p < 0.001).
This trend improved when they excluded studies that administered a steroid alongside TCZ, with a significant HR of 0.04 (p < 0.001).
They also found some evidence for reduced invasive ventilation or ICU admission, but only when excluding all studies except a small number whose estimates were adjusted for the possible bias introduced by the challenges of stringency during the enrollment process.
-A systematic analysis of sixteen case-control studies of TCZ estimated an odds ratio of 0.453 (95% CI 0.376–0.547, p < 0.001), suggesting possible benefits associated with TCZ treatment [526].
+A systematic analysis of sixteen case-control studies of TCZ estimated an odds ratio of 0.453 (95% CI 0.376–0.547, p < 0.001), suggesting possible benefits associated with TCZ treatment [527].
Although these estimates are similar, it is important to note that they are drawing from the same literature and are therefore likely to be affected by the same biases in publication.
-A second systematic review of studies investigating TCZ treatment for COVID-19 analyzed 31 studies that had been published or released as pre-prints and reported that none carried a low risk of bias (RoB) [527].
+A second systematic review of studies investigating TCZ treatment for COVID-19 analyzed 31 studies that had been published or released as pre-prints and reported that none carried a low risk of bias [528].
Therefore, the present evidence is not likely to be sufficient for conclusions about the efficacy of TCZ.
Additionally, there are possible risks associated with the administration of TCZ for COVID-19.
-TCZ has been used for over a decade to treat RA [528], and a recent study found the drug to be safe for pregnant and breastfeeding women [529].
-However, TCZ may increase the risk of developing infections [528], and RA patients with chronic hepatitis B infections had a high risk of hepatitis B virus reactivation when TCZ was administered in combination with other RA drugs [530].
-As a result, TCZ is contraindicated in patients with active infections such as tuberculosis [531].
-Previous studies have investigated, with varying results, a possible increased risk of infection in RA patients administered TCZ [532,533], although another study reported that the incidence rate of infections was higher in clinical practice RA patients treated with TCZ than in the rates reported by clinical trials [534].
-In the investigation of 544 Italian COVID-19 patients, the group treated with TCZ was found to be more likely to develop secondary infections, with 24% compared to 4% in the control group [520].
+TCZ has been used for over a decade to treat RA [529], and a recent study found the drug to be safe for pregnant and breastfeeding women [530].
+However, TCZ may increase the risk of developing infections [529], and RA patients with chronic hepatitis B infections had a high risk of hepatitis B virus reactivation when TCZ was administered in combination with other RA drugs [531].
+As a result, TCZ is contraindicated in patients with active infections such as tuberculosis [532].
+Previous studies have investigated, with varying results, a possible increased risk of infection in RA patients administered TCZ [533,534], although another study reported that the incidence rate of infections was higher in clinical practice RA patients treated with TCZ than in the rates reported by clinical trials [535].
+In the investigation of 544 Italian COVID-19 patients, the group treated with TCZ was found to be more likely to develop secondary infections, with 24% compared to 4% in the control group [521].
Reactivation of hepatitis B and herpes simplex virus 1 was also reported in a small number of patients in this study, all of whom were receiving TCZ.
-A July 2020 case report described negative outcomes of two COVID-19 patients after receiving TCZ, including one death; however, both patients were intubated and had entered septic shock prior to receiving TCZ [535], likely indicating a severe level of cytokine production.
-Additionally, D-dimer and sIL2R levels were reported by one study to increase in patients treated with TCZ, which raised concerns because of the potential association between elevated D-dimer levels and thrombosis and between sIL2R and diseases where T-cell regulation is compromised [521].
-An increased risk of bacterial infection was also identified in a systematic review of the literature, based on the unadjusted estimates reported [525].
-In summary, TCZ administration to COVID-19 patients is not without risks, may introduce additional risk of developing secondary infections, and should be approached especially cautiously for patients who have latent viral infections.
-In summary, approximately 25% of coronavirus patients develop ARDS, which is caused by an excessive early response of the immune system which can be a component of cytokine release syndrome [521] and cytokine storm syndrome [531].
+A July 2020 case report described negative outcomes of two COVID-19 patients after receiving TCZ, including one death; however, both patients were intubated and had entered septic shock prior to receiving TCZ [536], likely indicating a severe level of cytokine production.
+Additionally, D-dimer and sIL2R levels were reported by one study to increase in patients treated with TCZ, which raised concerns because of the potential association between elevated D-dimer levels and thrombosis and between sIL2R and diseases where T-cell regulation is compromised [522].
+An increased risk of bacterial infection was also identified in a systematic review of the literature, based on the unadjusted estimates reported [526].
+TCZ administration to COVID-19 patients is not without risks, may introduce additional risk of developing secondary infections, and should be approached especially cautiously for patients who have latent viral infections.
+In summary, approximately 25% of coronavirus patients develop ARDS, which is caused by an excessive early response of the immune system which can be a component of CRS [522] and CSS [532].
This overwhelming inflammation is triggered by IL-6.
TCZ is an inhibitor of IL-6 and therefore may neutralize the inflammatory pathway that leads to the cytokine storm.
While the mechanism suggests TCZ could be beneficial for the treatment of COVID-19 patients experiencing excessive immune activity, no randomized controlled trials are available assessing its effect.
However, small initial studies have found preliminary indications that TCZ may reduce progression to invasive medical ventilation and/or death.
It should be noted that SOC varied widely across retrospective studies, with one study administering HCQ, lopinavir-ritonavir, antibiotics, and/or heparin as part of SOC.
-Interest in TCZ as a treatment for COVID-19 was supported by two meta-analyses [525,536], but a third meta-analysis found that all of the available literature carries a risk of bias, with even the largest available TCZ studies to date carrying a moderate risk of bias under the ROBINS-I criteria [527].
-Additionally, different studies used different dosages, number of doses, and methods of administration; ongoing research may be needed to optimize administration of TCZ [537], although similar results were reported by one study for intravenous and subcutaneous administration [520].
+Interest in TCZ as a treatment for COVID-19 was supported by two meta-analyses [526,537], but a third meta-analysis found that all of the available literature carries a risk of bias, with even the largest available TCZ studies to date carrying a moderate risk of bias under the ROBINS-I criteria [528].
+Additionally, different studies used different dosages, number of doses, and methods of administration.
+Ongoing research may be needed to optimize administration of TCZ [538], although similar results were reported by one study for intravenous and subcutaneous administration [521].
Clinical trials that are in progress are likely to provide additional insight into the effectiveness of this drug for the treatment of COVID-19 along with how it should be administered.
5.5.2 Neutralizing Antibodies
Monoclonal antibodies have revolutionized the way we treat human diseases.
-They have become some of the best-selling drugs in the pharmaceutical market in recent years [538].
-There are currently 79 FDA approved mAbs on the market, including antibodies for viral infections (e.g. Ibalizumab for HIV and Palivizumab for RSV) [538,539].
-Virus-specific neutralizing antibodies commonly target viral surface glycoproteins or host structures, thereby inhibiting viral entry through receptor binding interference [540,541].
-This section discusses current efforts in developing neutralizing antibodies against SARS-CoV-2 and how expertise gained from previous approaches for MERS-CoV and SARS-CoV-1 may benefit antibody development.
+They have become some of the best-selling drugs in the pharmaceutical market in recent years [539].
+There are currently 79 FDA approved mAbs on the market, including antibodies for viral infections (e.g. Ibalizumab for HIV and Palivizumab for RSV) [539,540].
+Virus-specific nAbs commonly target viral surface glycoproteins or host structures, thereby inhibiting viral entry through receptor binding interference [541,542].
+This section discusses current efforts in developing nAbs against SARS-CoV-2 and how expertise gained from previous approaches for MERS-CoV and SARS-CoV-1 may benefit antibody development.
5.5.2.1 Spike (S) Neutralizing Antibody
-During the first SARS epidemic in 2002, nAbs were found in SARS-CoV-1-infected patients [542,543].
-Several studies following up on these findings identified various S-glycoprotein epitopes as the major targets of neutralizing antibodies against SARS-CoV-1 [544].
-The passive transfer of immune serum containing nAbs from SARS-CoV-1-infected mice resulted in protection of naïve mice from viral lower respiratory tract infection upon intranasal challenge [545].
-Similarly, a meta-analysis suggested that administration of plasma from recovered SARS-CoV-1 patients reduced mortality upon SARS-CoV-1 infection [546].
+
During the first SARS epidemic in 2002, nAbs were found in SARS-CoV-1-infected patients [543,544].
+Several studies following up on these findings identified various S-glycoprotein epitopes as the major targets of nAbs against SARS-CoV-1 [545].
+The passive transfer of immune serum containing nAbs from SARS-CoV-1-infected mice resulted in protection of naïve mice from viral lower respiratory tract infection upon intranasal challenge [546].
+Similarly, a meta-analysis suggested that administration of plasma from recovered SARS-CoV-1 patients reduced mortality upon SARS-CoV-1 infection [547].
Similar results were observed in MERS-CoV infection during the second coronavirus-related epidemic of the 21st century.
-In these cases, neutralizing antibodies were identified against various epitopes of the receptor binding domain (RBD) of the S glycoprotein [547,548].
-Coronaviruses use trimeric spike (S) glycoproteins on their surface to bind to the host cell, allowing for cell entry [64,67].
+In these cases, nAbs were identified against various epitopes of the receptor binding domain (RBD) of the S glycoprotein [548,549].
+Coronaviruses use trimeric spike (S) glycoproteins on their surface to bind to the host cell, allowing for cell entry [66,69].
Each S glycoprotein protomer is comprised of an S1 domain, also called the RBD, and an S2 domain.
-The S1 domain binds to the host cell while the S2 domain facilitates the fusion between the viral envelope and host cell membranes [544].
-Although targeting of the host cell enzyme ACE2 shows efficacy in inhibiting SARS-CoV-2 infection [75], given the physiological relevance of ACE2 [549], it would be favorable to target virus-specific structures rather than host receptors.
-This concern underlies the rationale for developing neutralizing antibodies against the S glycoprotein, disrupting its interaction with ACE2 and other potential entry points and thereby inhibiting viral entry.
-The first human neutralizing antibody against SARS-CoV-2 targeting the S glycoproteins was developed using hybridoma technology [550], where antibody-producing B-cells developed by mice can be inserted into myeloma cells to produce a hybrid cell line (the hybridoma) that is grown in culture.
+The S1 domain binds to the host cell while the S2 domain facilitates the fusion between the viral envelope and host cell membranes [545].
+Although targeting of the host cell enzyme ACE2 shows efficacy in inhibiting SARS-CoV-2 infection [77], given the physiological relevance of ACE2 [550], it would be favorable to target virus-specific structures rather than host receptors.
+This concern underlies the rationale for developing nAbs against the S glycoprotein, disrupting its interaction with ACE2 and other potential entry points and thereby inhibiting viral entry.
+The first human nAb against SARS-CoV-2 targeting the S glycoproteins was developed using hybridoma technology [551], where antibody-producing B-cells developed by mice can be inserted into myeloma cells to produce a hybrid cell line (the hybridoma) that is grown in culture.
The 47D11 clone was able to cross-neutralize SARS-CoV-1 and SARS-CoV-2 by a mechanism that is different from receptor binding interference.
-The exact mechanism of how this clone neutralizes SARS-CoV-2 and inhibits infection in vitro remains unknown, but a potential mechanism might be antibody-induced destabilization of the membrane prefusion structure [550,551].
-The ability of this antibody to prevent infection at a feasible dose needs to be validated in vivo, especially since in vitro neutralization effects have been shown to not be reflective of in vivo efficacy [552].
-Only a week later, a different group successfully isolated multiple nAbs targeting the RBD of the S glycoprotein from blood samples taken from COVID-19 patients in China [154].
+The exact mechanism of how this clone neutralizes SARS-CoV-2 and inhibits infection in vitro remains unknown, but a potential mechanism might be antibody-induced destabilization of the membrane prefusion structure [551,552].
+The ability of this antibody to prevent infection at a feasible dose needs to be validated in vivo, especially since in vitro neutralization effects have been shown to not be reflective of in vivo efficacy [553].
+Only a week later, a different group successfully isolated multiple nAbs targeting the RBD of the S glycoprotein from blood samples taken from COVID-19 patients in China [156].
Interestingly, the patient-isolated antibodies did not cross-react with RBDs from SARS-CoV-1 and MERS-CoV, although cross-reactivity to the trimeric spike proteins of SARS-CoV-1 and MERS-CoV was observed.
This finding suggests that the RBDs between the three coronavirus species are immunologically distinct and that the isolated nAbs targeting the RBD of SARS-CoV-2 are species specific.
While this specificity is desirable, it also raises the question of whether these antibodies are more susceptible to viral escape mechanisms.
-Viral escape is a common resistance mechanism to nAb therapy due to selective pressure from neutralizing antibodies [553,554].
-For HIV, broadly neutralizing antibodies (bnAbs) targeting the CD4 binding site (CD4bs) show greater neutralization breadth than monoclonal antibodies, which target only specific HIV strains [555].
-For MERS-CoV, a combination of multiple neutralizing antibodies targeting different antigenic sites prevented neutralization escape [556].
-It was found that the different antibody isolates did not target the same epitopes, suggesting that using them in combination might produce a synergistic effect that prevents viral escape [154].
+Viral escape is a common resistance mechanism to nAb therapy due to selective pressure from nAbs [554,555].
+For HIV, broadly neutralizing antibodies (bnAbs) targeting the CD4 binding site (CD4bs) show greater neutralization breadth than monoclonal antibodies, which target only specific HIV strains [556].
+For MERS-CoV, a combination of multiple nAbs targeting different antigenic sites prevented neutralization escape [557].
+It was found that the different antibody isolates did not target the same epitopes, suggesting that using them in combination might produce a synergistic effect that prevents viral escape [156].
It was also demonstrated that binding affinity of the antibodies does not reflect their capability to compete with ACE2 binding.
-Furthermore, no conclusions about correlations between the severity of disease and the ability to produce neutralizing antibodies can be drawn at this point.
-Rather, higher neutralizing antibody titers were more frequently found in patients with severe disease.
-Correspondingly, higher levels of anti-spike IgG were observed in patients that deceased from infection compared to patient that recovered [557].
-Results from the SARS and MERS epidemics thus provide valuable lessons for the design of neutralizing antibodies for the current outbreak.
+Furthermore, no conclusions about correlations between the severity of disease and the ability to produce nAbs can be drawn at this point.
+Rather, higher nAb titers were more frequently found in patients with severe disease.
+Correspondingly, higher levels of anti-spike IgG were observed in patients that deceased from infection compared to patient that recovered [558].
+Results from the SARS and MERS epidemics thus provide valuable lessons for the design of nAbs for the current outbreak.
The findings for SARS-CoV-1 and MERS-CoV can aid in identifying which structures constitute suitable targets for nAbs, despite the fact that the RBD appears to be distinct between the three coronavirus species.
-These studies also suggest that a combination of nAbs targeting distinct antigens might be necessary to provide protection [556].
+These studies also suggest that a combination of nAbs targeting distinct antigens might be necessary to provide protection [557].
The biggest challenge remains identifying antibodies that not only bind to their target, but also prove to be beneficial for disease management.
-On that note, a recently published study indicates that anti-spike antibodies could make the disease worse rather than eliminating the virus [557].
+On that note, a recently published study indicates that anti-spike antibodies could make the disease worse rather than eliminating the virus [558].
These findings underscores our current lack of understanding the full immune response to SARS-CoV-2.
5.5.3 Interferons
IFNs are a family of cytokines critical to activating the innate immune response against viral infections.
-Interferons are classified into three categories based on their receptor specificity: types I, II and III [114].
-Specifically, IFNs I (IFN-𝛼 and 𝛽) and II (IFN-𝛾) induce the expression of antiviral proteins [558].
-Among these IFNs, IFN-𝛽 has already been found to strongly inhibit the replication of other coronaviruses, such as SARS-CoV-1, in cell culture, while IFN-𝛼 and 𝛾 were shown to be less effective in this context [558].
+Interferons are classified into three categories based on their receptor specificity: types I, II and III [116].
+Specifically, IFNs I (IFN-𝛼 and 𝛽) and II (IFN-𝛾) induce the expression of antiviral proteins [559].
+Among these IFNs, IFN-𝛽 has already been found to strongly inhibit the replication of other coronaviruses, such as SARS-CoV-1, in cell culture, while IFN-𝛼 and 𝛾 were shown to be less effective in this context [559].
There is evidence that patients with higher susceptibility to ARDS indeed show deficiency in IFN-𝛽.
-For instance, infection with other coronaviruses impairs IFN-𝛽 expression and synthesis, allowing the virus to escape the innate immune response [559].
-On March 18 2020, Synairgen plc received approval to start a phase II trial for SNG001, an IFN-𝛽-1a formulation to be delivered to the lungs via inhalation [560].
-SNG001, which contains recombinant interferon beta-1a, was previously shown to be effective in reducing viral load in an in vivo model of swine flu and in vitro models of other coronavirus infections [561].
-In July, a press release from Synairgen stated that SNG001 reduced progression to ventilation in a double-blind, placebo-controlled, multi-center study of 101 patients with an average age in the late 50s [562].
-These results were subsequently published in November 2020 [563].
+For instance, infection with other coronaviruses impairs IFN-𝛽 expression and synthesis, allowing the virus to escape the innate immune response [560].
+On March 18 2020, Synairgen plc received approval to start a phase II trial for SNG001, an IFN-𝛽-1a formulation to be delivered to the lungs via inhalation [561].
+SNG001, which contains recombinant interferon beta-1a, was previously shown to be effective in reducing viral load in an in vivo model of swine flu and in vitro models of other coronavirus infections [562].
+In July, a press release from Synairgen stated that SNG001 reduced progression to ventilation in a double-blind, placebo-controlled, multi-center study of 101 patients with an average age in the late 50s [563].
+These results were subsequently published in November 2020 [564].
The study reports that the participants were assigned at a ratio of 1:1 to receive either SNG001 or a placebo that lacked the active compound, by inhalation for up to 14 days.
The primary outcome they assessed was the change in patients’ score on the WHO Ordinal Scale for Clinical Improvement (OSCI) at trial day 15 or 16.
SNG001 was associated with an odds ratio (OR) of 2.32 (95% CI 1.07 – 5.04, p = 0.033) in the intention-to-treat analysis and 2.80 (95% CI 1.21 – 6.52, p = 0.017) in the per-protocol analysis, corresponding to significant improvement in the SNG001 group on the OSCI at day 15/16.
Some of the secondary endpoints analyzed also showed differences: at day 28, the OR for clinical improvement on the OSCI was 3.15 (95% CI 1.39 – 7.14, p = 0.006), and the odds of recovery at day 15/16 and at day 28 were also significant between the two groups.
Thus, this study suggested that IFN-𝛽1 administered via SNG001 may improve clinical outcomes.
-In contrast, the WHO Solidarity trial reported no significant effect of IFN-𝛽1a on patient survival during hospitalization [390].
-Here, the primary outcome analyzed was in-hospital mortality, and the rate ratio for the two groups was 1.16 (95% CI, 0.96 to 1.39; p = 0.11) administering IFN-𝛽-1a to 2050 patients and comparing their response to 2050 controls..
+
In contrast, the WHO Solidarity trial reported no significant effect of IFN-𝛽1a on patient survival during hospitalization [391].
+Here, the primary outcome analyzed was in-hospital mortality, and the rate ratio for the two groups was 1.16 (95% CI, 0.96 to 1.39; p = 0.11) administering IFN-𝛽-1a to 2050 patients and comparing their response to 2,050 controls.
However, there are a few reasons that the different findings of the two trials might not speak to the underlying efficacy of this treatment strategy.
One important consideration is the stage of COVID-19 infection analyzed in each study.
-The Synairgen trial enrolled only patients who were not receiving invasive ventilation, corresponding to a less severe stage of disease than many patients enrolled in the SOLIDARITY trial, as well as a lower overall rate of mortality [564].
-Additionally, the methods of administration differed between the two trials, with the SOLIDARITY trial administering IFN-𝛽-1a subcutaneously [564].
+The Synairgen trial enrolled only patients who were not receiving invasive ventilation, corresponding to a less severe stage of disease than many patients enrolled in the SOLIDARITY trial, as well as a lower overall rate of mortality [565].
+Additionally, the methods of administration differed between the two trials, with the SOLIDARITY trial administering IFN-𝛽-1a subcutaneously [565].
The differences in findings between the studies suggests that the method of administration might be relevant to outcomes, with nebulized IFN-𝛽-1a more directly targeting receptors in the lungs.
-A trial that analyzed the effect of subcutaneously administered IFN-β-1a on patients with ARDS between 2015 and 2017 had also reported no effect on 28-day mortality [565], while a smaller study analyzing the effect of subcutaneous IFN administration did find a significant improvement in 28-day mortality for COVID-19 [566].
-At present, several ongoing clinical trials are investigating the potential effects of IFN-𝛽-1a, including in combination with therapeutics such as remdesivir [567] and administered via inhalation [560].
+A trial that analyzed the effect of subcutaneously administered IFN-β-1a on patients with ARDS between 2015 and 2017 had also reported no effect on 28-day mortality [566], while a smaller study analyzing the effect of subcutaneous IFN administration did find a significant improvement in 28-day mortality for COVID-19 [567].
+At present, several ongoing clinical trials are investigating the potential effects of IFN-𝛽-1a, including in combination with therapeutics such as remdesivir [568] and administered via inhalation [561].
Thus, as additional information becomes available, a more detailed understanding of whether and under which circumstances IFN-𝛽-1a is beneficial to COVID-19 patients should develop.
5.6 Discussion
-With the emergence of the COVID-19 pandemic caused by the coronavirus SARS-CoV-2, the development and/or identification of therapeutic and prophylactic interventions became an issue of international urgency.
+
With the emergence of the COVID-19 pandemic caused by the coronavirus SARS-CoV-2, the development and identification of therapeutic and prophylactic interventions became issues of international urgency.
In previous outbreaks of HCoV, namely SARS and MERS, the development of these interventions was very limited.
-As research has progressed, several potential approaches to treatment have emerged (Figure 4)..
+As research has progressed, several potential approaches to treatment have emerged (Figure 4).
Most notably, remdesivir has been approved by the FDA for the treatment of COVID-19, and dexamethasone, which was approved by the FDA in 1958, has been found to improve outcomes for patients with severe COVID-19.
Other potential therapies are being still being explored and require additional data (Figure 3).
As more evidence becomes available, the potential for existing and novel therapies to improve outcomes for COVID-19 patients will become better understood.
@@ -2228,12 +2228,12 @@ 5.6
-Insights into the pathogenesis of and immune response to SARS-CoV-2 (see [367]) have also guided the identification of potential prophylactics and therapeutics.
+
Insights into the pathogenesis of and immune response to SARS-CoV-2 (see [1]) have also guided the identification of potential prophylactics and therapeutics.
As cases have become better characterized, it has become evident that many patients experience an initial immune response to the virus that is typically characterized by fever, cough, dyspnea, and related symptoms.
-However, the most serious concern is cytokine release syndrome, when the body’s immune response becomes dysregulated, resulting in an extreme inflammatory response.
-The RECOVERY trial, a large-scale, multi-arm trial enrolling about 15% of all COVID-19 patients in the United Kingdom, was the first to identify that the widely available steroid dexamethasone seems to be beneficial for patients suffering from this immune dysregulation [502].
+However, the most serious concern is CRS, when the body’s immune response becomes dysregulated, resulting in an extreme inflammatory response.
+The RECOVERY trial, a large-scale, multi-arm trial enrolling about 15% of all COVID-19 patients in the United Kingdom, was the first to identify that the widely available steroid dexamethasone seems to be beneficial for patients suffering from this immune dysregulation [503].
The results of efforts to identify therapeutic treatments to treat patients early in the course of infection have been more ambiguous.
-Early interest in the drugs hydroxychloroquine and chloroquine yielded no promising results from studies with robust experimental designs.
+Early interest in the drugs HCQ and CQ yielded no promising results from studies with robust experimental designs.
On the other hand, the experimental drug remdesivir, which was developed as a candidate therapeutic for EVD, has received enough support from early analyses to receive FDA approval, although results have been mixed.
The potential for other drugs, such as tocilizumab, to reduce recovery time remains unclear, but some early results were promising.
One additional concern is that the presentation of COVID-19 appears to be heterogeneous across the lifespan.
@@ -2245,33 +2245,33 @@
[568]
.
-Several other anti-inflammatory agents used for the treatment of autoimmune diseases may also be able to counter the effects of the cytokine storm induced by the virus, and some of these, such as cyclosporine, are likely to be more cost-effective and readily available than biologics [569].
+At the doses used for RA patients, the cost for tocilizumab ranges from $179.20 to $896 per dose for the IV form and $355 for the pre-filled syringe [569].
+Several other anti-inflammatory agents used for the treatment of autoimmune diseases may also be able to counter the effects of the cytokine storm induced by the virus, and some of these, such as cyclosporine, are likely to be more cost-effective and readily available than biologics [570].
While tocilizumab targets IL-6, several other inflammatory markers could be potential targets, including TNF-α.
-Inhibition of TNF-α by a compound such as Etanercept was previously suggested for treatment of SARS-CoV-1 [570] and may be relevant for SARS-CoV-2 as well.
-Another anti-IL-6 antibody, sarilumab, is also being investigated [571,572].
-Baricitinib and other small molecule inhibitors of the Janus-activated kinase pathway also curtail the inflammatory response and have been suggested as potential options for SARS-CoV-2 infections [573].
-Baricitinib, in particular, may be able to reduce the ability of SARS-CoV-2 to infect lung cells [574].
-Clinical trials studying baricitinib in COVID-19 have already begun in the US and in Italy [575,576].
+Inhibition of TNF-α by a compound such as Etanercept was previously suggested for treatment of SARS-CoV-1 [571] and may be relevant for SARS-CoV-2 as well.
+Another anti-IL-6 antibody, sarilumab, is also being investigated [572,573].
+Baricitinib and other small molecule inhibitors of the Janus-activated kinase pathway also curtail the inflammatory response and have been suggested as potential options for SARS-CoV-2 infections [574].
+Baricitinib, in particular, may be able to reduce the ability of SARS-CoV-2 to infect lung cells [575].
+Clinical trials studying baricitinib in COVID-19 have already begun in the US and in Italy [576,577].
Identification and targeting of further inflammatory markers that are relevant in SARS-CoV-2 infection may be of value for curtailing the inflammatory response and lung damage.
In addition to immunosuppressive treatments, which are most beneficial late in disease progression, much research is focused on identifying therapeutics for early-stage patients.
-For example, although studies of hydroxychloroquine have not supported the early theory-driven interest in this antiviral treatment, alternative compounds with related mechanisms may still have potential.
-Hydroxyferroquine derivatives of HCQ have been described as a class of bioorganometallic compounds that exert antiviral effects with some selectivity for SARS-CoV-1 in vitro [577].
+For example, although studies of HCQ have not supported the early theory-driven interest in this antiviral treatment, alternative compounds with related mechanisms may still have potential.
+Hydroxyferroquine derivatives of HCQ have been described as a class of bioorganometallic compounds that exert antiviral effects with some selectivity for SARS-CoV-1 in vitro [578].
Future work could explore whether such compounds exert antiviral effects against SARS-CoV-2 and whether they would be safer for use in COVID-19.
Another potential approach is the development of antivirals, which could be broad-spectrum, specific to coronaviruses, or targeted to SARS-CoV-2.
Development of new antivirals is complicated by the fact that none have yet been approved for human coronaviruses.
Intriguing new options are emerging, however.
-Beta-D-N4-hydroxycytidine (NHC) is an orally bioavailable ribonucleotide analog showing broad-spectrum activity against RNA viruses, which may inhibit SARS-CoV-2 replication in vitro and in vivo in mouse models of HCoVs [578].
+Beta-D-N4-hydroxycytidine (NHC) is an orally bioavailable ribonucleotide analog showing broad-spectrum activity against RNA viruses, which may inhibit SARS-CoV-2 replication in vitro and in vivo in mouse models of HCoVs [579].
A range of other antivirals are also in development.
Development of antivirals will be further facilitated as research reveals more information about the interaction of SARS-CoV-2 with the host cell and host cell genome, mechanisms of viral replication, mechanisms of viral assembly, and mechanisms of viral release to other cells; this can allow researchers to target specific stages and structures of the viral life cycle.
Finally, antibodies against viruses, also known as antiviral monoclonal antibodies, could be an alternative as well and are described in detail in an above section.
-The goal of antiviral antibodies is to neutralize viruses through either cell-killing activity or blocking of viral replication [579].
+The goal of antiviral antibodies is to neutralize viruses through either cell-killing activity or blocking of viral replication [580].
They may also engage the host immune response, encouraging the immune system to hone in on the virus.
-Given the cytokine storm that results from immune system activation in response to the virus, which has been implicated in worsening of the disease, a neutralizing antibody (nAb) may be preferable.
+Given the cytokine storm that results from immune system activation in response to the virus, which has been implicated in worsening of the disease, an nAb may be preferable.
Upcoming work may explore the specificity of nAbs for their target, mechanisms by which the nAbs impede the virus, and improvements to antibody structure that may enhance the ability of the antibody to block viral activity.
Some research is also investigating potential therapeutics and prophylactics that would interact with components of the innate immune response.
-For example, TLRs are PRRs that recognize pathogen- and damage-associated molecular patterns and contribute to innate immune recognition and, more generally, promotion of both the innate and adaptive immune responses [110].
-In mouse models, poly(I:C) and CpG, which are agonists of Toll-like receptors TLR3 and TLR9, respectively, showed protective effects when administered prior to SARS-CoV-1 infection [580].
+For example, TLRs are pattern recognition receptors that recognize pathogen- and damage-associated molecular patterns and contribute to innate immune recognition and, more generally, promotion of both the innate and adaptive immune responses [112].
+In mouse models, poly(I:C) and CpG, which are agonists of Toll-like receptors TLR3 and TLR9, respectively, showed protective effects when administered prior to SARS-CoV-1 infection [581].
Therefore, TLR agonists hold some potential for broad-spectrum prophylaxis.
Given that a large number of clinical trials are currently in progress, more information about the potential of these and other therapeutics should become available over time.
This information, combined with advances in understanding the molecular structure and viral pathogenesis of SARS-CoV-2, may lead to a more complete understanding of how the virus affects the human host and what strategies can improve outcomes.
@@ -2280,11 +2280,12 @@
[424,581]
, and efforts are already in place to perform screens for small molecule inhibitors of the main protease, which have yielded potential hits [424].
+Currently, crystal structures of the SARS-CoV-2 main protease have recently been resolved [425,582], and efforts are already in place to perform screens for small molecule inhibitors of the main protease, which have yielded potential hits [425].
Much work remains to be done to determine further crystal structures of other viral components, understand the relative utility of targeting different viral components, perform additional small molecule inhibitor screens, and determine the safety and efficacy of the potential inhibitors.
While still nascent, work in this area is promising.
-Over the longer term, this approach and others may lead to the development of novel therapeutics specifically for COVID-19 and SARS-CoV-2.
-5.6.2 Conclusions of the Present Analysis
+Over the longer term, this approach and others may lead to the development of novel therapeutics specifically for COVID-19 and SARS-CoV-2.
+
+5.6.2 Conclusions
Due to the large number of clinical trials currently under examination (Figure 3), not all candidates are examined here.
Instead, this review seeks to provide an overview of the range of mechanisms that have been explored and to examine some prominent candidates in the context of the pathogenesis of and immune response to SARS-CoV-2.
As more research becomes available, this review will be updated to include additional therapeutics that emerge and to include new findings that are released about those discussed here.
@@ -2315,140 +2316,140 @@
6.
This rapid effort led to the identification of some promising pharmaceutical therapies for hospitalized patients, such as remdesivir and dexamethasone.
Furthermore, most societies have adopted non-pharmacological preventative measures such as utilizing public health strategies that reduce the transmission of SARS-CoV-2.
However, during this time, many individuals sought additional protections via the consumption of various dietary supplements and nutraceuticals that they believed to confer beneficial effects.
-While a patient’s nutritional status does seem to play a role in COVID-19 susceptibility and outcomes [582,583,584,585,586], the beginning of the pandemic saw sales of vitamins and other supplements to soar despite a lack of any evidence supporting their use against COVID-19.
-In the United States, for example, dietary supplement and nutraceutical sales have shown modest annual growth in recent years (approximately 5%, or a $345 million increase in 2019), but during the six-week period preceding April 5, 2020, they increased by 44% ($435 million) relative to the same period in 2019 [587].
-While growth subsequently leveled off, sales continued to boom, with a further 16% ($151 million) increase during the six weeks preceding May 17, 2020 relative to 2019 [587].
-In France, New Zealand, India, and China, similar trends in sales were reported [588,589,590,591].
-The increase in sales was driven by a consumer perception that dietary supplements and nutraceuticals would protect consumers from infection and/or mitigate the impact of infection due to the various “immune-boosting” claims of these products [592,593].
+While a patient’s nutritional status does seem to play a role in COVID-19 susceptibility and outcomes [583,584,585,586,587], the beginning of the pandemic saw sales of vitamins and other supplements to soar despite a lack of any evidence supporting their use against COVID-19.
+In the United States, for example, dietary supplement and nutraceutical sales have shown modest annual growth in recent years (approximately 5%, or a $345 million increase in 2019), but during the six-week period preceding April 5, 2020, they increased by 44% ($435 million) relative to the same period in 2019 [588].
+While growth subsequently leveled off, sales continued to boom, with a further 16% ($151 million) increase during the six weeks preceding May 17, 2020 relative to 2019 [588].
+In France, New Zealand, India, and China, similar trends in sales were reported [589,590,591,592].
+The increase in sales was driven by a consumer perception that dietary supplements and nutraceuticals would protect consumers from infection and/or mitigate the impact of infection due to the various “immune-boosting” claims of these products [593,594].
Due to the significant interest from the general public in dietary additives, whether and to what extent nutraceuticals or dietary supplements can provide any prophylactic or therapeutic benefit remains a topic of interest for the scientific community.
Nutraceuticals and dietary supplements are related but distinct non-pharmaceutical products.
-Nutraceuticals are classified as supplements with health benefits beyond their basic nutritional value [594,595].
-The key difference between a dietary supplement and a nutraceutical is that nutraceuticals should not only supplement the diet, but also aid in the prophylaxis and/or treatment of a disorder or disease [596].
+Nutraceuticals are classified as supplements with health benefits beyond their basic nutritional value [595,596].
+The key difference between a dietary supplement and a nutraceutical is that nutraceuticals should not only supplement the diet, but also aid in the prophylaxis and/or treatment of a disorder or disease [597].
However, dietary supplements and nutraceuticals, unlike pharmaceuticals, are not subject to the same regulatory protocols that protect consumers of medicines.
-Indeed, nutraceuticals do not entirely fall under the responsibility of the Food and Drug Administration (FDA), but they are monitored as dietary supplements according to the Dietary Supplement, Health and Education Act 1994 (DSHEA) [597] and the Food and Drug Administration Modernization Act 1997 (FDAMA) [598].
+Indeed, nutraceuticals do not entirely fall under the responsibility of the Food and Drug Administration (FDA), but they are monitored as dietary supplements according to the Dietary Supplement, Health and Education Act 1994 (DSHEA) [598] and the Food and Drug Administration Modernization Act 1997 (FDAMA) [599].
Due to increases in sales of dietary supplements and nutraceuticals, in 1996 the FDA established the Office of Dietary Supplement Programs (ODSP) to increase surveillance.
Novel products or nutraceuticals must now submit a new dietary ingredient notification to the ODSP for review.
-There are significant concerns that these legislations do not adequately protect the consumer as they ascribe responsibility to the manufacturers to ensure the safety of the product before manufacturing or marketing [599].
+There are significant concerns that these legislations do not adequately protect the consumer as they ascribe responsibility to the manufacturers to ensure the safety of the product before manufacturing or marketing [600].
Manufacturers are not required to register or even seek approval from the FDA to produce or sell food supplements or nutraceuticals.
-Health or nutrient content claims for labeling purposes are approved based on an authoritative statement from the Academy of Sciences or relevant federal authorities once the FDA has been notified and on the basis that the information is known to be true and not deceptive [599].
+Health or nutrient content claims for labeling purposes are approved based on an authoritative statement from the Academy of Sciences or relevant federal authorities once the FDA has been notified and on the basis that the information is known to be true and not deceptive [600].
Therefore, there is often a gap between perceptions by the American public about a nutraceutical or dietary supplement and the actual clinical evidence surrounding its effects.
Despite differences in regulations, similar challenges exist outside of the United States.
-In Europe, where the safety of supplements are monitored by the European Union (EU) under Directive 2002/46/EC [600].
+In Europe, where the safety of supplements are monitored by the European Union (EU) under Directive 2002/46/EC [601].
However, nutraceuticals are not directly mentioned.
-Consequently, nutraceuticals can be generally described as either a medicinal product under Directive 2004/27/EC [601] or as a ‘foodstuff’ under Directive 2002/46/EC of the European council.
+Consequently, nutraceuticals can be generally described as either a medicinal product under Directive 2004/27/EC [602] or as a ‘foodstuff’ under Directive 2002/46/EC of the European council.
In order to synchronize the various existing legislations, Regulation EC 1924/2006 on nutrition and health claims was put into effect to assure customers of safety and efficacy of products and to deliver understandable information to consumers.
However, specific legislation for nutraceuticals is still elusive.
-Health claims are permitted on a product label only following compliance and authorization according to the European Food Safety Authority (EFSA) guidelines on nutrition and health claims [602].
-EFSA does not currently distinguish between food supplements and nutraceuticals for health claim applications of new products, as claim authorization is dependent on the availability of clinical data in order to substantiate efficacy [603].
-These guidelines seem to provide more protection to consumers than the FDA regulations but potentially at the cost of innovation in the sector [604].
-The situation becomes even more complicated when comparing regulations at a global level, as countries such as China and India have existing regulatory frameworks for traditional medicines and phytomedicines not commonly consumed in Western society [605].
-Currently, there is debate among scientists and regulatory authorities surrounding the development of a widespread regulatory framework to deal with the challenges of safety and health claim substantiation for nutraceuticals [599,603], as these products do not necessarily follow the same rigorous clinical trial frameworks used to approve the use of pharmaceuticals.
+Health claims are permitted on a product label only following compliance and authorization according to the European Food Safety Authority (EFSA) guidelines on nutrition and health claims [603].
+EFSA does not currently distinguish between food supplements and nutraceuticals for health claim applications of new products, as claim authorization is dependent on the availability of clinical data in order to substantiate efficacy [604].
+These guidelines seem to provide more protection to consumers than the FDA regulations but potentially at the cost of innovation in the sector [605].
+The situation becomes even more complicated when comparing regulations at a global level, as countries such as China and India have existing regulatory frameworks for traditional medicines and phytomedicines not commonly consumed in Western society [606].
+Currently, there is debate among scientists and regulatory authorities surrounding the development of a widespread regulatory framework to deal with the challenges of safety and health claim substantiation for nutraceuticals [600,604], as these products do not necessarily follow the same rigorous clinical trial frameworks used to approve the use of pharmaceuticals.
Such regulatory disparities have been highlighted by the pandemic, as many individuals and companies have attempted to profit from the vulnerabilities of others by overstating claims in relation to the treatment of COVID-19 using supplements and nutraceuticals.
-The FDA has written several letters to prevent companies marketing or selling products based on false hyperbolic promises about preventing SARS-CoV-2 infection or treating COVID-19 [606,607,608].
-These letters came in response to efforts to market nutraceutical prophylactics against COVID-19, some of which charged the consumer as much as $23,000 [609].
-There have even been some incidents highlighted in the media because of their potentially life threatening consequences; for example, the use of oleandrin was touted as a potential “cure” by individuals close to the former President of the United States despite its high toxicity [610].
+The FDA has written several letters to prevent companies marketing or selling products based on false hyperbolic promises about preventing SARS-CoV-2 infection or treating COVID-19 [607,608,609].
+These letters came in response to efforts to market nutraceutical prophylactics against COVID-19, some of which charged the consumer as much as $23,000 [610].
+There have even been some incidents highlighted in the media because of their potentially life threatening consequences; for example, the use of oleandrin was touted as a potential “cure” by individuals close to the former President of the United States despite its high toxicity [611].
Thus, heterogeneous and at times relaxed regulatory standards have permitted high-profile cases of the sale of nutraceuticals and dietary supplements that are purported to provide protection against COVID-19, despite a lack of research into these compounds.
Notwithstanding the issues of poor safety, efficacy, and regulatory oversight, some dietary supplements and nutraceuticals have exhibited therapeutic and prophylactic potential.
-Some have been linked with reduced immunopathology, antiviral and anti-inflammatory activities, or even the prevention of acute respiratory distress syndrome (ARDS) [592,611,612].
+Some have been linked with reduced immunopathology, antiviral and anti-inflammatory activities, or even the prevention of acute respiratory distress syndrome (ARDS) [593,612,613].
A host of potential candidates have been highlighted in the literature that target various aspects of the COVID-19 viral pathology, while others are thought to prime the host immune system.
-These candidates include vitamins and minerals along with extracts and omega-3 polyunsaturated fatty acids (n-3 PUFA) [613].
-In vitro and in vivo studies suggest that nutraceuticals containing phycocyanobilin, N-acetylcysteine, glucosamine, selenium or phase 2 inductive nutraceuticals (e.g. ferulic acid, lipoic acid, or sulforaphane) can prevent or modulate RNA virus infections via amplification of the signaling activity of mitochondrial antiviral-signaling protein (MAVS) and activation of Toll-like receptor 7 [614].
+These candidates include vitamins and minerals along with extracts and omega-3 polyunsaturated fatty acids (n-3 PUFA) [614].
+In vitro and in vivo studies suggest that nutraceuticals containing phycocyanobilin, N-acetylcysteine, glucosamine, selenium or phase 2 inductive nutraceuticals (e.g. ferulic acid, lipoic acid, or sulforaphane) can prevent or modulate RNA virus infections via amplification of the signaling activity of mitochondrial antiviral-signaling protein (MAVS) and activation of Toll-like receptor 7 [615].
While promising, further animal and human studies are required to assess the therapeutic potential of these various nutrients and nutraceuticals against COVID-19.
For the purpose of this review, we have highlighted some of the main dietary supplements and nutraceuticals that are currently under investigation for their potential prophylactic and therapeutic applications.
These include n-3 PUFA, zinc, vitamins C and D, and probiotics.
6.4 n-3 PUFA
-One category of supplements that has been explored for beneficial effects against various viral infections are the n-3 PUFAs [613], commonly referred to as omega-3 fatty acids, which include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
-EPA and DHA intake can come from a diet high in fish or through dietary supplementation with fish oils or purified oils [615].
-Other, more sustainable sources of EPA and DHA include algae [616,617], which can also be exploited for their rich abundance of other bioactive compounds such as angiotensin converting enzyme inhibitor peptides and antiviral agents including phycobiliproteins, sulfated polysaccharides, and calcium-spirulan [618].
-n-3 PUFAs have been investigated for many years for their therapeutic potential [619].
-Supplementation with fish oils is generally well tolerated [619], and intake of n-3 PUFAs through dietary sources or supplementation is specifically encouraged for vulnerable groups such as pregnant and lactating women [620,621].
+
One category of supplements that has been explored for beneficial effects against various viral infections are the n-3 PUFAs [614], commonly referred to as omega-3 fatty acids, which include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
+EPA and DHA intake can come from a diet high in fish or through dietary supplementation with fish oils or purified oils [616].
+Other, more sustainable sources of EPA and DHA include algae [617,618], which can also be exploited for their rich abundance of other bioactive compounds such as angiotensin converting enzyme inhibitor peptides and antiviral agents including phycobiliproteins, sulfated polysaccharides, and calcium-spirulan [619].
+n-3 PUFAs have been investigated for many years for their therapeutic potential [620].
+Supplementation with fish oils is generally well tolerated [620], and intake of n-3 PUFAs through dietary sources or supplementation is specifically encouraged for vulnerable groups such as pregnant and lactating women [621,622].
As a result, these well-established compounds have drawn significant interest for their potential immune effects and therapeutic potential.
Particular interest has arisen in n-3 PUFAs as potential therapeutics against diseases associated with inflammation.
-n-3 PUFAs have been found to mediate inflammation by influencing processes such as leukocyte chemotaxis, adhesion molecule expression, and the production of eicosanoids [622,623].
-This and other evidence indicates that n-3 PUFAs may have the capacity to modulate the adaptive immune response [595,615,622]; for example, they have been found to influence antigen presentation and the production of CD4(+) Th1 cells, among other relevant effects [624].
-Certainly, preliminary evidence from banked blood samples from 100 COVID-19 patients suggests that patients with a higher omega-3 index, a measure of n-3 and n-6 fatty acids in red blood cells, had a lower risk of death due to COVID-19 [625].
-Interest has also arisen as to whether nutritional status related to n-3 PUFAs can also affect inflammation associated with severe disease, such as ARDS or sepsis [626,627].
-ARDS and sepsis hold particular concern in the treatment of severe COVID-19; an analysis of 82 deceased COVID-19 patients in Wuhan during January to February 2020 reported that respiratory failure (associated with ARDS) was the cause of death in 69.5% of cases, and sepsis or multi-organ failure accounted for 28.0% of deaths [628].
+n-3 PUFAs have been found to mediate inflammation by influencing processes such as leukocyte chemotaxis, adhesion molecule expression, and the production of eicosanoids [623,624].
+This and other evidence indicates that n-3 PUFAs may have the capacity to modulate the adaptive immune response [596,616,623]; for example, they have been found to influence antigen presentation and the production of CD4(+) Th1 cells, among other relevant effects [625].
+Certainly, preliminary evidence from banked blood samples from 100 COVID-19 patients suggests that patients with a higher omega-3 index, a measure of n-3 and n-6 fatty acids in red blood cells, had a lower risk of death due to COVID-19 [626].
+Interest has also arisen as to whether nutritional status related to n-3 PUFAs can also affect inflammation associated with severe disease, such as ARDS or sepsis [627,628].
+ARDS and sepsis hold particular concern in the treatment of severe COVID-19; an analysis of 82 deceased COVID-19 patients in Wuhan during January to February 2020 reported that respiratory failure (associated with ARDS) was the cause of death in 69.5% of cases, and sepsis or multi-organ failure accounted for 28.0% of deaths [629].
Research in ARDS prior to current pandemic suggests that n-3 PUFAs may hold some therapeutic potential.
-One study randomized 16 consecutive ARDS patients to receive either a fish oil-enriched lipid emulsion or a control lipid emulsion (comprised of 100% long-chain triglycerides) under a double-blinded design [629].
+One study randomized 16 consecutive ARDS patients to receive either a fish oil-enriched lipid emulsion or a control lipid emulsion (comprised of 100% long-chain triglycerides) under a double-blinded design [630].
They reported a statistically significant reduction in leukotriene B4 levels in the group receiving the fish oil-enriched emulsion, suggesting that the fish oil supplementation may have reduced inflammation.
However, they also reported that most of their tests were not statistically significant, and therefore it seems that additional research using larger sample sizes is required.
-A recent meta-analysis of 10 randomized controlled trials (RCTs) examining the effects of n-3 PUFAs on ARDS patients did not find evidence of any effect on mortality, although the effect on secondary outcomes could not be determined due to a low quality of evidence [630].
-However, another meta-analysis that examined 24 RCTs studying the effects of n-3 fatty acids on sepsis, including ARDS-induced sepsis, did find support for an effect on mortality when n-3 fatty acids were administered via enteral nutrition, although a paucity of high-quality evidence again limited conclusions [631].
+A recent meta-analysis of 10 randomized controlled trials (RCTs) examining the effects of n-3 PUFAs on ARDS patients did not find evidence of any effect on mortality, although the effect on secondary outcomes could not be determined due to a low quality of evidence [631].
+However, another meta-analysis that examined 24 RCTs studying the effects of n-3 fatty acids on sepsis, including ARDS-induced sepsis, did find support for an effect on mortality when n-3 fatty acids were administered via enteral nutrition, although a paucity of high-quality evidence again limited conclusions [632].
Therefore, despite theoretical support for an immunomodulatory effect of n-3 PUFAs in COVID-19, evidence from existing RCTs is insufficient to determine whether supplementation offers an advantage in a clinical setting that would be relevant to COVID-19.
-Another potential mechanism that has led to interest in n-3 PUFAs as protective against viral infections including COVID-19 is its potential as a precursor molecule for the biosynthesis of endogenous specialized proresolving mediators (SPM), such as protectins and resolvins, that actively resolve inflammation and infection [632].
-SPM have exhibited beneficial effects against a variety of lung infections, including some caused by RNA viruses [633,634].
-Indeed, protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [635].
-Several mechanisms for SPM have been proposed, including preventing the release of pro-inflammatory cytokines and chemokines or increasing phagocytosis of cellular debris by macrophages [636].
-In influenza, SPM promote antiviral B lymphocytic activities [637], and protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [635].
-It has thus been hypothesized that SPM could aid in the resolution of the cytokine storm and pulmonary inflammation associated with COVID-19 [638,639].
-Another theory is that some comorbidities, such as obesity, could lead to deficiencies of SPM, which could in turn be related to the occurrence of adverse outcomes for COVID-19 [640].
-However, not all studies are in agreement that n-3 PUFAs or their resulting SPM are effective against infections [641].
-At a minimum, the effectiveness of n-3 PUFAs against infections would be dependent on the dosage, timing, and the specific pathogens responsible [642].
-On another level, there is still the question of whether fish oils can raise the levels of SPM levels upon ingestion and in response to acute inflammation in humans [643].
-Currently, Karolinska University Hospital is running a trial that will measure the levels of SPM as a secondary outcome following intravenous supplementation of n-3 PUFAs in hospitalized COVID-19 patients to determine whether n-3 PUFAs provides therapeutic value [644,645].
+
Another potential mechanism that has led to interest in n-3 PUFAs as protective against viral infections including COVID-19 is its potential as a precursor molecule for the biosynthesis of endogenous specialized proresolving mediators (SPM), such as protectins and resolvins, that actively resolve inflammation and infection [633].
+SPM have exhibited beneficial effects against a variety of lung infections, including some caused by RNA viruses [634,635].
+Indeed, protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [636].
+Several mechanisms for SPM have been proposed, including preventing the release of pro-inflammatory cytokines and chemokines or increasing phagocytosis of cellular debris by macrophages [637].
+In influenza, SPM promote antiviral B lymphocytic activities [638], and protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [636].
+It has thus been hypothesized that SPM could aid in the resolution of the cytokine storm and pulmonary inflammation associated with COVID-19 [639,640].
+Another theory is that some comorbidities, such as obesity, could lead to deficiencies of SPM, which could in turn be related to the occurrence of adverse outcomes for COVID-19 [641].
+However, not all studies are in agreement that n-3 PUFAs or their resulting SPM are effective against infections [642].
+At a minimum, the effectiveness of n-3 PUFAs against infections would be dependent on the dosage, timing, and the specific pathogens responsible [643].
+On another level, there is still the question of whether fish oils can raise the levels of SPM levels upon ingestion and in response to acute inflammation in humans [644].
+Currently, Karolinska University Hospital is running a trial that will measure the levels of SPM as a secondary outcome following intravenous supplementation of n-3 PUFAs in hospitalized COVID-19 patients to determine whether n-3 PUFAs provides therapeutic value [645,646].
Therefore, while this mechanism provides theoretical support for a role for n-3 PUFAs against COVID-19, experimental support is still needed.
-A third possible mechanism by which n-3 PUFAs could benefit COVID-19 patients arises from the fact that some COVID-19 patients, particularly those with comorbidities, are at a significant risk of thrombotic complications including arterial and venous thrombosis [107,646].
-Therefore, the use of prophylactic and therapeutic anticoagulants and antithrombotic agents is under consideration [647,648].
-Considering that there is significant evidence that n-3 fatty acids and other fish oil-derived lipids possess antithrombotic properties and anti-inflammatory properties [615,649,650], they may have therapeutic value against the prothrombotic complications of COVID-19.
-In particular, concerns have been raised within the medical community about using investigational therapeutics on COVID-19 patients who are already on antiplatelet therapies due to pre-existing comorbidities because the introduction of such therapeutics could lead to issues with dosing and drug choice and/or negative drug-drug interactions [647].
+
A third possible mechanism by which n-3 PUFAs could benefit COVID-19 patients arises from the fact that some COVID-19 patients, particularly those with comorbidities, are at a significant risk of thrombotic complications including arterial and venous thrombosis [109,647].
+Therefore, the use of prophylactic and therapeutic anticoagulants and antithrombotic agents is under consideration [648,649].
+Considering that there is significant evidence that n-3 fatty acids and other fish oil-derived lipids possess antithrombotic properties and anti-inflammatory properties [616,650,651], they may have therapeutic value against the prothrombotic complications of COVID-19.
+In particular, concerns have been raised within the medical community about using investigational therapeutics on COVID-19 patients who are already on antiplatelet therapies due to pre-existing comorbidities because the introduction of such therapeutics could lead to issues with dosing and drug choice and/or negative drug-drug interactions [648].
In such cases, dietary sources of n-3 fatty acids or other nutraceuticals with antiplatelet activities could hold particular value for reducing the risk of thrombotic complications in patients already receiving pharmaceutical antiplatelet therapies.
-A new clinical trial [651] is currently recruiting COVID-19 positive patients to investigate the anti-inflammatory activity of a recently developed, highly purified nutraceutical derivative of EPA known as icosapent ethyl (VascepaTM) [652].
-Other randomized controlled trials that are in the preparatory stages intend to investigate the administration of EPA and other bioactive compounds to COVID-19 positive patients in order to observe whether anti-inflammatory effects or disease state improvements occur [653,654].
-Finally, while there have been studies investigating the therapeutic value of n-3 fatty acids against ARDS in humans, there is still limited evidence of their effectiveness [655].
+A new clinical trial [652] is currently recruiting COVID-19 positive patients to investigate the anti-inflammatory activity of a recently developed, highly purified nutraceutical derivative of EPA known as icosapent ethyl (VascepaTM) [653].
+Other randomized controlled trials that are in the preparatory stages intend to investigate the administration of EPA and other bioactive compounds to COVID-19 positive patients in order to observe whether anti-inflammatory effects or disease state improvements occur [654,655].
+Finally, while there have been studies investigating the therapeutic value of n-3 fatty acids against ARDS in humans, there is still limited evidence of their effectiveness [656].
It should be noted that the overall lack of human studies in this area means there is limited evidence as to whether these supplements could affect COVID-19 infection.
Consequently, the clinical trials that are underway and those that have been proposed will provide valuable insight into whether the anti-inflammatory potential of n-3 PUFAs and their derivatives can be beneficial to the treatment of COVID-19.
All the same, while the evidence is not present to draw conclusions about whether n-3 PUFAs will be useful in treating COVID-19, there is likely little harm associated with a diet rich in fish oils, and interest in n-3 PUFA supplementation by the general public is unlikely to have negative effects.
6.5 Zinc
Zinc is nutrient supplement that may exhibit some benefits against RNA viral infections.
-Zinc is a trace metal obtained from dietary sources or supplementation and is important for the maintenance of immune cells involved in adaptive and innate immunity [656].
+Zinc is a trace metal obtained from dietary sources or supplementation and is important for the maintenance of immune cells involved in adaptive and innate immunity [657].
Supplements can be administered orally as a tablet or as a lozenge and are available in many forms, such as zinc picolinate, zinc acetate, and zinc citrate.
Zinc is also available from dietary sources including meat, seafood, nuts, seeds, legumes, and dairy.
-The role of zinc in immune function has been extensively reviewed [656].
+The role of zinc in immune function has been extensively reviewed [657].
Zinc is an important signaling molecule, and zinc levels can alter host defense systems.
-In inflammatory situations such as an infection, zinc can regulate leukocyte immune responses and activate the nuclear factor kappa-light-chain-enhancer of activated B cells, thus altering cytokine production [657,658].
-In particular, zinc supplementation can increase natural killer cell levels, which are important cells for host defense against viral infections [656,659].
+In inflammatory situations such as an infection, zinc can regulate leukocyte immune responses and activate the nuclear factor kappa-light-chain-enhancer of activated B cells, thus altering cytokine production [658,659].
+In particular, zinc supplementation can increase natural killer cell levels, which are important cells for host defense against viral infections [657,660].
As a result of these immune-related functions, zinc is also under consideration for possible benefits against COVID-19.
-Adequate zinc intake has been associated with reduced incidence of infection [660] and antiviral immunity [661].
-A randomized, double-blind, placebo-controlled trial that administered zinc supplementation to elderly subjects over the course of a year found zinc deficiency to be associated with increased susceptibility to infection and that zinc deficiency could be prevented through supplementation [660].
-Clinical trial data supports the utility of zinc to diminish the duration and severity of symptoms associated with common colds when it is provided within 24 hours of the onset of symptoms [662,663].
-An observational study showed that COVID-19 patients had significantly lower zinc levels in comparison to healthy controls and that zinc-deficient COVID-19 patients (those with levels less than 80 μg/dl) tended to have more complications (70.4% vs 30.0%, p = 0.009) and potentially prolonged hospital stays (7.9 vs 5.7 days, p = 0.048) relative to patients who were not zinc deficient [664].
-In coronaviruses specifically, in vitro evidence has demonstrated that the combination of zinc (Zn2+) and zinc ionophores (pyrithione) can interrupt the replication mechanisms of SARS-CoV-GFP (a fluorescently tagged SARS-CoV-1) and a variety of other RNA viruses [665,666].
+
Adequate zinc intake has been associated with reduced incidence of infection [661] and antiviral immunity [662].
+A randomized, double-blind, placebo-controlled trial that administered zinc supplementation to elderly subjects over the course of a year found zinc deficiency to be associated with increased susceptibility to infection and that zinc deficiency could be prevented through supplementation [661].
+Clinical trial data supports the utility of zinc to diminish the duration and severity of symptoms associated with common colds when it is provided within 24 hours of the onset of symptoms [663,664].
+An observational study showed that COVID-19 patients had significantly lower zinc levels in comparison to healthy controls and that zinc-deficient COVID-19 patients (those with levels less than 80 μg/dl) tended to have more complications (70.4% vs 30.0%, p = 0.009) and potentially prolonged hospital stays (7.9 vs 5.7 days, p = 0.048) relative to patients who were not zinc deficient [665].
+In coronaviruses specifically, in vitro evidence has demonstrated that the combination of zinc (Zn2+) and zinc ionophores (pyrithione) can interrupt the replication mechanisms of SARS-CoV-GFP (a fluorescently tagged SARS-CoV-1) and a variety of other RNA viruses [666,667].
Currently, there are over twenty clinical trials registered with the intention to use zinc in a preventative or therapeutic manner for COVID-19.
-However, many of these trials proposed the use of zinc in conjunction with hydroxychloroquine and azithromycin [667,668,669,670], and it is not known how the lack of evidence supporting the use of hydroxychloroquine will affect investigation of zinc.
+However, many of these trials proposed the use of zinc in conjunction with hydroxychloroquine and azithromycin [668,669,670,671], and it is not known how the lack of evidence supporting the use of hydroxychloroquine will affect investigation of zinc.
One retrospective observational study of New York University Langone hospitals in New York compared outcomes among hospitalized COVID-19 patients administered hydroxychloroquine and azithromycin with zinc sulfate (n = 411) versus hydroxychloroquine and azithromycin alone (n = 521).
-Notably, zinc is the only treatment that was used in this trial that is still under consideration as a therapeutic agent due to the lack of efficacy and potential adverse events associated with hydroxychloroquine and azithromycin against COVID-19 [671,672,673].
-While the addition of zinc sulfate did not affect the duration of hospitalization, the length of ICU stays or patient ventilation duration, univariate analyses indicated that zinc did increase the frequency of patients discharged and decreased the requirement for ventilation, referrals to the ICU, mortality [674].
-However, a smaller retrospective study at Hoboken University Medical Center New Jersey failed to find an association between zinc supplementation and survival of hospitalized patients [675].
+Notably, zinc is the only treatment that was used in this trial that is still under consideration as a therapeutic agent due to the lack of efficacy and potential adverse events associated with hydroxychloroquine and azithromycin against COVID-19 [672,673,674].
+While the addition of zinc sulfate did not affect the duration of hospitalization, the length of ICU stays or patient ventilation duration, univariate analyses indicated that zinc did increase the frequency of patients discharged and decreased the requirement for ventilation, referrals to the ICU, mortality [675].
+However, a smaller retrospective study at Hoboken University Medical Center New Jersey failed to find an association between zinc supplementation and survival of hospitalized patients [676].
Therefore, whether zinc contributes to COVID-19 recovery remains unclear.
-Other trials are now investigating zinc in conjunction with other supplements such as vitamin C or n-3 PUFA [654,676].
+Other trials are now investigating zinc in conjunction with other supplements such as vitamin C or n-3 PUFA [655,677].
Though there is, overall, encouraging data for zinc supplementation against the common cold and viral infections, there is currently limited evidence to suggest zinc supplementation has any beneficial effects against the current novel COVID-19; thus, the clinical trials that are currently underway will provide vital information on the efficacious use of zinc in COVID-19 prevention and/or treatment.
However, given the limited risk and the potential association between zinc deficiency and illness, maintaining a healthy diet to ensure an adequate zinc status may be advisable for individuals seeking to reduce their likelihood of infection.
6.6 Vitamin C
-Vitamins B, C, D, and E have also been suggested as potential nutrient supplement interventions for COVID-19 [613,677].
-In particular vitamin C has been proposed as a potential therapeutic agent against COVID-19 due to its long history of use against the common cold and other respiratory infections [678,679].
+
Vitamins B, C, D, and E have also been suggested as potential nutrient supplement interventions for COVID-19 [614,678].
+In particular vitamin C has been proposed as a potential therapeutic agent against COVID-19 due to its long history of use against the common cold and other respiratory infections [679,680].
Vitamin C can be obtained via dietary sources such as fruits and vegetables or via supplementation.
Vitamin C plays a significant role in promoting immune function due to its effects on various immune cells.
-It affects inflammation by modulating cytokine production, decreasing histamine levels, enhancing the differentiation and proliferation of T- and B-lymphocytes, increasing antibody levels, and protecting against the negative effects of reactive oxygen species, among other effects related to COVID-19 pathology [680,681,682].
+It affects inflammation by modulating cytokine production, decreasing histamine levels, enhancing the differentiation and proliferation of T- and B-lymphocytes, increasing antibody levels, and protecting against the negative effects of reactive oxygen species, among other effects related to COVID-19 pathology [681,682,683].
Vitamin C is utilized by the body during viral infections, as evinced by lower concentrations in leukocytes and lower concentrations of urinary vitamin C.
-Post-infection, these levels return to baseline ranges [683,684,685,686,687].
-It has been shown that as little as 0.1 g/d of vitamin C can maintain normal plasma levels of vitamin C in healthy individuals, but higher doses of at least 1-3 g/d are required for critically ill patients in ICUs [688].
-Indeed, vitamin C deficiency appears to be common among COVID-19 patients [689,690].
-COVID-19 is also associated with the formation of microthrombi and coagulopathy [109] that contribute to its characteristic lung pathology [691], but these symptoms can be ameliorated by early infusions of vitamin C to inhibit endothelial surface P-selectin expression and platelet-endothelial adhesion [692].
-Intravenous vitamin C also reduced D-dimer levels, which are notably elevated in COVID-19 patients [105,106], in a case study of 17 COVID-19 patients [693].
+Post-infection, these levels return to baseline ranges [684,685,686,687,688].
+It has been shown that as little as 0.1 g/d of vitamin C can maintain normal plasma levels of vitamin C in healthy individuals, but higher doses of at least 1-3 g/d are required for critically ill patients in ICUs [689].
+Indeed, vitamin C deficiency appears to be common among COVID-19 patients [690,691].
+COVID-19 is also associated with the formation of microthrombi and coagulopathy [111] that contribute to its characteristic lung pathology [692], but these symptoms can be ameliorated by early infusions of vitamin C to inhibit endothelial surface P-selectin expression and platelet-endothelial adhesion [693].
+Intravenous vitamin C also reduced D-dimer levels, which are notably elevated in COVID-19 patients [107,108], in a case study of 17 COVID-19 patients [694].
There is therefore preliminary evidence suggesting that vitamin C status and vitamin C administration may be relevant to COVID-19 outcomes.
Larger-scale studies of vitamin C, however, have provided mixed results.
-A recent meta-analysis found consistent support for regular vitamin C supplementation reducing the duration of the common cold, but that supplementation with vitamin C (> 200 mg) failed to reduce the incidence of colds [694].
-Individual studies have found Vitamin C to reduce the susceptibility of patients to lower respiratory tract infections, such as pneumonia [695].
+A recent meta-analysis found consistent support for regular vitamin C supplementation reducing the duration of the common cold, but that supplementation with vitamin C (> 200 mg) failed to reduce the incidence of colds [695].
+Individual studies have found Vitamin C to reduce the susceptibility of patients to lower respiratory tract infections, such as pneumonia [696].
Another meta-analysis demonstrated that in twelve trials, vitamin C supplementation reduced the length of stay of patients in intensive care units (ICUs) by 7.8% (95% CI: 4.2% to 11.2%; p = 0.00003).
Furthermore, high doses (1-3 g/day) significantly reduced the length of an ICU stay by 8.6% in six trials (p = 0.003).
-Vitamin C also shortened the duration of mechanical ventilation by 18.2% in three trials in which patients required intervention for over 24 hours (95% CI 7.7% to 27%; p = 0.001) [688].
-Despite these findings, an RCT of 167 patients known as CITRUS ALI failed to show a benefit of a 96-hour infusion of vitamin C to treat ARDS [696].
-Clinical trials specifically investigating vitamin C in the context of COVID-19 have now begun, as highlighted by Carr et al. [679].
+Vitamin C also shortened the duration of mechanical ventilation by 18.2% in three trials in which patients required intervention for over 24 hours (95% CI 7.7% to 27%; p = 0.001) [689].
+Despite these findings, an RCT of 167 patients known as CITRUS ALI failed to show a benefit of a 96-hour infusion of vitamin C to treat ARDS [697].
+Clinical trials specifically investigating vitamin C in the context of COVID-19 have now begun, as highlighted by Carr et al. [680].
These trials intend to investigate the use of intravenous vitamin C in hospitalized COVID-19 patients.
-The first trial to report initial results took place in Wuhan, China [697].
-These initial results indicated that the administration of 12 g/12 hr of intravenous vitamin C for 7 days in 56 critically ill COVID-19 patients resulted in a promising reduction of 28-day mortality (p = 0.06) in univariate survival analysis [698].
-Indeed, the same study reported a significant decrease in IL-6 levels by day 7 of vitamin C infusion (p = 0.04) [699].
+The first trial to report initial results took place in Wuhan, China [698].
+These initial results indicated that the administration of 12 g/12 hr of intravenous vitamin C for 7 days in 56 critically ill COVID-19 patients resulted in a promising reduction of 28-day mortality (p = 0.06) in univariate survival analysis [699].
+Indeed, the same study reported a significant decrease in IL-6 levels by day 7 of vitamin C infusion (p = 0.04) [700].
Additional studies that are being conducted in Canada, China, Iran, and the USA will provide additional insight into whether vitamin C supplementation affects COVID-19 outcomes on a larger scale.
Even though evidence supporting the use of vitamin C is beginning to emerge, we will not know how effective vitamin C is as a therapeutic for quite some time.
Currently (as of January 2021) over fifteen trials are registered with clinicaltrials.gov that are either recruiting, active or are currently in preparation.
@@ -2456,166 +2457,166 @@
6.6[582].
-The recommended dietary allowance according to the FDA is 75-90 mg/d, whereas EFSA recommends 110 mg/d [700].
+To maintain vitamin C status, it would be prudent for individuals to ensure that they consume the recommended dietary allowance of vitamin C to maintain a healthy immune system [583].
+The recommended dietary allowance according to the FDA is 75-90 mg/d, whereas EFSA recommends 110 mg/d [701].
6.7 Vitamin D
Of all of the supplements currently under investigation, vitamin D has become a leading prophylactic and therapeutic candidate against SARS-CoV-2.
-Vitamin D can modulate both the adaptive and innate immune system and is associated with various aspects of immune health and antiviral defense [701,702,703,704,705].
+Vitamin D can modulate both the adaptive and innate immune system and is associated with various aspects of immune health and antiviral defense [702,703,704,705,706].
Vitamin D can be sourced through diet or supplementation, but it is mainly biosynthesized by the body on exposure to ultraviolet light (UVB) from sunlight.
-Vitamin D deficiency is associated with an increased susceptibility to infection [706].
-In particular, vitamin D deficient patients are at risk of developing acute respiratory infections [707] and ARDS [707].
+Vitamin D deficiency is associated with an increased susceptibility to infection [707].
+In particular, vitamin D deficient patients are at risk of developing acute respiratory infections [708] and ARDS [708].
1,25-dihydroxyvitamin D3 is the active form of vitamin D that is involved in adaptive and innate responses; however, due to its low concentration and a short half life of a few hours, vitamin D levels are typically measured by the longer lasting and more abundant precursor 25-hydroxyvitamin D.
-The vitamin D receptor is expressed in various immune cells, and vitamin D is an immunomodulator of antigen presenting cells, dendritic cells, macrophages, monocytes, and T- and B-lymphocytes [706,708].
+The vitamin D receptor is expressed in various immune cells, and vitamin D is an immunomodulator of antigen presenting cells, dendritic cells, macrophages, monocytes, and T- and B-lymphocytes [707,709].
Due to its potential immunomodulating properties, vitamin D supplementation may be advantageous to maintain a healthy immune system.
-Early in the pandemic it was postulated that an individual’s vitamin D status could significantly affect their risk of developing COVID-19 [709].
+
Early in the pandemic it was postulated that an individual’s vitamin D status could significantly affect their risk of developing COVID-19 [710].
This hypothesis was derived from the fact that the current pandemic emerged in Wuhan China during winter, when 25-hydroxyvitamin D concentrations are at their lowest due to a lack of sunlight, whereas in the Southern Hemisphere, where it was nearing the end of the summer and higher 25-hydroxyvitamin D concentrations would be higher, the number of cases was low.
-This led researchers to question whether there was a seasonal component to the SARS-CoV-2 pandemic and whether vitamin D levels might play a role [709,710,711,712].
+This led researchers to question whether there was a seasonal component to the SARS-CoV-2 pandemic and whether vitamin D levels might play a role [710,711,712,713].
Though it is assumed that COVID-19 is seasonal, multiple other factors that can affect vitamin D levels should also be considered.
These factors include an individual’s nutritional status, their age, their occupation, skin pigmentation, potential comorbidities, and the variation of exposure to sunlight due to latitude amongst others.
-Indeed, it has been estimated that each degree of latitude north of 28 degrees corresponded to a 4.4% increase of COVID-19 mortality, indirectly linking a persons vitamin D levels via exposure to UVB light to COVID-19 mortality [710].
-As the pandemic has evolved, additional research of varying quality has investigated some of the potential links identified early in the pandemic [709] between vitamin D and COVID-19.
+Indeed, it has been estimated that each degree of latitude north of 28 degrees corresponded to a 4.4% increase of COVID-19 mortality, indirectly linking a persons vitamin D levels via exposure to UVB light to COVID-19 mortality [711].
+As the pandemic has evolved, additional research of varying quality has investigated some of the potential links identified early in the pandemic [710] between vitamin D and COVID-19.
Indeed, studies are beginning to investigate whether there is any prophylactic and/or therapeutic relationship between vitamin D and COVID-19.
-A study in Switzerland demonstrated that 27 SARS-CoV-2 positive patients exhibited 25-hydroxyvitamin D plasma concentrations that were significantly lower (11.1 ng/ml) than those of SARS-CoV-2 negative patients (24.6 ng/ml; p = 0.004), an association that held when stratifying patients greater than 70 years old [713].
-These findings seem to be supported by a Belgian observational study of 186 SARS-CoV-2 positive patients exhibiting symptoms of pneumonia, where 25-hydroxyvitamin D plasma concentrations were measured and CT scans of the lungs were obtained upon hospitalization [714].
+A study in Switzerland demonstrated that 27 SARS-CoV-2 positive patients exhibited 25-hydroxyvitamin D plasma concentrations that were significantly lower (11.1 ng/ml) than those of SARS-CoV-2 negative patients (24.6 ng/ml; p = 0.004), an association that held when stratifying patients greater than 70 years old [714].
+These findings seem to be supported by a Belgian observational study of 186 SARS-CoV-2 positive patients exhibiting symptoms of pneumonia, where 25-hydroxyvitamin D plasma concentrations were measured and CT scans of the lungs were obtained upon hospitalization [715].
A significant difference in 25-hydroxyvitamin D levels was observed between the SARS-CoV-2 patients and 2,717 season-matched diseased controls.
Both female and male patients possessed lower median 25-hydroxyvitamin D concentrations than the control group as a whole (18.6 ng/ml versus 21.5 ng/ml; p = 0.0016) and a higher rate of vitamin D deficiency (58.6% versus 42.5%).
However, when comparisons were stratified by sex, evidence of sexual dimorphism became apparent, as female patients had equivalent levels of 25-hydroxyvitamin D to females in the control group, whereas male patients were deficient in 25-hydroxyvitamin D relative to male controls (67% versus 49%; p = 0.0006).
Notably, vitamin D deficiency was progressively lower in males with advancing radiological disease stages (p = 0.001).
-These studies are supported by several others that indicate that vitamin D status may be an independent risk factor for the severity of COVID-19 [715,716,717,718] and in COVID-19 patients relative to population-based controls [719].
-Indeed, serum concentrations of 25-hydroxyvitamin D above 30 ng/ml, which indicate vitamin D sufficiency, seems to be associated with a reduction in serum C-reactive protein, an inflammatory marker, along with increased lymphocyte levels, which suggests that vitamin D levels may modulate the immune response by reducing risk for cytokine storm in response to SARS-CoV-2 infection [719].
-A study in India determined that COVID-19 fatality was higher in patients with severe COVID-19 and low serum 25-hydroxyvitamin D (mean level 6.2 ng/ml; 97% vitamin D deficient) levels versus asymptomatic non-severe patients with higher levels of vitamin D (mean level 27.9 ng/ml; 33% vitamin D deficient) [720].
+These studies are supported by several others that indicate that vitamin D status may be an independent risk factor for the severity of COVID-19 [716,717,718,719] and in COVID-19 patients relative to population-based controls [720].
+Indeed, serum concentrations of 25-hydroxyvitamin D above 30 ng/ml, which indicate vitamin D sufficiency, seems to be associated with a reduction in serum C-reactive protein, an inflammatory marker, along with increased lymphocyte levels, which suggests that vitamin D levels may modulate the immune response by reducing risk for cytokine storm in response to SARS-CoV-2 infection [720].
+A study in India determined that COVID-19 fatality was higher in patients with severe COVID-19 and low serum 25-hydroxyvitamin D (mean level 6.2 ng/ml; 97% vitamin D deficient) levels versus asymptomatic non-severe patients with higher levels of vitamin D (mean level 27.9 ng/ml; 33% vitamin D deficient) [721].
In the same study, vitamin D deficiency was associated with higher levels of inflammatory markers including IL-6, ferritin, and tumor necrosis factor α.
-Collectively, these studies add to a multitude of observational studies reporting potential associations between low levels of 25-hydroxyvitamin D and COVID-19 incidence and severity [713,718,719,721,722,723,724,725,726,727].
-Despite the large number of studies establishing a link between vitamin D status and COVID-19 severity, an examination of data from the UK Biobank did not support this thesis [728,729].
+Collectively, these studies add to a multitude of observational studies reporting potential associations between low levels of 25-hydroxyvitamin D and COVID-19 incidence and severity [714,719,720,722,723,724,725,726,727,728].
+Despite the large number of studies establishing a link between vitamin D status and COVID-19 severity, an examination of data from the UK Biobank did not support this thesis [729,730].
These analyses examined 25-hydroxyvitamin D concentrations alongside SARS-CoV-2 positivity and COVID-19 mortality in over 340,000 UK Biobank participants.
-However, these studies have caused considerable debate that will likely be settled following further studies [730,731].
-Overall, while the evidence suggests that there is likely an association between low serum 25-hydroxyvitamin D and COVID-19 incidence, these studies must be interpreted with caution, as there is the potential for reverse causality, bias, and other confounding factors including that vitamin D deficiency is also associated with numerous pre-existing conditions and risk factors that can increase the risk for severe COVID-19 [582,710,732,733].
+However, these studies have caused considerable debate that will likely be settled following further studies [731,732].
+Overall, while the evidence suggests that there is likely an association between low serum 25-hydroxyvitamin D and COVID-19 incidence, these studies must be interpreted with caution, as there is the potential for reverse causality, bias, and other confounding factors including that vitamin D deficiency is also associated with numerous pre-existing conditions and risk factors that can increase the risk for severe COVID-19 [583,711,733,734].
While these studies inform us of the potential importance of vitamin D sufficiency and the risk of SARS-CoV-2 infection and severe COVID-19, they fail to conclusively determine whether vitamin D supplementation can therapeutically affect the clinical course of COVID-19.
In one study, 40 vitamin D deficient asymptomatic or mildly symptomatic participants patients were either randomized to receive 60,000 IU of cholecalciferol daily for at least 7 days (n = 16) or a placebo (n = 24) with a target serum 25-hydroxyvitamin D level >50 ng/ml.
At day 7, 10 patients achieved >50 ng/ml, followed by another 2 by day 14.
-By the end of the study, the treatment group had a greater proportion of vitamin D-deficient participants that tested negative for SARS-CoV-2 RNA, and they had a significantly lower fibrinogen levels, potentially indicating a beneficial effect [734].
-A pilot study in Spain determined that early administration of high dose calcifediol (~21,000 IU days 1-2 and ~11,000 IU days 3-7 of hospital admission) with hydroxychloroquine and azithromycin to 50 hospitalized COVID-19 patients significantly reduced ICU admissions and may have reduced disease severity versus hydroxychloroquine and azithromycin alone [735].
-Although this study received significant criticism from the National Institute for Health and Care Excellence (NICE) in the UK [736], an independent follow-up statistical analysis supported the findings of the study with respect to the results of cholecalciferol treatment [737].
-Another trial of 986 patients hospitalized for COVID-19 in three UK hospitals administered cholecalciferol supplementation (≥ 280,000 IU in a time period of 7 weeks) to 151 patients and found an association with a reduced risk of COVID-19 mortality, regardless of baseline 25-hydroxyvitamin D levels [738].
+By the end of the study, the treatment group had a greater proportion of vitamin D-deficient participants that tested negative for SARS-CoV-2 RNA, and they had a significantly lower fibrinogen levels, potentially indicating a beneficial effect [735].
+A pilot study in Spain determined that early administration of high dose calcifediol (~21,000 IU days 1-2 and ~11,000 IU days 3-7 of hospital admission) with hydroxychloroquine and azithromycin to 50 hospitalized COVID-19 patients significantly reduced ICU admissions and may have reduced disease severity versus hydroxychloroquine and azithromycin alone [736].
+Although this study received significant criticism from the National Institute for Health and Care Excellence (NICE) in the UK [737], an independent follow-up statistical analysis supported the findings of the study with respect to the results of cholecalciferol treatment [738].
+Another trial of 986 patients hospitalized for COVID-19 in three UK hospitals administered cholecalciferol supplementation (≥ 280,000 IU in a time period of 7 weeks) to 151 patients and found an association with a reduced risk of COVID-19 mortality, regardless of baseline 25-hydroxyvitamin D levels [739].
However, a double-blind, randomized, placebo-controlled trial of 240 hospitalized COVID-19 patients in São Paulo, Brazil administered a single 200,000 IU oral dose of vitamin D.
-While levels of 25-hydroxyvitamin D did increase from 21% to ~27% (p = 0.001) and the supplementation was well tolerated, there was no reduction in the length of hospital stay or mortality and no change to any other relevant secondary outcomes [739].
+While levels of 25-hydroxyvitamin D did increase from 21% to ~27% (p = 0.001) and the supplementation was well tolerated, there was no reduction in the length of hospital stay or mortality and no change to any other relevant secondary outcomes [740].
These early findings are thus still inconclusive with regards to the therapeutic value of vitamin D supplementation.
-However, other trials are underway, including one trial that is investigating the utility of vitamin D as an immune-modulating agent by monitoring whether administration of vitamin D precipitates an improvement of health status in non-severe symptomatic COVID-19 patients and whether vitamin D prevents patient deterioration [740].
-Other trials are examining various factors including mortality, symptom recovery, severity of disease, rates of ventilation, inflammatory markers such as C-reactive protein and IL-6, blood cell counts, and the prophylactic capacity of vitamin D administration [740,741,742,743].
-Concomitant administration of vitamin D with pharmaceuticals such as aspirin [744] and bioactive molecules such as resveratrol [745] are also under investigation.
+However, other trials are underway, including one trial that is investigating the utility of vitamin D as an immune-modulating agent by monitoring whether administration of vitamin D precipitates an improvement of health status in non-severe symptomatic COVID-19 patients and whether vitamin D prevents patient deterioration [741].
+Other trials are examining various factors including mortality, symptom recovery, severity of disease, rates of ventilation, inflammatory markers such as C-reactive protein and IL-6, blood cell counts, and the prophylactic capacity of vitamin D administration [741,742,743,744].
+Concomitant administration of vitamin D with pharmaceuticals such as aspirin [745] and bioactive molecules such as resveratrol [746] are also under investigation.
The effectiveness of vitamin D supplementation against COVID-19 remains open for debate.
-All the same, there is no doubt that vitamin D deficiency is a widespread issue and should be addressed not only because of its potential link to SARS-CoV-2 incidence [746], but also due to its importance for overall health.
+All the same, there is no doubt that vitamin D deficiency is a widespread issue and should be addressed not only because of its potential link to SARS-CoV-2 incidence [747], but also due to its importance for overall health.
There is a possibility that safe exposure to sunlight could improve endogenous synthesis of vitamin D, potentially strengthening the immune system.
However, sun exposure is not sufficient on its own, particularly in the winter months.
Indeed, while the possible link between vitamin D status and COVID-19 is further investigated, preemptive supplementation of vitamin D and encouraging people to maintain a healthy diet for optimum vitamin D status is likely to raise serum levels of 25-hydroxyvitamin D while being unlikely to carry major health risks.
These principles seem to be the basis of a number of guidelines issued by some countries and scientific organizations that have advised supplementation of vitamin D during the pandemic.
The Académie Nationale de Médecine in France recommends rapid testing of 25-hydroxyvitamin D for people over 60 years old to identify those most at risk of vitamin D deficiency and advises them to obtain a bolus dose of 50,000 to 100,000 IU vitamin D to limit respiratory complications.
-It has also recommended that those under 60 years old should take 800 to 1,000 IU daily if they receive a SARS-CoV-2 positive test [747].
-In Slovenia, doctors have been advised to provide nursing home patients with vitamin D [748].
-Both Public Health England and Public Health Scotland have advised members of the Black, Asian, and minority ethnic communities to supplement for vitamin D in light of evidence that they may be at higher risk for vitamin D deficiency along with other COVID-19 risk factors, a trend that has also been observed in the United States [749,750].
+It has also recommended that those under 60 years old should take 800 to 1,000 IU daily if they receive a SARS-CoV-2 positive test [748].
+In Slovenia, doctors have been advised to provide nursing home patients with vitamin D [749].
+Both Public Health England and Public Health Scotland have advised members of the Black, Asian, and minority ethnic communities to supplement for vitamin D in light of evidence that they may be at higher risk for vitamin D deficiency along with other COVID-19 risk factors, a trend that has also been observed in the United States [750,751].
However, other UK scientific bodies including the NICE recommend that individuals supplement for vitamin D as per usual UK government advice but warn that people should not supplement for vitamin D solely to prevent COVID-19.
-All the same, the NICE has provided guidelines for research to investigate the supplementation of vitamin D in the context of COVID-19 [751].
-Despite vitamin D deficiency being a widespread issue in the United States [752], the National Institutes of Health have stated that there is “insufficient data to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19” [753].
+All the same, the NICE has provided guidelines for research to investigate the supplementation of vitamin D in the context of COVID-19 [752].
+Despite vitamin D deficiency being a widespread issue in the United States [753], the National Institutes of Health have stated that there is “insufficient data to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19” [754].
These are just some examples of how public health guidance has responded to the emerging evidence regarding vitamin D and COVID-19.
-Outside of official recommendations, there is also evidence that individuals may be paying increased attention to their vitamin D levels, as a survey of Polish consumers showed that 56% of respondents used vitamin D during the pandemic [754].
-However, some companies have used the emerging evidence surrounding vitamin D to sell products that claim to prevent and treat COVID-19, which in one incident required a federal court to intervene and issue an injunction barring the sale of vitamin-D-related products due to the lack of clinical data supporting these claims [755].
+Outside of official recommendations, there is also evidence that individuals may be paying increased attention to their vitamin D levels, as a survey of Polish consumers showed that 56% of respondents used vitamin D during the pandemic [755].
+However, some companies have used the emerging evidence surrounding vitamin D to sell products that claim to prevent and treat COVID-19, which in one incident required a federal court to intervene and issue an injunction barring the sale of vitamin-D-related products due to the lack of clinical data supporting these claims [756].
It is clear that further studies and clinical trials are required to conclusively determine the prophylactic and therapeutic potential of vitamin D supplementation against COVID-19.
Until such time that sufficient evidence emerges, individuals should follow their national guidelines surrounding vitamin D intake to achieve vitamin D sufficiency.
6.8 Probiotics
-Probiotics are “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” [756].
-Some studies suggest that probiotics are beneficial against common viral infections, and there is modest evidence to suggest that they can modulate the immune response [757,758].
-As a result, it has been hypothesized that probiotics may have therapeutic value worthy of investigation against SARS-CoV-2 [759].
-Probiotics and next-generation probiotics, which are more akin to pharmacological-grade supplements, have been associated with multiple potential beneficial effects for allergies, digestive tract disorders, and even metabolic diseases through their anti-inflammatory and immunomodulatory effects [760,761].
-However, the mechanisms by which probiotics affect these various conditions would likely differ among strains, with the ultimate effect of the probiotic depending on the heterogeneous set of bacteria present [761].
-Some of the beneficial effects of probiotics include reducing inflammation by promoting the expression of anti-inflammatory mediators, inhibiting Toll-like receptors 2 and 4, competing directly with pathogens, synthesizing antimicrobial substances or other metabolites, improving intestinal barrier function, and/or favorably altering the gut microbiota and the brain-gut axis [761,762,763].
-It is also thought that lactobacilli such as Lactobacillus paracasei, Lactobacillus plantarum and Lactobacillus rhamnosus have the capacity to bind to and inactivate some viruses via adsorptive and/or trapping mechanisms [764].
-Other probiotic lactobacilli and even non-viable bacterium-like particles have been shown to reduce both viral attachment to host cells and viral titers, along with reducing cytokine synthesis, enhancing the antiviral IFN-α response, and inducing various other antiviral mechanisms [764,765,766,767,768,769,770,771,772].
-These antiviral and immunobiotic mechanisms and others have been reviewed in detail elsewhere [612,759,773].
-However, there is also a bi-directional relationship between the lungs and gut microbiota known as the gut-lung axis [774], whereby gut microbial metabolites and endotoxins may affect the lungs via the circulatory system and the lung microbiota in return may affect the gut [775].
-Therefore, the gut-lung axis may play role in our future understanding of COVID-19 pathogenesis and become a target for probiotic treatments [776].
-Moreover, as microbial dysbiosis of the respiratory tract and gut may play a role in some viral infections, it has been suggested that SARS-CoV-2 may interact with our commensal microbiota [612; 777; 10.3389/fmicb.2020.01840] and that the lung microbiome could play a role in developing immunity to viral infections [778].
+
Probiotics are “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” [757].
+Some studies suggest that probiotics are beneficial against common viral infections, and there is modest evidence to suggest that they can modulate the immune response [758,759].
+As a result, it has been hypothesized that probiotics may have therapeutic value worthy of investigation against SARS-CoV-2 [760].
+Probiotics and next-generation probiotics, which are more akin to pharmacological-grade supplements, have been associated with multiple potential beneficial effects for allergies, digestive tract disorders, and even metabolic diseases through their anti-inflammatory and immunomodulatory effects [761,762].
+However, the mechanisms by which probiotics affect these various conditions would likely differ among strains, with the ultimate effect of the probiotic depending on the heterogeneous set of bacteria present [762].
+Some of the beneficial effects of probiotics include reducing inflammation by promoting the expression of anti-inflammatory mediators, inhibiting Toll-like receptors 2 and 4, competing directly with pathogens, synthesizing antimicrobial substances or other metabolites, improving intestinal barrier function, and/or favorably altering the gut microbiota and the brain-gut axis [762,763,764].
+It is also thought that lactobacilli such as Lactobacillus paracasei, Lactobacillus plantarum and Lactobacillus rhamnosus have the capacity to bind to and inactivate some viruses via adsorptive and/or trapping mechanisms [765].
+Other probiotic lactobacilli and even non-viable bacterium-like particles have been shown to reduce both viral attachment to host cells and viral titers, along with reducing cytokine synthesis, enhancing the antiviral IFN-α response, and inducing various other antiviral mechanisms [765,766,767,768,769,770,771,772,773].
+These antiviral and immunobiotic mechanisms and others have been reviewed in detail elsewhere [613,760,774].
+However, there is also a bi-directional relationship between the lungs and gut microbiota known as the gut-lung axis [775], whereby gut microbial metabolites and endotoxins may affect the lungs via the circulatory system and the lung microbiota in return may affect the gut [776].
+Therefore, the gut-lung axis may play role in our future understanding of COVID-19 pathogenesis and become a target for probiotic treatments [777].
+Moreover, as microbial dysbiosis of the respiratory tract and gut may play a role in some viral infections, it has been suggested that SARS-CoV-2 may interact with our commensal microbiota [613; 778; 10.3389/fmicb.2020.01840] and that the lung microbiome could play a role in developing immunity to viral infections [779].
These postulations, if correct, could lead to the development of novel probiotic and prebiotic treatments.
However, significant research is required to confirm these associations and their relevance to patient care, if any.
Probiotic therapies and prophylactics may also confer some advantages for managing symptoms of COVID-19 or risks associated with its treatment.
-Probiotics have tentatively been associated with the reduction of risk and duration of viral upper respiratory tract infections [779,780,781].
-Some meta-analyses that have assessed the efficacy of probiotics in viral respiratory infections have reported moderate reductions in the incidence and duration of infection [780,782].
-Indeed, randomized controlled trials have shown that administering Bacillus subtilis and Enterococcus faecalis [783], Lactobacillus rhamnosus GG [784], or Lactobacillus casei and Bifidobacterium breve with galactooligosaccharides [785] via the nasogastric tube to ventilated patients reduced the occurrence of ventilator-associated pneumonia in comparison to the respective control groups in studies of viral infections and sepsis.
-These findings were also supported by a recent meta-analysis [786].
-Additionally, COVID-19 patients carry a significant risk of ventilator-associated bacterial pneumonia [787], but it can be challenging for clinicians to diagnose this infection due to the fact that severe COVID-19 infection presents with the symptoms of pneumonia [788].
+Probiotics have tentatively been associated with the reduction of risk and duration of viral upper respiratory tract infections [780,781,782].
+Some meta-analyses that have assessed the efficacy of probiotics in viral respiratory infections have reported moderate reductions in the incidence and duration of infection [781,783].
+Indeed, randomized controlled trials have shown that administering Bacillus subtilis and Enterococcus faecalis [784], Lactobacillus rhamnosus GG [785], or Lactobacillus casei and Bifidobacterium breve with galactooligosaccharides [786] via the nasogastric tube to ventilated patients reduced the occurrence of ventilator-associated pneumonia in comparison to the respective control groups in studies of viral infections and sepsis.
+These findings were also supported by a recent meta-analysis [787].
+Additionally, COVID-19 patients carry a significant risk of ventilator-associated bacterial pneumonia [788], but it can be challenging for clinicians to diagnose this infection due to the fact that severe COVID-19 infection presents with the symptoms of pneumonia [789].
Therefore, an effective prophylactic therapy for ventilator-associated pneumonia in severe COVID-19 patients would carry significant therapeutic value.
-Additionally, in recent years, probiotics have become almost synonymous with the treatment of gastrointestinal issues due to their supposed anti-inflammatory and immunomodulatory effects [789].
-Notably, gastrointestinal symptoms commonly occur in COVID-19 patients [790], and angiotensin-converting enzyme 2, the portal by which SARS-CoV-2 enters human cells, is highly expressed in enterocytes of the ileum and colon, suggesting that these organs may be a potential route of infection [791,792].
-Indeed, SARS-CoV-2 viral RNA has been detected in human feces [89,793], and fecal-oral transmission of the virus has not yet been ruled out [794].
-Rectal swabs of some SARS-CoV-2 positive pediatric patients persistently tested positive for several days despite negative nasopharyngeal tests, indicating the potential for fecal viral shedding [795].
-However, there is conflicting evidence for the therapeutic value of various probiotics against the incidence or severity of gastrointestinal symptoms in viral or bacterial infections such as gastroenteritis [796,797].
-Nevertheless, it has been proposed that the administration of probiotics to COVID-19 patients and healthcare workers may prevent or ameliorate the gastrointestinal symptoms of COVID-19, a hypothesis that several clinical trials are now preparing to investigate [798,799].
-Other studies are investigating whether probiotics may affect patient outcomes following SARS-CoV-2 infection [800].
+Additionally, in recent years, probiotics have become almost synonymous with the treatment of gastrointestinal issues due to their supposed anti-inflammatory and immunomodulatory effects [790].
+Notably, gastrointestinal symptoms commonly occur in COVID-19 patients [791], and angiotensin-converting enzyme 2, the portal by which SARS-CoV-2 enters human cells, is highly expressed in enterocytes of the ileum and colon, suggesting that these organs may be a potential route of infection [792,793].
+Indeed, SARS-CoV-2 viral RNA has been detected in human feces [91,794], and fecal-oral transmission of the virus has not yet been ruled out [795].
+Rectal swabs of some SARS-CoV-2 positive pediatric patients persistently tested positive for several days despite negative nasopharyngeal tests, indicating the potential for fecal viral shedding [796].
+However, there is conflicting evidence for the therapeutic value of various probiotics against the incidence or severity of gastrointestinal symptoms in viral or bacterial infections such as gastroenteritis [797,798].
+Nevertheless, it has been proposed that the administration of probiotics to COVID-19 patients and healthcare workers may prevent or ameliorate the gastrointestinal symptoms of COVID-19, a hypothesis that several clinical trials are now preparing to investigate [799,800].
+Other studies are investigating whether probiotics may affect patient outcomes following SARS-CoV-2 infection [801].
Generally, the efficacy of probiotic use is a controversial topic among scientists.
-In Europe, EFSA has banned the term probiotics on products labels, which has elicited either criticism for EFSA or support for probiotics from researchers in the field [756,801,802].
+In Europe, EFSA has banned the term probiotics on products labels, which has elicited either criticism for EFSA or support for probiotics from researchers in the field [757,802,803].
This regulation is due to the hyperbolic claims placed on the labels of various probiotic products, which lack rigorous scientific data to support their efficacy.
-Overall, the data supporting probiotics in the treatment or prevention of many different disorders and diseases is not conclusive, as the quality of the evidence is generally considered low [779].
+Overall, the data supporting probiotics in the treatment or prevention of many different disorders and diseases is not conclusive, as the quality of the evidence is generally considered low [780].
However, in the case of probiotics and respiratory infections, the evidence seems to be supportive of their potential therapeutic value.
Consequently, several investigations are underway to investigate the prophylactic and therapeutic potential of probiotics for COVID-19.
-The blind use of conventional probiotics for COVID-19 is currently cautioned against until the pathogenesis of SARS-CoV-2 can be further established [803].
+The blind use of conventional probiotics for COVID-19 is currently cautioned against until the pathogenesis of SARS-CoV-2 can be further established [804].
Until clinical trials investigating the prophylactic and therapeutic potential of probiotics for COVID-19 are complete, it is not possible to provide an evidence-based recommendation for their use.
-Despite these concerns, complementary use of probiotics as an adjuvant therapeutic has been proposed by the Chinese National Health Commission and National Administration of Traditional Chinese Medicine [90].
-While supply issues prevented the probiotics market from showing the same rapid response to the COVID-19 as some other supplements, many suppliers are reporting growth during the pandemic [804].
+Despite these concerns, complementary use of probiotics as an adjuvant therapeutic has been proposed by the Chinese National Health Commission and National Administration of Traditional Chinese Medicine [92].
+While supply issues prevented the probiotics market from showing the same rapid response to the COVID-19 as some other supplements, many suppliers are reporting growth during the pandemic [805].
Therefore, the public response once again seems to have adopted supplements promoted as bolstering the immune response despite a lack of evidence suggesting they are beneficial for preventing or mitigating COVID-19.
6.9 Discussion
In this review, we report the findings to date of analyses of several dietary supplements and nutraceuticals.
While existing evidence suggests potential benefits of n-3 PUFA and probiotic supplementation for COVID-19 treatment and prophylaxis, clinical data is still lacking, although trials are underway.
Both zinc and vitamin C supplementation in hospitalized patients seem to be associated with positive outcomes; however, further clinical trials are required.
In any case, both vitamin C and zinc intake are part of a healthy diet and both likely presents minimal risk when supplemented for, though their potential prophylactic or therapeutic effects against COVID-19 are yet to be determined.
-On the other hand, mounting evidence from observational studies indicates that there is an association between vitamin D deficiency and COVID-19 incidence has also been supported by meta-analysis [805].
+On the other hand, mounting evidence from observational studies indicates that there is an association between vitamin D deficiency and COVID-19 incidence has also been supported by meta-analysis [806].
Indeed, scientists are working to confirm these findings and to determine whether a patient’s serum 25-hydroxyvitamin D levels are also associated with COVID-19 severity.
Clinical trials are required to determine whether preemptive vitamin D supplementation may mitigate against severe COVID-19.
-In terms of the therapeutic potential of vitamin D, initial evidence from clinical trials are conflicting, but seem to indicate that vitamin D supplementation may reduce COVID-19 severity [735].
+In terms of the therapeutic potential of vitamin D, initial evidence from clinical trials are conflicting, but seem to indicate that vitamin D supplementation may reduce COVID-19 severity [736].
The various clinical trials currently underway will be imperative to provide information on the efficacious use of vitamin D supplementation for COVID-19 prevention and/or treatment.
The purported prophylactic and therapeutic benefits of dietary supplements and nutraceuticals for multiple disorders, diseases, and infections has been the subject of significant research and debate for the last few decades.
Inevitably, scientists are also investigating the potential for these various products to treat or prevent COVID-19.
This interest also extends to consumers, which led to a remarkable increase of sales of dietary supplements and nutraceuticals throughout the pandemic due to a desire to obtain additional protections from infection and disease.
The nutraceuticals discussed in this review, namely vitamin C, vitamin D, n-3 PUFA, zinc, and probiotics, were selected because of potential biological mechanisms that could beneficially affect viral and respiratory infections and because they are currently under clinical investigation.
Specifically, these compounds have all been found to influence cellular processes related to inflammation.
-Inflammation is particularly relevant to COVID-19 because of the negative outcomes (often death) observed in a large number of patients whose immune response becomes hyperactive in response to SARS-CoV-2, leading to severe outcomes such as ARDS and sepsis [806].
-Additionally, there is a well-established link between diet and inflammation [807], potentially mediated in part by the microbiome [808].
+Inflammation is particularly relevant to COVID-19 because of the negative outcomes (often death) observed in a large number of patients whose immune response becomes hyperactive in response to SARS-CoV-2, leading to severe outcomes such as ARDS and sepsis [807].
+Additionally, there is a well-established link between diet and inflammation [808], potentially mediated in part by the microbiome [809].
Thus, the idea that dietary modifications or supplementation could be used to modify the inflammatory response is tied to a broader view of how diet and the immune system are interconnected.
-The supplements and nutraceuticals discussed here therefore lie in sharp contrast to other alleged nutraceutical or dietary supplements that have attracted during the pandemic, such as colloidal silver [809], which have no known nutritional function and can be harmful.
+The supplements and nutraceuticals discussed here therefore lie in sharp contrast to other alleged nutraceutical or dietary supplements that have attracted during the pandemic, such as colloidal silver [810], which have no known nutritional function and can be harmful.
Importantly, while little clinical evidence is available about the effects of any supplements against COVID-19, the risks associated with those discussed above are likely to be low, and in some cases, they can be obtained from dietary sources alone.
There are various other products and molecules that have garnered scientific interest and could merit further investigation.
-These include polyphenols, lipid extracts, and tomato-based nutraceuticals, all of which have been suggested for the potential prevention of cardiovascular complications of COVID-19 such as thrombosis [612,648].
-Melatonin is another supplement that has been identified as a potential antiviral agent against SARS-CoV-2 using computational methods [810], and it has also been highlighted as a potential therapeutic agent for COVID-19 due to its documented antioxidant, anti-apoptotic, immunomodulatory, and anti-inflammatory effects [648,811,812].
-Notably, melatonin, vitamin D and zinc have attracted public attention because they were included in the treatment plan of the former President of the United States upon his hospitalization due to COVID-19 [813].
+These include polyphenols, lipid extracts, and tomato-based nutraceuticals, all of which have been suggested for the potential prevention of cardiovascular complications of COVID-19 such as thrombosis [613,649].
+Melatonin is another supplement that has been identified as a potential antiviral agent against SARS-CoV-2 using computational methods [811], and it has also been highlighted as a potential therapeutic agent for COVID-19 due to its documented antioxidant, anti-apoptotic, immunomodulatory, and anti-inflammatory effects [649,812,813].
+Notably, melatonin, vitamin D and zinc have attracted public attention because they were included in the treatment plan of the former President of the United States upon his hospitalization due to COVID-19 [814].
These are just some of the many substances and supplements that are currently under investigation but as of yet lack evidence to support their use for the prevention or treatment of COVID-19.
-While there is plenty of skepticism put forward by physicians and scientists surrounding the use of supplements, these statements have not stopped consumers from purchasing these products, with one study reporting that online searches for dietary supplements in Poland began trending with the start of the pandemic [754].
+While there is plenty of skepticism put forward by physicians and scientists surrounding the use of supplements, these statements have not stopped consumers from purchasing these products, with one study reporting that online searches for dietary supplements in Poland began trending with the start of the pandemic [755].
Additionally, supplement usage increased between the first and second wave of the pandemic.
Participants reported various reasons for their use of supplements, including to improve immunity (60%), to improve overall health (57%), and to fill nutrient gaps in their diet (53%).
Other efforts to collect large datasets regarding such behavior have also sought to explore a possible association between vitamin or supplement consumption and COVID-19.
-An observational analysis of survey responses from 327,720 users of the COVID Symptom Study App found that the consumption of n-3 PUFA supplements, probiotics, multivitamins, and vitamin D was associated with a lower risk of SARS-CoV-2 infection in women but not men after adjusting for potential confounders [814].
-According to the authors, the sexual dimorphism observed may in part be because supplements may better support females due to known differences between the male and female immune systems, or it could be due to behavioral and health consciousness differences between the sexes [814].
+An observational analysis of survey responses from 327,720 users of the COVID Symptom Study App found that the consumption of n-3 PUFA supplements, probiotics, multivitamins, and vitamin D was associated with a lower risk of SARS-CoV-2 infection in women but not men after adjusting for potential confounders [815].
+According to the authors, the sexual dimorphism observed may in part be because supplements may better support females due to known differences between the male and female immune systems, or it could be due to behavioral and health consciousness differences between the sexes [815].
Certainly, randomized controlled trials are required to investigate these findings further.
-Finally, it is known that a patient’s nutritional status affects health outcomes in various infectious diseases [586], and COVID-19 is no different [584,815,816].
-Some of the main risk factors for severe COVID-19, which also happen to be linked to poor nutritional status, include obesity, hypertension, cardiovascular diseases, type II diabetes mellitus, and indeed age-related malnutrition [582,584,817].
+
Finally, it is known that a patient’s nutritional status affects health outcomes in various infectious diseases [587], and COVID-19 is no different [585,816,817].
+Some of the main risk factors for severe COVID-19, which also happen to be linked to poor nutritional status, include obesity, hypertension, cardiovascular diseases, type II diabetes mellitus, and indeed age-related malnutrition [583,585,818].
Although not the main focus of this review, it is important to consider the nutritional challenges associated with severe COVID-19 patients.
-Hospitalized COVID-19 patients tend to report an unusually high loss of appetite preceding admission, some suffer diarrhea and gastrointestinal symptoms that result in significantly lower food intake, and patients with poorer nutritional status were more likely to have worse outcomes and require nutrition therapy [818].
-Dysphagia also seems to be a significant problem in pediatric patients that suffered multisystem inflammatory syndrome [819] and rehabilitating COVID-19 patients, potentially contributing to poor nutritional status [820].
-Almost two-thirds of discharged COVID-19 ICU patients exhibit significant weight loss, of which 26% had weight loss greater than 10% [816].
-As investigated in this review, hospitalized patients also tend to exhibit vitamin D deficiency or insufficiency, which may be associated with greater disease severity [805].
+Hospitalized COVID-19 patients tend to report an unusually high loss of appetite preceding admission, some suffer diarrhea and gastrointestinal symptoms that result in significantly lower food intake, and patients with poorer nutritional status were more likely to have worse outcomes and require nutrition therapy [819].
+Dysphagia also seems to be a significant problem in pediatric patients that suffered multisystem inflammatory syndrome [820] and rehabilitating COVID-19 patients, potentially contributing to poor nutritional status [821].
+Almost two-thirds of discharged COVID-19 ICU patients exhibit significant weight loss, of which 26% had weight loss greater than 10% [817].
+As investigated in this review, hospitalized patients also tend to exhibit vitamin D deficiency or insufficiency, which may be associated with greater disease severity [806].
Therefore, further research is required to determine how dietary supplements and nutraceuticals may contribute to the treatment of severely ill and rehabilitating patients, who often rely on enteral nutrition.
-6.10 Conclusions
+6.10 Conclusions
Despite all the potential benefits of nutraceutical and dietary supplement interventions presented, currently there is a paucity of clinical evidence to support their use for the prevention or mitigation of COVID-19 infection.
-Nevertheless, optimal nutritional status can prime an individual’s immune system to protect against the effects of acute respiratory viral infections by supporting normal maintenance of the immune system [582,586].
-Nutritional strategies can also play a role in the treatment of hospitalized patients, as malnutrition is a risk to COVID-19 patients [820].
+Nevertheless, optimal nutritional status can prime an individual’s immune system to protect against the effects of acute respiratory viral infections by supporting normal maintenance of the immune system [583,587].
+Nutritional strategies can also play a role in the treatment of hospitalized patients, as malnutrition is a risk to COVID-19 patients [821].
Overall, supplementation of vitamin C, vitamin D, and zinc may be an effective method of ensuring their adequate intake to maintain optimal immune function, which may also convey beneficial effects against viral infections due to their immunomodulatory effects.
Individuals should pay attention to their nutritional status, particularly their intake of vitamin D, considering that vitamin D deficiency is widespread.
-The prevailing evidence seems to indicate an association between vitamin D deficiency with COVID-19 incidence and, potentially, severity [710].
+The prevailing evidence seems to indicate an association between vitamin D deficiency with COVID-19 incidence and, potentially, severity [711].
As a result, some international authorities have advised the general public, particularly those at high risk of infection, to consider vitamin D supplementation.
However, further well-controlled clinical trials are required to confirm these observations.
-Many supplements and nutraceuticals designed for various ailments that are available in the United States and beyond are not strictly regulated [821].
+
Many supplements and nutraceuticals designed for various ailments that are available in the United States and beyond are not strictly regulated [822].
Consequently, there can be safety and efficacy concerns associated with many of these products.
Often, the vulnerable members of society can be exploited in this regard and, unfortunately, the COVID-19 pandemic has proven no different.
-As mentioned above, the FDA has issued warnings to several companies for advertising falsified claims in relation to the preventative and therapeutic capabilities of their products against COVID-19 [822].
+As mentioned above, the FDA has issued warnings to several companies for advertising falsified claims in relation to the preventative and therapeutic capabilities of their products against COVID-19 [823].
Further intensive investigation is required to establish the effects of these nutraceuticals, if any, against COVID-19.
-Until more effective therapeutics are established, the most effective mitigation strategies consist of encouraging standard public health practices such as regular hand washing with soap, wearing a face mask, and covering a cough with your elbow [823], along with following social distancing measures, “stay at home” guidelines, expansive testing, and contact tracing [824,825].
+Until more effective therapeutics are established, the most effective mitigation strategies consist of encouraging standard public health practices such as regular hand washing with soap, wearing a face mask, and covering a cough with your elbow [824], along with following social distancing measures, “stay at home” guidelines, expansive testing, and contact tracing [825,826].
Indeed, in light of this review, it would also be pertinent to adopt a healthy diet and lifestyle following national guidelines in order to maintain optimal immune health.
Because of the broad public appeal of dietary supplements and nutraceuticals, it is important to evaluate the evidence regarding the use of such products.
We will continue to update this review as more findings become available.
@@ -2624,21 +2625,21 @@ 7.17.2 Importance
7.3 Introduction
For a highly infectious virus like SARS-CoV-2, a vaccine would hold particular value because it could bolster the immune response to the virus of the population broadly, thereby driving a lower rate of infection and likely significantly reducing fatalities.
-However, the vaccine development process has historically been slow, and vaccines fail to provide immediate prophylactic protection or treat ongoing infections [826].
+However, the vaccine development process has historically been slow, and vaccines fail to provide immediate prophylactic protection or treat ongoing infections [827].
Flu-like illnesses caused by viruses are a common target of vaccine development programs, and influenza vaccine technology in particular has made many strides.
During the H1N1 influenza outbreak, vaccine development was accelerated because of the existing infrastructure, along with the fact that regulatory agencies had already decided that vaccines produced using egg- and cell-based platforms could be licensed under the regulations used for a strain change.
Critiques of the production and distribution of the H1N1 vaccine have stressed the need for alternative development-and-manufacturing platforms that can be readily adapted to new pathogens.
-Although a monovalent H1N1 vaccine was not available before the pandemic peaked in the United States and Europe, it was available soon afterward as a stand-alone vaccine that was eventually incorporated into commercially available seasonal influenza vaccines [827].
+Although a monovalent H1N1 vaccine was not available before the pandemic peaked in the United States and Europe, it was available soon afterward as a stand-alone vaccine that was eventually incorporated into commercially available seasonal influenza vaccines [828].
If H1N1 vaccine development provides any indication, considering developing and manufacturing platforms for promising COVID-19 vaccine trials early could hasten the emergence of an effective prophylactic vaccine against SARS-CoV-2.
-The first critical step towards developing a vaccine against SARS-CoV-2 was characterizing the target, which fortunately happened early in the COVID-19 outbreak with the sequencing and dissemination of the viral genome [828].
+
The first critical step towards developing a vaccine against SARS-CoV-2 was characterizing the target, which fortunately happened early in the COVID-19 outbreak with the sequencing and dissemination of the viral genome [829].
The Coalition for Epidemic Preparedness Innovations (CEPI) is coordinating global health agencies and pharmaceutical companies to develop vaccines against SARS-CoV-2.
-As of September 2020, there were over 180 vaccine candidates against SARS-CoV-2 in development [829].
+As of September 2020, there were over 180 vaccine candidates against SARS-CoV-2 in development [830].
Unlike many global vaccine development programs previously, such as with H1N1, the vaccine development landscape for COVID-19 includes vaccines produced by a wide array of technologies.
-Experience in the field of oncology is encouraging COVID-19 vaccine developers to use next-generation approaches to vaccine development, which have led to the great diversity of vaccine development programs [830].
+Experience in the field of oncology is encouraging COVID-19 vaccine developers to use next-generation approaches to vaccine development, which have led to the great diversity of vaccine development programs [831].
These diverse technology platforms include DNA, RNA, virus-like particle, recombinant protein, both replicating and non-replicating viral vectors, live attenuated virus, and inactivated virus approaches (Figure 5).
Given the wide range of vaccines under development, it is possible that some vaccine products may eventually be shown to be more effective in certain subpopulations, such as children, pregnant women, immunocompromised patients, the elderly, etc.
-The requirements for a successful vaccine trial and deployment are complex and may require coordination between government, industry, academia, and philanthropic entities [831].
-While little is currently known about immunity to SARS-CoV-2, vaccine development typically tests for serum neutralizing activity, as this has been established as a biomarker for adaptive immunity in other respiratory illnesses [832].
+The requirements for a successful vaccine trial and deployment are complex and may require coordination between government, industry, academia, and philanthropic entities [832].
+While little is currently known about immunity to SARS-CoV-2, vaccine development typically tests for serum neutralizing activity, as this has been established as a biomarker for adaptive immunity in other respiratory illnesses [833].
Figure 5: Vaccine Development Strategies.
@@ -2647,13 +2648,13 @@ 7.
7.4 DNA Vaccines
-This vaccination method involves the direct introduction of a plasmid containing a DNA sequence encoding the antigen(s) against which an immune response is sought into appropriate tissues [833].
+
This vaccination method involves the direct introduction of a plasmid containing a DNA sequence encoding the antigen(s) against which an immune response is sought into appropriate tissues [834].
This approach may offer several advantages over traditional vaccination approaches, such as the stimulation of both B- as well as T-cell responses and the absence of any infectious agent.
-Currently, a Phase I safety and immunogenicity clinical trial of INO-4800, a prophylactic vaccine against SARS-CoV-2, is underway [834].
+Currently, a Phase I safety and immunogenicity clinical trial of INO-4800, a prophylactic vaccine against SARS-CoV-2, is underway [835].
The vaccine developer Inovio Pharmaceuticals Technology is overseeing administration of INO-4800 by intradermal injection followed by electroporation with the CELLECTRA® device to healthy volunteers.
Electroporation is the application of brief electric pulses to tissues in order to permeabilize cell membranes in a transient and reversible manner.
-It has been shown that electroporation can enhance vaccine efficacy by up to 100-fold, as measured by increases in antigen-specific antibody titers [835].
-The safety of the CELLECTRA® device has been studied for over seven years, and these studies support the further development of electroporation as a safe vaccine delivery method [836].
+It has been shown that electroporation can enhance vaccine efficacy by up to 100-fold, as measured by increases in antigen-specific antibody titers [836].
+The safety of the CELLECTRA® device has been studied for over seven years, and these studies support the further development of electroporation as a safe vaccine delivery method [837].
The temporary formation of pores through electroporation facilitates the successful transportation of macromolecules into cells, allowing cells to robustly take up INO-4800 for the production of an antibody response.
Approved by the U.S. FDA on April 6, 2020, the Phase I study is enrolling up to 40 healthy adult volunteers in Philadelphia, PA at the Perelman School of Medicine and at the Center for Pharmaceutical Research in Kansas City, MO.
The trial has two experimental arms corresponding to the two locations.
@@ -2664,98 +2665,98 @@
7.4<
Although exciting, the cost of vaccine manufacturing and electroporation may make scaling the use of this technology for prophylactic use for the general public difficult.
7.5 RNA Vaccines
RNA vaccines are nucleic-acid based modalities that code for viral antigens against which the human body elicits a humoral and cellular immune response.
-The mRNA technology is transcribed in vitro and delivered to cells via lipid nanoparticles (LNP) [837].
-They are recognized by ribosomes in vivo and then translated and modified into functional proteins [838].
-The resulting intracellular viral proteins are displayed on surface MHC proteins, provoking a strong CD8+ T cell response as well as a CD4+ T cell and B cell-associated antibody responses [838].
+The mRNA technology is transcribed in vitro and delivered to cells via lipid nanoparticles (LNP) [838].
+They are recognized by ribosomes in vivo and then translated and modified into functional proteins [839].
+The resulting intracellular viral proteins are displayed on surface MHC proteins, provoking a strong CD8+ T cell response as well as a CD4+ T cell and B cell-associated antibody responses [839].
Naturally, mRNA is not very stable and can degrade quickly in the extracellular environment or the cytoplasm.
-The LNP covering protects the mRNA from enzymatic degradation outside of the cell [839].
+The LNP covering protects the mRNA from enzymatic degradation outside of the cell [840].
Codon optimization to prevent secondary structure formation and modifications of the poly-A tail as well as the 5’ untranslated region to promote ribosomal complex binding can increase mRNA expression in cells.
-Furthermore, purifying out double-stranded RNA and immature RNA with FPLC (fast performance liquid chromatography) and HPLC (high performance liquid chromatography) technology will improve translation of the mRNA in the cell [838,840].
+Furthermore, purifying out double-stranded RNA and immature RNA with FPLC (fast performance liquid chromatography) and HPLC (high performance liquid chromatography) technology will improve translation of the mRNA in the cell [839,841].
Vaccines based on mRNA delivery confer many advantages over traditional viral vectored vaccines and DNA vaccines.
-In comparison to live attenuated viruses, mRNA vaccines are non-infectious and can be synthetically produced in an egg-free, cell-free environment, thereby reducing the risk of a detrimental immune response in the host [841].
-Unlike DNA vaccines, mRNA technologies are naturally degradable and non-integrating, and they do not need to cross the nuclear membrane in addition to the plasma membrane for their effects to be seen [838].
+In comparison to live attenuated viruses, mRNA vaccines are non-infectious and can be synthetically produced in an egg-free, cell-free environment, thereby reducing the risk of a detrimental immune response in the host [842].
+Unlike DNA vaccines, mRNA technologies are naturally degradable and non-integrating, and they do not need to cross the nuclear membrane in addition to the plasma membrane for their effects to be seen [839].
Furthermore, mRNA vaccines are easily, affordably, and rapidly scalable.
Although mRNA vaccines have been developed for therapeutic and prophylactic purposes, none have previously been licensed or commercialized.
-Nevertheless, they have shown promise in animal models and preliminary clinical trials for several indications, including rabies, coronavirus, influenza, and cytomegalovirus [842].
-Preclinical data previously identified effective antibody generation against full-length FPLC-purified influenza hemagglutinin stalk-encoding mRNA in mice, rabbits, and ferrets [843].
-Similar immunological responses for mRNA vaccines were observed in humans in Phase I and II clinical trials operated by the pharmaceutical-development companies Curevac and Moderna for rabies, flu, and zika [840].
-Positively charged bilayer LNPs carrying the mRNA attract negatively charged cell membranes, endocytose into the cytoplasm [839], and facilitate endosomal escape.
-LNPs can be coated with modalities recognized and engulfed by specific cell types, and LNPs that are 150 nm or less effectively enter into lymphatic vessels [839,844].
+Nevertheless, they have shown promise in animal models and preliminary clinical trials for several indications, including rabies, coronavirus, influenza, and cytomegalovirus [843].
+Preclinical data previously identified effective antibody generation against full-length FPLC-purified influenza hemagglutinin stalk-encoding mRNA in mice, rabbits, and ferrets [844].
+Similar immunological responses for mRNA vaccines were observed in humans in Phase I and II clinical trials operated by the pharmaceutical-development companies Curevac and Moderna for rabies, flu, and zika [841].
+Positively charged bilayer LNPs carrying the mRNA attract negatively charged cell membranes, endocytose into the cytoplasm [840], and facilitate endosomal escape.
+LNPs can be coated with modalities recognized and engulfed by specific cell types, and LNPs that are 150 nm or less effectively enter into lymphatic vessels [840,845].
Therefore, this technology holds great potential for targeted delivery of modified mRNA.
-There are three types of RNA vaccines: non-replicating, in vivo self-replicating, and in vitro dendritic cell non-replicating [845].
+
There are three types of RNA vaccines: non-replicating, in vivo self-replicating, and in vitro dendritic cell non-replicating [846].
Non-replicating mRNA vaccines consist of a simple open reading frame (ORF) for the viral antigen flanked by the 5’ UTR and 3’ poly-A tail.
-In vivo self-replicating vaccines encode a modified viral genome derived from single-stranded, positive sense RNA alphaviruses [838,840].
+In vivo self-replicating vaccines encode a modified viral genome derived from single-stranded, positive sense RNA alphaviruses [839,841].
The RNA genome encodes the viral antigen along with proteins of the genome replication machinery, including an RNA polymerase.
-Structural proteins required for viral assembly are not included in the engineered genome [838].
-Self-replicating vaccines produce more viral antigens over a longer period of time, thereby evoking a more robust immune response [845].
+Structural proteins required for viral assembly are not included in the engineered genome [839].
+Self-replicating vaccines produce more viral antigens over a longer period of time, thereby evoking a more robust immune response [846].
Finally, in vitro dendritic cell non-replicating RNA vaccines limit transfection to dendritic cells.
Dendritic cells are potent antigen-presenting immune cells that easily take up mRNA and present fragments of the translated peptide on their MHC proteins, which can then interact with T cell receptors.
-Ultimately, primed T follicular helper cells can stimulate germinal center B cells that also present the viral antigen to produce antibodies against the virus [846].
-These cells are isolated from the patient, grown and transfected ex vivo, and reintroduced to the patient [847].
+Ultimately, primed T follicular helper cells can stimulate germinal center B cells that also present the viral antigen to produce antibodies against the virus [847].
+These cells are isolated from the patient, grown and transfected ex vivo, and reintroduced to the patient [848].
Given the potential for this technology to be quickly adapted for a new pathogen, it has held significant interest for the treatment of COVID-19.
-In the vaccines developed under this approach, the spike protein, which is immunogenic [39], can be furnished to the immune system in order to train its response.
-The vaccine candidates developed against SARS-CoV-2 using mRNA vectors utilize similar principles and technologies, although there are slight differences in implementation among candidates such as the formulation of the platform and the specific components of the spike protein encapsulated (e.g., the full Spike protein vs. the RBD alone) [848].
+In the vaccines developed under this approach, the spike protein, which is immunogenic [41], can be furnished to the immune system in order to train its response.
+The vaccine candidates developed against SARS-CoV-2 using mRNA vectors utilize similar principles and technologies, although there are slight differences in implementation among candidates such as the formulation of the platform and the specific components of the spike protein encapsulated (e.g., the full Spike protein vs. the RBD alone) [849].
The results of the interim analyses of two mRNA vaccine candidates became available at the end of 2020 and provided strong support for this emerging approach to vaccination.
Below we describe the results available as of February 2021 for two such candidates, mRNA-1273 produced by ModernaTX and BNT162b2 produced by Pfizer, Inc. and BioNTech.
7.5.1 ModernaTX mRNA Vaccine
ModernaTX’s mRNA-1273 vaccine, which is an was the first COVID-19 vaccine to enter a phase I clinical trial in the United States.
-In this trial, Moderna spearheaded an investigation on the immunogenicity and reactogenicity of mRNA-1273, a conventional lipid nanoparticle encapsulated RNA encoding a full-length prefusion stabilized S protein for SARS-CoV-2 [849].
-An initial report described the results of enrolling forty-five participants who were administered intramuscular injections of mRNA-1273 in their deltoid muscle on day 1 and day 29, and then followed for the next twelve months [832].
+In this trial, Moderna spearheaded an investigation on the immunogenicity and reactogenicity of mRNA-1273, a conventional lipid nanoparticle encapsulated RNA encoding a full-length prefusion stabilized S protein for SARS-CoV-2 [850].
+An initial report described the results of enrolling forty-five participants who were administered intramuscular injections of mRNA-1273 in their deltoid muscle on day 1 and day 29, and then followed for the next twelve months [833].
Healthy males and non-pregnant females aged 18-55 years were recruited for this study and divided into three groups receiving 25, 100, or 250 micrograms (μg) of mRNA-1273.
-IgG ELISA assays on patient serology samples were used to examine the immunogenicity of the vaccine [849].
+IgG ELISA assays on patient serology samples were used to examine the immunogenicity of the vaccine [850].
Binding antibodies were observed at two weeks after the first dose at all concentrations.
At the time point one week after the second dose was administered on day 29, the pseudotyped lentivirus reporter single-round-of-infection neutralization assay (PsVNA), which was used to assess neutralizing activity, reached a median level similar to the median observed in convalescent plasma samples.
Participants reported mild and moderate systemic adverse events after the day 1 injection, and one severe local event was observed in each of the two highest dose levels.
The second injection led to severe systemic adverse events for three of the participants at the highest dose levels, with one participant in the group being evaluated at an urgent care center on the day after the second dose.
The reported localized adverse events from the second dose were similar to those from the first.
-Several months later, a press release from ModernaTX described the results of the first interim analysis of the vaccine [850].
-On November 16, 2020, a report was released describing the initial results from Phase III testing, corresponding to the first 95 cases of COVID-19 in the 30,000 enrolled participants [850], with additional data released to the FDA on December 17, 2020 [851].
-These results were subsequently published in a peer-reviewed journal (The New England Journal of Medicine) on December 30, 2020 [852].
-The first group of 30,420 study participants were randomized to receive the vaccine or a placebo at a ratio of 1:1 [852].
-Administration occurred at 99 sites within the United States in two sessions, spaced 28 days apart [852,853].
-Patients reporting COVID-19 symptoms upon follow-up were tested for SARS-CoV-2 using a nasopharyngeal swab that was evaluated with RT-PCR [853].
+
Several months later, a press release from ModernaTX described the results of the first interim analysis of the vaccine [851].
+On November 16, 2020, a report was released describing the initial results from Phase III testing, corresponding to the first 95 cases of COVID-19 in the 30,000 enrolled participants [851], with additional data released to the FDA on December 17, 2020 [852].
+These results were subsequently published in a peer-reviewed journal (The New England Journal of Medicine) on December 30, 2020 [853].
+The first group of 30,420 study participants were randomized to receive the vaccine or a placebo at a ratio of 1:1 [853].
+Administration occurred at 99 sites within the United States in two sessions, spaced 28 days apart [853,854].
+Patients reporting COVID-19 symptoms upon follow-up were tested for SARS-CoV-2 using a nasopharyngeal swab that was evaluated with RT-PCR [854].
The initial preliminary analysis reported the results of the cases observed up until a cut-off date of November 11, 2020.
-Of these first 95 cases reported, 90 occurred in participants receiving the placebo compared to 5 cases in the group receiving the vaccine [850].
+Of these first 95 cases reported, 90 occurred in participants receiving the placebo compared to 5 cases in the group receiving the vaccine [851].
These results suggested the vaccine is 94.5% effective in preventing COVID-19.
Additionally, eleven severe cases of COVID-19 were observed, and all eleven occurred in participants receiving the placebo.
-The publication reported the results through an extended cut-off date of November 21, 2020, corresponding to 196 cases [852].
+The publication reported the results through an extended cut-off date of November 21, 2020, corresponding to 196 cases [853].
Of these, 11 occurred in the vaccine group and 185 in the placebo group, corresponding to an efficacy of 94.1%.
Once again, all of the severe cases of COVID-19 observed (n=30) occurred in the placebo group, including one death.
Thus, as more cases are reported, the efficacy of the vaccine has remained above 90%, and no cases of severe COVID-19 have yet been reported in participants receiving the vaccine.
These findings suggest the possibility that the vaccine might bolster immune defenses even for subjects who do still develop a SARS-CoV-2 infection.
-The study was designed with an explicit goal of including individuals at high risk for COVID-19, including older adults, people with underlying health conditions, and people of color [854].
-The Phase III trial population was comprised by approximately 25.3% adults over age 65 in the initial report and 24.8% in the publication [853].
-Among the cases reported by both interim analyses, 16-17% occurred in older adults [850,852]..
-Additionally, approximately 10% of participants identified a Black or African-American background and 20% identified Hispanic or Latino ethnicity [852,853].
-Among the first 95 cases, 12.6% occurred in participants identifying a Hispanic or Latino background and 4% in participants reporting a Black or African-American background [850]; in the publication, they indicated only that 41 of the cases reported in the placebo group and 1 case in the treatment group occurred in “communities of color”, corresponding to 21.4% of all cases [852].
+The study was designed with an explicit goal of including individuals at high risk for COVID-19, including older adults, people with underlying health conditions, and people of color [855].
+The Phase III trial population was comprised by approximately 25.3% adults over age 65 in the initial report and 24.8% in the publication [854].
+Among the cases reported by both interim analyses, 16-17% occurred in older adults [851,853]..
+Additionally, approximately 10% of participants identified a Black or African-American background and 20% identified Hispanic or Latino ethnicity [853,854].
+Among the first 95 cases, 12.6% occurred in participants identifying a Hispanic or Latino background and 4% in participants reporting a Black or African-American background [851]; in the publication, they indicated only that 41 of the cases reported in the placebo group and 1 case in the treatment group occurred in “communities of color”, corresponding to 21.4% of all cases [853].
While the sample size in both analyses is small relative to the study population of over 30,000, these results suggest that the vaccine is likely to be effective in people from a variety of backgrounds.
By all indications, this vaccine is likely to be highly useful in mitigating the damage of SARS-CoV-2.
-In-depth safety data was released by ModernaTX as part of their application for an EUA from the FDA and summarized in the associated publication [852,853].
+
In-depth safety data was released by ModernaTX as part of their application for an EUA from the FDA and summarized in the associated publication [853,854].
Because the detail provided in the report is greater than that provided in the publication, here we emphasize the results observed at the time of the first analysis.
-Overall, a large percentage of participants reported adverse effects when solicited, and these reports were higher in the vaccine group than in the placebo group (94.5% versus 59.5%, respectively, at the time of the initial analysis) [853].
-Some of these events met the criteria for grade 3 (local or systemic) or grade 4 (systemic only) toxicity [853], but most were grade 1 or grade 2 and lasted 2-3 days [852].
-The most common local adverse reaction was pain at the injection site, reported by 83.7% of participants receiving the first dose of the vaccine and 88.4% upon receiving the second dose, compared to 19.8% and 19.8% and 17.0%, respectively, of patients in the placebo condition [853].
+Overall, a large percentage of participants reported adverse effects when solicited, and these reports were higher in the vaccine group than in the placebo group (94.5% versus 59.5%, respectively, at the time of the initial analysis) [854].
+Some of these events met the criteria for grade 3 (local or systemic) or grade 4 (systemic only) toxicity [854], but most were grade 1 or grade 2 and lasted 2-3 days [853].
+The most common local adverse reaction was pain at the injection site, reported by 83.7% of participants receiving the first dose of the vaccine and 88.4% upon receiving the second dose, compared to 19.8% and 19.8% and 17.0%, respectively, of patients in the placebo condition [854].
Fewer than 5% of vaccine recipients reported grade 3 pain at either administration.
-Other frequent local reactions included erythema, swelling, and lymphadenopathy [853].
-For systemic adverse reactions, fatigue was the most common [853].
-Among participants receiving either dose of the vaccine, 68.5% reported fatigue compared to 36.1% participants receiving the placebo [853].
-The level of fatigue experienced was usually fairly mild, with only 9.6% and 1.3% of participants in the vaccine and placebo conditions, respectively, reporting grade 3 fatigue [853], which corresponds to significant interference with daily activity [855].
-Based on the results of the report, an EUA was issued on December 18, 2020 to allow distribution of this vaccine in the United States [856], and it was shortly followed by an Interim Order authorizing distribution of the vaccine in Canada [857] and a conditional marketing authorization by the European Medicines Agency to facilitate distribution in the European Union [858].
+Other frequent local reactions included erythema, swelling, and lymphadenopathy [854].
+For systemic adverse reactions, fatigue was the most common [854].
+Among participants receiving either dose of the vaccine, 68.5% reported fatigue compared to 36.1% participants receiving the placebo [854].
+The level of fatigue experienced was usually fairly mild, with only 9.6% and 1.3% of participants in the vaccine and placebo conditions, respectively, reporting grade 3 fatigue [854], which corresponds to significant interference with daily activity [856].
+Based on the results of the report, an EUA was issued on December 18, 2020 to allow distribution of this vaccine in the United States [857], and it was shortly followed by an Interim Order authorizing distribution of the vaccine in Canada [858] and a conditional marketing authorization by the European Medicines Agency to facilitate distribution in the European Union [859].
7.5.2 Pfizer/BioNTech BNT162b2
ModernaTX was, in fact, the second company to release news of a successful interim analysis of an mRNA vaccine and receive an EUA.
-The first report came from Pfizer and BioNTech’s mRNA vaccine BNT162b2 on November 9, 2020 [859], and a preliminary report was published in the New England Journal of Medicine one month later [304].
-The vaccine candidate is contains the full prefusion stabilized, membrane-anchored SARS-CoV-2 spike protein in a vaccine formulation based on modified mRNA (modRNA) technology [860,861].
-This vaccine candidate should not be confused with a similar candidate from Pfizer/BioNTech, BNT162b1, that delivered only the RBD of the spike protein [862,863], which was not advanced to a stage III trial because of the improved reactogenicity/immunogenicity profile of BNT162b2 [305].
-During the Phase III trial of BNT162b2, 43,538 participants were enrolled 1:1 in the placebo and the vaccine candidate and received two 30-μg doses 21 days apart [304].
-Of these enrolled participants, 21,720 received BNT162b2 and 21,728 received a placebo [304].
+The first report came from Pfizer and BioNTech’s mRNA vaccine BNT162b2 on November 9, 2020 [860], and a preliminary report was published in the New England Journal of Medicine one month later [306].
+The vaccine candidate is contains the full prefusion stabilized, membrane-anchored SARS-CoV-2 spike protein in a vaccine formulation based on modified mRNA (modRNA) technology [861,862].
+This vaccine candidate should not be confused with a similar candidate from Pfizer/BioNTech, BNT162b1, that delivered only the RBD of the spike protein [863,864], which was not advanced to a stage III trial because of the improved reactogenicity/immunogenicity profile of BNT162b2 [307].
+During the Phase III trial of BNT162b2, 43,538 participants were enrolled 1:1 in the placebo and the vaccine candidate and received two 30-μg doses 21 days apart [306].
+Of these enrolled participants, 21,720 received BNT162b2 and 21,728 received a placebo [306].
Recruitment occurred at 135 sites across six countries: Argentina, Brazil, Germany, South Africa, Turkey, and the United States.
-An initial press release described the first 94 cases, which were consistent with 90% efficacy of the vaccine at 7 days following the second dose [859].
+An initial press release described the first 94 cases, which were consistent with 90% efficacy of the vaccine at 7 days following the second dose [860].
The release of the full trial information covered a longer period and analyzed the first 170 cases occurring at least 7 days after the second dose, 8 of which occurred in patients who had received BNT162b2.
-The press release characterized the study population as diverse, reporting that 42% of the participants worldwide came from non-white backgrounds, including 10% Black and 26% Hispanic or Latino [864].
-Within the United States, 10% and 13% of participants, respectively, identified themselves as having Black or Hispanic/Latino backgrounds [864].
-Additionally, 41% of participants worldwide were 56 years of age or older [864], and they reported that the efficacy of the vaccine in adults over 65 was 94% [865].
-The primary efficacy analysis of the Phase III study was concluded on November 18, 2020 [865], and the final results indicted 94.6% efficacy of the vaccine [304]v.
-The safety profile of the vaccine was also assessed [304].
+The press release characterized the study population as diverse, reporting that 42% of the participants worldwide came from non-white backgrounds, including 10% Black and 26% Hispanic or Latino [865].
+Within the United States, 10% and 13% of participants, respectively, identified themselves as having Black or Hispanic/Latino backgrounds [865].
+Additionally, 41% of participants worldwide were 56 years of age or older [865], and they reported that the efficacy of the vaccine in adults over 65 was 94% [866].
+The primary efficacy analysis of the Phase III study was concluded on November 18, 2020 [866], and the final results indicted 94.6% efficacy of the vaccine [306]v.
+The safety profile of the vaccine was also assessed [306].
A subset of patients were followed for reactogenicity using electronic diaries, with the data collected from these 8,183 participants comprising the solicited safety events analyzed.
Much like those who received the ModernaTX vaccine candidate, a large proportion of participants reported experiencing site injection pain within 7 days of vaccination.
While percentages are broken down by age group in the publication, these proportions correspond to approximately 78% and 73% of all participants after the first and second doses, respectively, overall.
@@ -2764,8 +2765,8 @@
[866,867].
-As of December 11, 2020, the United States FDA approved this vaccine under an emergency use authorization [868].
+Based on the efficacy and safety information released, the vaccine was approved in early December by the United Kingdom’s Medicines and Healthcare Products Regulatory Agency with administration outside of a clinical trial beginning on December 8, 2020 [867,868].
+As of December 11, 2020, the United States FDA approved this vaccine under an emergency use authorization [869].
7.6 Viral Vector Vaccines
7.6.1 COVID-19 Vaccine AstraZeneca
7.6.2 Sputnik-V
@@ -2784,121 +2785,121 @@ also included a brief summary of the potential of adjuvants for these vaccines, including a brief description of some already commonly used adjuvants.
+A review on the development of SARS-CoV-2 vaccines [870] also included a brief summary of the potential of adjuvants for these vaccines, including a brief description of some already commonly used adjuvants.
Different adjuvants can regulate different types of immune responses, so the type or combination of adjuvants used in a vaccine will depend on both the type of vaccine and concern related to efficacy and safety.
-A variety of possible mechanisms for adjuvants have been researched [870,871,872], including the following: induction of DAMPs that can be recognized by certain PRRs of the innate immune system; functioning as PAMP that can also be recognized by certain PRRs; and more generally enhancing the humoral or cellular immune responses.
+A variety of possible mechanisms for adjuvants have been researched [871,872,873], including the following: induction of DAMPs that can be recognized by certain PRRs of the innate immune system; functioning as PAMP that can also be recognized by certain PRRs; and more generally enhancing the humoral or cellular immune responses.
Selection of one or more adjuvants requires considering how to promote the advantageous effects of the components and/or immune response and, likewise, to inhibit possible deleterious effects.
There are also considerations related to the method of delivering (or co-delivering) the adjuvant and antigen components of a vaccine.
7.10.2 Trained Immunity
Another approach that is being investigated explores the potential for vaccines that are not made from the SARS-CoV-2 virus to confer what has been termed trained immunity.
-In a recent review [873], trained immunity was defined as forms of memory that are temporary (e.g., months or years) and reversible.
+In a recent review [874], trained immunity was defined as forms of memory that are temporary (e.g., months or years) and reversible.
It is induced by exposure to whole-microorganism vaccines or other microbial stimuli that generates heterologous protective effects.
Trained immunity can be displayed by innate immune cells or innate immune features of other cells, and it is characterized by alterations to immune responsiveness to future immune challenges due to epigenetic and metabolic mechanisms.
These alterations can take the form of either an increased or decreased response to immune challenge by a pathogen.
-Trained immunity elicited by non-SARS-CoV-2 whole-microorganism vaccines could potentially improve SARS-CoV-2 susceptibility or severity [874].
+Trained immunity elicited by non-SARS-CoV-2 whole-microorganism vaccines could potentially improve SARS-CoV-2 susceptibility or severity [875].
One type of stimulus which research indicates can induce trained immunity is bacillus Calmette-Guerin (BCG) vaccination.
BCG is an attenuated form of bacteria Mycobacterium bovis.
The vaccine is most commonly administered for the prevention of tuberculosis in humans.
Clinical trials in non-SARS-CoV-2-infected adults have been designed to assess whether BCG vaccination could have prophylactic effects against SARS-CoV-2 by reducing susceptibility, preventing infection, or reducing disease severity.
-A number of trials are now evaluating the effects of the BCG vaccine or the related vaccine VPM1002 [874,875,876,877,878,879,880,881,882,883,884,885,886,887,888].
+A number of trials are now evaluating the effects of the BCG vaccine or the related vaccine VPM1002 [875,876,877,878,879,880,881,882,883,884,885,886,887,888,889].
The ongoing trials are using a number of different approaches.
Some trials enroll healthcare workers, other trials hospitalized elderly adults without immunosuppression who get vaccinated with placebo or BCG at hospital discharge, and yet another set of trials older adults (>50 years) under chronic care for conditions like hypertension and diabetes.
One set of trials, for example, uses time until first infection as the primary study endpoint; more generally, outcomes measured in some of these trials are related to incidence of disease and disease severity or symptoms.
-Some analyses have suggested a possible correlation at the country level between the frequency of BCG vaccination (or BCG vaccination policies) and the severity of COVID-19 [874].
+Some analyses have suggested a possible correlation at the country level between the frequency of BCG vaccination (or BCG vaccination policies) and the severity of COVID-19 [875].
Currently it is unclear whether this correlation has any connection to trained immunity.
Many possible confounding factors are also likely to vary among countries, such as age distribution, detection efficiency, stochastic epidemic dynamic effects, differences in healthcare capacity over time in relation to epidemic dynamics, and these have not been adequately accounted for in current analyses.
It is unclear whether there is an effect of the timing of BCG vaccination, both during an individual’s life cycle and relative to the COVID-19 pandemic.
-Additionally, given that severe SARS-CoV-2 may be associated with a dysregulated immune response, it is unclear what alterations to the immune response would be most likely to be protective versus pathogenic (e.g., [112,874,889,890]).
-The article [874] proposes that trained immunity might lead to an earlier and stronger response, which could in turn reduce viremia and the risk of later, detrimental immunopathology.
+Additionally, given that severe SARS-CoV-2 may be associated with a dysregulated immune response, it is unclear what alterations to the immune response would be most likely to be protective versus pathogenic (e.g., [114,875,890,891]).
+The article [875] proposes that trained immunity might lead to an earlier and stronger response, which could in turn reduce viremia and the risk of later, detrimental immunopathology.
While trained immunity is an interesting possible avenue to complement vaccine development efforts through the use of an existing vaccine, additional research is required to assess whether the BCG vaccine is likely to confer trained immunity in the case of SARS-CoV-2.
7.11 Discussion
Additionally, major advances in vaccines using mRNA and adenoviruses that have led to three vaccines becoming available or close to becoming available in late 2020 (Figure 4).
Though some concerns remain about the duration of sustained immunity for convalescents, vaccine development efforts are ongoing and show initial promising results.
The Moderna trial, for example, reported that the neutralizing activity in participants who received two doses of the vaccine was similar to that observed in convalescent plasma.
-One of the two mRNA vaccines, Pfizer and BioNTech’s BNT162b2, has been issued an EUA for patients as young as 16 [891], while ModernaTX has begun a clinical trial to assess its mRNA vaccine in adolescents ages 12 to 18 [892].
+One of the two mRNA vaccines, Pfizer and BioNTech’s BNT162b2, has been issued an EUA for patients as young as 16 [892], while ModernaTX has begun a clinical trial to assess its mRNA vaccine in adolescents ages 12 to 18 [893].
8 Social Factors Influencing COVID-19 Exposure and Outcomes
8.1 Social Factors Influencing COVID-19 Outcomes
In addition to understanding the fundamental biology of the SARS-CoV-2 virus and COVID-19, it is critical to consider how the broader environment can influence both COVID-19 outcomes and efforts to develop and implement treatments for the disease.
The evidence clearly indicates that social environmental factors are critical determinants of individuals’ and communities’ risks related to COVID-19.
There are distinct components to COVID-19 susceptibility, and an individual’s risk can be elevated at one or all stages from exposure to recovery/mortality: an individual may be more likely to be exposed to the virus, more likely to get infected once exposed, more likely to have serious complications once infected, and be less likely to receive adequate care once they are seriously ill.
-The fact that differences in survival between Black and white patients were no longer significant after controlling for comorbidities and socioeconomic status (type of insurance, neighborhood deprivation score, and hospital where treatment was received) in addition to sex and age [893] underscores the relevance of social factors to understanding mortality differences between racial and ethnic groups.
-Moreover, the Black patients were younger and more likely to be female than white patients, yet still had a higher mortality rate without correction for the other variables [893].
+The fact that differences in survival between Black and white patients were no longer significant after controlling for comorbidities and socioeconomic status (type of insurance, neighborhood deprivation score, and hospital where treatment was received) in addition to sex and age [894] underscores the relevance of social factors to understanding mortality differences between racial and ethnic groups.
+Moreover, the Black patients were younger and more likely to be female than white patients, yet still had a higher mortality rate without correction for the other variables [894].
Here, we outline a few systemic reasons that may exacerbate the COVID-19 pandemic in communities of color.
8.2 Factors Observed to be Associated with Susceptibility
As COVID-19 has spread into communities around the globe, it has become clear that the risks associated with this disease are not equally shared by all individuals or all communities.
Significant disparities in outcomes have led to interest in the demographic, biomedical, and social factors that influence COVID-19 severity.
Untangling the factors influencing COVID-19 susceptibility is a complex undertaking.
-Among patients who are admitted to the hospital, outcomes have generally been poor, with rates of admission to the intensive care unit (ICU) upwards of 15% in both Wuhan, China and Italy [34,894,895].
-However, hospitalization rates vary by location [896].
+Among patients who are admitted to the hospital, outcomes have generally been poor, with rates of admission to the intensive care unit (ICU) upwards of 15% in both Wuhan, China and Italy [36,895,896].
+However, hospitalization rates vary by location [897].
This variation may be influenced by demographic (e.g., average age in the area), medical (e.g., the prevalence of comorbid conditions such as diabetes), and social (e.g., income or healthcare availability) factors that vary geographically.
Additionally, some of the same factors may influence an individual’s probability of exposure to SARS-CoV-2, their risk of developing a more serious case of COVID-19 that would require hospitalization, and their access to medical support.
As a result, quantifying or comparing susceptibility among individuals, communities, or other groups requires consideration of a number of complex phenomena that intersect across many disciplines of research.
In this section, the term “risk factor” is used to refer to variables that are statistically associated with more severe COVID-19 outcomes.
Some are intrinsic characteristics that have been observed to carry an association with variation in outcomes, whereas others may be more functionally linked to the pathophysiology of COVID-19.
8.2.1 Patient Traits Associated with Increased Risk
-Two traits that have been consistently associated with more severe COVID-19 outcomes are male sex and advanced age (typically defined as 60 or older, with the greatest risk among those 85 and older [897]).
-In the United States, males and older individuals diagnosed with COVID-19 were found to be more likely to require hospitalization [898,899].
-A retrospective study of hospitalized Chinese patients [35] found that a higher probability of mortality was associated with older age, and world-wide, population age structure has been found to be an important variable for explaining differences in outbreak severity [900].
-The CFR for adults over 80 has been estimated upwards of 14% or even 20% [901].
-Male sex has also been identified as a risk factor for severe COVID-19 outcomes, including death [902,903,904].
-Early reports from China and Europe indicated that even though the case rates were similar across males and females, males were at elevated risk for hospital admission, ICU admission, and death [903], although data from some US states indicates more cases among females, potentially due to gender representation in care-taking professions [905].
-In older age groups (e.g., age 60 and older), comparable absolute numbers of male and female cases actually suggests a higher rate of occurrence in males, due to increased skew in the sex ratio [903].
-Current estimates based on worldwide data suggest that, compared to females, males may be 30% more likely to be hospitalized, 80% more likely to be admitted to the ICU, and 40% more likely to die as a result of COVID-19 [904].
-There also may be a compounding effect of advanced age and male sex, with differences time to recovery worst for males over 60 years old relative to female members of their age cohort [906].
+Two traits that have been consistently associated with more severe COVID-19 outcomes are male sex and advanced age (typically defined as 60 or older, with the greatest risk among those 85 and older [898]).
+In the United States, males and older individuals diagnosed with COVID-19 were found to be more likely to require hospitalization [899,900].
+A retrospective study of hospitalized Chinese patients [37] found that a higher probability of mortality was associated with older age, and world-wide, population age structure has been found to be an important variable for explaining differences in outbreak severity [901].
+The CFR for adults over 80 has been estimated upwards of 14% or even 20% [902].
+Male sex has also been identified as a risk factor for severe COVID-19 outcomes, including death [903,904,905].
+Early reports from China and Europe indicated that even though the case rates were similar across males and females, males were at elevated risk for hospital admission, ICU admission, and death [904], although data from some US states indicates more cases among females, potentially due to gender representation in care-taking professions [906].
+In older age groups (e.g., age 60 and older), comparable absolute numbers of male and female cases actually suggests a higher rate of occurrence in males, due to increased skew in the sex ratio [904].
+Current estimates based on worldwide data suggest that, compared to females, males may be 30% more likely to be hospitalized, 80% more likely to be admitted to the ICU, and 40% more likely to die as a result of COVID-19 [905].
+There also may be a compounding effect of advanced age and male sex, with differences time to recovery worst for males over 60 years old relative to female members of their age cohort [907].
Both of these risk factors can be approached through the lens of biology.
-The biological basis for greater susceptibility with age is likely linked to the prevalence of extenuating health conditions such as heart failure or diabetes [901].
+The biological basis for greater susceptibility with age is likely linked to the prevalence of extenuating health conditions such as heart failure or diabetes [902].
Several hypotheses have been proposed to account for differences in severity between males and females.
-For example, some evidence suggests that female sex hormones may be protective [903,905].
-ACE2 expression in the kidneys of male mice was observed to be twice as high as that of females, and a regulatory effect of estradiol on ACE2 expression was demonstrated by removing the gonads and then supplementing with estradiol [905,907].
-Other work in mice has shown an inverse association between mortality due to SARS-CoV-1 and estradiol, suggesting a protective role for the sex hormone [905].
+For example, some evidence suggests that female sex hormones may be protective [904,906].
+ACE2 expression in the kidneys of male mice was observed to be twice as high as that of females, and a regulatory effect of estradiol on ACE2 expression was demonstrated by removing the gonads and then supplementing with estradiol [906,908].
+Other work in mice has shown an inverse association between mortality due to SARS-CoV-1 and estradiol, suggesting a protective role for the sex hormone [906].
Similarly, evidence suggests that similar patterns might be found in other tissues.
-A preliminary analysis identified higher levels of ACE2 expression in the myocardium of male patients with aortic valve stenosis showed than female patients, although this pattern was not found in controls [903].
-Additionally, research has indicated that females respond to lower doses than males of heart medications that act on the Renin angiotensin aldosterone system (RAAS) pathway, which is shared with ACE2 [903].
-Additionally, several components of the immune response, including the inflammatory response, may differ in intensity and timing between males and females [905,907].
-This hypothesis is supported by some preliminary evidence showing that female patients who recovered from severe COVID-19 had higher antibody titers than males [905].
-Sex steroids can also bind to immune cell receptors to influence cytokine production [903].
-Additionally, social factors may influence risks related to both age and sex: for example, older adults are more likely to live in care facilities, which have been a source for a large number of outbreaks [908], and gender roles may also influence exposure and/or susceptibility due to differences in care-taking and/or risky behaviors (e.g., caring for elder relatives and smoking, respectively) [903] among men and women (however, it should be noted that both transgender men and women are suspected to be at heightened risk [909].)
+A preliminary analysis identified higher levels of ACE2 expression in the myocardium of male patients with aortic valve stenosis showed than female patients, although this pattern was not found in controls [904].
+Additionally, research has indicated that females respond to lower doses than males of heart medications that act on the Renin angiotensin aldosterone system (RAAS) pathway, which is shared with ACE2 [904].
+Additionally, several components of the immune response, including the inflammatory response, may differ in intensity and timing between males and females [906,908].
+This hypothesis is supported by some preliminary evidence showing that female patients who recovered from severe COVID-19 had higher antibody titers than males [906].
+Sex steroids can also bind to immune cell receptors to influence cytokine production [904].
+Additionally, social factors may influence risks related to both age and sex: for example, older adults are more likely to live in care facilities, which have been a source for a large number of outbreaks [909], and gender roles may also influence exposure and/or susceptibility due to differences in care-taking and/or risky behaviors (e.g., caring for elder relatives and smoking, respectively) [904] among men and women (however, it should be noted that both transgender men and women are suspected to be at heightened risk [910].)
8.2.2 Comorbid Health Conditions
A number of pre-existing or comorbid conditions have repeatedly been identified as risk factors for more severe COVID-19 outcomes.
-Several underlying health conditions were identified at high prevalence among hospitalized patients, including obesity, diabetes, hypertension, lung disease, and cardiovascular disease [896].
-Higher Sequential Organ Failure Assessment (SOFA) scores have been associated with a higher probability of mortality [35], and comorbid conditions such as cardiovascular and lung disease as well as obesity were also associated with an increased risk of hospitalization and death, even when correcting for age and sex [902].
-Diabetes may increase the risk of lengthy hospitalization [910] or of death [910,911].
-[912] and [913] discuss possible ways in which COVID-19 and diabetes may interact.
-Obesity also appears to be associated with higher risk of severe outcomes from SARS-CoV-2 [914,915].
-Obesity is considered an underlying risk factor for other health problems, and the mechanism for its contributions to COVID-19 hospitalization or mortality is not yet clear [916].
-Dementia and cancer were also associated with the risk of death in an analysis of a large number (more than 20,000) COVID-19 patients in the United Kingdom [902].
-It should be noted that comorbid conditions are inextricably tied to age, as conditions tend to be accumulated over time, but that the prevalence of individual comorbidities or of population health overall can vary regionally [917].
-Several comorbidities that are highly prevalent in older adults, such as COPD, hypertension, cardiovascular disease, and diabetes, have been associated with CFRs upwards of 8% compared to an estimate of 1.4% in people without comorbidities [901,918].
-Therefore, both age and health are important considerations when predicting the impact of COVID-19 on a population [917].
-However, other associations may exist, such as patients with sepsis having higher SOFA scores – in fact, SOFA was developed for the assessment of organ failure in the context of sepsis, and the acronym originally stood for Sepsis-Related Organ Failure Assessment [919,920].
+Several underlying health conditions were identified at high prevalence among hospitalized patients, including obesity, diabetes, hypertension, lung disease, and cardiovascular disease [897].
+Higher Sequential Organ Failure Assessment (SOFA) scores have been associated with a higher probability of mortality [37], and comorbid conditions such as cardiovascular and lung disease as well as obesity were also associated with an increased risk of hospitalization and death, even when correcting for age and sex [903].
+Diabetes may increase the risk of lengthy hospitalization [911] or of death [911,912].
+[913] and [914] discuss possible ways in which COVID-19 and diabetes may interact.
+Obesity also appears to be associated with higher risk of severe outcomes from SARS-CoV-2 [915,916].
+Obesity is considered an underlying risk factor for other health problems, and the mechanism for its contributions to COVID-19 hospitalization or mortality is not yet clear [917].
+Dementia and cancer were also associated with the risk of death in an analysis of a large number (more than 20,000) COVID-19 patients in the United Kingdom [903].
+It should be noted that comorbid conditions are inextricably tied to age, as conditions tend to be accumulated over time, but that the prevalence of individual comorbidities or of population health overall can vary regionally [918].
+Several comorbidities that are highly prevalent in older adults, such as COPD, hypertension, cardiovascular disease, and diabetes, have been associated with CFRs upwards of 8% compared to an estimate of 1.4% in people without comorbidities [902,919].
+Therefore, both age and health are important considerations when predicting the impact of COVID-19 on a population [918].
+However, other associations may exist, such as patients with sepsis having higher SOFA scores – in fact, SOFA was developed for the assessment of organ failure in the context of sepsis, and the acronym originally stood for Sepsis-Related Organ Failure Assessment [920,921].
Additionally, certain conditions are likely to be more prevalent under or exacerbated by social conditions, especially poverty, as is discussed further below.
8.2.3 Ancestry
A number of studies have suggested associations between individuals’ racial and ethnic backgrounds and their COVID-19 risk.
-In particular, Black Americans are consistently identified as carrying a higher burden of COVID-19 than white Americans [898,899], with differences in the rates of kidney complications from COVID-19 particularly pronounced [94].
-Statistics from a number of cities indicate significant discrepancies between the proportion of COVID-19 cases and deaths in Black Americans relative to their representation in the general population [921].
-In addition to Black Americans, disproportionate harm and mortality from COVID-19 has also been noted in Latino/Hispanic Americans and in Native American and Alaskan Native communities, including the Navajo nation [922,923,924,925,926,927].
-In Brazil, indigenous communities likewise carry an increased burden of COVID-19 [928].
-In the United Kingdom, nonwhite ethnicity (principally Black or South Asian) was one of several factors found to be associated with a higher risk of death from COVID-19 [929].
+In particular, Black Americans are consistently identified as carrying a higher burden of COVID-19 than white Americans [899,900], with differences in the rates of kidney complications from COVID-19 particularly pronounced [96].
+Statistics from a number of cities indicate significant discrepancies between the proportion of COVID-19 cases and deaths in Black Americans relative to their representation in the general population [922].
+In addition to Black Americans, disproportionate harm and mortality from COVID-19 has also been noted in Latino/Hispanic Americans and in Native American and Alaskan Native communities, including the Navajo nation [923,924,925,926,927,928].
+In Brazil, indigenous communities likewise carry an increased burden of COVID-19 [929].
+In the United Kingdom, nonwhite ethnicity (principally Black or South Asian) was one of several factors found to be associated with a higher risk of death from COVID-19 [930].
From a genetic standpoint, it is highly unlikely that ancestry itself predisposes individuals to contracting COVID-19 or to experiencing severe COVID-19 outcomes.
-Examining human genetic diversity indicates variation over a geographic continuum, and that most human genetic variation is associated with the African continent [930].
-African-Americans are also a more genetically diverse group relative to European-Americans, with a large number of rare alleles and a much smaller fraction of common alleles identified in African-Americans [931].
-Therefore, the idea that African ancestry (at the continent level) might convey some sort of genetic risk for severe COVID-19 contrasts with what is known about worldwide human genetic diversity [932].
+Examining human genetic diversity indicates variation over a geographic continuum, and that most human genetic variation is associated with the African continent [931].
+African-Americans are also a more genetically diverse group relative to European-Americans, with a large number of rare alleles and a much smaller fraction of common alleles identified in African-Americans [932].
+Therefore, the idea that African ancestry (at the continent level) might convey some sort of genetic risk for severe COVID-19 contrasts with what is known about worldwide human genetic diversity [933].
The possibility for genetic variants that confer some risk or some protection remains possible, but has not been widely explored, especially at a global level.
-Research in Beijing of a small number (n=80) hospitalized COVID-19 patients revealed an association between severe COVID-19 outcomes and homozygosity for an allele in the interferon-induced transmembrane protein 3 (IFITM3) gene, which was selected as a candidate because it was previously found to be associated with influenza outcomes in Chinese patients [933].
-Genetic factors may also play a role in the risk of respiratory failure for COVID-19 [934,935,936].
+Research in Beijing of a small number (n=80) hospitalized COVID-19 patients revealed an association between severe COVID-19 outcomes and homozygosity for an allele in the interferon-induced transmembrane protein 3 (IFITM3) gene, which was selected as a candidate because it was previously found to be associated with influenza outcomes in Chinese patients [934].
+Genetic factors may also play a role in the risk of respiratory failure for COVID-19 [935,936,937].
However, genetic variants associated with outcomes within ancestral groups are far less surprising than genetic variants explaining outcomes between groups.
-Alleles in ACE2 and TMPRSS2 have been identified that vary in frequency among ancestral groups [937], but whether these variants are associated with COVID-19 susceptibility has not been explored.
+Alleles in ACE2 and TMPRSS2 have been identified that vary in frequency among ancestral groups [938], but whether these variants are associated with COVID-19 susceptibility has not been explored.
Instead, examining patterns of COVID-19 susceptibility on a global scale that suggest that social factors are of primary importance in predicting mortality.
Reports from several sub-Saharan African countries have indicated that the effects of the COVID-19 pandemic have been less severe than expected based on the outbreaks in China and Italy.
-In Kenya, for example, estimates of national prevalence based on testing blood donors for SARS-CoV-2 antibodies were consistent with 5% of Kenyan adults having recovered from COVID-19 [938].
-This high seroprevalence of antibodies lies in sharp contrast to the low number of COVID-19 fatalities in Kenya, which at the time was 71 out of 2093 known cases [938].
-Likewise, a serosurvey of health care workers in Blantyre City, Malawi reported an adjusted antibody prevalence of 12.3%, suggesting that the virus had been circulating more widely than thought and that the death rate was up eight times lower than models had predicted [939].
-While several possible hypotheses for the apparent reduced impact of COVID-19 on the African continent are being explored, such as young demographics in many places [940], these reports present a stark contrast to the severity of COVID-19 in Americans and Europeans of African descent.
-Additionally, ethnic minorities in the United Kingdom also tend to be younger than white British living in the same areas, yet the burden of COVID-19 is still more serious for minorities, especially people of Black Caribbean ancestry, both in absolute numbers and when controlling for age and location [941].
+In Kenya, for example, estimates of national prevalence based on testing blood donors for SARS-CoV-2 antibodies were consistent with 5% of Kenyan adults having recovered from COVID-19 [939].
+This high seroprevalence of antibodies lies in sharp contrast to the low number of COVID-19 fatalities in Kenya, which at the time was 71 out of 2093 known cases [939].
+Likewise, a serosurvey of health care workers in Blantyre City, Malawi reported an adjusted antibody prevalence of 12.3%, suggesting that the virus had been circulating more widely than thought and that the death rate was up eight times lower than models had predicted [940].
+While several possible hypotheses for the apparent reduced impact of COVID-19 on the African continent are being explored, such as young demographics in many places [941], these reports present a stark contrast to the severity of COVID-19 in Americans and Europeans of African descent.
+Additionally, ethnic minorities in the United Kingdom also tend to be younger than white British living in the same areas, yet the burden of COVID-19 is still more serious for minorities, especially people of Black Caribbean ancestry, both in absolute numbers and when controlling for age and location [942].
Furthermore, the groups in the United States and United Kingdom that have been identified as carrying elevated COVID-19 burden, namely Black American, indigenous American, and Black and South Asian British, are quite distinct in their position on the human ancestral tree.
What is shared across these groups is instead a history of disenfranchisement under colonialism and ongoing systematic racism.
-A large analysis of over 11,000 COVID-19 patients hospitalized in 92 hospitals across U.S. states revealed that Black patients were younger, more often female, more likely to be on Medicaid, more likely to have comorbidities, and came from neighborhoods identified as more economically deprived than white patients [893].
+A large analysis of over 11,000 COVID-19 patients hospitalized in 92 hospitals across U.S. states revealed that Black patients were younger, more often female, more likely to be on Medicaid, more likely to have comorbidities, and came from neighborhoods identified as more economically deprived than white patients [894].
This study reported that when these factors were accounted for, the differences in mortality between Black and white patients were no longer significant.
Thus, the current evidence suggests that the apparent correlations between ancestry and health outcomes must be examined in the appropriate social context.
8.3 Environmental Influences on Susceptibility
@@ -2906,83 +2907,83 @@ .
-A linear relationship was observed between counties’ reduction in mobility and their wealth and health, as measured by access to health care, food security, income, space, and other factors [942].
-Counties with greater reductions in mobility were also found to have much lower child poverty and household crowding and to be more racially segregated, and to have fewer youth and more elderly residents [942].
-Similar associations between wealth and decreased mobility were observed in cellphone GPS data from Colombia, Indonesia, and Mexico collected between January and May 2020 [943], as well as in a very large data set from several US cities [944].
+In U.S. counties with and without stay-at-home orders, smartphone tracking indicated a significant decrease in the general population’s mobility in April relative to February through March of 2020 (-52.3% and -60.8%, respectively) [943].
+A linear relationship was observed between counties’ reduction in mobility and their wealth and health, as measured by access to health care, food security, income, space, and other factors [943].
+Counties with greater reductions in mobility were also found to have much lower child poverty and household crowding and to be more racially segregated, and to have fewer youth and more elderly residents [943].
+Similar associations between wealth and decreased mobility were observed in cellphone GPS data from Colombia, Indonesia, and Mexico collected between January and May 2020 [944], as well as in a very large data set from several US cities [945].
These disparities in mobility are likely to be related to the role that essential workers have played during the pandemic.
-Essential workers are disproportionately likely to be female, people of color, immigrants, and to have an income below 200% of the poverty line [945].
-Black Americans in particular are over-represented among front-line workers and in professions where social distancing is infeasible [946].
-Health care work in particular presents an increased risk of exposure to SARS-CoV-2 [946,947,948,949,950].
-In the United Kingdom, (South) Asians are more likely than their white counterparts to be medical professionals [941], although BAME medical professionals are still disproportionately represented in the proportion of National Health Service staff deaths [951].
-Similar trends have been reported for nurses, especially nurses of color, in the United States [952].
-Furthermore, beyond the risks associated with work itself, use of public transportation may also impact COVID-19 risk [953].
+Essential workers are disproportionately likely to be female, people of color, immigrants, and to have an income below 200% of the poverty line [946].
+Black Americans in particular are over-represented among front-line workers and in professions where social distancing is infeasible [947].
+Health care work in particular presents an increased risk of exposure to SARS-CoV-2 [947,948,949,950,951].
+In the United Kingdom, (South) Asians are more likely than their white counterparts to be medical professionals [942], although BAME medical professionals are still disproportionately represented in the proportion of National Health Service staff deaths [952].
+Similar trends have been reported for nurses, especially nurses of color, in the United States [953].
+Furthermore, beyond the risks associated with work itself, use of public transportation may also impact COVID-19 risk [954].
The socioeconomic and racial/ethnic gaps in who is working on the front lines of the pandemic make it clear that socioeconomic privilege is likely to decrease the probability of exposure to SARS-CoV-2.
Increased risk of exposure can also arise outside the workplace.
-Nursing homes and skilled nursing facilities received attention early on as high-risk locations for COVID-19 outbreaks [954].
-Prisons and detention centers also confer a high risk of exposure or infection [955,956].
-Populations in care facilities are largely older adults, and in the United States, incarcerated people are more likely to be male and persons of color, especially Black [957].
-Additionally, multi-generational households are less common among non-Hispanic white Americans than people of other racial and ethnic backgrounds [958], increasing the risk of exposure for more susceptible family members.
-Analysis suggests that household crowding may also be associated with increased risk of COVID-19 exposure [942], and household crowding is associated with poverty [959].
-Forms of economic insecurity like housing insecurity, which is associated with poverty and more pronounced in communities subjected to racism [960,961], would be likely to increase household crowding and other possible sources of exposure.
+Nursing homes and skilled nursing facilities received attention early on as high-risk locations for COVID-19 outbreaks [955].
+Prisons and detention centers also confer a high risk of exposure or infection [956,957].
+Populations in care facilities are largely older adults, and in the United States, incarcerated people are more likely to be male and persons of color, especially Black [958].
+Additionally, multi-generational households are less common among non-Hispanic white Americans than people of other racial and ethnic backgrounds [959], increasing the risk of exposure for more susceptible family members.
+Analysis suggests that household crowding may also be associated with increased risk of COVID-19 exposure [943], and household crowding is associated with poverty [960].
+Forms of economic insecurity like housing insecurity, which is associated with poverty and more pronounced in communities subjected to racism [961,962], would be likely to increase household crowding and other possible sources of exposure.
As a result, facets of systemic inequality such as mass incarceration of Black Americans and poverty are likely to increase the risk of exposure outside of the workplace.
8.3.2 Severity of COVID-19 Following Exposure
Following exposure to SARS-CoV-2, the likelihood that an individual develops COVID-19 and the severity of the disease presentation can be influenced by a number of social factors.
As discussed above, a number of patient characteristics are associated with the likelihood of severe COVID-19 symptoms.
-In some cases, these trends run counter to those expected given rates of exposure: for example, although women are more likely to be exposed, men are more likely to be diagnosed with, hospitalized from, or die from COVID-19 [905].
+In some cases, these trends run counter to those expected given rates of exposure: for example, although women are more likely to be exposed, men are more likely to be diagnosed with, hospitalized from, or die from COVID-19 [906].
In the case of comorbid conditions and racial/ethnic demographics, however, social factors are highly likely to modulate or at least influence the apparent association between these traits and the increased risk from COVID-19.
In particular, the comorbidities and racial/ethnic correlates of severe COVID-19 outcomes suggest that poverty confers additional risk for COVID-19.
In order to explore the relationship between poverty and COVID-19 outcomes, it is necessary to consider how poverty impacts biology.
In particular, we focus on the United States and the United Kingdom.
-Comorbidities that increase risk for COVID-19, including obesity, type II diabetes, hypertension, and cardiovascular disease, are known to be intercorrelated [962].
-Metabolic conditions related to heightened inflammation, like obesity, type II diabetes, and hypertension, are more strongly associated with negative COVID-19 outcomes than other comorbid conditions, such as chronic heart disease [963].
+Comorbidities that increase risk for COVID-19, including obesity, type II diabetes, hypertension, and cardiovascular disease, are known to be intercorrelated [963].
+Metabolic conditions related to heightened inflammation, like obesity, type II diabetes, and hypertension, are more strongly associated with negative COVID-19 outcomes than other comorbid conditions, such as chronic heart disease [964].
As discussed above, dysregulated inflammation characteristic of cytokine release syndrome is one of the greatest concerns for COVID-19-related death.
-Therefore, it is possible that chronic inflammation characteristic of these metabolic conditions predisposes patients to COVID-19-related death [963].
-The association between these diseases and severe COVID-19 outcomes is a concern from a health equity perspective because poverty exposes people to “obesogenic” conditions [964] and is therefore unsurprisingly associated with higher incidence of obesity and associated disorders [965].
-Furthermore, cell phone GPS data suggests that lower socioeconomic status may also be associated with decreased access to healthy food choices during the COVID-19 pandemic [966,967], suggesting that health-related risk factors for COVID-19 may be exacerbated as the pandemic continues [968].
-Chronic inflammation is a known outcome of chronic stress (e.g., [969,970,971,972]).
-Therefore, the chronic stress of poverty is likely to influence health broadly (as summarized in [973]) and especially during the stress of the ongoing pandemic.
-A preprint [974] provided observational evidence that geographical areas in the United States that suffer from worse air pollution by fine particulate matter have also suffered more COVID-19 deaths per capita, after adjusting for demographic covariates.
-Although lack of individual-level exposure data and the impossibility of randomization make it difficult to elucidate the exact causal mechanism, this finding would be consistent with similar findings for all-cause mortality (e.g., [975]).
-Exposure to air pollution is associated with both poverty (e.g., [976]) and chronic inflammation [977].
-Other outcomes of environmental racism, such as the proximity of abandoned uranium mines to Navajo land, can also cause respiratory illnesses and other health issues [927].
-Similarly, preliminary findings indicate that nutritional status (e.g., vitamin D deficiency [719]) may be associated with COVID-19 outcomes, and reduced access to grocery stores and fresh food often co-occurs with environmental racism [927,978].
+Therefore, it is possible that chronic inflammation characteristic of these metabolic conditions predisposes patients to COVID-19-related death [964].
+The association between these diseases and severe COVID-19 outcomes is a concern from a health equity perspective because poverty exposes people to “obesogenic” conditions [965] and is therefore unsurprisingly associated with higher incidence of obesity and associated disorders [966].
+Furthermore, cell phone GPS data suggests that lower socioeconomic status may also be associated with decreased access to healthy food choices during the COVID-19 pandemic [967,968], suggesting that health-related risk factors for COVID-19 may be exacerbated as the pandemic continues [969].
+Chronic inflammation is a known outcome of chronic stress (e.g., [970,971,972,973]).
+Therefore, the chronic stress of poverty is likely to influence health broadly (as summarized in [974]) and especially during the stress of the ongoing pandemic.
+A preprint [975] provided observational evidence that geographical areas in the United States that suffer from worse air pollution by fine particulate matter have also suffered more COVID-19 deaths per capita, after adjusting for demographic covariates.
+Although lack of individual-level exposure data and the impossibility of randomization make it difficult to elucidate the exact causal mechanism, this finding would be consistent with similar findings for all-cause mortality (e.g., [976]).
+Exposure to air pollution is associated with both poverty (e.g., [977]) and chronic inflammation [978].
+Other outcomes of environmental racism, such as the proximity of abandoned uranium mines to Navajo land, can also cause respiratory illnesses and other health issues [928].
+Similarly, preliminary findings indicate that nutritional status (e.g., vitamin D deficiency [720]) may be associated with COVID-19 outcomes, and reduced access to grocery stores and fresh food often co-occurs with environmental racism [928,979].
Taken together, the evidence suggests that low-income workers who face greater exposure to SARS-CoV-2 due to their home or work conditions are also more likely to face environmental and social stressors associated with increased inflammation, and therefore with increased risk from COVID-19.
In particular, structural racism can play an important role on disease severity after SARS-CoV-2 exposure, due to consequences of racism which include an increased likelihood of poverty and its associated food and housing instability.
-COVID-19 can thus be considered a “syndemic”, or a synergistic interaction between several epidemics [979].
+COVID-19 can thus be considered a “syndemic”, or a synergistic interaction between several epidemics [980].
As a result, it is not surprising that people from minoritized backgrounds and/or with certain pre-existing conditions are more likely to suffer severe effects of COVID-19, but these “risk factors” are likely to be causally linked to poverty.
8.3.3 Access to Treatment
Finally, COVID-19 outcomes can be influenced by access to healthcare.
Receiving care for COVID-19 can, but does not always, include receiving a positive test for the SARS-CoV-2 virus.
-For example, it is common to see treatment guidelines for suspected cases regardless of whether the presence of SARS-CoV-2 has been confirmed (e.g., [980]).
+For example, it is common to see treatment guidelines for suspected cases regardless of whether the presence of SARS-CoV-2 has been confirmed (e.g., [981]).
Whether and where a patient is diagnosed can depend on their access to testing, which can vary both between and within countries.
-In the United States, it is not always clear whether an individual will have access to free testing [981,982].
-The concern has been raised that more economic privilege is likely to correspond to increased access to testing, at least within the United States [983].
-This is supported by the fact that African Americans seem to be more likely to be diagnosed in the hospital, while individuals from other groups were more likely to have been diagnosed in ambulatory settings in the community [898].
-Any delays in treatment are a cause for concern [983], which could potentially be increased by an inability to acquire testing because in the United States, insurance coverage for care received can depend on a positive test [984].
+In the United States, it is not always clear whether an individual will have access to free testing [982,983].
+The concern has been raised that more economic privilege is likely to correspond to increased access to testing, at least within the United States [984].
+This is supported by the fact that African Americans seem to be more likely to be diagnosed in the hospital, while individuals from other groups were more likely to have been diagnosed in ambulatory settings in the community [899].
+Any delays in treatment are a cause for concern [984], which could potentially be increased by an inability to acquire testing because in the United States, insurance coverage for care received can depend on a positive test [985].
Another important question is whether patients with moderate to severe cases are able to access hospital facilities and treatments, to the extent that they have been identified.
-Early findings from China as of February 2020 suggested the COVID-19 mortality rate to be much lower in the most developed regions of the country [985], although reported mortality is generally an estimate of CFR, which is dependent on rates of testing.
-Efforts to make treatment accessible for all confirmed and suspected cases of COVID-19 in China are credited with expanding care to people with fewer economic resources [986].
-In the United States, access to healthcare varies widely, with certain sectors of the workforce less likely to have health insurance; many essential workers in transportation, food service, and other frontline fields are among those likely to be uninsured or underinsured [983].
-As of 2018, Hispanic Americans of all races were much less likely to have health insurance than people from non-Hispanic backgrounds [987].
+Early findings from China as of February 2020 suggested the COVID-19 mortality rate to be much lower in the most developed regions of the country [986], although reported mortality is generally an estimate of CFR, which is dependent on rates of testing.
+Efforts to make treatment accessible for all confirmed and suspected cases of COVID-19 in China are credited with expanding care to people with fewer economic resources [987].
+In the United States, access to healthcare varies widely, with certain sectors of the workforce less likely to have health insurance; many essential workers in transportation, food service, and other frontline fields are among those likely to be uninsured or underinsured [984].
+As of 2018, Hispanic Americans of all races were much less likely to have health insurance than people from non-Hispanic backgrounds [988].
Therefore, access to diagnostics and care prior to the development of severe COVID-19 is likely to vary depending on socioeconomic and social factors, many of which overlap with the risks of exposure and of developing more severe COVID-19 symptoms.
This discrepancy ties into concerns about broad infrastructural challenges imposed by COVID-19.
-A major concern in many countries has been the saturation of healthcare systems due to the volume of COVID-19 hospitalizations (e.g., [240]).
-Similarly, there have been shortages of supplies such as ventilators that are critical to the survival of many COVID-19 patients, leading to extensive ethical discussions about how to allocate limited resources among patients [988,989,990,991].
-Although it is generally considered unethical to consider demographic factors such as age, sex, race, or ethnicity while making such decisions, and ideally this information would not be shared with triage teams tasked with allocating limited resources among patients [992], there are substantial concerns about implicit and explicit biases against older adults [993], premature infants [994], and people with disabilities or comorbidities [992,995,996].
-Because of the greater burden of chronic disease in populations subjected to systemic racism, algorithms intended to be blind to race and ethnicity could, in fact, reinforce systemic inequalities caused by structural racism [997,998,999].
-Because of this inequality, it has been argued that groups facing health disparities should be prioritized by these algorithms [1000].
-This approach would carry its own ethical concerns, including the fact that many resources that need to be distributed do not have well-established risks and benefits [1000].
-As the pandemic has progressed, it has become clear that ICU beds and ventilators are not the only limited resources that needs to be allocated, and, in fact, the survival rate for patients who receive mechanical ventilation is lower than these discussions would suggest [1001].
-Allocation of interventions that may reduce suffering, including palliative care, has become critically important [1001,1002].
-The ambiguities surrounding the risks and benefits associated with therapeutics that have been approved under emergency use authorizations also present ethical concerns related to the distribution of resources [1000].
-For example, remdesivir, discussed above, is currently available for the treatment of COVID-19 under compassionate use guidelines and through expanded access programs, and in many cases has been donated to hospitals by Gilead [1003,1004].
-Regulations guiding the distribution of drugs in situations like these typically do not address how to determine which patients receive them [1004].
-Prioritizing marginalized groups for treatment with a drug like remdesivir would also be unethical because it would entail disproportionately exposing these groups to a therapeutic that may or not be beneficial [1000].
+A major concern in many countries has been the saturation of healthcare systems due to the volume of COVID-19 hospitalizations (e.g., [242]).
+Similarly, there have been shortages of supplies such as ventilators that are critical to the survival of many COVID-19 patients, leading to extensive ethical discussions about how to allocate limited resources among patients [989,990,991,992].
+Although it is generally considered unethical to consider demographic factors such as age, sex, race, or ethnicity while making such decisions, and ideally this information would not be shared with triage teams tasked with allocating limited resources among patients [993], there are substantial concerns about implicit and explicit biases against older adults [994], premature infants [995], and people with disabilities or comorbidities [993,996,997].
+Because of the greater burden of chronic disease in populations subjected to systemic racism, algorithms intended to be blind to race and ethnicity could, in fact, reinforce systemic inequalities caused by structural racism [998,999,1000].
+Because of this inequality, it has been argued that groups facing health disparities should be prioritized by these algorithms [1001].
+This approach would carry its own ethical concerns, including the fact that many resources that need to be distributed do not have well-established risks and benefits [1001].
+As the pandemic has progressed, it has become clear that ICU beds and ventilators are not the only limited resources that needs to be allocated, and, in fact, the survival rate for patients who receive mechanical ventilation is lower than these discussions would suggest [1002].
+Allocation of interventions that may reduce suffering, including palliative care, has become critically important [1002,1003].
+The ambiguities surrounding the risks and benefits associated with therapeutics that have been approved under emergency use authorizations also present ethical concerns related to the distribution of resources [1001].
+For example, remdesivir, discussed above, is currently available for the treatment of COVID-19 under compassionate use guidelines and through expanded access programs, and in many cases has been donated to hospitals by Gilead [1004,1005].
+Regulations guiding the distribution of drugs in situations like these typically do not address how to determine which patients receive them [1005].
+Prioritizing marginalized groups for treatment with a drug like remdesivir would also be unethical because it would entail disproportionately exposing these groups to a therapeutic that may or not be beneficial [1001].
On the other hand, given that the drug is one of the most promising treatments available for many patients, using a framework that tacitly feeds into structural biases would also be unethical.
-At present, the report prepared for the Director of the CDC by Ethics Subcommittee of the CDC fails to address the complexity of this ethical question given the state of structural racism in the United States, instead stating that “prioritizing individuals according to their chances for short-term survival also avoids ethically irrelevant considerations, such as race or socioeconomic status” [1005].
-In many cases, experimental therapeutics are made available only through participation in clinical trials [1006].
-However, given the history of medical trials abusing minority communities, especially Black Americans, there is a history of unequal representation in clinical trial enrollment [1006].
+At present, the report prepared for the Director of the CDC by Ethics Subcommittee of the CDC fails to address the complexity of this ethical question given the state of structural racism in the United States, instead stating that “prioritizing individuals according to their chances for short-term survival also avoids ethically irrelevant considerations, such as race or socioeconomic status” [1006].
+In many cases, experimental therapeutics are made available only through participation in clinical trials [1007].
+However, given the history of medical trials abusing minority communities, especially Black Americans, there is a history of unequal representation in clinical trial enrollment [1007].
As a result, the standard practice of requiring enrollment in a clinical trial in order to receive experimental treatment may also reinforce patterns established by systemic racism.
8.3.4 Access to and Representation in Clinical Trials
@@ -2999,7 +3000,7 @@ [1007]
.
+The WHO Director‐General Tedros Adhanom Ghebreyesus stated his condemnation of utilizing low and middle income countries as test subjects for clinical trials, yet having highly developed countries as the majority of clinical trial representation is also not the answer [1008].
Figure 6 showcases two choropleths detailing COVID-19 clinical trial recruitment by country.
China, the United States, and France are among the countries with the most clinical trial recruiting for trials with single-country enrollment.
Many countries have little to no clinical trial recruiting, with the continents of Africa and South America much less represented than Asia, Europe, and North America.
@@ -3008,46 +3009,46 @@
Figure 6: Geographic distribution of COVID-19 clinical trials.
The density of clinical trials is reported at the country level.
-As of November 9, 2020, there are 6,417 trials in the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [371].
+As of November 9, 2020, there are 6,417 trials in the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [372].
The top figure demonstrates the density of trials recruiting only from a singular country, while the bottom shows the distribution of recruitment for trials that involve more than one country.
A few different concerns arise from this skewed geographic representation in clinical trial recruitment.
First, treatments such as remdesivir that are promising but primarily available to clinical trial participants are unlikely to be accessible by people in many countries.
Second, it raises the concern that the findings of clinical trials will be based on participants from many of the wealthiest countries, which may lead to ambiguity in whether the findings can be extrapolated to COVID-19 patients elsewhere.
-Especially with the global nature of COVID-19, equitable access to therapeutics and vaccines has been a concern at the forefront of many discussions about policy (e.g., [1008], yet data like that shown in Figure 6 demonstrates that accessibility is likely to be a significant issue.
-Another concern with the heterogeneous international distribution of clinical trials is that the governments of countries leading these clinical trials might prioritize their own populations once vaccines are developed, causing unequal health outcomes [1009].
-Additionally, even within a single state in the United States (Maryland), geography was found to influence the likelihood of being recruited into or enrolled in a clinical trial, with patients in under-served rural areas less likely to enroll [1010].
+Especially with the global nature of COVID-19, equitable access to therapeutics and vaccines has been a concern at the forefront of many discussions about policy (e.g., [1009], yet data like that shown in Figure 6 demonstrates that accessibility is likely to be a significant issue.
+Another concern with the heterogeneous international distribution of clinical trials is that the governments of countries leading these clinical trials might prioritize their own populations once vaccines are developed, causing unequal health outcomes [1010].
+Additionally, even within a single state in the United States (Maryland), geography was found to influence the likelihood of being recruited into or enrolled in a clinical trial, with patients in under-served rural areas less likely to enroll [1011].
Thus, geography both on the global and local levels may influence when treatments and vaccines are available and who is able to access them.
-Efforts such as the African Union’s efforts to coordinate and promote vaccine development [1011] are therefore critical to promoting equity in the COVID-19 response.
+Efforts such as the African Union’s efforts to coordinate and promote vaccine development [1012] are therefore critical to promoting equity in the COVID-19 response.
Even when patients are located within the geographic recruitment area of clinical trials, however, there can still be demographic inequalities in enrollment.
-When efforts are made to ensure equal opportunity to participate in clinical trials, there is no significant difference in participation among racial/ethnic groups [1012].
-However, within the United States, real clinical trial recruitment numbers have indicated for many years that racial minorities, especially African-Americans, tend to be under-represented (e.g., [1013,1014,1015,1016]).
+When efforts are made to ensure equal opportunity to participate in clinical trials, there is no significant difference in participation among racial/ethnic groups [1013].
+However, within the United States, real clinical trial recruitment numbers have indicated for many years that racial minorities, especially African-Americans, tend to be under-represented (e.g., [1014,1015,1016,1017]).
This trend is especially concerning given the disproportionate impact of COVID-19 on African-Americans.
-Early evidence suggests that the proportion of Black, Latinx, and Native American participants in clinical trials for drugs such as remdesivir is much lower than the representation of these groups among COVID-19 patients [1017].
+Early evidence suggests that the proportion of Black, Latinx, and Native American participants in clinical trials for drugs such as remdesivir is much lower than the representation of these groups among COVID-19 patients [1018].
One proposed explanation for differences among racial and ethnic groups in clinical trial enrollment refers to different experiences in healthcare settings.
-While some plausible reasons for the disparity in communication between physicians and patients could be a lack of awareness and education, mistrust in healthcare professionals, and a lack of health insurance [1012], a major concern is that patients from certain racial and ethnic groups are marginalized even while seeking healthcare.
-In the United States, many patients experience “othering” from physicians and other medical professionals due to their race or other external characteristics such as gender (e.g., [1018]).
+While some plausible reasons for the disparity in communication between physicians and patients could be a lack of awareness and education, mistrust in healthcare professionals, and a lack of health insurance [1013], a major concern is that patients from certain racial and ethnic groups are marginalized even while seeking healthcare.
+In the United States, many patients experience “othering” from physicians and other medical professionals due to their race or other external characteristics such as gender (e.g., [1019]).
Many studies have sought to characterize implicit biases in healthcare providers and whether they affect their perceptions or treatment of patients.
-A systematic review that examined 37 such studies reported that most (31) identified racial and/or ethnic biases in healthcare providers in many different roles, although the evidence about whether these biases translated to different attitudes towards patients was mixed [1019], with similar findings reported by a second systematic review [1020].
-However, data about real-world patient outcomes are very limited, with most studies relying on clinical vignette-based exercises [1019], and other analyses suggest that physician implicit bias could impact the patient’s perception of the negativity/positivity of the interaction regardless of the physician’s explicit behavior towards the patient [1021].
-Because racism is a common factor in both, negative patient experiences with medical professionals are likely to compound other issues of systemic inequality, such as a lack of access to adequate care, a lack of insurance, or increased exposure to SARS-CoV-2 [1022].
+A systematic review that examined 37 such studies reported that most (31) identified racial and/or ethnic biases in healthcare providers in many different roles, although the evidence about whether these biases translated to different attitudes towards patients was mixed [1020], with similar findings reported by a second systematic review [1021].
+However, data about real-world patient outcomes are very limited, with most studies relying on clinical vignette-based exercises [1020], and other analyses suggest that physician implicit bias could impact the patient’s perception of the negativity/positivity of the interaction regardless of the physician’s explicit behavior towards the patient [1022].
+Because racism is a common factor in both, negative patient experiences with medical professionals are likely to compound other issues of systemic inequality, such as a lack of access to adequate care, a lack of insurance, or increased exposure to SARS-CoV-2 [1023].
Furthermore, the experience of being othered is not only expected to impact patients’ trust in and comfort with their provider, but also may directly impact whether or not the patient is offered the opportunity to participate in a clinical trial at all.
Some studies suggest communication between physicians and patients impacts whether or not a physician offers a patient participation in a clinical trial.
-For example, researchers utilized a linguistic analysis to assess mean word count of phrases related to clinical trial enrollment, such as voluntary participation, clinical trial, etc. [1012].
+For example, researchers utilized a linguistic analysis to assess mean word count of phrases related to clinical trial enrollment, such as voluntary participation, clinical trial, etc. [1013].
The data indicated that the mean word count of the entire visit was 1.5 times more for white patients in comparison to Black patients.
-In addition, the greatest disparity between white and Black patients’ experience was the discussion of risks, with over 2 times as many risk-related words spoken with white patients than Black patients [1012].
+In addition, the greatest disparity between white and Black patients’ experience was the discussion of risks, with over 2 times as many risk-related words spoken with white patients than Black patients [1013].
The trends observed for other clinical trials raise the concern that COVID-19 clinical trial information may not be discussed as thoroughly or as often with Black patients compared to white patients.
These discrepancies are especially concerning given that many COVID-19 treatments are being or are considered being made available to patients prior to FDA approval through Emergency Use Authorizations.
-In the past, African-Americans have been over-represented relative to national demographics in use of the FDA’s Exception From Informed Consent (EFIC) pathway [1023].
+In the past, African-Americans have been over-represented relative to national demographics in use of the FDA’s Exception From Informed Consent (EFIC) pathway [1024].
Through this pathway, people who are incapacitated can receive an experimental treatment even if they are not able to consent and there is not sufficient time to seek approval from an authorized representative.
-This pathway presents concerns, however, when it is considered in the context of a long history of systematic abuses in medical experimentation where informed consent was not obtained from people of color, such as the Tuskegee syphilis experiments [1024].
+This pathway presents concerns, however, when it is considered in the context of a long history of systematic abuses in medical experimentation where informed consent was not obtained from people of color, such as the Tuskegee syphilis experiments [1025].
While the goal of EFIC approval is to provide treatment to patients who urgently need it, the combination of the ongoing legacy of racism in medicine renders this trend concerning.
-With COVID-19, efforts to prioritize people who suffer from systemic racism are often designed with the goal of righting some of these inequalities (e.g., [1025]), but particular attention to informed consent will be imperative in ensuring these trials are ethical given that the benefits and risks of emerging treatments are still poorly characterized.
+With COVID-19, efforts to prioritize people who suffer from systemic racism are often designed with the goal of righting some of these inequalities (e.g., [1026]), but particular attention to informed consent will be imperative in ensuring these trials are ethical given that the benefits and risks of emerging treatments are still poorly characterized.
Making a substantial effort to run inclusive clinical trials is also important because of the possibility that racism could impact how a patient responds to a treatment.
For example, as discussed above, dexamethasone has been identified as a promising treatment for patients experiencing cytokine release syndrome, but the mechanism of action is tied to the stress response.
-A study from 2005 reported that Black asthma patients showed reduced responsiveness to dexamethasone in comparison to white patients and suggested Black patients might therefore require higher doses of the drug [1026].
-In the context of chronic stress caused by systemic racism, this result is not surprising: chronic stress is associated with dysregulated production of glucocorticoids [1027] and glucocorticoid receptor resistance [1028].
+A study from 2005 reported that Black asthma patients showed reduced responsiveness to dexamethasone in comparison to white patients and suggested Black patients might therefore require higher doses of the drug [1027].
+In the context of chronic stress caused by systemic racism, this result is not surprising: chronic stress is associated with dysregulated production of glucocorticoids [1028] and glucocorticoid receptor resistance [1029].
However, it underscores the critical need for treatment guidelines to take into account differences in life experience, which would be facilitated by the recruitment of patients from a wide range of backgrounds.
Attention to the social aspects of clinical trial enrollment must therefore be an essential component of the medical research community’s response to COVID-19.
-Our primary goal is to sort and distill informative content out of the overwhelming flood of information [5] and help the broader scientific community become more conversant on this critical subject.
+Our primary goal is to sort and distill informative content out of the overwhelming flood of information [7] and help the broader scientific community become more conversant on this critical subject.
Thus, our approach has been to develop a real-time, collaborative effort that welcomes submissions from scientists worldwide into this ongoing effort.
This document represents the first snapshot, which aims to reflect the state of the field as of October, 2020.
We plan to refine and expand this document until technologies to mitigate the pandemic are widely available.
-In an effort to keep pace as new information about COVID-19 and SARS-CoV-2 becomes available, this project is an open, collaborative effort that invited contributions from the scientific community broadly, similar to previous efforts to develop collaborative reviews [1029,1030].
+
In an effort to keep pace as new information about COVID-19 and SARS-CoV-2 becomes available, this project is an open, collaborative effort that invited contributions from the scientific community broadly, similar to previous efforts to develop collaborative reviews [1030,1031].
Contributors were recruited by word of mouth and on Twitter.
-Existing efforts to train early-career scientists were also integrated: Appendix A contains summaries written by the students, post-docs, and faculty of the Immunology Institute at the Mount Sinai School of Medicine [1031,1032], and two of the authors were recruited through the American Physician Scientist Association’s Virtual Summer Research Program [1033].
-The project was managed through GitHub [1034] using Manubot [6] to continuously generate a version of the manuscript online [1035].
+Existing efforts to train early-career scientists were also integrated: Appendix A contains summaries written by the students, post-docs, and faculty of the Immunology Institute at the Mount Sinai School of Medicine [1032,1033], and two of the authors were recruited through the American Physician Scientist Association’s Virtual Summer Research Program [1034].
+The project was managed through GitHub [1035] using Manubot [8] to continuously generate a version of the manuscript online [1036].
Contributors developed text that was proposed through GitHub’s pull request system and then reviewed and approved by at least one other author.
While this document reflects the current version of record, the online version will continue to be developed as information about the pandemic emerges.
Below, we will describe the processes used to synthesize the literature.
10.3 Technical Infrastructure
10.3.1 Collaborative Writing and Manuscript Generation
-Manubot [6] is a collaborative framework developed to adapt open-source software development techniques and version control for manuscript writing.
+
Manubot [8] is a collaborative framework developed to adapt open-source software development techniques and version control for manuscript writing.
Here, Manubot was used to generate a manuscript from text maintained using GitHub, a popular, online version control interface.
The GitHub implementation allowed users to contribute either using git on the command line or using the GitHub user interface, and we developed documentation for users with less experience with this platform.
Manubot also provides a functionality to create a bibliography using digital object identifiers (DOIs), website URLs, or other identifiers such as PubMed identifiers and arXiv IDs.
Due to the needs of this project, project contributors also implemented new features in Manubot and Zotero, which Manubot uses to extract metadata for some types of citations.
-These features support directly citing clinical trial identifiers such as clinicaltrials:NCT04292899 [399] and generating the complete review manuscript along with the individual manuscripts reviewing specific topics.
+These features support directly citing clinical trial identifiers such as clinicaltrials:NCT04292899 [400] and generating the complete review manuscript along with the individual manuscripts reviewing specific topics.
Finally, Manubot and GitHub Actions continuous integration allowed for scripted updates to be run each time the manuscript was generated.
These scripts were used to check that the manuscript was built correctly, run spellchecking, and cross-reference the manuscripts cited in this review, summarized in Appendix A, and discussed in the project’s issues and pull requests.
10.3.2 Data Analysis and Visualization
The combination of Manubot and GitHub Actions also made it possible to dynamically update information such as statistics and visualizations in the manuscript.
-Data about worldwide cases and deaths from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [368] were read using a Python script.
-Similarly, the clinical trials statistics and figure were generated based on data from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [371].
-In both cases, frequency data were plotted using Matplotlib [1036] in Python.
+Data about worldwide cases and deaths from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [369] were read using a Python script.
+Similarly, the clinical trials statistics and figure were generated based on data from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [372].
+In both cases, frequency data were plotted using Matplotlib [1037] in Python.
The figure showing the geographic distribution of COVID-19 clinical trials was generated using the countries associated with the trials listed in the COVID-19 TrialsTracker, converting the country names to 3-letter ISO codes using pycountry or manual adjustment when necessary, and visualizing the geographic distribution of trial recruitment using geopandas.
GitHub Actions runs a nightly workflow to update these external data and regenerate the statistics and figures for the manuscript.
The workflow uses the GitHub API to detect and save the latest commit of the external data sources, which are both GitHub repositories.
@@ -3202,7 +3203,7 @@
10.4 Article Selection and Evaluation
Relevant articles were identified and submitted as issues on GitHub for review.
Articles were classified as diagnostic, therapeutic, or other, and a template was developed to guide the review of papers and preprints in each category.
-Following a framework often used for assessing medical literature, the review consisted of examining methods used in each relevant article, assignment (whether the study was observational or randomized), assessment, results, interpretation, and how well the study extrapolates [1037].
+Following a framework often used for assessing medical literature, the review consisted of examining methods used in each relevant article, assignment (whether the study was observational or randomized), assessment, results, interpretation, and how well the study extrapolates [1038].
For examples of each template, please see Appendices B-D.
10.4.1 Diagnostic Papers
10.4.1.1 Methods
@@ -3245,15 +3246,15 @@ 10.4.2.6 Extrapolation
Reviewers describe how the study may extrapolate to a different species or population.
-10.5 Conclusions
+10.5 Conclusions
Figure 7: Summary of the relationships among topics covered in this review.
Several review articles on aspects of COVID-19 have already been published.
-These have included reviews on the disease epidemiology [38], immunological response [39], diagnostics [40], and pharmacological treatments [39,41].
-Others [42,43] provide narrative reviews of progress on some important ongoing COVID-19 research questions.
+These have included reviews on the disease epidemiology [40], immunological response [41], diagnostics [42], and pharmacological treatments [41,43].
+Others [44,45] provide narrative reviews of progress on some important ongoing COVID-19 research questions.
With the worldwide scientific community uniting during 2020 to investigate SARS-CoV-2 and COVID-19 from a wide range of perspectives, findings from many disciplines are relevant on a rapid timescale to a broad scientific audience.
Additionally, many findings are published as preprints, which are available prior to going through the peer review process.
As a result, centralizing, summarizing, and critiquing new literature broadly relevant to COVID-19 can help to expedite the interdisciplinary scientific process that is currently happening at an advanced pace.
@@ -3724,6631 +3725,6636 @@
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Nipith Charoenngam, Michael F. Holick
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Jonathan M. Rhodes, Sreedhar Subramanian, Eamon Laird, Rose A. Kenny
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714. 25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2
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718. Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: an Israeli population‐based study
Eugene Merzon, Dmitry Tworowski, Alessandro Gorohovski, Shlomo Vinker, Avivit Golan Cohen, Ilan Green, Milana Frenkel‐Morgenstern
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David O. Meltzer, Thomas J. Best, Hui Zhang, Tamara Vokes, Vineet Arora, Julian Solway
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José L Hernández, Daniel Nan, Marta Fernandez-Ayala, Mayte García-Unzueta, Miguel A Hernández-Hernández, Marcos López-Hoyos, Pedro Muñoz-Cacho, José M Olmos, Manuel Gutiérrez-Cuadra, Juan J Ruiz-Cubillán, … Víctor M Martínez-Taboada
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Alex Pizzini, Magdalena Aichner, Sabina Sahanic, Anna Böhm, Alexander Egger, Gregor Hoermann, Katharina Kurz, Gerlig Widmann, Rosa Bellmann-Weiler, Günter Weiss, … Judith Löffler-Ragg
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Kun Ye, Fen Tang, Xin Liao, Benjamin A. Shaw, Meiqiu Deng, Guangyi Huang, Zhiqiang Qin, Xiaomei Peng, Hewei Xiao, Chunxia Chen, … Jianrong Yang
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728. Vitamin D Deficiency Is Associated with COVID-19 Incidence and Disease Severity in Chinese People
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Virna Margarita Martín Giménez, Felipe Inserra, León Ferder, Joxel García, Walter Manucha
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Ali Daneshkhah, Vasundhara Agrawal, Adam Eshein, Hariharan Subramanian, Hemant Kumar Roy, Vadim Backman
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735. Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study)
Ashu Rastogi, Anil Bhansali, Niranjan Khare, Vikas Suri, Narayana Yaddanapudi, Naresh Sachdeva, GD Puri, Pankaj Malhotra
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Stephanie F. Ling, Eleanor Broad, Rebecca Murphy, Joseph M. Pappachan, Satveer Pardesi-Newton, Marie-France Kong, Edward B. Jude
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Igor H. Murai, Alan L. Fernandes, Lucas P. Sales, Ana J. Pinto, Karla F. Goessler, Camila S. C. Duran, Carla B. R. Silva, André S. Franco, Marina B. Macedo, Henrique H. H. Dalmolin, … Rosa M. R. Pereira
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Manuel Castillo Garzón
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745. The LEAD COVID-19 Trial: Low-risk, Early Aspirin and Vitamin D to Reduce COVID-19 Hospitalizations
Louisiana State University Health Sciences Center in New Orleans
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Marvin McCreary MD
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886. A Randomized Clinical Trial for Enhanced Trained Immune Responses Through Bacillus Calmette-Guérin Vaccination to Prevent Infections by COVID-19: The ACTIVATE II Trial
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William B. Feldman, Spencer Phillips Hey, Aaron S. Kesselheim
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1025. The legacy of the tuskegee syphilis experiments for emergency exception from informed consent
Terri A. Schmidt
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-1025. CDC officials are considering a plan to distribute COVID-19 vaccines to the most vulnerable first — including people of color
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1026. CDC officials are considering a plan to distribute COVID-19 vaccines to the most vulnerable first — including people of color
Sarah Al-Arshani
Business Insider https://www.businessinsider.com/cdc-official-considering-giving-covid-19-vaccine-most-vulnerable-first-2020-10
-1026. Racial Differences in T-Lymphocyte Response to Glucocorticoids
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1027. Racial Differences in T-Lymphocyte Response to Glucocorticoids
Monica J. Federico, Ronina A. Covar, Eleanor E. Brown, Donald Y. M. Leung, Joseph D. Spahn
Chest (2005-02) https://doi.org/bjfcf6
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-1027. ENDOCRINOLOGY OF THE STRESS RESPONSE
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1028. ENDOCRINOLOGY OF THE STRESS RESPONSE
Evangelia Charmandari, Constantine Tsigos, George Chrousos
Annual Review of Physiology (2005-03-17) https://doi.org/brcm9n
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-1028. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk
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1029. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk
S. Cohen, D. Janicki-Deverts, W. J. Doyle, G. E. Miller, E. Frank, B. S. Rabin, R. B. Turner
Proceedings of the National Academy of Sciences (2012-04-02) https://doi.org/f4n6r8
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-1029. Opportunities and obstacles for deep learning in biology and medicine
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1030. Opportunities and obstacles for deep learning in biology and medicine
Travers Ching, Daniel S. Himmelstein, Brett K. Beaulieu-Jones, Alexandr A. Kalinin, Brian T. Do, Gregory P. Way, Enrico Ferrero, Paul-Michael Agapow, Michael Zietz, Michael M. Hoffman, … Casey S. Greene
Journal of The Royal Society Interface (2018-04-04) https://doi.org/gddkhn
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-1030. Opportunities and obstacles for deep learning in biology and medicine [update in progress]
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1031. Opportunities and obstacles for deep learning in biology and medicine [update in progress]
Casey S. Greene, Daniel S. Himmelstein, Daniel C. Elton, Brock C. Christensen, Anthony Gitter, Alexander J. Titus, Joshua J. Levy
Manubot (2020-11-10) https://greenelab.github.io/deep-review/
-1031. ismms-himc/covid-19_sinai_reviews
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1032. ismms-himc/covid-19_sinai_reviews
Human Immune Monitoring Center at Mount Sinai
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-1032. Advancing scientific knowledge in times of pandemics
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1033. Advancing scientific knowledge in times of pandemics
Nicolas Vabret, Robert Samstein, Nicolas Fernandez, Miriam Merad, The Sinai Immunology Review Project, Trainees, Faculty
Nature Reviews Immunology (2020-04-23) https://doi.org/ghjs79
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-1033. Undergraduate Mentoring - American Physician Scientists Association https://www.physicianscientists.org/page/summer-research-pilot-program
+1034. Undergraduate Mentoring - American Physician Scientists Association https://www.physicianscientists.org/page/summer-research-pilot-program
-1034. greenelab/covid19-review
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1035. greenelab/covid19-review
Greene Laboratory
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-1035. SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics
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1036. SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics
Halie M. Rando, Casey S. Greene, Michael P. Robson, Simina M. Boca, Nils Wellhausen, Ronan Lordan, Christian Brueffer, Sandipan Ray, Lucy D\’Agostino McGowan, Anthony Gitter, … Rishi Raj Goel
Manubot (2021-02-08) https://greenelab.github.io/covid19-review/
-1036. Matplotlib: A 2D Graphics Environment
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John D. Hunter
Computing in Science & Engineering (2007) https://doi.org/drbjhg
DOI: 10.1109/mcse.2007.55
-1037. Using the MAARIE Framework To Read the Research Literature
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1038. Using the MAARIE Framework To Read the Research Literature
M. Corcoran
American Journal of Occupational Therapy (2006-07-01) https://doi.org/bqh97x
DOI: 10.5014/ajot.60.4.367 · PMID: 16915865
-1038. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody
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1039. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody
Xiaolong Tian, Cheng Li, Ailing Huang, Shuai Xia, Sicong Lu, Zhengli Shi, Lu Lu, Shibo Jiang, Zhenlin Yang, Yanling Wu, Tianlei Ying
Cold Spring Harbor Laboratory (2020-01-28) https://doi.org/ggjqfd
DOI: 10.1101/2020.01.28.923011
-1039. Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of 2019-nCoV
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1040. Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of 2019-nCoV
Xiang He, Lei Zhang, Qin Ran, Junyi Wang, Anying Xiong, Dehong Wu, Feng Chen, Guoping Li
Cold Spring Harbor Laboratory (2020-02-05) https://doi.org/ggrbd8
DOI: 10.1101/2020.02.03.20020206
-1040. Diarrhea may be underestimated: a missing link in 2019 novel coronavirus
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1041. Diarrhea may be underestimated: a missing link in 2019 novel coronavirus
Weicheng Liang, Zhijie Feng, Shitao Rao, Cuicui Xiao, Ze-Xiao Lin, Qi Zhang, Qi Wei
Cold Spring Harbor Laboratory (2020-02-17) https://doi.org/ggrbdw
DOI: 10.1101/2020.02.03.20020289
-1041. Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection
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1042. Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection
Xiaoqiang Chai, Longfei Hu, Yan Zhang, Weiyu Han, Zhou Lu, Aiwu Ke, Jian Zhou, Guoming Shi, Nan Fang, Jia Fan, … Fei Lan
Cold Spring Harbor Laboratory (2020-02-04) https://doi.org/ggq626
DOI: 10.1101/2020.02.03.931766
-1042. Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids
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1043. Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids
Bing Zhao, Chao Ni, Ran Gao, Yuyan Wang, Li Yang, Jinsong Wei, Ting Lv, Jianqing Liang, Qisheng Zhang, Wei Xu, … Xinhua Lin
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq648
DOI: 10.1101/2020.03.16.990317
-1043. ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism
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1044. ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism
Jun Wang, Shanmeizi Zhao, Ming Liu, Zhiyao Zhao, Yiping Xu, Ping Wang, Meng Lin, Yanhui Xu, Bing Huang, Xiaoyu Zuo, … Yuxia Zhang
Cold Spring Harbor Laboratory (2020-02-07) https://doi.org/ggrfbx
DOI: 10.1101/2020.02.05.20020545
-1044. The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice
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1045. The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice
Linlin Bao, Wei Deng, Baoying Huang, Hong Gao, Jiangning Liu, Lili Ren, Qiang Wei, Pin Yu, Yanfeng Xu, Feifei Qi, … Chuan Qin
Cold Spring Harbor Laboratory (2020-02-28) https://doi.org/dph2
DOI: 10.1101/2020.02.07.939389
-1045. Caution on Kidney Dysfunctions of COVID-19 Patients
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1046. Caution on Kidney Dysfunctions of COVID-19 Patients
Zhen Li, Ming Wu, Jiwei Yao, Jie Guo, Xiang Liao, Siji Song, Jiali Li, Guangjie Duan, Yuanxiu Zhou, Xiaojun Wu, … Junan Yan
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq627
DOI: 10.1101/2020.02.08.20021212
-1046. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome
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1047. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome
Kwok Hong Chu, Wai Kay Tsang, Colin S. Tang, Man Fai Lam, Fernand M. Lai, Ka Fai To, Ka Shun Fung, Hon Lok Tang, Wing Wa Yan, Hilda W. H. Chan, … Kar Neng Lai
Kidney International (2005-02) https://doi.org/b7tgtx
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-1047. Single-cell Analysis of ACE2 Expression in Human Kidneys and Bladders Reveals a Potential Route of 2019-nCoV Infection
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1048. Single-cell Analysis of ACE2 Expression in Human Kidneys and Bladders Reveals a Potential Route of 2019-nCoV Infection
Wei Lin, Longfei Hu, Yan Zhang, Joshua D. Ooi, Ting Meng, Peng Jin, Xiang Ding, Longkai Peng, Lei Song, Zhou Xiao, … Yong Zhong
Cold Spring Harbor Laboratory (2020-02-18) https://doi.org/ggq629
DOI: 10.1101/2020.02.08.939892
-1048. The immune vulnerability landscape of the 2019 Novel Coronavirus, SARS-CoV-2
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1049. The immune vulnerability landscape of the 2019 Novel Coronavirus, SARS-CoV-2
James Zhu, Jiwoong Kim, Xue Xiao, Yunguan Wang, Danni Luo, Shuang Jiang, Ran Chen, Lin Xu, He Zhang, Lenny Moise, … Yang Xie
Cold Spring Harbor Laboratory (2020-09-04) https://doi.org/ggq628
DOI: 10.1101/2020.02.08.939553 · PMID: 32908981
-1049. Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection
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1050. Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection
Yaseen M. Arabi, Ahmed A. Arifi, Hanan H. Balkhy, Hani Najm, Abdulaziz S. Aldawood, Alaa Ghabashi, Hassan Hawa, Adel Alothman, Abdulaziz Khaldi, Basel Al Raiy
Annals of Internal Medicine (2014-03-18) https://doi.org/ggptxw
DOI: 10.7326/m13-2486 · PMID: 24474051
-1050. Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage
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1051. Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage
Jingyuan Liu, Yao Liu, Pan Xiang, Lin Pu, Haofeng Xiong, Chuansheng Li, Ming Zhang, Jianbo Tan, Yanli Xu, Rui Song, … Xianbo Wang
Cold Spring Harbor Laboratory (2020-02-12) https://doi.org/ggrbdx
DOI: 10.1101/2020.02.10.20021584
-1051. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China
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1052. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China
Chuan Qin, Luoqi Zhou, Ziwei Hu, Shuoqi Zhang, Sheng Yang, Yu Tao, Cuihong Xie, Ke Ma, Ke Shang, Wei Wang, Dai-Shi Tian
Clinical Infectious Diseases (2020-08-01) https://doi.org/ggpxcf
DOI: 10.1093/cid/ciaa248 · PMID: 32161940 · PMCID: PMC7108125
-1052. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)
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1053. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)
Suxin Wan, Qingjie Yi, Shibing Fan, Jinglong Lv, Xianxiang Zhang, Lian Guo, Chunhui Lang, Qing Xiao, Kaihu Xiao, Zhengjun Yi, … Yongping Chen
Cold Spring Harbor Laboratory (2020-02-12) https://doi.org/ggq63b
DOI: 10.1101/2020.02.10.20021832
-1053. Longitudinal Characteristics of Lymphocyte Responses and Cytokine Profiles in the Peripheral Blood of SARS-CoV-2 Infected Patients
+
1054. Longitudinal Characteristics of Lymphocyte Responses and Cytokine Profiles in the Peripheral Blood of SARS-CoV-2 Infected Patients
Jing Liu, Sumeng Li, Jia Liu, Boyun Liang, Xiaobei Wang, Wei Li, Hua Wang, Qiaoxia Tong, Jianhua Yi, Lei Zhao, … Xin Zheng
SSRN Electronic Journal (2020) https://doi.org/ggq655
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-1054. Epidemiological and Clinical Characteristics of 17 Hospitalized Patients with 2019 Novel Coronavirus Infections Outside Wuhan, China
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1055. Epidemiological and Clinical Characteristics of 17 Hospitalized Patients with 2019 Novel Coronavirus Infections Outside Wuhan, China
Jie Li, Shilin Li, Yurui Cai, Qin Liu, Xue Li, Zhaoping Zeng, Yanpeng Chu, Fangcheng Zhu, Fanxin Zeng
Cold Spring Harbor Laboratory (2020-02-12) https://doi.org/ggq63c
DOI: 10.1101/2020.02.11.20022053
-1055. ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection
+
1056. ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection
Caibin Fan, Kai Li, Yanhong Ding, Wei Lu, Jianqing Wang
Cold Spring Harbor Laboratory (2020-02-13) https://doi.org/ggq63d
DOI: 10.1101/2020.02.12.20022418
-1056. Aberrant pathogenic GM-CSF + T cells and inflammatory CD14 + CD16 + monocytes in severe pulmonary syndrome patients of a new coronavirus
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1057. Aberrant pathogenic GM-CSF + T cells and inflammatory CD14 + CD16 + monocytes in severe pulmonary syndrome patients of a new coronavirus
Yonggang Zhou, Binqing Fu, Xiaohu Zheng, Dongsheng Wang, Changcheng Zhao, Yingjie qi, Rui Sun, Zhigang Tian, Xiaoling Xu, Haiming Wei
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggq63f
DOI: 10.1101/2020.02.12.945576
-1057. Clinical Characteristics of 2019 Novel Infected Coronavirus Pneumonia: A Systemic Review and Meta-analysis
+
1058. Clinical Characteristics of 2019 Novel Infected Coronavirus Pneumonia: A Systemic Review and Meta-analysis
Kai Qian, Yi Deng, Yong-Hang Tai, Jun Peng, Hao Peng, Li-Hong Jiang
Cold Spring Harbor Laboratory (2020-02-17) https://doi.org/ggrgbq
DOI: 10.1101/2020.02.14.20021535
-1058. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients
+
1059. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients
Jing Liu, Sumeng Li, Jia Liu, Boyun Liang, Xiaobei Wang, Hua Wang, Wei Li, Qiaoxia Tong, Jianhua Yi, Lei Zhao, … Xin Zheng
Cold Spring Harbor Laboratory (2020-02-22) https://doi.org/ggq63g
DOI: 10.1101/2020.02.16.20023671
-1059. Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019
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1060. Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019
Guang Chen, Di Wu, Wei Guo, Yong Cao, Da Huang, Hongwu Wang, Tao Wang, Xiaoyun Zhang, Huilong Chen, Haijing Yu, … Qin Ning
Cold Spring Harbor Laboratory (2020-02-19) https://doi.org/ggq63h
DOI: 10.1101/2020.02.16.20023903
-1060. SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development
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1061. SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development
Chunyun Sun, Long Chen, Ji Yang, Chunxia Luo, Yanjing Zhang, Jing Li, Jiahui Yang, Jie Zhang, Liangzhi Xie
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggq63j
DOI: 10.1101/2020.02.16.951723
-1061. Protection of Rhesus Macaque from SARS-Coronavirus challenge by recombinant adenovirus vaccine
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1062. Protection of Rhesus Macaque from SARS-Coronavirus challenge by recombinant adenovirus vaccine
Yiyou Chen, Qiang Wei, Ruobing Li, Hong Gao, Hua Zhu, Wei Deng, Linlin Bao, Wei Tong, Zhe Cong, Hong Jiang, Chuan Qin
Cold Spring Harbor Laboratory (2020-02-21) https://doi.org/ggq63k
DOI: 10.1101/2020.02.17.951939
-1062. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)
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1063. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)
Bo Diao, Chenhui Wang, Yingjun Tan, Xiewan Chen, Ying Liu, Lifen Ning, Li Chen, Min Li, Yueping Liu, Gang Wang, … Yongwen Chen
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggq63m
DOI: 10.1101/2020.02.18.20024364
-1063. Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China
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1064. Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China
Xun Li, Luwen Wang, Shaonan Yan, Fan Yang, Longkui Xiang, Jiling Zhu, Bo Shen, Zuojiong Gong
Cold Spring Harbor Laboratory (2020-02-25) https://doi.org/ggq63n
DOI: 10.1101/2020.02.19.20025239
-1064. SARS-CoV-2 infection does not significantly cause acute renal injury: an analysis of 116 hospitalized patients with COVID-19 in a single hospital, Wuhan, China
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1065. SARS-CoV-2 infection does not significantly cause acute renal injury: an analysis of 116 hospitalized patients with COVID-19 in a single hospital, Wuhan, China
Luwen Wang, Xun Li, Hui Chen, Shaonan Yan, Yan Li, Dong Li, Zuojiong Gong
Cold Spring Harbor Laboratory (2020-02-23) https://doi.org/ggq63p
DOI: 10.1101/2020.02.19.20025288
-1065. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China
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1066. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China
Dawei Wang, Bo Hu, Chang Hu, Fangfang Zhu, Xing Liu, Jing Zhang, Binbin Wang, Hui Xiang, Zhenshun Cheng, Yong Xiong, … Zhiyong Peng
JAMA (2020-03-17) https://doi.org/ggkh48
DOI: 10.1001/jama.2020.1585 · PMID: 32031570 · PMCID: PMC7042881
-1066. Clinical characteristics of 2019 novel coronavirus infection in China
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1067. Clinical characteristics of 2019 novel coronavirus infection in China
Wei-jie Guan, Zheng-yi Ni, Yu Hu, Wen-hua Liang, Chun-quan Ou, Jian-xing He, Lei Liu, Hong Shan, Chun-liang Lei, David S. C. Hui, … Nan-shan Zhong
Cold Spring Harbor Laboratory (2020-02-09) https://doi.org/ggkj9s
DOI: 10.1101/2020.02.06.20020974
-1067. Potential T-cell and B-cell Epitopes of 2019-nCoV
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1068. Potential T-cell and B-cell Epitopes of 2019-nCoV
Ethan Fast, Russ B. Altman, Binbin Chen
Cold Spring Harbor Laboratory (2020-03-18) https://doi.org/ggq63q
DOI: 10.1101/2020.02.19.955484
-1068. Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein
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1069. Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein
Alexandra C. Walls, Young-Jun Park, M. Alexandra Tortorici, Abigail Wall, Andrew T. McGuire, David Veesler
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggrgbr
DOI: 10.1101/2020.02.19.956581
-1069. Breadth of concomitant immune responses underpinning viral clearance and patient recovery in a non-severe case of COVID-19
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1070. Breadth of concomitant immune responses underpinning viral clearance and patient recovery in a non-severe case of COVID-19
Irani Thevarajan, Thi HO Nguyen, Marios Koutsakos, Julian Druce, Leon Caly, Carolien E van de Sandt, Xiaoxiao Jia, Suellen Nicholson, Mike Catton, Benjamin Cowie, … Katherine Kedzierska
Cold Spring Harbor Laboratory (2020-02-23) https://doi.org/ggq63r
DOI: 10.1101/2020.02.20.20025841
-1070. The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing
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1071. The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing
Minfeng Liao, Yang Liu, Jin Yuan, Yanling Wen, Gang Xu, Juanjuan Zhao, Lin Chen, Jinxiu Li, Xin Wang, Fuxiang Wang, … Zheng Zhang
Cold Spring Harbor Laboratory (2020-02-26) https://doi.org/ggq63s
DOI: 10.1101/2020.02.23.20026690
-1071. Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells
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1072. Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells
Marlena Scharenberg, Sindhu Vangeti, Eliisa Kekäläinen, Per Bergman, Mamdoh Al-Ameri, Niclas Johansson, Klara Sondén, Sara Falck-Jones, Anna Färnert, Hans-Gustaf Ljunggren, … Nicole Marquardt
Frontiers in Immunology (2019-05-17) https://doi.org/ggq656
DOI: 10.3389/fimmu.2019.01116 · PMID: 31156653 · PMCID: PMC6534051
-1072. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
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1073. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
Chaolin Huang, Yeming Wang, Xingwang Li, Lili Ren, Jianping Zhao, Yi Hu, Li Zhang, Guohui Fan, Jiuyang Xu, Xiaoying Gu, … Bin Cao
The Lancet (2020-02) https://doi.org/ggjfnn
DOI: 10.1016/s0140-6736(20)30183-5
-1073. Alveolar Macrophages in the Resolution of Inflammation, Tissue Repair, and Tolerance to Infection
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1074. Alveolar Macrophages in the Resolution of Inflammation, Tissue Repair, and Tolerance to Infection
Benoit Allard, Alice Panariti, James G. Martin
Frontiers in Immunology (2018-07-31) https://doi.org/gd3bnz
DOI: 10.3389/fimmu.2018.01777 · PMID: 30108592 · PMCID: PMC6079255
-1074. PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery following Respiratory Viral Infection
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1075. PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery following Respiratory Viral Infection
Su Huang, Bibo Zhu, In Su Cheon, Nick P. Goplen, Li Jiang, Ruixuan Zhang, R. Stokes Peebles, Matthias Mack, Mark H. Kaplan, Andrew H. Limper, Jie Sun
Journal of Virology (2019-04-17) https://doi.org/ggq652
DOI: 10.1128/jvi.00030-19 · PMID: 30787149 · PMCID: PMC6475778
-1075. Can routine laboratory tests discriminate 2019 novel coronavirus infected pneumonia from other community-acquired pneumonia?
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1076. Can routine laboratory tests discriminate 2019 novel coronavirus infected pneumonia from other community-acquired pneumonia?
Yunbao Pan, Guangming Ye, Xiantao Zeng, Guohong Liu, Xiaojiao Zeng, Xianghu Jiang, Jin Zhao, Liangjun Chen, Shuang Guo, Qiaoling Deng, … Xinghuan Wang
Cold Spring Harbor Laboratory (2020-02-25) https://doi.org/ggq63t
DOI: 10.1101/2020.02.25.20024711
-1076. Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia
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1077. Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia
Jing Gong, Hui Dong, Qingsong Xia, Zhaoyi Huang, Dingkun Wang, Yan Zhao, Wenhua Liu, Shenghao Tu, Mingmin Zhang, Qi Wang, Fuer Lu
Cold Spring Harbor Laboratory (2020-02-26) https://doi.org/ggq63v
DOI: 10.1101/2020.02.25.20025643
-1077. An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors’ CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design
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1078. An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors’ CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design
CV Herst, S Burkholz, J Sidney, A Sette, PE Harris, S Massey, T Brasel, E Cunha-Neto, DS Rosa, WCH Chao, … R Rubsamen
Cold Spring Harbor Laboratory (2020-04-06) https://doi.org/ggq63x
DOI: 10.1101/2020.02.25.963546
-1078. Epitope-based peptide vaccine design and target site characterization against novel coronavirus disease caused by SARS-CoV-2
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1079. Epitope-based peptide vaccine design and target site characterization against novel coronavirus disease caused by SARS-CoV-2
Lin Li, Ting Sun, Yufei He, Wendong Li, Yubo Fan, Jing Zhang
Cold Spring Harbor Laboratory (2020-02-27) https://doi.org/ggnqwt
DOI: 10.1101/2020.02.25.965434
-1079. The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and Retrospective Analysis
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1080. The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and Retrospective Analysis
Wang Wenjun, Liu Xiaoqing, Wu Sipei, Lie Puyi, Huang Liyan, Li Yimin, Cheng Linling, Chen Sibei, Nong Lingbo, Lin Yongping, He Jianxing
Cold Spring Harbor Laboratory (2020-02-27) https://doi.org/ggrgbs
DOI: 10.1101/2020.02.26.20026989
-1080. Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China
+
1081. Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China
Ying Huang, Rui Yang, Ying Xu, Ping Gong
Cold Spring Harbor Laboratory (2020-03-05) https://doi.org/ggq63z
DOI: 10.1101/2020.02.27.20029009
-1081. Risk factors related to hepatic injury in patients with corona virus disease 2019
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1082. Risk factors related to hepatic injury in patients with corona virus disease 2019
Lu Li, Shuang Li, Manman Xu, Pengfei Yu, Sujun Zheng, Zhongping Duan, Jing Liu, Yu Chen, Junfeng Li
Cold Spring Harbor Laboratory (2020-03-10) https://doi.org/ggq632
DOI: 10.1101/2020.02.28.20028514
-1082. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients
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1083. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients
Xiaohua Chen, Binghong Zhao, Yueming Qu, Yurou Chen, Jie Xiong, Yong Feng, Dong Men, Qianchuan Huang, Ying Liu, Bo Yang, … Feng Li
Cold Spring Harbor Laboratory (2020-03-03) https://doi.org/ggq633
DOI: 10.1101/2020.02.29.20029520
-1083. Prognostic factors in the acute respiratory distress syndrome
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1084. Prognostic factors in the acute respiratory distress syndrome
Wei Chen, Lorraine B Ware
Clinical and Translational Medicine (2015-07-02) https://doi.org/ggq653
DOI: 10.1186/s40169-015-0065-2 · PMID: 26162279 · PMCID: PMC4534483
-1084. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study
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1085. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study
Li Tan, Qi Wang, Duanyang Zhang, Jinya Ding, Qianchuan Huang, Yi-Quan Tang, Qiongshu Wang, Hongming Miao
Cold Spring Harbor Laboratory (2020-03-03) https://doi.org/ggq634
DOI: 10.1101/2020.03.01.20029074
-1085. The potential role of IL-6 in monitoring severe case of coronavirus disease 2019
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1086. The potential role of IL-6 in monitoring severe case of coronavirus disease 2019
Tao Liu, Jieying Zhang, Yuhui Yang, Hong Ma, Zhengyu Li, Jiaoyu Zhang, Ji Cheng, Xiaoyun Zhang, Yanxia Zhao, Zihan Xia, … Jianhua Yi
Cold Spring Harbor Laboratory (2020-03-10) https://doi.org/ggq635
DOI: 10.1101/2020.03.01.20029769
-1086. Clinical and Laboratory Profiles of 75 Hospitalized Patients with Novel Coronavirus Disease 2019 in Hefei, China
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1087. Clinical and Laboratory Profiles of 75 Hospitalized Patients with Novel Coronavirus Disease 2019 in Hefei, China
Zonghao Zhao, Jiajia Xie, Ming Yin, Yun Yang, Hongliang He, Tengchuan Jin, Wenting Li, Xiaowu Zhu, Jing Xu, Changcheng Zhao, … Xiaoling Ma
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq636
DOI: 10.1101/2020.03.01.20029785
-1087. Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome
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1088. Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome
Yang Yang, Chenguang Shen, Jinxiu Li, Jing Yuan, Minghui Yang, Fuxiang Wang, Guobao Li, Yanjie Li, Li Xing, Ling Peng, … Yingxia Liu
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq637
DOI: 10.1101/2020.03.02.20029975
-1088. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019
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1089. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019
Juanjuan Zhao, Quan Yuan, Haiyan Wang, Wei Liu, Xuejiao Liao, Yingying Su, Xin Wang, Jing Yuan, Tingdong Li, Jinxiu Li, … Zheng Zhang
Cold Spring Harbor Laboratory (2020-03-02) https://doi.org/ggrbj6
DOI: 10.1101/2020.03.02.20030189
-1089. Restoration of leukomonocyte counts is associated with viral clearance in COVID-19 hospitalized patients
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1090. Restoration of leukomonocyte counts is associated with viral clearance in COVID-19 hospitalized patients
Xiaoping Chen, Jiaxin Ling, Pingzheng Mo, Yongxi Zhang, Qunqun Jiang, Zhiyong Ma, Qian Cao, Wenjia Hu, Shi Zou, Liangjun Chen, … Yong Xiong
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq639
DOI: 10.1101/2020.03.03.20030437
-1090. Effects of Systemically Administered Hydrocortisone on the Human Immunome
+
1091. Effects of Systemically Administered Hydrocortisone on the Human Immunome
Matthew J. Olnes, Yuri Kotliarov, Angélique Biancotto, Foo Cheung, Jinguo Chen, Rongye Shi, Huizhi Zhou, Ena Wang, John S. Tsang, Robert Nussenblatt, The CHI Consortium
Scientific Reports (2016-03-14) https://doi.org/f8dmvw
DOI: 10.1038/srep23002 · PMID: 26972611 · PMCID: PMC4789739
-1091. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis
+
1092. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis
Giuseppe Lippi, Mario Plebani
Clinica Chimica Acta (2020-06) https://doi.org/ggpxp7
DOI: 10.1016/j.cca.2020.03.004 · PMID: 32145275 · PMCID: PMC7094472
-1092. Clinical findings in critically ill patients infected with SARS-CoV-2 in Guangdong Province, China: a multi-center, retrospective, observational study
+
1093. Clinical findings in critically ill patients infected with SARS-CoV-2 in Guangdong Province, China: a multi-center, retrospective, observational study
Yonghao Xu, Zhiheng Xu, Xuesong Liu, Lihua Cai, Haichong Zheng, Yongbo Huang, Lixin Zhou, Linxi Huang, Yun Lin, Liehua Deng, … Yimin Li
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq64b
DOI: 10.1101/2020.03.03.20030668
-1093. Multi-epitope vaccine design using an immunoinformatics approach for 2019 novel coronavirus (SARS-CoV-2)
+
1094. Multi-epitope vaccine design using an immunoinformatics approach for 2019 novel coronavirus (SARS-CoV-2)
Ye Feng, Min Qiu, Liang Liu, Shengmei Zou, Yun Li, Kai Luo, Qianpeng Guo, Ning Han, Yingqiang Sun, Kui Wang, … Fan Mo
Cold Spring Harbor Laboratory (2020-06-30) https://doi.org/ggq64c
DOI: 10.1101/2020.03.03.962332
-1094. Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19) in Shanghai, China
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1095. Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19) in Shanghai, China
Min Cao, Dandan Zhang, Youhua Wang, Yunfei Lu, Xiangdong Zhu, Ying Li, Honghao Xue, Yunxiao Lin, Min Zhang, Yiguo Sun, … Hongzhou Lu
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq64d
DOI: 10.1101/2020.03.04.20030395 · PMID: 32511465
-1095. Serological detection of 2019-nCoV respond to the epidemic: A useful complement to nucleic acid testing
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1096. Serological detection of 2019-nCoV respond to the epidemic: A useful complement to nucleic acid testing
Jin Zhang, Jianhua Liu, Na Li, Yong Liu, Rui Ye, Xiaosong Qin, Rui Zheng
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq64f
DOI: 10.1101/2020.03.04.20030916
-1096. Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection
+
1097. Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection
Bo Diao, Chenhui Wang, Rongshuai Wang, Zeqing Feng, Yingjun Tan, Huiming Wang, Changsong Wang, Liang Liu, Ying Liu, Yueping Liu, … Yongwen Chen
Cold Spring Harbor Laboratory (2020-04-10) https://doi.org/ggq64g
DOI: 10.1101/2020.03.04.20031120
-1097. COVID-19 early warning score: a multi-parameter screening tool to identify highly suspected patients
+
1098. COVID-19 early warning score: a multi-parameter screening tool to identify highly suspected patients
Cong-Ying Song, Jia Xu, Jian-Qin He, Yuan-Qiang Lu
Cold Spring Harbor Laboratory (2020-03-08) https://doi.org/ggq64h
DOI: 10.1101/2020.03.05.20031906
-1098. LY6E impairs coronavirus fusion and confers immune control of viral disease
+
1099. LY6E impairs coronavirus fusion and confers immune control of viral disease
Stephanie Pfaender, Katrina B. Mar, Eleftherios Michailidis, Annika Kratzel, Dagny Hirt, Philip V’kovski, Wenchun Fan, Nadine Ebert, Hanspeter Stalder, Hannah Kleine-Weber, … Volker Thiel
Cold Spring Harbor Laboratory (2020-03-07) https://doi.org/dpvn
DOI: 10.1101/2020.03.05.979260 · PMID: 32511345
-1099. A preliminary study on serological assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 238 admitted hospital patients
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1100. A preliminary study on serological assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 238 admitted hospital patients
Lei Liu, Wanbing Liu, Yaqiong Zheng, Xiaojing Jiang, Guomei Kou, Jinya Ding, Qiongshu Wang, Qianchuan Huang, Yinjuan Ding, Wenxu Ni, … Shangen Zheng
Cold Spring Harbor Laboratory (2020-03-08) https://doi.org/ggq64j
DOI: 10.1101/2020.03.06.20031856
-1100. Monoclonal antibodies for the S2 subunit of spike of SARS-CoV cross-react with the newly-emerged SARS-CoV-2
+
1101. Monoclonal antibodies for the S2 subunit of spike of SARS-CoV cross-react with the newly-emerged SARS-CoV-2
Zhiqiang Zheng, Vanessa M. Monteil, Sebastian Maurer-Stroh, Chow Wenn Yew, Carol Leong, Nur Khairiah Mohd-Ismail, Suganya Cheyyatraivendran Arularasu, Vincent Tak Kwong Chow, Raymond Lin Tzer Pin, Ali Mirazimi, … Yee-Joo Tan
Cold Spring Harbor Laboratory (2020-03-07) https://doi.org/ggrbj7
DOI: 10.1101/2020.03.06.980037
-1101. Mortality of COVID-19 is Associated with Cellular Immune Function Compared to Immune Function in Chinese Han Population
+
1102. Mortality of COVID-19 is Associated with Cellular Immune Function Compared to Immune Function in Chinese Han Population
Qiang Zeng, Yong-zhe Li, Gang Huang, Wei Wu, Sheng-yong Dong, Yang Xu
Cold Spring Harbor Laboratory (2020-03-13) https://doi.org/ggq64k
DOI: 10.1101/2020.03.08.20031229
-1102. Retrospective Analysis of Clinical Features in 101 Death Cases with COVID-19
+
1103. Retrospective Analysis of Clinical Features in 101 Death Cases with COVID-19
Hua Fan, Lin Zhang, Bin Huang, Muxin Zhu, Yong Zhou, Huan Zhang, Xiaogen Tao, Shaohui Cheng, Wenhu Yu, Liping Zhu, Jian Chen
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq64n
DOI: 10.1101/2020.03.09.20033068
-1103. Relationship between the ABO Blood Group and the COVID-19 Susceptibility
+
1104. Relationship between the ABO Blood Group and the COVID-19 Susceptibility
Jiao Zhao, Yan Yang, Hanping Huang, Dong Li, Dongfeng Gu, Xiangfeng Lu, Zheng Zhang, Lei Liu, Ting Liu, Yukun Liu, … Peng George Wang
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggpn3d
DOI: 10.1101/2020.03.11.20031096
-1104. The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15
+
1105. The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15
Shutoku Matsuyama, Miyuki Kawase, Naganori Nao, Kazuya Shirato, Makoto Ujike, Wataru Kamitani, Masayuki Shimojima, Shuetsu Fukushi
Cold Spring Harbor Laboratory (2020-03-12) https://doi.org/ggq64p
DOI: 10.1101/2020.03.11.987016
-1105. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19
+
1106. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19
Bicheng Zhang, Xiaoyang Zhou, Chengliang Zhu, Fan Feng, Yanru Qiu, Jia Feng, Qingzhu Jia, Qibin Song, Bo Zhu, Jun Wang
Cold Spring Harbor Laboratory (2020-03-16) https://doi.org/ggq64q
DOI: 10.1101/2020.03.12.20035048
-1106. Lack of Reinfection in Rhesus Macaques Infected with SARS-CoV-2
+
1107. Lack of Reinfection in Rhesus Macaques Infected with SARS-CoV-2
Linlin Bao, Wei Deng, Hong Gao, Chong Xiao, Jiayi Liu, Jing Xue, Qi Lv, Jiangning Liu, Pin Yu, Yanfeng Xu, … Chuan Qin
Cold Spring Harbor Laboratory (2020-05-01) https://doi.org/ggn8r8
DOI: 10.1101/2020.03.13.990226
-1107. A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV
+
1108. A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV
Meng Yuan, Nicholas C. Wu, Xueyong Zhu, Chang-Chun D. Lee, Ray T. Y. So, Huibin Lv, Chris K. P. Mok, Ian A. Wilson
Cold Spring Harbor Laboratory (2020-03-14) https://doi.org/ggq64s
DOI: 10.1101/2020.03.13.991570
-1108. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein
+
1109. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein
Ke Wang, Wei Chen, Yu-Sen Zhou, Jian-Qi Lian, Zheng Zhang, Peng Du, Li Gong, Yang Zhang, Hong-Yong Cui, Jie-Jie Geng, … Zhi-Nan Chen
Cold Spring Harbor Laboratory (2020-03-14) https://doi.org/ggq64t
DOI: 10.1101/2020.03.14.988345
-1109. CD147 (EMMPRIN/Basigin) in kidney diseases: from an inflammation and immune system viewpoint
+
1110. CD147 (EMMPRIN/Basigin) in kidney diseases: from an inflammation and immune system viewpoint
Tomoki Kosugi, Kayaho Maeda, Waichi Sato, Shoichi Maruyama, Kenji Kadomatsu
Nephrology Dialysis Transplantation (2015-07) https://doi.org/ggq624
DOI: 10.1093/ndt/gfu302 · PMID: 25248362
-1110. The roles of CyPA and CD147 in cardiac remodelling
+
1111. The roles of CyPA and CD147 in cardiac remodelling
Hongyan Su, Yi Yang
Experimental and Molecular Pathology (2018-06) https://doi.org/ggq622
DOI: 10.1016/j.yexmp.2018.05.001 · PMID: 29772453
-1111. Cancer-related issues of CD147.
+
1112. Cancer-related issues of CD147.
Ulrich H Weidle, Werner Scheuer, Daniela Eggle, Stefan Klostermann, Hannes Stockinger
Cancer genomics & proteomics https://www.ncbi.nlm.nih.gov/pubmed/20551248
PMID: 20551248
-1112. Blood single cell immune profiling reveals the interferon-MAPK pathway mediated adaptive immune response for COVID-19
+
1113. Blood single cell immune profiling reveals the interferon-MAPK pathway mediated adaptive immune response for COVID-19
Lulin Huang, Yi Shi, Bo Gong, Li Jiang, Xiaoqi Liu, Jialiang Yang, Juan Tang, Chunfang You, Qi Jiang, Bo Long, … Zhenglin Yang
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq64v
DOI: 10.1101/2020.03.15.20033472
-1113. Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections
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1114. Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections
Huibin Lv, Nicholas C. Wu, Owen Tak-Yin Tsang, Meng Yuan, Ranawaka A. P. M. Perera, Wai Shing Leung, Ray T. Y. So, Jacky Man Chun Chan, Garrick K. Yip, Thomas Shiu Hong Chik, … Chris K. P. Mok
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq64w
DOI: 10.1101/2020.03.15.993097 · PMID: 32511317
-1114. The feasibility of convalescent plasma therapy in severe COVID- 19 patients: a pilot study
+
1115. The feasibility of convalescent plasma therapy in severe COVID- 19 patients: a pilot study
Kai Duan, Bende Liu, Cesheng Li, Huajun Zhang, Ting Yu, Jieming Qu, Min Zhou, Li Chen, Shengli Meng, Yong Hu, … Xiaoming Yang
Cold Spring Harbor Laboratory (2020-03-23) https://doi.org/dqrs
DOI: 10.1101/2020.03.16.20036145
-1115. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial
+
1116. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial
Philippe Gautret, Jean-Christophe Lagier, Philippe Parola, Van Thuan Hoang, Line Meddeb, Morgane Mailhe, Barbara Doudier, Johan Courjon, Valérie Giordanengo, Vera Esteves Vieira, … Didier Raoult
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/dqbv
DOI: 10.1101/2020.03.16.20037135
-1116. Chloroquine: Modes of action of an undervalued drug
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1117. Chloroquine: Modes of action of an undervalued drug
Rodolfo Thomé, Stefanie Costa Pinto Lopes, Fabio Trindade Maranhão Costa, Liana Verinaud
Immunology Letters (2013-06) https://doi.org/f5b5cr
DOI: 10.1016/j.imlet.2013.07.004 · PMID: 23891850
-1117. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy
+
1118. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy
B. Lo, K. Zhang, W. Lu, L. Zheng, Q. Zhang, C. Kanellopoulou, Y. Zhang, Z. Liu, J. M. Fritz, R. Marsh, … M. B. Jordan
Science (2015-07-23) https://doi.org/f7kc8d
DOI: 10.1126/science.aaa1663 · PMID: 26206937
-1118. The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2
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1119. The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2
Erik Procko
Cold Spring Harbor Laboratory (2020-05-11) https://doi.org/ggrbj8
DOI: 10.1101/2020.03.16.994236 · PMID: 32511321
-1119. Comparative Pathogenesis Of COVID-19, MERS And SARS In A Non-Human Primate Model
+
1120. Comparative Pathogenesis Of COVID-19, MERS And SARS In A Non-Human Primate Model
Barry Rockx, Thijs Kuiken, Sander Herfst, Theo Bestebroer, Mart M. Lamers, Dennis de Meulder, Geert van Amerongen, Judith van den Brand, Nisreen M. A. Okba, Debby Schipper, … Bart L. Haagmans
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq649
DOI: 10.1101/2020.03.17.995639
-1120. Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus
+
1121. Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus
Paul B. McCray, Lecia Pewe, Christine Wohlford-Lenane, Melissa Hickey, Lori Manzel, Lei Shi, Jason Netland, Hong Peng Jia, Carmen Halabi, Curt D. Sigmund, … Stanley Perlman
Journal of Virology (2007-01-15) https://doi.org/b2dr3s
DOI: 10.1128/jvi.02012-06 · PMID: 17079315 · PMCID: PMC1797474
-1121. Modeling the Impact of Asymptomatic Carriers on COVID-19 Transmission Dynamics During Lockdown
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1122. Modeling the Impact of Asymptomatic Carriers on COVID-19 Transmission Dynamics During Lockdown
Jacob B. Aguilar, Jeremy Samuel Faust, Lauren M. Westafer, Juan B. Gutierrez
Cold Spring Harbor Laboratory (2020-08-11) https://doi.org/ggqnvp
DOI: 10.1101/2020.03.18.20037994
-1122. Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice
+
1123. Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice
Quan-xin Long, Hai-jun Deng, Juan Chen, Jie-li Hu, Bei-zhong Liu, Pu Liao, Yong Lin, Li-hua Yu, Zhan Mo, Yin-yin Xu, … Ai-long Huang
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggpvz3
DOI: 10.1101/2020.03.18.20038018
-1123. Heat inactivation of serum interferes with the immunoanalysis of antibodies to SARS-CoV-2
+
1124. Heat inactivation of serum interferes with the immunoanalysis of antibodies to SARS-CoV-2
Xiumei Hu, Taixue An, Bo Situ, Yuhai Hu, Zihao Ou, Qiang Li, Xiaojing He, Ye Zhang, Peifu Tian, Dehua Sun, … Lei Zheng
Cold Spring Harbor Laboratory (2020-03-16) https://doi.org/ggq646
DOI: 10.1101/2020.03.12.20034231
-1124. SARS-CoV-2 specific antibody responses in COVID-19 patients
+
1125. SARS-CoV-2 specific antibody responses in COVID-19 patients
Nisreen M. A. Okba, Marcel A. Müller, Wentao Li, Chunyan Wang, Corine H. GeurtsvanKessel, Victor M. Corman, Mart M. Lamers, Reina S. Sikkema, Erwin de Bruin, Felicity D. Chandler, … Bart L. Haagmans
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggpvz2
DOI: 10.1101/2020.03.18.20038059
-1125. A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19
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1126. A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19
Drifa Belhadi, Nathan Peiffer-Smadja, François-Xavier Lescure, Yazdan Yazdanpanah, France Mentré, Cédric Laouénan
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65b
DOI: 10.1101/2020.03.18.20038190
-1126. ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19
+
1127. ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19
Janice M. Leung, Chen X. Yang, Anthony Tam, Tawimas Shaipanich, Tillie-Louise Hackett, Gurpreet K. Singhera, Delbert R. Dorscheid, Don D. Sin
Cold Spring Harbor Laboratory (2020-03-23) https://doi.org/dqx2
DOI: 10.1101/2020.03.18.20038455
-1127. Dynamic profile of severe or critical COVID-19 cases
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1128. Dynamic profile of severe or critical COVID-19 cases
Yang Xu
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggrbj9
DOI: 10.1101/2020.03.18.20038513
-1128. Association between Clinical, Laboratory and CT Characteristics and RT-PCR Results in the Follow-up of COVID-19 patients
+
1129. Association between Clinical, Laboratory and CT Characteristics and RT-PCR Results in the Follow-up of COVID-19 patients
Hang Fu, Huayan Xu, Na Zhang, Hong Xu, Zhenlin Li, Huizhu Chen, Rong Xu, Ran Sun, Lingyi Wen, Linjun Xie, … Yingkun Guo
Cold Spring Harbor Laboratory (2020-03-23) https://doi.org/ggq65c
DOI: 10.1101/2020.03.19.20038315
-1129. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus
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1130. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus
Timothy P. Sheahan, Amy C. Sims, Shuntai Zhou, Rachel L. Graham, Collin S. Hill, Sarah R. Leist, Alexandra Schäfer, Kenneth H. Dinnon, Stephanie A. Montgomery, Maria L. Agostini, … Ralph S. Baric
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggrbkb
DOI: 10.1101/2020.03.19.997890
-1130. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs
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1131. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs
Sangeun Jeon, Meehyun Ko, Jihye Lee, Inhee Choi, Soo Young Byun, Soonju Park, David Shum, Seungtaek Kim
Cold Spring Harbor Laboratory (2020-03-28) https://doi.org/ggq65h
DOI: 10.1101/2020.03.20.999730
-1131. Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2
+
1132. Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2
Vincent J. Munster, Friederike Feldmann, Brandi N. Williamson, Neeltje van Doremalen, Lizzette Pérez-Pérez, Jonathan Schulz, Kimberly Meade-White, Atsushi Okumura, Julie Callison, Beniah Brumbaugh, … Emmie de Wit
Cold Spring Harbor Laboratory (2020-03-21) https://doi.org/ggq65j
DOI: 10.1101/2020.03.21.001628 · PMID: 32511299
-1132. Ocular conjunctival inoculation of SARS-CoV-2 can cause mild COVID-19 in Rhesus macaques
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1133. Ocular conjunctival inoculation of SARS-CoV-2 can cause mild COVID-19 in Rhesus macaques
Wei Deng, Linlin Bao, Hong Gao, Zhiguang Xiang, Yajin Qu, Zhiqi Song, Shunran Gong, Jiayi Liu, Jiangning Liu, Pin Yu, … Chuan Qin
Cold Spring Harbor Laboratory (2020-03-30) https://doi.org/ggq64r
DOI: 10.1101/2020.03.13.990036
-1133. ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19
+
1134. ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19
Bruna G. G. Pinto, Antonio E. R. Oliveira, Youvika Singh, Leandro Jimenez, Andre N A. Gonçalves, Rodrigo L. T. Ogava, Rachel Creighton, Jean Pierre Schatzmann Peron, Helder I. Nakaya
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65k
DOI: 10.1101/2020.03.21.20040261 · PMID: 32511627
-1134. Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial
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1135. Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial
Huijie Bian, Zhao-Hui Zheng, Ding Wei, Zheng Zhang, Wen-Zhen Kang, Chun-Qiu Hao, Ke Dong, Wen Kang, Jie-Lai Xia, Jin-Lin Miao, … Ping Zhu
Cold Spring Harbor Laboratory (2020-07-15) https://doi.org/ggq65m
DOI: 10.1101/2020.03.21.20040691
-1135. CD147 facilitates HIV-1 infection by interacting with virus-associated cyclophilin A
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1136. CD147 facilitates HIV-1 infection by interacting with virus-associated cyclophilin A
T. Pushkarsky, G. Zybarth, L. Dubrovsky, V. Yurchenko, H. Tang, H. Guo, B. Toole, B. Sherry, M. Bukrinsky
Proceedings of the National Academy of Sciences (2001-05-15) https://doi.org/cc4c7p
DOI: 10.1073/pnas.111583198 · PMID: 11353871 · PMCID: PMC33473
-1136. CD147/EMMPRIN Acts as a Functional Entry Receptor for Measles Virus on Epithelial Cells
+
1137. CD147/EMMPRIN Acts as a Functional Entry Receptor for Measles Virus on Epithelial Cells
Akira Watanabe, Misako Yoneda, Fusako Ikeda, Yuri Terao-Muto, Hiroki Sato, Chieko Kai
Journal of Virology (2010-05-01) https://doi.org/dpcsqg
DOI: 10.1128/jvi.02168-09 · PMID: 20147391 · PMCID: PMC2863760
-1137. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum
+
1138. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum
Cécile Crosnier, Leyla Y. Bustamante, S. Josefin Bartholdson, Amy K. Bei, Michel Theron, Makoto Uchikawa, Souleymane Mboup, Omar Ndir, Dominic P. Kwiatkowski, Manoj T. Duraisingh, … Gavin J. Wright
Nature (2011-11-09) https://doi.org/dm59hf
DOI: 10.1038/nature10606 · PMID: 22080952 · PMCID: PMC3245779
-1138. Function of HAb18G/CD147 in Invasion of Host Cells by Severe Acute Respiratory Syndrome Coronavirus
+
1139. Function of HAb18G/CD147 in Invasion of Host Cells by Severe Acute Respiratory Syndrome Coronavirus
Zhinan Chen, Li Mi, Jing Xu, Jiyun Yu, Xianhui Wang, Jianli Jiang, Jinliang Xing, Peng Shang, Airong Qian, Yu Li, … Ping Zhu
The Journal of Infectious Diseases (2005-03) https://doi.org/cd8snd
DOI: 10.1086/427811 · PMID: 15688292 · PMCID: PMC7110046
-1139. CD147 mediates intrahepatic leukocyte aggregation and determines the extent of liver injury
+
1140. CD147 mediates intrahepatic leukocyte aggregation and determines the extent of liver injury
Christine Yee, Nathan M. Main, Alexandra Terry, Igor Stevanovski, Annette Maczurek, Alison J. Morgan, Sarah Calabro, Alison J. Potter, Tina L. Iemma, David G. Bowen, … Nicholas A. Shackel
PLOS ONE (2019-07-10) https://doi.org/ggq654
DOI: 10.1371/journal.pone.0215557 · PMID: 31291257 · PMCID: PMC6619953
-1140. Characterisation of the transcriptome and proteome of SARS-CoV-2 using direct RNA sequencing and tandem mass spectrometry reveals evidence for a cell passage induced in-frame deletion in the spike glycoprotein that removes the furin-like cleavage site
+
1141. Characterisation of the transcriptome and proteome of SARS-CoV-2 using direct RNA sequencing and tandem mass spectrometry reveals evidence for a cell passage induced in-frame deletion in the spike glycoprotein that removes the furin-like cleavage site
Andrew D. Davidson, Maia Kavanagh Williamson, Sebastian Lewis, Deborah Shoemark, Miles W. Carroll, Kate Heesom, Maria Zambon, Joanna Ellis, Phillip A. Lewis, Julian A. Hiscox, David A. Matthews
Cold Spring Harbor Laboratory (2020-03-24) https://doi.org/ggq65n
DOI: 10.1101/2020.03.22.002204
-1141. Modifications to the Hemagglutinin Cleavage Site Control the Virulence of a Neurotropic H1N1 Influenza Virus
+
1142. Modifications to the Hemagglutinin Cleavage Site Control the Virulence of a Neurotropic H1N1 Influenza Virus
Xiangjie Sun, Longping V. Tse, A Damon Ferguson, Gary R. Whittaker
Journal of Virology (2010-09-01) https://doi.org/drs2zt
DOI: 10.1128/jvi.00797-10 · PMID: 20554779 · PMCID: PMC2919019
-1142. The architecture of SARS-CoV-2 transcriptome
+
1143. The architecture of SARS-CoV-2 transcriptome
Dongwan Kim, Joo-Yeon Lee, Jeong-Sun Yang, Jun Won Kim, V. Narry Kim, Hyeshik Chang
Cold Spring Harbor Laboratory (2020-03-14) https://doi.org/ggpx9q
DOI: 10.1101/2020.03.12.988865
-1143. First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naïve and Experienced COVID-19 Patients
+
1144. First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naïve and Experienced COVID-19 Patients
Hongyi Chen, Zhicheng Zhang, Li Wang, Zhihua Huang, Fanghua Gong, Xiaodong Li, Yahong Chen, Jinzi J. Wu
Cold Spring Harbor Laboratory (2020-03-24) https://doi.org/ggrgbt
DOI: 10.1101/2020.03.22.20034041
-1144. Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)
+
1145. Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)
Scott D. Seiwert, Steven W. Andrews, Yutong Jiang, Vladimir Serebryany, Hua Tan, Karl Kossen, P. T. Ravi Rajagopalan, Shawn Misialek, Sarah K. Stevens, Antitsa Stoycheva, … Lawrence M. Blatt
Antimicrobial Agents and Chemotherapy (2008-12) https://doi.org/btpg52
DOI: 10.1128/aac.00699-08 · PMID: 18824605 · PMCID: PMC2592891
-1145. Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China
+
1146. Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China
Xiaoyuan Xu, Bo Feng, Yujuan Guan, Sujun Zheng, Jifang Sheng, Xingxiang Yang, Yuanji Ma, Yan Huang, Yi Kang, Xiaofeng Wen, … Lai Wei
Journal of Clinical and Translational Hepatology (2019-09-30) https://doi.org/ggrbkd
DOI: 10.14218/jcth.2019.00033 · PMID: 31608212 · PMCID: PMC6783683
-1146. Potentially highly potent drugs for 2019-nCoV
+
1147. Potentially highly potent drugs for 2019-nCoV
Duc Duy Nguyen, Kaifu Gao, Jiahui Chen, Rui Wang, Guo-Wei Wei
Cold Spring Harbor Laboratory (2020-02-13) https://doi.org/ggrbj5
DOI: 10.1101/2020.02.05.936013 · PMID: 32511344
-1147. Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset
+
1148. Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset
Bin Lou, Ting-Dong Li, Shu-Fa Zheng, Ying-Ying Su, Zhi-Yong Li, Wei Liu, Fei Yu, Sheng-Xiang Ge, Qian-Da Zou, Quan Yuan, … Yu Chen
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggrbkc
DOI: 10.1101/2020.03.23.20041707
-1148. SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems
+
1149. SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems
Daniel Blanco-Melo, Benjamin E. Nilsson-Payant, Wen-Chun Liu, Rasmus Møller, Maryline Panis, David Sachs, Randy A. Albrecht, Benjamin R. tenOever
Cold Spring Harbor Laboratory (2020-03-24) https://doi.org/ggq65q
DOI: 10.1101/2020.03.24.004655
-1149. A New Predictor of Disease Severity in Patients with COVID-19 in Wuhan, China
+
1150. A New Predictor of Disease Severity in Patients with COVID-19 in Wuhan, China
Ying Zhou, Zhen Yang, Yanan Guo, Shuang Geng, Shan Gao, Shenglan Ye, Yi Hu, Yafei Wang
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65r
DOI: 10.1101/2020.03.24.20042119
-1150. Metabolic disturbances and inflammatory dysfunction predict severity of coronavirus disease 2019 (COVID-19): a retrospective study
+
1151. Metabolic disturbances and inflammatory dysfunction predict severity of coronavirus disease 2019 (COVID-19): a retrospective study
Shuke Nie, Xueqing Zhao, Kang Zhao, Zhaohui Zhang, Zhentao Zhang, Zhan Zhang
Cold Spring Harbor Laboratory (2020-03-26) https://doi.org/ggq65s
DOI: 10.1101/2020.03.24.20042283
-1151. Viral Kinetics and Antibody Responses in Patients with COVID-19
+
1152. Viral Kinetics and Antibody Responses in Patients with COVID-19
Wenting Tan, Yanqiu Lu, Juan Zhang, Jing Wang, Yunjie Dan, Zhaoxia Tan, Xiaoqing He, Chunfang Qian, Qiangzhong Sun, Qingli Hu, … Guohong Deng
Cold Spring Harbor Laboratory (2020-03-26) https://doi.org/ggq65t
DOI: 10.1101/2020.03.24.20042382
-1152. Global profiling of SARS-CoV-2 specific IgG/ IgM responses of convalescents using a proteome microarray
+
1153. Global profiling of SARS-CoV-2 specific IgG/ IgM responses of convalescents using a proteome microarray
He-wei Jiang, Yang Li, Hai-nan Zhang, Wei Wang, Dong Men, Xiao Yang, Huan Qi, Jie Zhou, Sheng-ce Tao
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65g
DOI: 10.1101/2020.03.20.20039495
-1153. COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome
+
1154. COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome
Dan Zhang, Rui Guo, Lei Lei, Hongjuan Liu, Yawen Wang, Yili Wang, Hongbo Qian, Tongxin Dai, Tianxiao Zhang, Yanjun Lai, … Jinsong Hu
Cold Spring Harbor Laboratory (2020-03-26) https://doi.org/ggq65v
DOI: 10.1101/2020.03.24.20042655
-1154. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study
+
1155. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study
Aaron Miller, Mac Josh Reandelar, Kimberly Fasciglione, Violeta Roumenova, Yan Li, Gonzalo H. Otazu
Cold Spring Harbor Laboratory (2020-03-28) https://doi.org/ggq65w
DOI: 10.1101/2020.03.24.20042937
-1155. Non-specific effects of BCG vaccine on viral infections
+
1156. Non-specific effects of BCG vaccine on viral infections
S. J. C. F. M. Moorlag, R. J. W. Arts, R. van Crevel, M. G. Netea
Clinical Microbiology and Infection (2019-12) https://doi.org/ggq62z
DOI: 10.1016/j.cmi.2019.04.020 · PMID: 31055165
-1156. BCG vaccination to reduce the impact of COVID-19 in healthcare workers (The BRACE Trial)
+
1157. BCG vaccination to reduce the impact of COVID-19 in healthcare workers (The BRACE Trial)
Murdoch Children’s Research Institute
https://www.mcri.edu.au/BRACE
-1157. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia
+
1158. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia
David H. Brann, Tatsuya Tsukahara, Caleb Weinreb, Marcela Lipovsek, Koen Van den Berge, Boying Gong, Rebecca Chance, Iain C. Macaulay, Hsin-jung Chou, Russell Fletcher, … Sandeep Robert Datta
Cold Spring Harbor Laboratory (2020-05-18) https://doi.org/ggqr4m
DOI: 10.1101/2020.03.25.009084
-1158. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract
+
1159. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract
Joan C. Smith, Erin L. Sausville, Vishruth Girish, Monet Lou Yuan, Kristen M. John, Jason M. Sheltzer
Cold Spring Harbor Laboratory (2020-04-26) https://doi.org/ggq65x
DOI: 10.1101/2020.03.28.013672
-1159. The comparative superiority of IgM-IgG antibody test to real-time reverse transcriptase PCR detection for SARS-CoV-2 infection diagnosis
+
1160. The comparative superiority of IgM-IgG antibody test to real-time reverse transcriptase PCR detection for SARS-CoV-2 infection diagnosis
Rui Liu, Xinghui Liu, Huan Han, Muhammad Adnan Shereen, Zhili Niu, Dong Li, Fang Liu, Kailang Wu, Zhen Luo, Chengliang Zhu
Cold Spring Harbor Laboratory (2020-03-30) https://doi.org/ggqtp5
DOI: 10.1101/2020.03.28.20045765
@@ -10360,7 +10366,7 @@
In the case of COVID-19, there is also concern about the immune system becoming over-active. One of the main immune responses contributing to the onset of acute respiratory distress syndrome (ARDS) in COVID-19 patients is cytokine storm syndrome (CSS), which causes an extreme inflammatory response due to a release of pro-inflammatory cytokines and chemokines by immune effector cells. -In addition to respiratory distress, this mechanism can lead to organ failure and death in severe COVID-19 cases [33].
+In addition to respiratory distress, this mechanism can lead to organ failure and death in severe COVID-19 cases [35].4.3 Molecular Tests
Molecular tests are used to identify distinct genomic subsequences of a viral molecule in a sample and thus to diagnose an active viral infection. This first requires identifying which biospecimens are likely to contain the virus during infection and then acquiring these samples from the patient(s) to be tested. -Common sampling sources for molecular tests include nasopharyngeal cavity samples, such as throat wash and saliva [310], and stool samples [311]. +Common sampling sources for molecular tests include nasopharyngeal cavity samples, such as throat wash and saliva [312], and stool samples [313]. Once a sample is acquired from a patient, molecular testing will utilize a number of steps, described below, to analyze a sample and identify whether evidence of SARS-CoV-2 is present. When testing for RNA viruses like SARS-CoV-2, pre-processing is necessary in order to create DNA from the RNA sample. The DNA can then be amplified with PCR. Some tests use the results of the PCR itself to determine whether the pathogen is present, but in other cases, it may be necessary to sequence the amplified DNA. Sequencing requires an additional pre-processing step: library preparation. -Library preparation is the process of preparing the sample for sequencing, typically by fragmenting the sequences and adding adapters [312]. +Library preparation is the process of preparing the sample for sequencing, typically by fragmenting the sequences and adding adapters [314]. In some cases, library preparation can involve other modifications of the sample, such as adding “barcoding” to identify a particular sample in the sequence data, which is useful for pooling samples from multiple sources. -There are different reagents used for library preparation that are specific to identifying one or more target sections with PCR [313]. +There are different reagents used for library preparation that are specific to identifying one or more target sections with PCR [315]. Sequential pattern matching is then used to identify unique subsequences of the virus that identify it in specific. If sufficient subsequences are found, the test is considered positive.
4.3.1 RT-PCR
Real-Time Polymerase Chain Reaction (RT-PCR) tests determine whether a target is present by measuring the rate of amplification during PCR compared to a standard. When the target is RNA, such as in the case of RNA viruses, the RNA must be converted into complementary DNA during pre-processing. The Drosten Lab, from Germany, was the first lab to establish and validate a diagnostic test to detect SARS-CoV-2. -This test uses RT-PCR with reverse transcription [309] to detect several regions of the viral genome: the ORF1b of the RNA-dependent RNA polymerase (RdRP), the Envelope protein gene (E), and the Nucleocapsid protein gene (N). +This test uses RT-PCR with reverse transcription [311] to detect several regions of the viral genome: the ORF1b of the RNA-dependent RNA polymerase (RdRP), the Envelope protein gene (E), and the Nucleocapsid protein gene (N). In collaboration with several other labs in Europe and in China, the researchers confirmed the specificity of this test with respect to other coronaviruses against specimens from 297 patients infected with a broad range of respiratory agents. -Specifically this test utilizes two probes against RdRP, one of which is specific to SARS-CoV-2 [309]. +Specifically this test utilizes two probes against RdRP, one of which is specific to SARS-CoV-2 [311]. Importantly, this assay was not found to return false positive results.
4.3.2 qRT-PCR
-Chinese researchers developed a quantitative real-time reverse transcription PCR (qRT-PCR) test to identify two gene regions of the viral genome, ORF1b and N [314]. +
Chinese researchers developed a quantitative real-time reverse transcription PCR (qRT-PCR) test to identify two gene regions of the viral genome, ORF1b and N [316]. This assay was tested on samples coming two COVID-19 patients and a panel of positive and negative controls consisting of RNA extracted from several cultured viruses. -The assay uses the N gene to screen patients, while the ORF1b gene region is used to confirm the infection [314]. +The assay uses the N gene to screen patients, while the ORF1b gene region is used to confirm the infection [316]. In this case the test was designed to detect sequences conserved across sarbecoviruses, or viruses within the same subgenus as SARS-CoV-2. Considering that SARS-CoV-1 and SARS-CoV-2 are the only sarbecoviruses currently known to infect humans, a positive test can be assumed to indicate that the patient is infected with SARS-CoV-2. However, this test is not able to discriminate the genetics of viruses within the sarbecovirus clade.
@@ -1384,15 +1385,15 @@4.3.2.1<
Digital PCR (dPCR) is a new generation of PCR technologies offering an alternative to traditional real-time quantitative PCR.
In dPCR, a sample is partitioned into thousands of compartments, such as nanodroplets (droplet dPCR or ddPCR) or nanowells, and a PCR reaction takes place in each compartment.
This design allows for a digital read-out where each partition is either positive or negative for the nucleic acid sequence being tested for, allowing for much higher throughput.
-While dPCR equipment is not yet as common as that for RT-PCR, dPCR for DNA targets generally achieves higher sensitivity than other PCR technologies while maintaining high specificity, though sensitivity is slightly lower for RNA targets [315].
+While dPCR equipment is not yet as common as that for RT-PCR, dPCR for DNA targets generally achieves higher sensitivity than other PCR technologies while maintaining high specificity, though sensitivity is slightly lower for RNA targets [317].
High sensitivity is particularly relevant for SARS-CoV-2 detection, since low viral load in clinical samples can lead to false negatives.
-Suo et al. [316] performed a double-blind evaluation of ddPCR for SARS-CoV-2 detection on 57 samples, comprised by 43 samples from suspected positive patients and 14 from supposed convalescents, that had all tested negative for SARS-CoV-2 using RT-PCR.
+Suo et al. [318] performed a double-blind evaluation of ddPCR for SARS-CoV-2 detection on 57 samples, comprised by 43 samples from suspected positive patients and 14 from supposed convalescents, that had all tested negative for SARS-CoV-2 using RT-PCR.
Despite the initial negative results, 33 out of 35 (94.3%) patients were later clinically confirmed positive.
All of these individuals tested positive using ddPCR.
Additionally, of 14 supposed convalescents who had received two consecutive negative RT-PCR tests, nine (64.2%) tested positive for SARS-CoV-2 using ddPCR.
Two symptomatic patients tested negative with both RT-PCR and ddPCR, but were later clinically diagnosed positive, and 5 of the 14 suspected convalescents tested negative by ddPCR.
While this study did not provide a complete head-to-head comparison to RT-PCR in all aspects, e.g., no samples testing positive using RT-PCR were evaluated by ddPCR, the study shows the potential of dPCR for viral detection even in highly diluted samples.
-In a second study, Dong et al. [317] compared the results of qRT-PCR and ddPCR testing for SARS-CoV-2 in 194 samples, including 103 samples from suspected patients, 75 from contacts and close contacts, and 16 from suspected convalescents.
+In a second study, Dong et al. [319] compared the results of qRT-PCR and ddPCR testing for SARS-CoV-2 in 194 samples, including 103 samples from suspected patients, 75 from contacts and close contacts, and 16 from suspected convalescents.
Of the 103 suspected patient samples, 29 were reported as positive, 25 as negative, and 49 as suspected by qRT-PCR; all patients were later confirmed to be SARS-CoV-2 positive.
Of the qRT-PCR negative or suspected samples, a total of 61 (17 negative and 44 suspected) were later confirmed to be positive by ddPCR, improving the overall detection rate among these patients from 28.2% to 87.4%.
Of 75 patient samples from contacts and close contacts, 48 tested negative with both methods, and these patients were observed to remain healthy.
@@ -1404,43 +1405,43 @@
4.3.2.1<
Overall, these studies suggest that dPCR is a promising tool for overcoming the problem of false-negative SARS-CoV-2 testing.
4.3.3 Pooled and Automated PCR Testing
Due to limited supplies and the need for more tests, several labs have found ways to pool or otherwise strategically design tests to increase throughput.
-The first such result came from Yelin et al. [318], who found they could pool up to 32 samples in a single qPCR run.
-This was followed by larger-scale pooling with slightly different methods [319].
+The first such result came from Yelin et al. [320], who found they could pool up to 32 samples in a single qPCR run.
+This was followed by larger-scale pooling with slightly different methods [321].
Although these approaches are also PCR based, they allow for more rapid scaling and higher efficiency for testing than the initial PCR-based methods developed.
4.3.3.1 CRISPR-based Detection
Two CRISPR-associated nucleases, Cas12 and Cas13, have been used for nucleic acid detection.
Multiple assays exploiting these nucleases have emerged as potential diagnostic tools for the rapid detection of SARS-CoV-2 genetic material and therefore SARS-CoV-2 infection.
-The SHERLOCK method (Specific High-sensitivity Enzymatic Reporter unLOCKing) from Sherlock Biosciences relies on Cas13a to discriminate between inputs that differ by a single nucleotide at very low concentrations [320].
+The SHERLOCK method (Specific High-sensitivity Enzymatic Reporter unLOCKing) from Sherlock Biosciences relies on Cas13a to discriminate between inputs that differ by a single nucleotide at very low concentrations [322].
The target RNA is amplified by RT-RPA and T7 transcription, and the amplified product activates Cas13a.
The nuclease then cleaves a reporter RNA, which liberates a fluorescent dye from a quencher.
Several groups have used the SHERLOCK method to detect SARS-CoV-2 viral RNA.
-An early study reported that the method could detect 7.5 copies of viral RNA in all 10 replicates, 2.5 copies in 6 out of 10, and 1.25 copies in 2 out of 10 runs [321].
+An early study reported that the method could detect 7.5 copies of viral RNA in all 10 replicates, 2.5 copies in 6 out of 10, and 1.25 copies in 2 out of 10 runs [323].
It also reported 100% specificity and sensitivity on 114 RNA samples from clinical respiratory samples (61 suspected cases, among which 52 were confirmed and nine were ruled out by metagenomic next-generation sequencing, 17 nCoV-/HCoV+ cases and 36 samples from healthy subjects), and a reaction turnaround time of 40 minutes.
A separate study screened four designs of SHERLOCK and extensively tested the best-performing assay.
-They determined the limit of detection to be 10 copies/μl using both fluorescent and lateral flow detection [322].
+They determined the limit of detection to be 10 copies/μl using both fluorescent and lateral flow detection [324].
Lateral flow test strips are simple to use and read, but there are limitations in terms of availability and cost per test.
-Another group therefore proposed the CREST protocol (Cas13-based, Rugged, Equitable, Scalable Testing), which uses a P51 cardboard fluorescence visualizer, powered by a 9V battery, for the detection of Cas13 activity instead of immunochromatography [323].
+Another group therefore proposed the CREST protocol (Cas13-based, Rugged, Equitable, Scalable Testing), which uses a P51 cardboard fluorescence visualizer, powered by a 9V battery, for the detection of Cas13 activity instead of immunochromatography [325].
CREST can be run, from RNA sample to result, with no need for AC power or a dedicated facility, with minimal handling in approximately 2 hours.
Testing was performed on 14 nasopharyngeal swabs.
CREST picked up the same positives as the CDC-recommended TaqMan assay with the exception of one borderline sample that displayed low-quality RNA.
The DETECTR method (DNA Endonuclease-Targeted CRISPR Trans Reporter) from Mammoth Biosciences involves purification of RNA extracted from patient specimens, amplification of extracted RNAs by loop-mediated amplification, which is a rapid, isothermal nucleic acid amplification technique, and application of their Cas12-based technology.
-In their assay, guide RNAs were designed to recognize portions of sequences corresponding to the SARS-CoV-2 genome, specifically the N2 and E regions [324].
+In their assay, guide RNAs were designed to recognize portions of sequences corresponding to the SARS-CoV-2 genome, specifically the N2 and E regions [326].
In the presence of SARS-CoV-2 genetic material, sequence recognition by the guide RNAs results in double-stranded DNA cleavage by Cas12, as well as cleavage of a single-stranded DNA molecular beacon.
The cleavage of this molecular beacon acts as a colorimetric reporter that is subsequently read out in a lateral flow assay and indicates the positive presence of SARS-CoV-2 genetic material and therefore SARS-CoV-2 infection.
The 40-minute assay is considered positive if there is detection of both the E and N genes or presumptive positive if there is detection of either of them.
The assay had 95% positive predictive agreement and 100% negative predictive agreement with the US Centers for Disease Control and Prevention SARS-CoV-2 real-time RT–PCR assay.
The estimated limit of detection was 10 copies per μl reaction, versus 1 copy per μl reaction for the CDC assay.
These results have been confirmed by other DETECTR approaches.
-Using RTRPA for amplification, another group detected 10 copies of synthetic SARS-CoV-2 RNA per μl of input within 60 minutes of RNA sample preparation in a proof-of-principle evaluation [325].
+Using RTRPA for amplification, another group detected 10 copies of synthetic SARS-CoV-2 RNA per μl of input within 60 minutes of RNA sample preparation in a proof-of-principle evaluation [327].
The DETECTR protocol was improved by combining RT-RPA and CRISPR-based detection in a one-pot reaction that incubates at a single temperature, and by using dual crRNAs (which increases sensitivity).
-This new assay, known as All-In-One Dual CRISPR-Cas12a (AIOD-CRISPR), detected 4.6 copies of SARS-CoV-2 RNA per μl of input in 40 minutes [326].
-Another single-tube, constant-temperature approach using Cas12b instead of Cas12a achieved a detection limit of 5 copies/μl in 40-60 minutes [327].
-It was also reported that electric field gradients can be used to control and accelerate CRISPR assays by co-focusing Cas12-gRNA, reporters, and target [328].
+This new assay, known as All-In-One Dual CRISPR-Cas12a (AIOD-CRISPR), detected 4.6 copies of SARS-CoV-2 RNA per μl of input in 40 minutes [328].
+Another single-tube, constant-temperature approach using Cas12b instead of Cas12a achieved a detection limit of 5 copies/μl in 40-60 minutes [329].
+It was also reported that electric field gradients can be used to control and accelerate CRISPR assays by co-focusing Cas12-gRNA, reporters, and target [330].
The authors generated an appropriate electric field gradient using a selective ionic focusing technique known as isotachophoresis (ITP) implemented on a microfluidic chip.
They also used ITP for automated purification of target RNA from raw nasopharyngeal swab samples.
Combining this ITP purification with loop-mediated isothermal amplification, their ITP-enhanced assay to achieved detection of SARS-CoV-2 RNA (from raw sample to result) in 30 minutes.
There is an increasing body of evidence that CRISPR-based assays offer a practical solution for rapid, low-barrier testing in areas that are at greater risk of infection, such as airports and local community hospitals.
-In the largest study to date, DETECTR was compared to qRT-PCR on 378 patient samples [329].
+In the largest study to date, DETECTR was compared to qRT-PCR on 378 patient samples [331].
The authors reported a 95% reproducibility.
Both techniques were equally sensitive in detecting SARS-CoV-2.
Lateral flow strips showed a 100% correlation to the high-throughput DETECTR assay.
@@ -1451,26 +1452,26 @@
False-negative responses, which can present a significant problem to large-scale testing.
-To reduce occurrence of false negatives, correct execution of the analysis is crucial [330].
-Uncertainty surrounding the SARS-CoV-2 viral shedding kinetics, which could affect the result of a test depending on when it was taken [330].
-Type of specimen, as it is not clear which clinical samples are best for detecting the virus [330].
-Expensive machinery, which might be present in major hospitals and/or diagnostic centers but is often not available to smaller facilities [331].
-Timing of the test, which might take up to 4 days to return results [331].
-The availability of supplies for testing, including swabs and testing media, has been limited [332].
+To reduce occurrence of false negatives, correct execution of the analysis is crucial [332].
+Uncertainty surrounding the SARS-CoV-2 viral shedding kinetics, which could affect the result of a test depending on when it was taken [332].
+Type of specimen, as it is not clear which clinical samples are best for detecting the virus [332].
+Expensive machinery, which might be present in major hospitals and/or diagnostic centers but is often not available to smaller facilities [333].
+Timing of the test, which might take up to 4 days to return results [333].
+The availability of supplies for testing, including swabs and testing media, has been limited [334].
Because the guide RNA can recognize other interspersed sequences on the patient’s genome, false positives and a loss of specificity can occur.
Similarly, in tests that use CRISPR, false positives can occur due to the specificity of the technique, as the guide RNA can recognize other interspersed sequences on the patient’s genome.
As noted above, false negatives are a significant concern for several reason.
-Importantly, clinical reports indicate that it is imperative to exercise caution when interpreting the results of molecular tests for SARS-CoV-2 because negative results do not necessarily mean a patient is virus-free [333].
+Importantly, clinical reports indicate that it is imperative to exercise caution when interpreting the results of molecular tests for SARS-CoV-2 because negative results do not necessarily mean a patient is virus-free [335].
4.4 Serological Tests
Although diagnostic tests based on the detection of genetic material can be quite sensitive, they cannot provide information about the extent of the disease over time.
Most importantly, they would not work on a patient who has fully recovered from the virus at the time of sample collection.
In this context, serological tests, which use serum to test for the presence of antibodies against SARS-CoV-2, are significantly more informative.
Additionally, serological tests can help scientists to understand why the disease has a different course among patients, as well as which strategies might work to manage the spread of the infection.
Furthermore, serological tests hold significant interest because of the possibility that they could provide information relevant to advancing economic recovery and allowing reopenings.
-For instance, people that had developed antibodies might be able to return to work, assuming (still-unproven) protective immunity [334].
+For instance, people that had developed antibodies might be able to return to work, assuming (still-unproven) protective immunity [336].
Some infectious agents can be controlled through “herd immunity”, which is when a critical mass within the population acquires immunity through vaccination and/or infection, preventing an infectious agent from spreading widely.
-A simple SIR model predicts that to achieve the required level of exposure for herd immunity to be effective, at least (1-(1/R0)) fraction of the population must be immune or, equivalently, less than (1/R0) fraction of the population susceptible [223].
+A simple SIR model predicts that to achieve the required level of exposure for herd immunity to be effective, at least (1-(1/R0)) fraction of the population must be immune or, equivalently, less than (1/R0) fraction of the population susceptible [225].
However, for SARS-CoV-2 and COVID-19, the R0 and mortality rates that have been observed suggest that relying on herd immunity without some combination of vaccines, proven treatment options, and strong non-pharmaceutical measures of prevention and control would likely result in a significant loss of life.
4.4.1 Sustained Immunity to COVID-19
In the process of mounting a response to a pathogen, the immune system produces antibodies specific to the pathogen.
@@ -1478,19 +1479,19 @@
[335].
-A two-year longitudinal study following convalesced SARS patients with a mean age of 29 found that IgG antibodies were detectable in all 56 patients surveyed for at least 16 months, and remained detectable in all but 4 (11.8%) of patients through the full two-year study period [336].
+IgG titers peaked by day 60, and persisted in all donors through the two-year duration of study [337].
+A two-year longitudinal study following convalesced SARS patients with a mean age of 29 found that IgG antibodies were detectable in all 56 patients surveyed for at least 16 months, and remained detectable in all but 4 (11.8%) of patients through the full two-year study period [338].
These results suggest that immunity to SARS-CoV-1 is sustained for at least a year.
The persistence of antibodies to SARS-CoV-2 remains under investigation.
-Circulating antibody titers to other coronaviruses have been reported to decline significantly after 1 year [337].
-Autopsies of lymph nodes and spleens from severe acute COVID-19 patients showed a loss of T follicular helper cells and germinal centers that may explain some of the impaired development of antibody responses [338].
-An early study (initially released on medRxiv on February 25, 2020) presented a chemiluminescence immunoassay to a synthetic peptide derived from the amino acid sequence of the SARS-CoV-2 S protein [339].
+Circulating antibody titers to other coronaviruses have been reported to decline significantly after 1 year [339].
+Autopsies of lymph nodes and spleens from severe acute COVID-19 patients showed a loss of T follicular helper cells and germinal centers that may explain some of the impaired development of antibody responses [340].
+An early study (initially released on medRxiv on February 25, 2020) presented a chemiluminescence immunoassay to a synthetic peptide derived from the amino acid sequence of the SARS-CoV-2 S protein [341].
This method was highly specific to SARS-CoV-2 and detected IgM in 57.2% and IgG in 71.4% and 57.2% of sera samples from 276 confirmed COVID-19 patients.
They reported that they could detect IgG within two days of the onset of fever and were not able to detect IgM any earlier, a pattern they compared to findings in MERS.
-Since then, several trials have reported the potential protective effect of antibodies in convalescent plasma obtained from recovered COVID-19 patients to treat critically ill COVID-19 patients [340,341,342].
+Since then, several trials have reported the potential protective effect of antibodies in convalescent plasma obtained from recovered COVID-19 patients to treat critically ill COVID-19 patients [342,343,344].
-Evidence to date suggests that sustained immunity to SARS-CoV-2 occurs for a period of at least 6-8 months [343,344,345].
-One study assessed sustained immunity using 245 blood samples from 188 COVID-19 positive patients [344].
+
Evidence to date suggests that sustained immunity to SARS-CoV-2 occurs for a period of at least 6-8 months [345,346,347].
+One study assessed sustained immunity using 245 blood samples from 188 COVID-19 positive patients [346].
The samples were collected at various time points between 6 and 240 days post-symptom onset, meaning some patients were assessed longitudinally.
Of the samples, 43 were collected at least 6 months after symptom onset.
After 1 month, 98% of patients were seropositive for Spike IgG.
@@ -1498,54 +1499,54 @@
[345,346], and this study confirms these finding and shows that these cells steadily increase over the 4-5 months post-symptom onset [344].
-Likewise, nucleocapsid-specific memory B cells seem to follow a similar pattern [344].
-SARS-CoV-2 memory CD8+ T cells were also detected in 70% of 169 COVID-19 patients after 1 month [344], which is consistent with previous research [347].
+RBD-specific memory B cells had been detected in COVID-19 patients 90 days post-symptom onset in previous studies [347,348], and this study confirms these finding and shows that these cells steadily increase over the 4-5 months post-symptom onset [346].
+Likewise, nucleocapsid-specific memory B cells seem to follow a similar pattern [346].
+SARS-CoV-2 memory CD8+ T cells were also detected in 70% of 169 COVID-19 patients after 1 month [346], which is consistent with previous research [349].
However, SARS-CoV-2 memory CD8+ T cells were slightly decreased (50%) 6 months post-symptom onset.
In this same subset of COVID-19 patients, 93% of subjects had detectable levels of SARS-CoV-2 memory CD4+ T cells, of which 42% had > 1% SARS-CoV-2-specific CD4+ T cells.
At 6 months, 92% of patients were positive for SARS-CoV-2 memory CD4+ T cells.
-Indeed, the spike-specific memory CD4+ T cells abundance over time were similar to the overall SARS-CoV-2-specific CD4+ T cells [344].
-T cell immunity to SARS-CoV-2 at 6-8 months post-symptom onset has also been confirmed by others [348,349].
+Indeed, the spike-specific memory CD4+ T cells abundance over time were similar to the overall SARS-CoV-2-specific CD4+ T cells [346].
+T cell immunity to SARS-CoV-2 at 6-8 months post-symptom onset has also been confirmed by others [350,351].
In another study, T cell reactivity to SARS-CoV-2 epitopes was also detected in some individuals never before exposed to SARS-CoV-2.
-This indicates that there is potential for cross-reactive T cell recognition between SARS-CoV-2 and pre-existing circulating coronaviruses that are responsible for the “common cold” [347], but further research is required.
-There is concern that immunity may wane over time, as there several reported cases of reinfection have been confirmed via genomic analysis that revealed distinct variants of SARS-CoV-2 within a single patient [350,351,352].
+This indicates that there is potential for cross-reactive T cell recognition between SARS-CoV-2 and pre-existing circulating coronaviruses that are responsible for the “common cold” [349], but further research is required.
+There is concern that immunity may wane over time, as there several reported cases of reinfection have been confirmed via genomic analysis that revealed distinct variants of SARS-CoV-2 within a single patient [352,353,354].
Further research is required to determine the full extent to which sustained immunity can be and is typically achieved following SARS-CoV-2 infection
-Furthermore, it is unclear whether previous infection may carry repercussions in terms of disease severity for patients [353] and what implications the possibility of reinfection holds for vaccine development and the long-term efficacy of vaccines [354,355].
+Furthermore, it is unclear whether previous infection may carry repercussions in terms of disease severity for patients [355] and what implications the possibility of reinfection holds for vaccine development and the long-term efficacy of vaccines [356,357].
4.4.2 Current Approaches
-
Several countries are now focused on implementing antibody tests, and in the United States, the FDA recently approved a serological test by Cellex for use under emergency conditions [356].
-Specifically, the Cellex qSARS-CoV-2 IgG/IgM Rapid Test is a chromatographic immunoassay designed to qualitatively detect IgM and IgG antibodies against SARS-CoV-2 in the plasma (from a blood sample) of patients suspected to have developed the SARS-CoV-2 infection [356].
+
Several countries are now focused on implementing antibody tests, and in the United States, the FDA recently approved a serological test by Cellex for use under emergency conditions [358].
+Specifically, the Cellex qSARS-CoV-2 IgG/IgM Rapid Test is a chromatographic immunoassay designed to qualitatively detect IgM and IgG antibodies against SARS-CoV-2 in the plasma (from a blood sample) of patients suspected to have developed the SARS-CoV-2 infection [358].
Such tests illuminate the progression of viral disease, as IgM are the first antibodies produced by the body and indicate that the infection is active.
-Once the body has responded to the infection, IgG are produced and gradually replace IgM, indicating that the body has developed immunogenic memory [357].
-The test cassette contains a pad of SARS-CoV-2 antigens and a nitrocellulose strip with lines for each of IgG and IgM, as well as a control (goat IgG) [356].
-In a specimen that contains antibodies against the SARS-CoV-2 antigen, the antibodies will bind to the strip and be captured by the IgM and/or IgG line(s), resulting in a change of color [356].
-With this particular assay, results can be read within 15-20 minutes [356].
-Other research groups, such as the Krammer lab of the Icahn School of Medicine at Mount Sinai, proposed an ELISA test that detects IgG and IgM that react against the receptor binding domain (RBD) of the spike proteins (S) of the virus [358].
-The authors are now working to get the assay into clinical use [359].
+Once the body has responded to the infection, IgG are produced and gradually replace IgM, indicating that the body has developed immunogenic memory [359].
+The test cassette contains a pad of SARS-CoV-2 antigens and a nitrocellulose strip with lines for each of IgG and IgM, as well as a control (goat IgG) [358].
+In a specimen that contains antibodies against the SARS-CoV-2 antigen, the antibodies will bind to the strip and be captured by the IgM and/or IgG line(s), resulting in a change of color [358].
+With this particular assay, results can be read within 15-20 minutes [358].
+Other research groups, such as the Krammer lab of the Icahn School of Medicine at Mount Sinai, proposed an ELISA test that detects IgG and IgM that react against the receptor binding domain (RBD) of the spike proteins (S) of the virus [360].
+The authors are now working to get the assay into clinical use [361].
4.4.3 Limitations of Serological Tests
-Importantly, false-positives can occur due to the cross-reactivity with other antibodies according to the clinical condition of the patient [356].
-Therefore, this test should be used in combination with RNA detection tests [356].
+
Importantly, false-positives can occur due to the cross-reactivity with other antibodies according to the clinical condition of the patient [358].
+Therefore, this test should be used in combination with RNA detection tests [358].
Due to the long incubation times and delayed immune responses of infected patients, serological tests are insufficiently sensitive for a diagnosis in the early stages of an infection.
The limitations due to timing make serological tests far less useful for enabling test-and-trace strategies.
4.5 Possible Alternatives to Current Practices for Identifying Active Cases
Clinical symptoms are too similar to other types of pneumonia to be sufficient as a sole diagnostics criterion.
In addition, as noted above, identifying asymptomatic cases is critical.
-Even among mildly symptomatic patients, a predictive model based on clinical symptoms had a sensitivity of only 56% and a specificity of 91% [360].
+Even among mildly symptomatic patients, a predictive model based on clinical symptoms had a sensitivity of only 56% and a specificity of 91% [362].
More problematic is that clinical symptom-based tests are only able to identify already symptomatic cases, not presymptomatic or asymptomatic cases.
They may still be important for clinical practice, and for reducing tests needed for patients deemed unlikely to have COVID-19.
-X-ray diagnostics have been reported to have high sensitivity but low specificity in some studies [361].
-Other studies have shown that specificity varies between radiologists [362], though the sensitivity reported here was lower than that published in the previous paper.
-However, preliminary machine-learning results have shown far higher sensitivity and specificity from analyzing chest X-rays than was possible with clinical examination [363].
+
X-ray diagnostics have been reported to have high sensitivity but low specificity in some studies [363].
+Other studies have shown that specificity varies between radiologists [364], though the sensitivity reported here was lower than that published in the previous paper.
+However, preliminary machine-learning results have shown far higher sensitivity and specificity from analyzing chest X-rays than was possible with clinical examination [365].
X-ray tests with machine learning can potentially detect asymptomatic or presymptomatic infections that show lung manifestations.
This approach would still not recognize entirely asymptomatic cases.
Given the above, the widespread use of X-ray tests on otherwise healthy adults is likely inadvisable.
4.6 Strategies and Considerations for Determining Whom to Test
-Early in the COVID-19 pandemic, testing was typically limited to individuals considered high risk for developing serious illness [364].
+
Early in the COVID-19 pandemic, testing was typically limited to individuals considered high risk for developing serious illness [366].
This approach often involved limiting testing to people with severe symptoms and people showing mild symptoms that had been in contact with a person who had tested positive.
Individuals who are asymptomatic (i.e., potential spreaders) and individuals who are able to recover at home are therefore often unaware of their status.
However, this method of testing administration misses a high proportion of infections and does not allow for test-and-trace methods to be used.
-For instance, a recent study from Imperial College estimates that in Italy, the true number of infections was around 5.9 million in a total population ~60 million, compared to the 70,000 detected as of March 28th [239].
-Another analysis, which examined New York state, indicated that as of May, 2020, approximately 300,000 cases had been reported in a total population of approximately 20 million [365].
-This corresponded to ~1.5% of the population, but ~12% of individuals sampled statewide were estimated as positive through antibody tests (along with indications of spatial heterogeneity at higher resolution) [365].
+For instance, a recent study from Imperial College estimates that in Italy, the true number of infections was around 5.9 million in a total population ~60 million, compared to the 70,000 detected as of March 28th [241].
+Another analysis, which examined New York state, indicated that as of May, 2020, approximately 300,000 cases had been reported in a total population of approximately 20 million [367].
+This corresponded to ~1.5% of the population, but ~12% of individuals sampled statewide were estimated as positive through antibody tests (along with indications of spatial heterogeneity at higher resolution) [367].
Technological advancements that facilitate widespread, rapid testing will therefore improve the potential to accurately assess the rate of infection and aid in controlling the virus’ spread.
4.7 Conclusions
Major advancements have been made in identifying diagnostic approaches.
@@ -1553,11 +1554,11 @@
4.7
As of October 2020, a range of diagnostic tests have become available.
One class of tests uses PCR (RT-PCR or qRT-PCR) to assess the presence of SARS-CoV-2 RNA, while another typically uses ELISA to test for the presence of antibodies to SARS-CoV-2.
The former approach is useful for identifying active infections, while the latter measures hallmarks of the immune response and therefore can detect either active infections or immunity gained from prior infection.
-Combining these tests leads to extremely accurate detection of SARS-CoV-2 infection (98.6%), but when used alone, PCR-based tests are recommended before 5.5 days after the onset of the illness and antibody tests after 5.5 days [366].
-Other strategies for testing can also influence the tests’ accuracy, such as the use of nasopharyngeal swabs versus BALF [366], which allow for trade-offs between patient’s comfort and test sensitivity.
+Combining these tests leads to extremely accurate detection of SARS-CoV-2 infection (98.6%), but when used alone, PCR-based tests are recommended before 5.5 days after the onset of the illness and antibody tests after 5.5 days [368].
+Other strategies for testing can also influence the tests’ accuracy, such as the use of nasopharyngeal swabs versus BALF [368], which allow for trade-offs between patient’s comfort and test sensitivity.
Additionally, technologies such as digital PCR may allow for scale-up in the throughput of diagnostic testing, facilitating widespread testing.
One major question that remains is whether people who recover from SARS-CoV-2 develop sustained immunity, and over what period this immunity is expected to last.
-Some reports have suggested that some patients may develop COVID-19 reinfections (e.g., [350]), but the rates of reinfection are currently unknown.
+Some reports have suggested that some patients may develop COVID-19 reinfections (e.g., [352]), but the rates of reinfection are currently unknown.
Serologic testing combined with PCR testing will be critical to confirming purported cases of reinfection and to identifying the duration over which immunity is retained and to understanding reinfection risks.
5 Identification and Development of Prophylactics and Therapeutics for COVID-19
5.1 Abstract
@@ -1566,7 +1567,7 @@ 5.1
5.2 Importance
@@ -1578,54 +1579,54 @@ 5.2<
This rapidly changing area of research provides important insight into how the ongoing pandemic can be managed and also demonstrates the power of interdisciplinary collaboration to rapidly understand a virus and match its characteristics with existing or novel pharmaceuticals.
5.3 Introduction
The novel coronavirus Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) emerged in late 2019 and quickly precipitated the worldwide spread of novel coronavirus disease 2019 (COVID-19).
-COVID-19 is associated with symptoms ranging from none (asymptomatic) to mild to severe, with approximately 2% of patients dying from COVID-19-related complications, such as acute respiratory disease syndrome (ARDS) [367].
-The virus is likely spread between people primarily by droplets, with the role of contact and aerosol transmission still in question [194,195].
+COVID-19 is associated with symptoms ranging from none (asymptomatic) to mild to severe, with approximately 2% of patients dying from COVID-19-related complications, such as acute respiratory disease syndrome (ARDS) [1].
+The virus is likely spread between people primarily by droplets, with the role of contact and aerosol transmission still in question [196,197].
As a result, public health guidelines have been critical to efforts to control the spread of the virus.
However, as of early 2021, COVID-19 remains a significant worldwide concern (Figure 2), with cases in some places surging far above the numbers reported during the initial outbreak in early 2020.
Due to the continued threat of the virus and the severity of the disease, the identification and development of prophylactic and therapeutic interventions have emerged as significant international priorities.
Both approaches hold valuable potential for controlling the impact of the disease.
Prophylactics bolster immunity to prevent an individual from contracting a disease, whereas therapeutics treat a disease in individuals who have already been infected.
While vaccine development programs have attracted significant attention and produced a number of promising candidates, there is also an immediate need for treatments that palliate symptoms and prevent the most severe outcomes from infection.
-Fortunately, prior developments during other recent pandemics, especially those caused by human coronaviruses (HCoV), has provided a number of hypotheses guiding a biomedical approach to the novel coronavirus infection.
+Fortunately, prior developments during other recent pandemics, especially those caused by human coronaviruses (HCoV), have provided a number of hypotheses guiding a biomedical approach to the novel coronavirus infection.
2,354,561 COVID-19 deaths had been reported worldwide as of February 10, 2021 (Figure 2).
Figure 2: Cumulative global COVID-19 deaths since January 22, 2020.
-Data are from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [368].
+Data are from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [369].
5.3.1 Lessons from Prior HCoV Outbreaks
SARS-CoV-2’s rapid shift from an unknown virus to a significant worldwide threat closely parallels the emergence of Severe acute respiratory syndrome-related coronavirus (SARS-CoV-1).
The first documented case of COVID-19 was reported in Wuhan, China in November 2019, and the disease quickly spread worldwide during the early months of 2020.
-Similarly, the first case of SARS was reported in November 2002 in the Guangdong Province of China, and it spread within China and then into several countries across continents over the following months [28,30].
-In fact, genome sequencing quickly revealed the virus causing COVID-19 to be a novel betacoronavirus closely related to SARS-CoV-1 [10].
+Similarly, the first case of SARS was reported in November 2002 in the Guangdong Province of China, and it spread within China and then into several countries across continents over the following months [30,32].
+In fact, genome sequencing quickly revealed the virus causing COVID-19 to be a novel betacoronavirus closely related to SARS-CoV-1 [12].
There are many similarities but also some differences in the characteristics of the two viruses that determine how they spread.
-SARS infection is severe, with an estimated death rate of 9.5% [30], while estimates of the death rate associated with COVID-19 are much lower, at approximately 2% [367].
-SARS-CoV-1 is highly contagious via droplet transmission and has a basic reproduction number (R0) of 4 (i.e., each person infected was estimated to infect four other people) [30].
-SARS-CoV-2 also appears to be spread primarily by droplet transmission [194,195], and most estimates of its R0 fall between 2.5 and 3 [367].
+SARS infection is severe, with an estimated death rate of 9.5% [32], while estimates of the death rate associated with COVID-19 are much lower, at approximately 2% [1].
+SARS-CoV-1 is highly contagious via droplet transmission and has a basic reproduction number (R0) of 4 (i.e., each person infected was estimated to infect four other people) [32].
+SARS-CoV-2 also appears to be spread primarily by droplet transmission [196,197], and most estimates of its R0 fall between 2.5 and 3 [1].
Furthermore, the 17-year difference in the timing of these two outbreaks has led to some major differences in the tools available for the international community’s response.
-At the time that SARS-CoV-1 emerged, no new HCoV had been identified in almost 40 years [28].
-The identity of the virus underlying the SARS disease remained unknown until April of 2003, when the SARS-CoV-1 virus was characterized through a worldwide scientific effort spearheaded by the WHO [28].
-In contrast, the SARS-CoV-2 genomic sequence was released on January 3, 2020 [10], only days after the international community became aware of the novel pneumonia-like illness now known as COVID-19.
-While SARS-CoV-1 belonged to a distinct lineage from the two other HCoV known at the time of its discovery [30], SARS-CoV-2 is closely related to SARS-CoV-1 and a more distant relative of another HCoV characterized in 2012, Middle East respiratory syndrome-related coronavirus [13,369].
-Thus, despite their phylogenetic similarity, SARS-CoV-2 emerged under very different circumstances than SARS-CoV-1 in terms of scientific knowledge about HCoV.
+At the time that SARS-CoV-1 emerged, no new HCoV had been identified in almost 40 years [30].
+The identity of the virus underlying the SARS disease remained unknown until April of 2003, when the SARS-CoV-1 virus was characterized through a worldwide scientific effort spearheaded by the World Health Organization (WHO) [30].
+In contrast, the SARS-CoV-2 genomic sequence was released on January 3, 2020 [12], only days after the international community became aware of the novel pneumonia-like illness now known as COVID-19.
+While SARS-CoV-1 belonged to a distinct lineage from the two other HCoV known at the time of its discovery [32], SARS-CoV-2 is closely related to SARS-CoV-1 and a more distant relative of another HCoV characterized in 2012, Middle East respiratory syndrome-related coronavirus [15,370].
+Despite their phylogenetic similarity, SARS-CoV-2 emerged under very different circumstances than SARS-CoV-1 in terms of scientific knowledge about HCoV.
The trajectories of the pandemics associated with each of the viruses have also diverged significantly.
-By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices such as mask wearing [28].
-In contrast, MERS is still circulating and remains a concern; although the fatality rate is very high at almost 35%, the disease is much less easily transmitted, as its R0 has been estimated to be 1 [30].
-The low R0 in combination with public health practices allowed for its spread to be contained [30].
+By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices such as mask wearing [30].
+In contrast, MERS is still circulating and remains a concern; although the fatality rate is very high at almost 35%, the disease is much less easily transmitted, as its R0 has been estimated to be 1 [32].
+The low R0 in combination with public health practices allowed for its spread to be contained [32].
Neither of these trajectories are comparable to that of SARS-CoV-2, which remains a serious threat worldwide more than a year after the first cases of COVID-19 emerged.
Early results suggest that pharmaceutical interventions for COVID-19 may be more successful than efforts to develop prophylactics and therapeutics for SARS and MERS were.
-Care for SARS and MERS patients prioritized supportive care and symptom management [30].
+Care for SARS and MERS patients prioritized supportive care and symptom management [32].
To the extent that clinical treatments for SARS and MERS were explored, there is generally a lack of evidence supporting their efficacy.
-For example, Ribavirin is an antiviral that was often used in combination with corticosteroids and sometimes interferon (IFN) medications to treat SARS and MERS [28], but its effects have been found to be inconclusive in retrospective and in vitro analyses of SARS and the SARS-CoV-1 virus, respectively [28].
-IFNs and Ribavirin have shown promise in in vitro analyses of MERS, but their clinical effectiveness remains unknown [28].
+For example, Ribavirin is an antiviral that was often used in combination with corticosteroids and sometimes interferon (IFN) medications to treat SARS and MERS [30], but its effects have been found to be inconclusive in retrospective and in vitro analyses of SARS and the SARS-CoV-1 virus, respectively [30].
+IFNs and Ribavirin have shown promise in in vitro analyses of MERS, but their clinical effectiveness remains unknown [30].
Therefore, only limited pharmaceutical advances from prior HCoV outbreaks can be adopted to COVID-19.
Importantly, though, prior analyses of the virological and pathogenic properties of SARS-CoV-1 and MERS-CoV provide a strong foundation for the development of hypotheses about SARS-CoV-2 that have served to accelerated the development and identification of potential prophylactic and therapeutic approaches.
5.3.2 Therapeutic Approaches
Therapeutic approaches to the current pandemic can utilize two potential avenues: they can reduce the symptoms that are harmful to COVID-19 patients, or they can directly target the virus to hinder the spread of infection.
The goal of the former is to reduce the severity and risks of an active infection, while for the latter, it is to inhibit the replication of the virus once an individual is infected.
A variety of symptom profiles with a range of severity are associated with COVID-19, many of which are not life-threatening.
-A study of COVID-19 patients in a hospital in Berlin, Germany found that the symptoms associated with the highest risk of death included infection-related symptoms, such as sepsis, respiratory symptoms such as ARDS, and cardiovascular failure or pulmonary embolism [370].
+A study of COVID-19 patients in a hospital in Berlin, Germany found that the symptoms associated with the highest risk of death included infection-related symptoms, such as sepsis, respiratory symptoms such as ARDS, and cardiovascular failure or pulmonary embolism [371].
Therapeutics that reduce the risks associated with these severe outcomes hold particular potential to reduce the pandemic death toll.
On the other hand, therapeutics that directly target the virus itself would hold the potential to prevent people infected with SARS-CoV-2 from developing potentially damaging symptoms.
These treatments typically fall into the broad category of antivirals.
@@ -1644,44 +1645,44 @@
[371].
+Trials data are from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [372].
5.4 Small Molecule Drugs
-
Small molecules are synthesized compounds of low molecular weight, typically less than 1 kilodalton (kDa) [372].
-Small-molecule pharmaceutical agents have been a backbone of drug development since the discovery of penicillin in the early twentieth century [373].
-It and other antibiotics have long been among the best known applications of small molecules to therapeutics, but biotechnological developments such as the prediction of protein-protein interactions have facilitated advances in precise targeting of specific structures using small molecules [373].
+
Small molecules are synthesized compounds of low molecular weight, typically less than 1 kilodalton (kDa) [373].
+Small-molecule pharmaceutical agents have been a backbone of drug development since the discovery of penicillin in the early twentieth century [374].
+It and other antibiotics have long been among the best known applications of small molecules to therapeutics, but biotechnological developments such as the prediction of protein-protein interactions have facilitated advances in precise targeting of specific structures using small molecules [374].
Small molecule drugs today encompass a wide range of therapeutics beyond antibiotics, including antivirals, protein inhibitors, and many broad-spectrum pharmaceuticals.
5.4.1 Small Molecule Antivirals
Antiviral drugs against SARS-CoV-2 are designed to inhibit replication of a virus within an epithelial host cell.
-This process requires inhibiting the replication cycle of a virus by disrupting one of six fundamental steps [374].
+This process requires inhibiting the replication cycle of a virus by disrupting one of six fundamental steps [375].
In the first of these steps, the virus attaches to and enters the host cell through endocytosis.
Then the virus undergoes uncoating, which is classically defined as the release of viral contents into the host cell.
Next, the viral genetic material enters the nucleus where it gets replicated during the biosynthesis stage.
During the assembly stage, viral proteins are translated, allowing new viral particles to be assembled.
In the final step new viruses are released into the extracellular environment.
Many antiviral drugs are designed to inhibit the replication of viral genetic material during the biosynthesis step.
-Unlike DNA viruses, which can use the host enzymes to propagate themselves, RNA viruses like SARS-CoV-2 depend on their own polymerase, the RNA-dependent RNA polymerase (RdRP), for replication [375,376].
-Targeting RdRP is therefore an effective strategy for antivirals against RNA viruses and is the proposed mechanism underlying the treatment of SARS and MERS with Ribavirin [377].
+Unlike DNA viruses, which can use the host enzymes to propagate themselves, RNA viruses like SARS-CoV-2 depend on their own polymerase, the RNA-dependent RNA polymerase (RdRP), for replication [376,377].
+Targeting RdRP is therefore an effective strategy for antivirals against RNA viruses and is the proposed mechanism underlying the treatment of SARS and MERS with Ribavirin [378].
However, although antivirals are designed to target a virus, they can also impact other processes in the host and may have unintended effects.
Therefore, these therapeutics must be evaluated for both efficacy and safety.
5.4.1.1 Nucleoside and Nucleotide Analogs
5.4.1.1.1 Favipiravir
-Favipiravir (Avigan), also known as T-705, was discovered by Toyama Chemical Co., Ltd. [378].
-The drug was found to be effective at blocking viral amplification in several influenza subtypes as well as other RNA viruses, such as Flaviviridae and Picornaviridae, through a reduction in plaque formation [379] and viral replication in Madin-Darby canine kidney cells [380].
-Furthermore, inoculation of mice with favipiravir was shown to increase survival of influenza infections [379,380].
-In 2014, the drug was approved in Japan for the treatment of influenza that was resistant to conventional treatments like neuraminidase inhibitors [381].
-Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) acts as a purine and purine nucleoside analogue that inhibits viral RNA polymerase in a dose-dependent manner across a range of RNA viruses, including influenza viruses [382,383,384,385,386].
+
Favipiravir (Avigan), also known as T-705, was discovered by Toyama Chemical Co., Ltd. [379].
+The drug was found to be effective at blocking viral amplification in several influenza subtypes as well as other RNA viruses, such as Flaviviridae and Picornaviridae, through a reduction in plaque formation [380] and viral replication in Madin-Darby canine kidney cells [381].
+Furthermore, inoculation of mice with favipiravir was shown to increase survival of influenza infections [380,381].
+In 2014, the drug was approved in Japan for the treatment of influenza that was resistant to conventional treatments like neuraminidase inhibitors [382].
+Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) acts as a purine and purine nucleoside analogue that inhibits viral RNA polymerase in a dose-dependent manner across a range of RNA viruses, including influenza viruses [383,384,385,386,387].
Nucleotides and nucleosides are the natural building blocks for RNA synthesis.
-Because of this, modifications to nucleotides and nucleosides can disrupt key processes including replication [387].
+Because of this, modifications to nucleotides and nucleosides can disrupt key processes including replication [388].
Biochemical experiments showed that favipiravir was recognized as a purine nucleoside analogue and incorporated into the viral RNA template.
-A single incorporation does not influence RNA transcription; however, multiple events of incorporation lead to the arrest of RNA synthesis [388].
-Evidence for T-705 inhibiting viral RNA polymerase are based on time-of-drug addition studies that found that viral loads were reduced with the addition of favipiravir in early times post-infection [382,385,386].
+A single incorporation does not influence RNA transcription; however, multiple events of incorporation lead to the arrest of RNA synthesis [389].
+Evidence for T-705 inhibiting viral RNA polymerase are based on time-of-drug addition studies that found that viral loads were reduced with the addition of favipiravir in early times post-infection [383,386,387].
The effectiveness of favipiravir for treating patients with COVID-19 is currently under investigation.
-An open-label, nonrandomized, before-after controlled study was recently conducted [389].
+An open-label, nonrandomized, before-after controlled study was recently conducted [390].
The study included 80 COVID-19 patients (35 treated with favipiravir, 45 control) from the isolation ward of the National Clinical Research Center for Infectious Diseases (The Third People’s Hospital of Shenzhen), Shenzhen, China.
The patients in the control group were treated with other antivirals, such as lopinavir and ritonavir.
-It should be noted that although the control patients received antivirals, two subsequent large-scale analyses, the WHO Solidarity trial and the RECOVERY trial, identified no effect of lopinavir or of a lopinavir-ritonavir combination, respectively, on the metrics of COVID-19-related mortality that each assessed [390,391,392].
+It should be noted that although the control patients received antivirals, two subsequent large-scale analyses, the WHO Solidarity trial and the RECOVERY trial, identified no effect of lopinavir or of a lopinavir-ritonavir combination, respectively, on the metrics of COVID-19-related mortality that each assessed [391,392,393].
Treatment was applied on days 2-14; treatment stopped either when viral clearance was confirmed or at day 14.
The efficacy of the treatment was measured by, first, the time until viral clearance using Kaplan-Meier survival curves, and, second, the improvement rate of chest computed tomography (CT) scans on day 14 after treatment.
The study found that favipiravir increased the speed of recovery, measured as viral clearance from the patient by RT-PCR, with patients receiving favipiravir recovering in four days compared to 11 days for patients receiving antivirals such as lopinavir and ritonavir.
@@ -1692,33 +1693,32 @@
[393].
-
In late 2020 and early 2021, the first randomized controlled trials of favipiravir for the treatment of COVID-19 released results [394,395,396].
-The first [394] used a randomized, controlled, open-label design to compare two drugs, favipiravir and baloxavir marboxil, to SOC alone.
+Additionally, it should be noted that this study was temporarily retracted and then restored without an explanation [394].
+In late 2020 and early 2021, the first randomized controlled trials of favipiravir for the treatment of COVID-19 released results [395,396,397].
+The first [395] used a randomized, controlled, open-label design to compare two drugs, favipiravir and baloxavir marboxil, to standard of care (SOC) alone.
Here, SOC included antivirals such as lopinavir/ritonavir and was administered to all patients.
The primary endpoint analyzed was viral clearance at day 14.
The sample size for this study was very small, with 29 total patients enrolled, and no significant effect of the treatments was found for the primary or any of the secondary outcomes analyzed, which included mortality.
The second study was larger, with 96 patients enrolled, and also utilized a randomized design.
-This study enrolled only patients with mild to moderate symptoms and randomized them into two groups: one receiving CQ in addition to SOC, and the other receiving favipiravir in addition to SOC.
+This study enrolled only patients with mild to moderate symptoms and randomized them into two groups: one receiving chloroquine (CQ) in addition to SOC, and the other receiving favipiravir in addition to SOC.
This study reported a non-significant trend for patients receiving favipiravir to have a shorter hospital stay and less likelihood of progressing to mechanical ventilation or to an oxygen saturation < 90%.
However, given the fact that favipiravir was being compared to CQ, which is now widely understood to be ineffective for treating COVID-19, these results do not suggest that favipiravir was likely to have had a strong effect on these outcomes.
-On the other hand, another trial of 60 patients reported a significant effect of favipiravir on viral clearance at four days (a secondary endpoint), but not at 10 days (the primary endpoint) [396].
-This study, as well as a prior study of favipiravir [397], also reported that the drug was generally well-tolerated.
+On the other hand, another trial of 60 patients reported a significant effect of favipiravir on viral clearance at four days (a secondary endpoint), but not at 10 days (the primary endpoint) [397].
+This study, as well as a prior study of favipiravir [398], also reported that the drug was generally well-tolerated.
Thus, in combination, these small studies suggest that the effects of favipiravir as a treatment for COVID-19 cannot be determined based on the available evidence, but additionally, none raise major concerns about the safety profile of the drug.
5.4.1.1.2 Remdesivir
Remdesivir (GS-5734) is an intravenous antiviral that was developed by Gilead Sciences to treat Ebola Virus Disease (EVD).
At the outset of the COVID-19 pandemic, it did not have any have any FDA-approved use.
-However, on May 1, 2020, the FDA issued an Emergency Use Authorization (EUA) for remdesivir for the treatment of hospitalized COVID-19 patients [398].
-The EUA was based on information from two clinical trials, NCT04280705 and NCT04292899 [399,400,401,402].
-Remdesivir is metabolized to GS-441524, an adenosine analog that inhibits a broad range of polymerases and then evades exonuclease repair, causing chain termination [403,404,405].
-A clinical trial in the Democratic Republic of Congo found some evidence of effectiveness against EVD, but two antibody preparations were found to be more effective, and remdesivir was not pursued [406].
-Although it was developed against EVD, remdesivir also inhibits polymerase and replication of the coronaviruses MERS-CoV and SARS-CoV-1 in cell culture assays with submicromolar IC50s [407].
-It has also been found to inhibit SARS-CoV-2, showing synergy with chloroquine in vitro [405].
-The effectiveness of remdesivir for treating patients with COVID-19 is currently under investigation.
-Remdesivir was first used on some COVID-19 patients under compassionate use guidelines [408,409].
+However, on May 1, 2020, the FDA issued an Emergency Use Authorization (EUA) for remdesivir for the treatment of hospitalized COVID-19 patients [399].
+The EUA was based on information from two clinical trials, NCT04280705 and NCT04292899 [400,401,402,403].
+Remdesivir is metabolized to GS-441524, an adenosine analog that inhibits a broad range of polymerases and then evades exonuclease repair, causing chain termination [404,405,406].
+A clinical trial in the Democratic Republic of Congo found some evidence of effectiveness against EVD, but two antibody preparations were found to be more effective, and remdesivir was not pursued [407].
+Although it was developed against EVD, remdesivir also inhibits polymerase and replication of the coronaviruses MERS-CoV and SARS-CoV-1 in cell culture assays with submicromolar IC50s [408].
+It has also been found to inhibit SARS-CoV-2, showing synergy with CQ in vitro [406].
+Remdesivir was first used on some COVID-19 patients under compassionate use guidelines [409,410].
All were in late stages of COVID-19 infection, and initial reports were inconclusive about the drug’s efficacy.
Gilead Sciences, the maker of remdesivir, led a recent publication that reported outcomes for compassionate use of the drug in 61 patients hospitalized with confirmed COVID-19.
-Here, 200 mg of remdesivir was administered intravenously on day 1, followed by a further 100 mg/day for 9 days [402].
+Here, 200 mg of remdesivir was administered intravenously on day 1, followed by a further 100 mg/day for 9 days [403].
There were significant issues with the study design, or lack thereof.
There was no randomized control group.
The inclusion criteria were variable: some patients only required low doses of oxygen, while others required ventilation.
@@ -1727,49 +1727,48 @@
There was a short follow-up period of investigation.
Some patients worsened, some patients died, and eight were excluded from the analysis mainly due to missing post-baseline information; thus, their health was unaccounted for.
Therefore, even though the study reported clinical improvement in 68% of the 53 patients ultimately evaluated, due to the significant issues with study design, it could not be determined whether treatment with remdesivir had an effect or whether these patients would have recovered regardless of treatment.
-Another study comparing 5- and 10-day treatment regimens reported similar results but was also limited because of the lack of a placebo control [411].
+Another study comparing 5- and 10-day treatment regimens reported similar results but was also limited because of the lack of a placebo control [412].
These studies did not alter the understanding of the efficacy of remdesivir in treating COVID-19, but the encouraging results provided motivation for placebo-controlled studies.
-Remdesivir was later tested in a double-blind placebo-controlled phase 3 clinical trial performed at 60 trial sites, 45 of which were in the United States [400,401].
+
Remdesivir was later tested in a double-blind placebo-controlled phase 3 clinical trial performed at 60 trial sites, 45 of which were in the United States [401,402].
The trial recruited 1,062 patients and randomly assigned them to placebo treatment or treatment with remdesivir.
-Patients were stratified for randomization based on site and the severity of disease presentation at baseline [401].
+Patients were stratified for randomization based on site and the severity of disease presentation at baseline [402].
The treatment was 200 mg on day 1, followed by 100 mg on days 2 through 10.
-Data was analyzed from a total of 1,059 patients who completed the 29-day course of the trial, with 517 assigned to remdesivir and 508 to placebo [401].
+Data was analyzed from a total of 1,059 patients who completed the 29-day course of the trial, with 517 assigned to remdesivir and 508 to placebo [402].
The two groups were well matched demographically and clinically at baseline.
Those who received remdesivir had a median recovery time of 10 days, as compared with 15 days in those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; p < 0.001).
The Kaplan-Meier estimates of mortality by 14 days were 6.7% with remdesivir and 11.9% with placebo, with a hazard ratio (HR) for death of 0.55 and a 95% CI of 0.36 to 0.83, and at day 29, remdesivir corresponded to 11.4% and the placebo to 15.2% (HR: 0.73; 95% CI: 0.52 to 1.03).
Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients in the placebo group (31.6%).
-This study also reported an association between remdesivir administration and both clinical improvement and a lack of progression to more invasive respiratory intervention in patients receiving non-invasive and invasive ventilation at randomization [401].
-Largely on the results of this trial, the FDA reissued and expanded the EUA for remdesivir for the treatment of hospitalized COVID-19 patients ages twelve and older [398].
-Additional clinical trials are currently underway to evaluate the use of remdesivir to treat COVID-19 patients at both early and late stages of infection and in combination with other drugs (Figure 3).
-These trials include [405,412,413,414,415].
-As of October 22, 2020, remdesivir received FDA approval based on three clinical trials [416].
-However, results suggesting no effect of remdesivir on survival were reported by the WHO Solidarity trial [390].
-This large-scale, open-label trial enrolled 11,330 adult in-patients at 405 hospitals in 30 countries around the world [390].
+This study also reported an association between remdesivir administration and both clinical improvement and a lack of progression to more invasive respiratory intervention in patients receiving non-invasive and invasive ventilation at randomization [402].
+Largely on the results of this trial, the FDA reissued and expanded the EUA for remdesivir for the treatment of hospitalized COVID-19 patients ages twelve and older [399].
+Additional clinical trials [406,413,414,415,416] are currently underway to evaluate the use of remdesivir to treat COVID-19 patients at both early and late stages of infection and in combination with other drugs (Figure 3).
+As of October 22, 2020, remdesivir received FDA approval based on three clinical trials [417].
+However, results suggesting no effect of remdesivir on survival were reported by the WHO Solidarity trial [391].
+This large-scale, open-label trial enrolled 11,330 adult in-patients at 405 hospitals in 30 countries around the world [391].
Patients were randomized in equal proportions into four experimental and a control conditions, corresponding to four candidate treatments for COVID-19 and SOC, respectively; no placebo was administered.
The 2,750 patients in the remdesivir group were administered 200 mg intravenously on the first day and 100 mg on each subsequent day until day 10 and assessed for in-hospital death (primary endpoint), duration of hospitalization, and progression to mechanical ventilation.
There were also 2,708 control patients who would have been eligible and able to receive remdesivir were they not assigned to the control group.
A total of 604 patients among these two cohorts deceased during initial hospitalization, with 301 in the remdesivir group and 303 in the control group.
The rate ratio of death between these two groups was therefore not significant (p = 0.50), suggesting that the administration of remdesivir did not affect survival.
The two secondary analyses similarly did not find any effect of remdesivir.
-Additionally, the authors compared data from their study with data from three other studies of remdesivir (including [401]) stratified by supplemental oxygen status.
+Additionally, the authors compared data from their study with data from three other studies of remdesivir (including [402]) stratified by supplemental oxygen status.
The adjusted rate ratio for death based on this meta-analysis was 0.91.
These results thus do not support the previous findings that remdesivir reduced median recovery time and mortality risk in COVID-19 patients.
-In response to the results of the Solidarity trial, Gilead, which manufactures remdesivir, released a statement pointing to the fact that the Solidarity trial was not placebo-controlled or double-blind and at the time of the statement had not been peer reviewed [417]; these sentiments have been echoed elsewhere [418].
-Other critiques of this study have noted that antivirals are not typically targeted at patients with severe illness, and therefore remdesivir could be more beneficial for patients with mild rather than severe cases [392,419].
-However, the publication associated with the trial sponsored by Gilead did purport an effect of remdesivir on patients with severe disease, identifying an 11 versus 18 day recovery period (rate ratio for recovery: 1.31, 95% CI 1.12 to 1.52), although the results of a significance test were not provided [401].
-Additionally, a smaller analysis of 598 patients, of whom two-thirds were randomized to receive remdesivir for either 5 or 10 days, reported a small effect of treatment with remdesivir for five days relative to standard of care in patients with moderate COVID-19 [420].
+
In response to the results of the Solidarity trial, Gilead, which manufactures remdesivir, released a statement pointing to the fact that the Solidarity trial was not placebo-controlled or double-blind and at the time of the statement had not been peer reviewed [418]; these sentiments have been echoed elsewhere [419].
+Other critiques of this study have noted that antivirals are not typically targeted at patients with severe illness, and therefore remdesivir could be more beneficial for patients with mild rather than severe cases [393,420].
+However, the publication associated with the trial sponsored by Gilead did purport an effect of remdesivir on patients with severe disease, identifying an 11 versus 18 day recovery period (rate ratio for recovery: 1.31, 95% CI 1.12 to 1.52), although the results of a significance test were not provided [402].
+Additionally, a smaller analysis of 598 patients, of whom two-thirds were randomized to receive remdesivir for either 5 or 10 days, reported a small effect of treatment with remdesivir for five days relative to standard of care in patients with moderate COVID-19 [421].
These results suggest that remdesivir could improve outcomes for patients with moderate COVID-19, but that additional information would be needed to understand the effects of different durations of treatment.
-Therefore, the arguments put forward in defense of remdesivir do not necessarily seem robust in light of the large sample size used in the Solidarity trial, especially since the broad international nature of the Solidarity clinical trial, which included countries with a wide range of economic profiles and a variety of healthcare systems, provides a much-needed global perspective in a pandemic [392].
-On the other hand, only 62% of patients in the Solidarity trial were randomized on the day of admission or one day afterwards [390], and concerns have been raised that differences in disease progression could influence the effectiveness of remdesivir [392].
+Therefore, the arguments put forward in defense of remdesivir do not necessarily seem robust in light of the large sample size used in the Solidarity trial, especially since the broad international nature of the Solidarity clinical trial, which included countries with a wide range of economic profiles and a variety of healthcare systems, provides a much-needed global perspective in a pandemic [393].
+On the other hand, only 62% of patients in the Solidarity trial were randomized on the day of admission or one day afterwards [391], and concerns have been raised that differences in disease progression could influence the effectiveness of remdesivir [393].
Despite the findings of the Solidarity trial, remdesivir remains available for the treatment of COVID-19 in many places.
-Follow-up studies are needed and, in many cases, are underway to further investigate remdesivir-related outcomes, with possibilities including combinations of remdesivir with other drugs such as baricitinib, which is an inhibitor of Janus kinase 1 and 2 [421].
+Follow-up studies are needed and, in many cases, are underway to further investigate remdesivir-related outcomes, with possibilities including combinations of remdesivir with other drugs such as baricitinib, which is an inhibitor of Janus kinase 1 and 2 [422].
Similarly, the extent to which the remdesivir dosing regimen could influence outcomes continues to be under consideration.
-In complement to the study that found that a 5-day course of remdesivir improved outcomes for patients with moderate COVID-19 but a 10-day course did not [420], a randomized, open-label trial compared the effect of remdesivir on 397 patients with severe COVID-19 over 5 versus 10 days [399,411].
+A randomized, open-label trial compared the effect of remdesivir on 397 patients with severe COVID-19 over 5 versus 10 days [400,412], complementing the study that found that a 5-day course of remdesivir improved outcomes for patients with moderate COVID-19 but a 10-day course did not [421].
Patients in the two groups were administered 200 mg of remdesivir intravenously on the first day, followed by 100 mg on the subsequent four or nine days, respectively.
The two groups differed significantly in their clinical status, with patients assigned to the 10-day group having more severe illness.
This study also differed from most because it included not only adults, but also pediatric patients as young as 12 years old.
It reported no significant differences across several outcomes for patients receiving a 5-day or 10-day course, when correcting for baseline clinical status.
-The data did suggest that the 10-day course might reduce mortality in the most severe patients at day 14, but the representation of this group in the study population was too low to justify any conclusions [411].
+The data did suggest that the 10-day course might reduce mortality in the most severe patients at day 14, but the representation of this group in the study population was too low to justify any conclusions [412].
Thus, additional research is also required to determine whether the dosage and duration of remdesivir administration influences outcomes.
In summary, remdesivir is a first in class drug due to its FDA approval.
Early investigations of this drug established proof of principle that drugs targeting the virus can benefit COVID-19 patients.
@@ -1781,43 +1780,43 @@
They are typically combined with protease inhibitors, integrase inhibitors, and even other polymerase inhibitors.
Additional clinical trials of remdesivir in different patient pools and in combination with other therapies will refine its use in the clinic.
5.4.1.2 Protease Inhibitors
-Several studies showed that viral proteases play an important role in the life cycle of viruses, including coronaviruses, by modulating the cleavage of viral polyprotein precursors [422].
+
Several studies showed that viral proteases play an important role in the life cycle of viruses, including coronaviruses, by modulating the cleavage of viral polyprotein precursors [423].
Several FDA-approved drugs target proteases, including lopinavir and ritonavir for HIV infection and simeprevir for hepatitis C virus infection.
-In particular, serine protease inhibitors were suggested for the treatment of SARS and MERS viruses [423].
-Recently, a study [67] suggested that camostat mesylate, an FDA-approved protease inhibitor (PI) could block the entry of SARS-CoV-2 into lung cells in vitro.
+In particular, serine protease inhibitors were suggested for the treatment of SARS and MERS viruses [424].
+Recently, a study [69] suggested that camostat mesylate, an FDA-approved protease inhibitor (PI) could block the entry of SARS-CoV-2 into lung cells in vitro.
Thus far, investigation of possible PIs that could work against SARS-CoV-2 has been driven by computational predictions.
Computer-aided design allowed for the development of a Michael acceptor inhibitor, now known as N3, to target a protease critical to SARS-CoV-2 replication.
-Discovery of the N3 mechanism arose from interest in the two polyproteins encoded by the SARS-CoV-2 replicase gene, pp1a and pp1ab, that are critical for viral replication and transcription [424].
+Discovery of the N3 mechanism arose from interest in the two polyproteins encoded by the SARS-CoV-2 replicase gene, pp1a and pp1ab, that are critical for viral replication and transcription [425].
These polyproteins must undergo proteolytic processing.
This processing is usually conducted by Mpro, a 33.8-kDa SARS-CoV-2 protease that is therefore fundamental to viral replication and transcription.
-N3 was designed computationally [425] to bind in the substrate binding pocket of the Mpro protease of SARS-like coronaviruses [426], therefore inhibiting proteolytic processing.
-Subsequently, the structure of N3-bound SARS-CoV-2 Mpro was solved [424], confirming the computational prediction.
-N3 was tested in vitro on SARS-CoV-2-infected Vero cells, which belong to a line of cells established from the kidney epithelial cells of an African green monkey, and was found to inhibit SARS-CoV-2 [424].
+N3 was designed computationally [426] to bind in the substrate binding pocket of the Mpro protease of SARS-like coronaviruses [427], therefore inhibiting proteolytic processing.
+Subsequently, the structure of N3-bound SARS-CoV-2 Mpro was solved [425], confirming the computational prediction.
+N3 was tested in vitro on SARS-CoV-2-infected Vero cells, which belong to a line of cells established from the kidney epithelial cells of an African green monkey, and was found to inhibit SARS-CoV-2 [425].
Although N3 is a strong inhibitor of SARS-CoV-2 in vitro, its safety and efficacy still need to be tested in healthy volunteers and patients.
-After the design and confirmation of N3 as a highly potent Michael acceptor inhibitor and the identification of Mpro’s structure [424,427], 10,000 compounds were screened for their in vitro anti-Mpro activity.
+After the design and confirmation of N3 as a highly potent Michael acceptor inhibitor and the identification of Mpro’s structure [425,428], 10,000 compounds were screened for their in vitro anti-Mpro activity.
The six leads that were identified were ebselen, disulfiram, tideglusib, carmofur, and PX-12.
-In vitro analysis revealed that Ebselen had the strongest potency in reducing the viral load in SARS-CoV-2-infected Vero cells [424].
-Ebselen is an organoselenium compound with anti-inflammatory and antioxidant properties [428].
-It has been proposed as a possible treatment for conditions ranging from bipolar disorder to diabetes to heart disease [428], and a preliminary investigation of ebselen as a treatment for noise-induced hearing loss provided promising reports of its safety [429].
-For COVID-19, the NSP5 in SARS-CoV-2 contains a cysteine at the active site of Mpro, and ebselen is able to inactivate the protease by bonding covalently with this cysteine to form a selenosulfide [428,430].
-Interestingly there has been some argument that selenium deficiency may be associated with more severe COVID-19 outcomes [431,432,433], possibly indicating that its antioxidative properties are protective [430].
-On the other hand, ebselen and the other compounds identified are likely to be promiscuous binders, which could diminish their therapeutic potential [424].
+In vitro analysis revealed that ebselen had the strongest potency in reducing the viral load in SARS-CoV-2-infected Vero cells [425].
+Ebselen is an organoselenium compound with anti-inflammatory and antioxidant properties [429].
+It has been proposed as a possible treatment for conditions ranging from bipolar disorder to diabetes to heart disease [429], and a preliminary investigation of ebselen as a treatment for noise-induced hearing loss provided promising reports of its safety [430].
+For COVID-19, the NSP5 in SARS-CoV-2 contains a cysteine at the active site of Mpro, and ebselen is able to inactivate the protease by bonding covalently with this cysteine to form a selenosulfide [429,431].
+Interestingly there has been some argument that selenium deficiency may be associated with more severe COVID-19 outcomes [432,433,434], possibly indicating that its antioxidative properties are protective [431].
+On the other hand, ebselen and the other compounds identified are likely to be promiscuous binders, which could diminish their therapeutic potential [425].
While there is clear computational and in vitro support for ebselen’s potential as a COVID-19 therapeutic, results from clinical trials are not yet available for this compound.
-However, as of July 2020, phase II clinical trials commenced to assess the effects of SPI-1005, an investigational drug from Sound Pharmaceuticals that contains ebselen [434], on 60 adults presenting with each of moderate [435] and severe [436] COVID-19.
+However, as of July 2020, phase II clinical trials commenced to assess the effects of SPI-1005, an investigational drug from Sound Pharmaceuticals that contains ebselen [435], on 60 adults presenting with each of moderate [436] and severe [437] COVID-19.
In summary, N3 is a computationally designed molecule that inhibits the viral transcription through inhibiting Mpro.
Ebselen is both a strong Mpro inhibitor and strong inhibitor of viral replication in vitro that was found to reduce SARS-CoV-2 viral load even more effectively than N3.
-Ebselen is a very promising compound since its safety has been demonstrated in other indications.
-However, ebselen may be a false positive, since it is a promiscuous compound that can have many targets [437].
+Ebselen is a promising compound since its safety has been demonstrated in other indications.
+However, ebselen may be a false positive, since it is a promiscuous compound that can have many targets [438].
Therefore, the results of ongoing clinical trials are expected to help establish whether compounds with higher specificity are required.
5.4.2 Broad-Spectrum Pharmaceuticals
-When a virus enters a host, the host becomes the virus’ environment.
+
When a virus enters a host, the host becomes the virus’s environment.
Therefore, the state of the host can also influence the virus’s ability to replicate and spread.
-Traditionally, viral targets have been favored for pharmaceutical interventions because altering host processes is likely to be less specific than targeting the virus directly [438].
-On the other hand, targeting the host offers potential for a complementary strategy to antivirals that could broadly limit the ability of viruses to replicate [438].
+Traditionally, viral targets have been favored for pharmaceutical interventions because altering host processes is likely to be less specific than targeting the virus directly [439].
+On the other hand, targeting the host offers potential for a complementary strategy to antivirals that could broadly limit the ability of viruses to replicate [439].
As a result, therapeutic approaches that target host proteins have become an area of interest for SARS-CoV-2.
Viral entry receptors in particular have been identified as a potential target.
-Entry of SARS-CoV-2 into the cell depends on binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which is catalyzed by the enzyme encoded by TMPRSS2 [67].
+Entry of SARS-CoV-2 into the cell depends on binding to angiotensin-converting enzyme 2 (ACE2), which is catalyzed by the enzyme encoded by TMPRSS2 [69].
In principle, drugs that reduce the expression of these proteins or sterically hinder viral interactions with them might reduce viral entry into cells.
Due to the urgent nature of the COVID-19 pandemic, many of the pharmaceutical agents that have been widely publicized as having possible therapeutic or prophylactic effects are broad-spectrum pharmaceuticals that pre-date the COVID-19 pandemic.
These treatments are not specifically targeted at the virus itself or at the host receptors it relies on, but rather induce broad shifts in host biology that are hypothesized to be potential inhibitors of the virus.
@@ -1825,56 +1824,56 @@
5.4.2.1 ACEi and ARB
-Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are among today’s most commonly prescribed medications [439,440].
+
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are among today’s most commonly prescribed medications [440,441].
In the United States, for example, they are prescribed well over 100,000,000 times annually.
-Data from some animal models suggest that several, but not all, ACE inhibitors and several ARBs increase ACE2 expression in the cells of some organs [441].
-Clinical studies have not established whether plasma ACE2 expression is increased in humans treated with these medications [442].
+Data from some animal models suggest that several, but not all, ACE inhibitors and several ARBs increase ACE2 expression in the cells of some organs [442].
+Clinical studies have not established whether plasma ACE2 expression is increased in humans treated with these medications [443].
While randomized clinical trials are ongoing, a variety of observational studies have examined the relationship between exposure to ACE inhibitors or ARBs and outcomes in patients with COVID-19.
-An observational study of the association of exposure to ACE inhibitors or ARB with outcomes in COVID-19 was retracted from the New England Journal of Medicine [443].
-Moreover, because observational studies are subject to confounding, randomized controlled trials are the standard means of assessing the effects of medications, and the findings of the various observational studies bearing on this topic cannot be interpreted as indicating a protective effect of the drug [444,445].
-Several clinical trials testing the effects of ACE inhibitors or ARBs on COVID-19 outcomes are ongoing [446,447,448,449,450,451].
+An observational study of the association of exposure to ACE inhibitors or ARB with outcomes in COVID-19 was retracted from the New England Journal of Medicine [444].
+Moreover, because observational studies are subject to confounding, randomized controlled trials are the standard means of assessing the effects of medications, and the findings of the various observational studies bearing on this topic cannot be interpreted as indicating a protective effect of the drug [445,446].
+Several clinical trials testing the effects of ACE inhibitors or ARBs on COVID-19 outcomes are ongoing [447,448,449,450,451,452].
These studies of randomized intervention will provide important data for understanding whether exposure to ACEis or ARBs is associated with COVID-19 outcomes.
-Additional information about ACE2, observational studies of ACE inhibitors and ARBs in COVID-19, and clinical trials on this topic have been summarized [452].
+Additional information about ACE2, observational studies of ACE inhibitors and ARBs in COVID-19, and clinical trials on this topic have been summarized [453].
5.4.2.2 Hydroxychloroquine and Chloroquine
-Chloroquine (CQ) and hydroxychloroquine (HCQ) are lysosomotropic agents, meaning they are weak bases that can pass through the plasma membrane.
-Both drugs increase cellular pH by accumulating in their protonated form inside lysosomes [453,454].
-This shift in pH inhibits the breakdown of proteins and peptides by the lysosomes during the process of proteolysis [454].
+
CQ and hydroxychloroquine (HCQ) are lysosomotropic agents, meaning they are weak bases that can pass through the plasma membrane.
+Both drugs increase cellular pH by accumulating in their protonated form inside lysosomes [454,455].
+This shift in pH inhibits the breakdown of proteins and peptides by the lysosomes during the process of proteolysis [455].
A number of mechanisms have been proposed through which these drugs could influence the immune response to pathogen challenge.
-For example, CQ/HCQ can interfere with digestion of antigens within the lysosome and inhibit CD4 T-cell stimulation while promoting the stimulation of CD8 T-cells [454].
-CQ/HCQ can also decrease the production of certain key cytokines involved in the immune response, including interleukin-6 (IL-6), and inhibit the stimulation of Toll-like receptors (TLR) and TLR signaling [454].
-The drugs also have anti-inflammatory and photoprotective effects and may also affect rates of cell death, blood clotting, glucose tolerance, and cholesterol levels [454].
+For example, CQ/HCQ can interfere with digestion of antigens within the lysosome and inhibit CD4 T-cell stimulation while promoting the stimulation of CD8 T-cells [455].
+CQ/HCQ can also decrease the production of certain key cytokines involved in the immune response, including interleukin-6 (IL-6), and inhibit the stimulation of Toll-like receptors (TLR) and TLR signaling [455].
+The drugs also have anti-inflammatory and photoprotective effects and may also affect rates of cell death, blood clotting, glucose tolerance, and cholesterol levels [455].
Interest in CQ and HCQ for treating COVID-19 was catalyzed by a mechanism observed in in vitro studies of both SARS-CoV-1 and SARS-CoV-2.
-In one study, CQ inhibited viral entry of SARS-CoV-1 into Vero E6 cells, a cell line that was derived from Vero cells in 1968, through the elevation of endosomal pH and the terminal glycosylation of the cellular entry receptor, ACE2 [455].
+In one study, CQ inhibited viral entry of SARS-CoV-1 into Vero E6 cells, a cell line that was derived from Vero cells in 1968, through the elevation of endosomal pH and the terminal glycosylation of ACE2 [456].
Increased pH within the cell, as discussed above, inhibits proteolysis, and terminal glycosylation of ACE2 is thought to interfere with virus-receptor binding.
-An in vitro study of SARS-CoV-2 infection of Vero cells found both HCQ and CQ to be effective in inhibiting viral replication, with HCQ being more potent [456].
-Additionally, an early case study of three COVID-19 patients reported the presence of antiphospholipid antibodies in all three patients [102].
-Antiphospholipid antibodies are central to the diagnosis of the antiphospholipid syndrome, a disorder that HCQ has often been used to treat [457,458,459].
-Because the 90% effective concentration (EC90) of CQ in Vero E6 cells (6.90 μM) can be achieved in and tolerated by rheumatoid arthritis (RA) patients, it was hypothesized that it might also be possible to achieve the effective concentration in COVID-19 patients [460].
-Additionally, HCQ has been found to be effective in treating HIV [461] and chronic Hepatitis C [462].
+An in vitro study of SARS-CoV-2 infection of Vero cells found both HCQ and CQ to be effective in inhibiting viral replication, with HCQ being more potent [457].
+Additionally, an early case study of three COVID-19 patients reported the presence of antiphospholipid antibodies in all three patients [104].
+Antiphospholipid antibodies are central to the diagnosis of the antiphospholipid syndrome, a disorder that HCQ has often been used to treat [458,459,460].
+Because the 90% effective concentration (EC90) of CQ in Vero E6 cells (6.90 μM) can be achieved in and tolerated by rheumatoid arthritis (RA) patients, it was hypothesized that it might also be possible to achieve the effective concentration in COVID-19 patients [461].
+Additionally, HCQ has been found to be effective in treating HIV [462] and chronic Hepatitis C [463].
Together, these studies triggered initial enthusiasm about the therapeutic potential for HCQ and CQ against COVID-19.
HCQ/CQ has been proposed both as a treatment for COVID-19 and a prophylaxis against SARS-CoV-2 exposure, and trials often investigated these drugs in combination with azithromycin (AZ) and/or zinc supplementation.
However, as more evidence has emerged, it has become clear that HCQ/CQ offer no benefits against SARS-CoV-2 or COVID-19.
5.4.2.2.1 Trials Assessing Therapeutic Administration of HCQ/CQ
-The initial study evaluating HCQ as a treatment for COVID-19 patients was published on March 20, 2020 by Gautret et al. [463].
-This non-randomized, non-blinded, non-placebo clinical trial compared HCQ to standard of care (SOC) in 42 hospitalized patients in southern France.
+
The initial study evaluating HCQ as a treatment for COVID-19 patients was published on March 20, 2020 by Gautret et al. [464].
+This non-randomized, non-blinded, non-placebo clinical trial compared HCQ to SOC in 42 hospitalized patients in southern France.
It reported that patients who received HCQ showed higher rates of virological clearance by nasopharyngeal swab on days 3-6 when compared to SOC.
This study also treated six patients with both HCQ + AZ and found this combination therapy to be more effective than HCQ alone.
However, the design and analyses used showed weaknesses that severely limit interpretability of results, including the lack of randomization, lack of blinding, lack of placebo, lack of Intention-To-Treat analysis, lack of correction for sequential multiple comparisons, trial arms entirely confounded by hospital, false negatives in outcome measurements, lack of trial pre-registration, and small sample size.
Two of these weaknesses are due to inappropriate data analysis and can therefore be corrected post hoc by recalculating the p-values (lack of Intention-To-Treat analysis and multiple comparisons).
However, all other weaknesses are fundamental design flaws and cannot be corrected for.
-Thus, conclusions cannot be generalized outside of the study.
-The International Society of Antimicrobial Chemotherapy, the scientific organization that publishes the journal where the article appeared, subsequently announced that the article did not meet its expected standard for publications [464], although it has not been officially retracted.
+Thus, the conclusions cannot be generalized outside of the study.
+The International Society of Antimicrobial Chemotherapy, the scientific organization that publishes the journal where the article appeared, subsequently announced that the article did not meet its expected standard for publications [465], although it has not been officially retracted.
Because of the preliminary data presented in this study, HCQ treatment was subsequently explored by other researchers.
-About one week later, a follow-up case study reported that 11 consecutive patients were treated with HCQ + AZ using the same dosing regimen [465].
+About one week later, a follow-up case study reported that 11 consecutive patients were treated with HCQ + AZ using the same dosing regimen [466].
One patient died, two were transferred to the intensive care unit (ICU), and one developed a prolonged QT interval, leading to discontinuation of HCQ + AZ administration.
As in the Gautret et al. study, the outcome assessed was virological clearance at day 6 post-treatment, as measured from nasopharyngeal swabs.
Of the ten living patients on day 6, eight remained positive for SARS-CoV-2 RNA.
Like in the original study, interpretability was severely limited by the lack of a comparison group and the small sample size.
However, these results stand in contrast to the claims by Gautret et al. that all six patients treated with HCQ + AZ tested negative for SARS-CoV-2 RNA by day 6 post-treatment.
This case study illustrated the need for further investigation using robust study design to evaluate the efficacy of HCQ and/or CQ.
-On April 10, 2020, a randomized, non-placebo trial of 62 COVID-19 patients at the Renmin Hospital of Wuhan University was released [466].
-This study investigated whether HCQ decreased time to fever break or time to cough relief when compared to SOC [466].
+
On April 10, 2020, a randomized, non-placebo trial of 62 COVID-19 patients at the Renmin Hospital of Wuhan University was released [467].
+This study investigated whether HCQ decreased time to fever break or time to cough relief when compared to SOC [467].
This trial found HCQ decreased both average time to fever break and average time to cough relief, defined as mild or no cough.
While this study improved on some of the methodological flaws in Gautret et al. by randomizing patients, it also had several flaws in trial design and data analysis that prevent generalization of the results.
These weaknesses include the lack of placebo, lack of correction for multiple primary outcomes, inappropriate choice of outcomes, lack of sufficient detail to understand analysis, drastic disparities between pre-registration and published protocol, and small sample size.
@@ -1883,67 +1882,67 @@
[467]
.
-The design limitations mean that the conclusions cannot be generalized outside of the study.
-A second randomized trial, conducted by the Shanghai Public Health Clinical Center, analyzed whether HCQ increased rates of virological clearance at day 7 in respiratory pharyngeal swabs compared to SOC [468].
+Additionally, the observation of drastic disparities between pre-registration and published protocol could indicate p-hacking [468].
+The design limitations mean that the conclusions cannot be generalized outside of the study.
+
4.3.3 Pooled and Automated PCR Testing
Due to limited supplies and the need for more tests, several labs have found ways to pool or otherwise strategically design tests to increase throughput. -The first such result came from Yelin et al. [318], who found they could pool up to 32 samples in a single qPCR run. -This was followed by larger-scale pooling with slightly different methods [319]. +The first such result came from Yelin et al. [320], who found they could pool up to 32 samples in a single qPCR run. +This was followed by larger-scale pooling with slightly different methods [321]. Although these approaches are also PCR based, they allow for more rapid scaling and higher efficiency for testing than the initial PCR-based methods developed.
4.3.3.1 CRISPR-based Detection
Two CRISPR-associated nucleases, Cas12 and Cas13, have been used for nucleic acid detection. Multiple assays exploiting these nucleases have emerged as potential diagnostic tools for the rapid detection of SARS-CoV-2 genetic material and therefore SARS-CoV-2 infection. -The SHERLOCK method (Specific High-sensitivity Enzymatic Reporter unLOCKing) from Sherlock Biosciences relies on Cas13a to discriminate between inputs that differ by a single nucleotide at very low concentrations [320]. +The SHERLOCK method (Specific High-sensitivity Enzymatic Reporter unLOCKing) from Sherlock Biosciences relies on Cas13a to discriminate between inputs that differ by a single nucleotide at very low concentrations [322]. The target RNA is amplified by RT-RPA and T7 transcription, and the amplified product activates Cas13a. The nuclease then cleaves a reporter RNA, which liberates a fluorescent dye from a quencher. Several groups have used the SHERLOCK method to detect SARS-CoV-2 viral RNA. -An early study reported that the method could detect 7.5 copies of viral RNA in all 10 replicates, 2.5 copies in 6 out of 10, and 1.25 copies in 2 out of 10 runs [321]. +An early study reported that the method could detect 7.5 copies of viral RNA in all 10 replicates, 2.5 copies in 6 out of 10, and 1.25 copies in 2 out of 10 runs [323]. It also reported 100% specificity and sensitivity on 114 RNA samples from clinical respiratory samples (61 suspected cases, among which 52 were confirmed and nine were ruled out by metagenomic next-generation sequencing, 17 nCoV-/HCoV+ cases and 36 samples from healthy subjects), and a reaction turnaround time of 40 minutes. A separate study screened four designs of SHERLOCK and extensively tested the best-performing assay. -They determined the limit of detection to be 10 copies/μl using both fluorescent and lateral flow detection [322]. +They determined the limit of detection to be 10 copies/μl using both fluorescent and lateral flow detection [324]. Lateral flow test strips are simple to use and read, but there are limitations in terms of availability and cost per test. -Another group therefore proposed the CREST protocol (Cas13-based, Rugged, Equitable, Scalable Testing), which uses a P51 cardboard fluorescence visualizer, powered by a 9V battery, for the detection of Cas13 activity instead of immunochromatography [323]. +Another group therefore proposed the CREST protocol (Cas13-based, Rugged, Equitable, Scalable Testing), which uses a P51 cardboard fluorescence visualizer, powered by a 9V battery, for the detection of Cas13 activity instead of immunochromatography [325]. CREST can be run, from RNA sample to result, with no need for AC power or a dedicated facility, with minimal handling in approximately 2 hours. Testing was performed on 14 nasopharyngeal swabs. CREST picked up the same positives as the CDC-recommended TaqMan assay with the exception of one borderline sample that displayed low-quality RNA.
The DETECTR method (DNA Endonuclease-Targeted CRISPR Trans Reporter) from Mammoth Biosciences involves purification of RNA extracted from patient specimens, amplification of extracted RNAs by loop-mediated amplification, which is a rapid, isothermal nucleic acid amplification technique, and application of their Cas12-based technology. -In their assay, guide RNAs were designed to recognize portions of sequences corresponding to the SARS-CoV-2 genome, specifically the N2 and E regions [324]. +In their assay, guide RNAs were designed to recognize portions of sequences corresponding to the SARS-CoV-2 genome, specifically the N2 and E regions [326]. In the presence of SARS-CoV-2 genetic material, sequence recognition by the guide RNAs results in double-stranded DNA cleavage by Cas12, as well as cleavage of a single-stranded DNA molecular beacon. The cleavage of this molecular beacon acts as a colorimetric reporter that is subsequently read out in a lateral flow assay and indicates the positive presence of SARS-CoV-2 genetic material and therefore SARS-CoV-2 infection. The 40-minute assay is considered positive if there is detection of both the E and N genes or presumptive positive if there is detection of either of them. The assay had 95% positive predictive agreement and 100% negative predictive agreement with the US Centers for Disease Control and Prevention SARS-CoV-2 real-time RT–PCR assay. The estimated limit of detection was 10 copies per μl reaction, versus 1 copy per μl reaction for the CDC assay. These results have been confirmed by other DETECTR approaches. -Using RTRPA for amplification, another group detected 10 copies of synthetic SARS-CoV-2 RNA per μl of input within 60 minutes of RNA sample preparation in a proof-of-principle evaluation [325]. +Using RTRPA for amplification, another group detected 10 copies of synthetic SARS-CoV-2 RNA per μl of input within 60 minutes of RNA sample preparation in a proof-of-principle evaluation [327]. The DETECTR protocol was improved by combining RT-RPA and CRISPR-based detection in a one-pot reaction that incubates at a single temperature, and by using dual crRNAs (which increases sensitivity). -This new assay, known as All-In-One Dual CRISPR-Cas12a (AIOD-CRISPR), detected 4.6 copies of SARS-CoV-2 RNA per μl of input in 40 minutes [326]. -Another single-tube, constant-temperature approach using Cas12b instead of Cas12a achieved a detection limit of 5 copies/μl in 40-60 minutes [327]. -It was also reported that electric field gradients can be used to control and accelerate CRISPR assays by co-focusing Cas12-gRNA, reporters, and target [328]. +This new assay, known as All-In-One Dual CRISPR-Cas12a (AIOD-CRISPR), detected 4.6 copies of SARS-CoV-2 RNA per μl of input in 40 minutes [328]. +Another single-tube, constant-temperature approach using Cas12b instead of Cas12a achieved a detection limit of 5 copies/μl in 40-60 minutes [329]. +It was also reported that electric field gradients can be used to control and accelerate CRISPR assays by co-focusing Cas12-gRNA, reporters, and target [330]. The authors generated an appropriate electric field gradient using a selective ionic focusing technique known as isotachophoresis (ITP) implemented on a microfluidic chip. They also used ITP for automated purification of target RNA from raw nasopharyngeal swab samples. Combining this ITP purification with loop-mediated isothermal amplification, their ITP-enhanced assay to achieved detection of SARS-CoV-2 RNA (from raw sample to result) in 30 minutes.
There is an increasing body of evidence that CRISPR-based assays offer a practical solution for rapid, low-barrier testing in areas that are at greater risk of infection, such as airports and local community hospitals. -In the largest study to date, DETECTR was compared to qRT-PCR on 378 patient samples [329]. +In the largest study to date, DETECTR was compared to qRT-PCR on 378 patient samples [331]. The authors reported a 95% reproducibility. Both techniques were equally sensitive in detecting SARS-CoV-2. Lateral flow strips showed a 100% correlation to the high-throughput DETECTR assay. @@ -1451,26 +1452,26 @@
False-negative responses, which can present a significant problem to large-scale testing.
-To reduce occurrence of false negatives, correct execution of the analysis is crucial [330].
-Uncertainty surrounding the SARS-CoV-2 viral shedding kinetics, which could affect the result of a test depending on when it was taken [330].
-Type of specimen, as it is not clear which clinical samples are best for detecting the virus [330].
-Expensive machinery, which might be present in major hospitals and/or diagnostic centers but is often not available to smaller facilities [331].
-Timing of the test, which might take up to 4 days to return results [331].
-The availability of supplies for testing, including swabs and testing media, has been limited [332].
+To reduce occurrence of false negatives, correct execution of the analysis is crucial [332].
+Uncertainty surrounding the SARS-CoV-2 viral shedding kinetics, which could affect the result of a test depending on when it was taken [332].
+Type of specimen, as it is not clear which clinical samples are best for detecting the virus [332].
+Expensive machinery, which might be present in major hospitals and/or diagnostic centers but is often not available to smaller facilities [333].
+Timing of the test, which might take up to 4 days to return results [333].
+The availability of supplies for testing, including swabs and testing media, has been limited [334].
Because the guide RNA can recognize other interspersed sequences on the patient’s genome, false positives and a loss of specificity can occur.
Similarly, in tests that use CRISPR, false positives can occur due to the specificity of the technique, as the guide RNA can recognize other interspersed sequences on the patient’s genome.
As noted above, false negatives are a significant concern for several reason.
-Importantly, clinical reports indicate that it is imperative to exercise caution when interpreting the results of molecular tests for SARS-CoV-2 because negative results do not necessarily mean a patient is virus-free [333].
+Importantly, clinical reports indicate that it is imperative to exercise caution when interpreting the results of molecular tests for SARS-CoV-2 because negative results do not necessarily mean a patient is virus-free [335].
4.4 Serological Tests
Although diagnostic tests based on the detection of genetic material can be quite sensitive, they cannot provide information about the extent of the disease over time.
Most importantly, they would not work on a patient who has fully recovered from the virus at the time of sample collection.
In this context, serological tests, which use serum to test for the presence of antibodies against SARS-CoV-2, are significantly more informative.
Additionally, serological tests can help scientists to understand why the disease has a different course among patients, as well as which strategies might work to manage the spread of the infection.
Furthermore, serological tests hold significant interest because of the possibility that they could provide information relevant to advancing economic recovery and allowing reopenings.
-For instance, people that had developed antibodies might be able to return to work, assuming (still-unproven) protective immunity [334].
+For instance, people that had developed antibodies might be able to return to work, assuming (still-unproven) protective immunity [336].
Some infectious agents can be controlled through “herd immunity”, which is when a critical mass within the population acquires immunity through vaccination and/or infection, preventing an infectious agent from spreading widely.
-A simple SIR model predicts that to achieve the required level of exposure for herd immunity to be effective, at least (1-(1/R0)) fraction of the population must be immune or, equivalently, less than (1/R0) fraction of the population susceptible [223].
+A simple SIR model predicts that to achieve the required level of exposure for herd immunity to be effective, at least (1-(1/R0)) fraction of the population must be immune or, equivalently, less than (1/R0) fraction of the population susceptible [225].
However, for SARS-CoV-2 and COVID-19, the R0 and mortality rates that have been observed suggest that relying on herd immunity without some combination of vaccines, proven treatment options, and strong non-pharmaceutical measures of prevention and control would likely result in a significant loss of life.
4.4.1 Sustained Immunity to COVID-19
In the process of mounting a response to a pathogen, the immune system produces antibodies specific to the pathogen.
@@ -1478,19 +1479,19 @@
[335].
-A two-year longitudinal study following convalesced SARS patients with a mean age of 29 found that IgG antibodies were detectable in all 56 patients surveyed for at least 16 months, and remained detectable in all but 4 (11.8%) of patients through the full two-year study period [336].
+IgG titers peaked by day 60, and persisted in all donors through the two-year duration of study [337].
+A two-year longitudinal study following convalesced SARS patients with a mean age of 29 found that IgG antibodies were detectable in all 56 patients surveyed for at least 16 months, and remained detectable in all but 4 (11.8%) of patients through the full two-year study period [338].
These results suggest that immunity to SARS-CoV-1 is sustained for at least a year.
The persistence of antibodies to SARS-CoV-2 remains under investigation.
-Circulating antibody titers to other coronaviruses have been reported to decline significantly after 1 year [337].
-Autopsies of lymph nodes and spleens from severe acute COVID-19 patients showed a loss of T follicular helper cells and germinal centers that may explain some of the impaired development of antibody responses [338].
-An early study (initially released on medRxiv on February 25, 2020) presented a chemiluminescence immunoassay to a synthetic peptide derived from the amino acid sequence of the SARS-CoV-2 S protein [339].
+Circulating antibody titers to other coronaviruses have been reported to decline significantly after 1 year [339].
+Autopsies of lymph nodes and spleens from severe acute COVID-19 patients showed a loss of T follicular helper cells and germinal centers that may explain some of the impaired development of antibody responses [340].
+An early study (initially released on medRxiv on February 25, 2020) presented a chemiluminescence immunoassay to a synthetic peptide derived from the amino acid sequence of the SARS-CoV-2 S protein [341].
This method was highly specific to SARS-CoV-2 and detected IgM in 57.2% and IgG in 71.4% and 57.2% of sera samples from 276 confirmed COVID-19 patients.
They reported that they could detect IgG within two days of the onset of fever and were not able to detect IgM any earlier, a pattern they compared to findings in MERS.
-Since then, several trials have reported the potential protective effect of antibodies in convalescent plasma obtained from recovered COVID-19 patients to treat critically ill COVID-19 patients [340,341,342].
+Since then, several trials have reported the potential protective effect of antibodies in convalescent plasma obtained from recovered COVID-19 patients to treat critically ill COVID-19 patients [342,343,344].
-Evidence to date suggests that sustained immunity to SARS-CoV-2 occurs for a period of at least 6-8 months [343,344,345].
-One study assessed sustained immunity using 245 blood samples from 188 COVID-19 positive patients [344].
+
Evidence to date suggests that sustained immunity to SARS-CoV-2 occurs for a period of at least 6-8 months [345,346,347].
+One study assessed sustained immunity using 245 blood samples from 188 COVID-19 positive patients [346].
The samples were collected at various time points between 6 and 240 days post-symptom onset, meaning some patients were assessed longitudinally.
Of the samples, 43 were collected at least 6 months after symptom onset.
After 1 month, 98% of patients were seropositive for Spike IgG.
@@ -1498,54 +1499,54 @@
[345,346], and this study confirms these finding and shows that these cells steadily increase over the 4-5 months post-symptom onset [344].
-Likewise, nucleocapsid-specific memory B cells seem to follow a similar pattern [344].
-SARS-CoV-2 memory CD8+ T cells were also detected in 70% of 169 COVID-19 patients after 1 month [344], which is consistent with previous research [347].
+RBD-specific memory B cells had been detected in COVID-19 patients 90 days post-symptom onset in previous studies [347,348], and this study confirms these finding and shows that these cells steadily increase over the 4-5 months post-symptom onset [346].
+Likewise, nucleocapsid-specific memory B cells seem to follow a similar pattern [346].
+SARS-CoV-2 memory CD8+ T cells were also detected in 70% of 169 COVID-19 patients after 1 month [346], which is consistent with previous research [349].
However, SARS-CoV-2 memory CD8+ T cells were slightly decreased (50%) 6 months post-symptom onset.
In this same subset of COVID-19 patients, 93% of subjects had detectable levels of SARS-CoV-2 memory CD4+ T cells, of which 42% had > 1% SARS-CoV-2-specific CD4+ T cells.
At 6 months, 92% of patients were positive for SARS-CoV-2 memory CD4+ T cells.
-Indeed, the spike-specific memory CD4+ T cells abundance over time were similar to the overall SARS-CoV-2-specific CD4+ T cells [344].
-T cell immunity to SARS-CoV-2 at 6-8 months post-symptom onset has also been confirmed by others [348,349].
+Indeed, the spike-specific memory CD4+ T cells abundance over time were similar to the overall SARS-CoV-2-specific CD4+ T cells [346].
+T cell immunity to SARS-CoV-2 at 6-8 months post-symptom onset has also been confirmed by others [350,351].
In another study, T cell reactivity to SARS-CoV-2 epitopes was also detected in some individuals never before exposed to SARS-CoV-2.
-This indicates that there is potential for cross-reactive T cell recognition between SARS-CoV-2 and pre-existing circulating coronaviruses that are responsible for the “common cold” [347], but further research is required.
-There is concern that immunity may wane over time, as there several reported cases of reinfection have been confirmed via genomic analysis that revealed distinct variants of SARS-CoV-2 within a single patient [350,351,352].
+This indicates that there is potential for cross-reactive T cell recognition between SARS-CoV-2 and pre-existing circulating coronaviruses that are responsible for the “common cold” [349], but further research is required.
+There is concern that immunity may wane over time, as there several reported cases of reinfection have been confirmed via genomic analysis that revealed distinct variants of SARS-CoV-2 within a single patient [352,353,354].
Further research is required to determine the full extent to which sustained immunity can be and is typically achieved following SARS-CoV-2 infection
-Furthermore, it is unclear whether previous infection may carry repercussions in terms of disease severity for patients [353] and what implications the possibility of reinfection holds for vaccine development and the long-term efficacy of vaccines [354,355].
+Furthermore, it is unclear whether previous infection may carry repercussions in terms of disease severity for patients [355] and what implications the possibility of reinfection holds for vaccine development and the long-term efficacy of vaccines [356,357].
4.4.2 Current Approaches
-
Several countries are now focused on implementing antibody tests, and in the United States, the FDA recently approved a serological test by Cellex for use under emergency conditions [356].
-Specifically, the Cellex qSARS-CoV-2 IgG/IgM Rapid Test is a chromatographic immunoassay designed to qualitatively detect IgM and IgG antibodies against SARS-CoV-2 in the plasma (from a blood sample) of patients suspected to have developed the SARS-CoV-2 infection [356].
+
Several countries are now focused on implementing antibody tests, and in the United States, the FDA recently approved a serological test by Cellex for use under emergency conditions [358].
+Specifically, the Cellex qSARS-CoV-2 IgG/IgM Rapid Test is a chromatographic immunoassay designed to qualitatively detect IgM and IgG antibodies against SARS-CoV-2 in the plasma (from a blood sample) of patients suspected to have developed the SARS-CoV-2 infection [358].
Such tests illuminate the progression of viral disease, as IgM are the first antibodies produced by the body and indicate that the infection is active.
-Once the body has responded to the infection, IgG are produced and gradually replace IgM, indicating that the body has developed immunogenic memory [357].
-The test cassette contains a pad of SARS-CoV-2 antigens and a nitrocellulose strip with lines for each of IgG and IgM, as well as a control (goat IgG) [356].
-In a specimen that contains antibodies against the SARS-CoV-2 antigen, the antibodies will bind to the strip and be captured by the IgM and/or IgG line(s), resulting in a change of color [356].
-With this particular assay, results can be read within 15-20 minutes [356].
-Other research groups, such as the Krammer lab of the Icahn School of Medicine at Mount Sinai, proposed an ELISA test that detects IgG and IgM that react against the receptor binding domain (RBD) of the spike proteins (S) of the virus [358].
-The authors are now working to get the assay into clinical use [359].
+Once the body has responded to the infection, IgG are produced and gradually replace IgM, indicating that the body has developed immunogenic memory [359].
+The test cassette contains a pad of SARS-CoV-2 antigens and a nitrocellulose strip with lines for each of IgG and IgM, as well as a control (goat IgG) [358].
+In a specimen that contains antibodies against the SARS-CoV-2 antigen, the antibodies will bind to the strip and be captured by the IgM and/or IgG line(s), resulting in a change of color [358].
+With this particular assay, results can be read within 15-20 minutes [358].
+Other research groups, such as the Krammer lab of the Icahn School of Medicine at Mount Sinai, proposed an ELISA test that detects IgG and IgM that react against the receptor binding domain (RBD) of the spike proteins (S) of the virus [360].
+The authors are now working to get the assay into clinical use [361].
4.4.3 Limitations of Serological Tests
-Importantly, false-positives can occur due to the cross-reactivity with other antibodies according to the clinical condition of the patient [356].
-Therefore, this test should be used in combination with RNA detection tests [356].
+
Importantly, false-positives can occur due to the cross-reactivity with other antibodies according to the clinical condition of the patient [358].
+Therefore, this test should be used in combination with RNA detection tests [358].
Due to the long incubation times and delayed immune responses of infected patients, serological tests are insufficiently sensitive for a diagnosis in the early stages of an infection.
The limitations due to timing make serological tests far less useful for enabling test-and-trace strategies.
4.5 Possible Alternatives to Current Practices for Identifying Active Cases
Clinical symptoms are too similar to other types of pneumonia to be sufficient as a sole diagnostics criterion.
In addition, as noted above, identifying asymptomatic cases is critical.
-Even among mildly symptomatic patients, a predictive model based on clinical symptoms had a sensitivity of only 56% and a specificity of 91% [360].
+Even among mildly symptomatic patients, a predictive model based on clinical symptoms had a sensitivity of only 56% and a specificity of 91% [362].
More problematic is that clinical symptom-based tests are only able to identify already symptomatic cases, not presymptomatic or asymptomatic cases.
They may still be important for clinical practice, and for reducing tests needed for patients deemed unlikely to have COVID-19.
-X-ray diagnostics have been reported to have high sensitivity but low specificity in some studies [361].
-Other studies have shown that specificity varies between radiologists [362], though the sensitivity reported here was lower than that published in the previous paper.
-However, preliminary machine-learning results have shown far higher sensitivity and specificity from analyzing chest X-rays than was possible with clinical examination [363].
+
X-ray diagnostics have been reported to have high sensitivity but low specificity in some studies [363].
+Other studies have shown that specificity varies between radiologists [364], though the sensitivity reported here was lower than that published in the previous paper.
+However, preliminary machine-learning results have shown far higher sensitivity and specificity from analyzing chest X-rays than was possible with clinical examination [365].
X-ray tests with machine learning can potentially detect asymptomatic or presymptomatic infections that show lung manifestations.
This approach would still not recognize entirely asymptomatic cases.
Given the above, the widespread use of X-ray tests on otherwise healthy adults is likely inadvisable.
4.6 Strategies and Considerations for Determining Whom to Test
-Early in the COVID-19 pandemic, testing was typically limited to individuals considered high risk for developing serious illness [364].
+
Early in the COVID-19 pandemic, testing was typically limited to individuals considered high risk for developing serious illness [366].
This approach often involved limiting testing to people with severe symptoms and people showing mild symptoms that had been in contact with a person who had tested positive.
Individuals who are asymptomatic (i.e., potential spreaders) and individuals who are able to recover at home are therefore often unaware of their status.
However, this method of testing administration misses a high proportion of infections and does not allow for test-and-trace methods to be used.
-For instance, a recent study from Imperial College estimates that in Italy, the true number of infections was around 5.9 million in a total population ~60 million, compared to the 70,000 detected as of March 28th [239].
-Another analysis, which examined New York state, indicated that as of May, 2020, approximately 300,000 cases had been reported in a total population of approximately 20 million [365].
-This corresponded to ~1.5% of the population, but ~12% of individuals sampled statewide were estimated as positive through antibody tests (along with indications of spatial heterogeneity at higher resolution) [365].
+For instance, a recent study from Imperial College estimates that in Italy, the true number of infections was around 5.9 million in a total population ~60 million, compared to the 70,000 detected as of March 28th [241].
+Another analysis, which examined New York state, indicated that as of May, 2020, approximately 300,000 cases had been reported in a total population of approximately 20 million [367].
+This corresponded to ~1.5% of the population, but ~12% of individuals sampled statewide were estimated as positive through antibody tests (along with indications of spatial heterogeneity at higher resolution) [367].
Technological advancements that facilitate widespread, rapid testing will therefore improve the potential to accurately assess the rate of infection and aid in controlling the virus’ spread.
4.7 Conclusions
Major advancements have been made in identifying diagnostic approaches.
@@ -1553,11 +1554,11 @@
4.7
As of October 2020, a range of diagnostic tests have become available.
One class of tests uses PCR (RT-PCR or qRT-PCR) to assess the presence of SARS-CoV-2 RNA, while another typically uses ELISA to test for the presence of antibodies to SARS-CoV-2.
The former approach is useful for identifying active infections, while the latter measures hallmarks of the immune response and therefore can detect either active infections or immunity gained from prior infection.
-Combining these tests leads to extremely accurate detection of SARS-CoV-2 infection (98.6%), but when used alone, PCR-based tests are recommended before 5.5 days after the onset of the illness and antibody tests after 5.5 days [366].
-Other strategies for testing can also influence the tests’ accuracy, such as the use of nasopharyngeal swabs versus BALF [366], which allow for trade-offs between patient’s comfort and test sensitivity.
+Combining these tests leads to extremely accurate detection of SARS-CoV-2 infection (98.6%), but when used alone, PCR-based tests are recommended before 5.5 days after the onset of the illness and antibody tests after 5.5 days [368].
+Other strategies for testing can also influence the tests’ accuracy, such as the use of nasopharyngeal swabs versus BALF [368], which allow for trade-offs between patient’s comfort and test sensitivity.
Additionally, technologies such as digital PCR may allow for scale-up in the throughput of diagnostic testing, facilitating widespread testing.
One major question that remains is whether people who recover from SARS-CoV-2 develop sustained immunity, and over what period this immunity is expected to last.
-Some reports have suggested that some patients may develop COVID-19 reinfections (e.g., [350]), but the rates of reinfection are currently unknown.
+Some reports have suggested that some patients may develop COVID-19 reinfections (e.g., [352]), but the rates of reinfection are currently unknown.
Serologic testing combined with PCR testing will be critical to confirming purported cases of reinfection and to identifying the duration over which immunity is retained and to understanding reinfection risks.
5 Identification and Development of Prophylactics and Therapeutics for COVID-19
5.1 Abstract
@@ -1566,7 +1567,7 @@ 5.1
5.2 Importance
@@ -1578,54 +1579,54 @@ 5.2<
This rapidly changing area of research provides important insight into how the ongoing pandemic can be managed and also demonstrates the power of interdisciplinary collaboration to rapidly understand a virus and match its characteristics with existing or novel pharmaceuticals.
5.3 Introduction
The novel coronavirus Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) emerged in late 2019 and quickly precipitated the worldwide spread of novel coronavirus disease 2019 (COVID-19).
-COVID-19 is associated with symptoms ranging from none (asymptomatic) to mild to severe, with approximately 2% of patients dying from COVID-19-related complications, such as acute respiratory disease syndrome (ARDS) [367].
-The virus is likely spread between people primarily by droplets, with the role of contact and aerosol transmission still in question [194,195].
+COVID-19 is associated with symptoms ranging from none (asymptomatic) to mild to severe, with approximately 2% of patients dying from COVID-19-related complications, such as acute respiratory disease syndrome (ARDS) [1].
+The virus is likely spread between people primarily by droplets, with the role of contact and aerosol transmission still in question [196,197].
As a result, public health guidelines have been critical to efforts to control the spread of the virus.
However, as of early 2021, COVID-19 remains a significant worldwide concern (Figure 2), with cases in some places surging far above the numbers reported during the initial outbreak in early 2020.
Due to the continued threat of the virus and the severity of the disease, the identification and development of prophylactic and therapeutic interventions have emerged as significant international priorities.
Both approaches hold valuable potential for controlling the impact of the disease.
Prophylactics bolster immunity to prevent an individual from contracting a disease, whereas therapeutics treat a disease in individuals who have already been infected.
While vaccine development programs have attracted significant attention and produced a number of promising candidates, there is also an immediate need for treatments that palliate symptoms and prevent the most severe outcomes from infection.
-Fortunately, prior developments during other recent pandemics, especially those caused by human coronaviruses (HCoV), has provided a number of hypotheses guiding a biomedical approach to the novel coronavirus infection.
+Fortunately, prior developments during other recent pandemics, especially those caused by human coronaviruses (HCoV), have provided a number of hypotheses guiding a biomedical approach to the novel coronavirus infection.
2,354,561 COVID-19 deaths had been reported worldwide as of February 10, 2021 (Figure 2).
Figure 2: Cumulative global COVID-19 deaths since January 22, 2020.
-Data are from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [368].
+Data are from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [369].
5.3.1 Lessons from Prior HCoV Outbreaks
SARS-CoV-2’s rapid shift from an unknown virus to a significant worldwide threat closely parallels the emergence of Severe acute respiratory syndrome-related coronavirus (SARS-CoV-1).
The first documented case of COVID-19 was reported in Wuhan, China in November 2019, and the disease quickly spread worldwide during the early months of 2020.
-Similarly, the first case of SARS was reported in November 2002 in the Guangdong Province of China, and it spread within China and then into several countries across continents over the following months [28,30].
-In fact, genome sequencing quickly revealed the virus causing COVID-19 to be a novel betacoronavirus closely related to SARS-CoV-1 [10].
+Similarly, the first case of SARS was reported in November 2002 in the Guangdong Province of China, and it spread within China and then into several countries across continents over the following months [30,32].
+In fact, genome sequencing quickly revealed the virus causing COVID-19 to be a novel betacoronavirus closely related to SARS-CoV-1 [12].
There are many similarities but also some differences in the characteristics of the two viruses that determine how they spread.
-SARS infection is severe, with an estimated death rate of 9.5% [30], while estimates of the death rate associated with COVID-19 are much lower, at approximately 2% [367].
-SARS-CoV-1 is highly contagious via droplet transmission and has a basic reproduction number (R0) of 4 (i.e., each person infected was estimated to infect four other people) [30].
-SARS-CoV-2 also appears to be spread primarily by droplet transmission [194,195], and most estimates of its R0 fall between 2.5 and 3 [367].
+SARS infection is severe, with an estimated death rate of 9.5% [32], while estimates of the death rate associated with COVID-19 are much lower, at approximately 2% [1].
+SARS-CoV-1 is highly contagious via droplet transmission and has a basic reproduction number (R0) of 4 (i.e., each person infected was estimated to infect four other people) [32].
+SARS-CoV-2 also appears to be spread primarily by droplet transmission [196,197], and most estimates of its R0 fall between 2.5 and 3 [1].
Furthermore, the 17-year difference in the timing of these two outbreaks has led to some major differences in the tools available for the international community’s response.
-At the time that SARS-CoV-1 emerged, no new HCoV had been identified in almost 40 years [28].
-The identity of the virus underlying the SARS disease remained unknown until April of 2003, when the SARS-CoV-1 virus was characterized through a worldwide scientific effort spearheaded by the WHO [28].
-In contrast, the SARS-CoV-2 genomic sequence was released on January 3, 2020 [10], only days after the international community became aware of the novel pneumonia-like illness now known as COVID-19.
-While SARS-CoV-1 belonged to a distinct lineage from the two other HCoV known at the time of its discovery [30], SARS-CoV-2 is closely related to SARS-CoV-1 and a more distant relative of another HCoV characterized in 2012, Middle East respiratory syndrome-related coronavirus [13,369].
-Thus, despite their phylogenetic similarity, SARS-CoV-2 emerged under very different circumstances than SARS-CoV-1 in terms of scientific knowledge about HCoV.
+At the time that SARS-CoV-1 emerged, no new HCoV had been identified in almost 40 years [30].
+The identity of the virus underlying the SARS disease remained unknown until April of 2003, when the SARS-CoV-1 virus was characterized through a worldwide scientific effort spearheaded by the World Health Organization (WHO) [30].
+In contrast, the SARS-CoV-2 genomic sequence was released on January 3, 2020 [12], only days after the international community became aware of the novel pneumonia-like illness now known as COVID-19.
+While SARS-CoV-1 belonged to a distinct lineage from the two other HCoV known at the time of its discovery [32], SARS-CoV-2 is closely related to SARS-CoV-1 and a more distant relative of another HCoV characterized in 2012, Middle East respiratory syndrome-related coronavirus [15,370].
+Despite their phylogenetic similarity, SARS-CoV-2 emerged under very different circumstances than SARS-CoV-1 in terms of scientific knowledge about HCoV.
The trajectories of the pandemics associated with each of the viruses have also diverged significantly.
-By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices such as mask wearing [28].
-In contrast, MERS is still circulating and remains a concern; although the fatality rate is very high at almost 35%, the disease is much less easily transmitted, as its R0 has been estimated to be 1 [30].
-The low R0 in combination with public health practices allowed for its spread to be contained [30].
+By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices such as mask wearing [30].
+In contrast, MERS is still circulating and remains a concern; although the fatality rate is very high at almost 35%, the disease is much less easily transmitted, as its R0 has been estimated to be 1 [32].
+The low R0 in combination with public health practices allowed for its spread to be contained [32].
Neither of these trajectories are comparable to that of SARS-CoV-2, which remains a serious threat worldwide more than a year after the first cases of COVID-19 emerged.
Early results suggest that pharmaceutical interventions for COVID-19 may be more successful than efforts to develop prophylactics and therapeutics for SARS and MERS were.
-Care for SARS and MERS patients prioritized supportive care and symptom management [30].
+Care for SARS and MERS patients prioritized supportive care and symptom management [32].
To the extent that clinical treatments for SARS and MERS were explored, there is generally a lack of evidence supporting their efficacy.
-For example, Ribavirin is an antiviral that was often used in combination with corticosteroids and sometimes interferon (IFN) medications to treat SARS and MERS [28], but its effects have been found to be inconclusive in retrospective and in vitro analyses of SARS and the SARS-CoV-1 virus, respectively [28].
-IFNs and Ribavirin have shown promise in in vitro analyses of MERS, but their clinical effectiveness remains unknown [28].
+For example, Ribavirin is an antiviral that was often used in combination with corticosteroids and sometimes interferon (IFN) medications to treat SARS and MERS [30], but its effects have been found to be inconclusive in retrospective and in vitro analyses of SARS and the SARS-CoV-1 virus, respectively [30].
+IFNs and Ribavirin have shown promise in in vitro analyses of MERS, but their clinical effectiveness remains unknown [30].
Therefore, only limited pharmaceutical advances from prior HCoV outbreaks can be adopted to COVID-19.
Importantly, though, prior analyses of the virological and pathogenic properties of SARS-CoV-1 and MERS-CoV provide a strong foundation for the development of hypotheses about SARS-CoV-2 that have served to accelerated the development and identification of potential prophylactic and therapeutic approaches.
5.3.2 Therapeutic Approaches
Therapeutic approaches to the current pandemic can utilize two potential avenues: they can reduce the symptoms that are harmful to COVID-19 patients, or they can directly target the virus to hinder the spread of infection.
The goal of the former is to reduce the severity and risks of an active infection, while for the latter, it is to inhibit the replication of the virus once an individual is infected.
A variety of symptom profiles with a range of severity are associated with COVID-19, many of which are not life-threatening.
-A study of COVID-19 patients in a hospital in Berlin, Germany found that the symptoms associated with the highest risk of death included infection-related symptoms, such as sepsis, respiratory symptoms such as ARDS, and cardiovascular failure or pulmonary embolism [370].
+A study of COVID-19 patients in a hospital in Berlin, Germany found that the symptoms associated with the highest risk of death included infection-related symptoms, such as sepsis, respiratory symptoms such as ARDS, and cardiovascular failure or pulmonary embolism [371].
Therapeutics that reduce the risks associated with these severe outcomes hold particular potential to reduce the pandemic death toll.
On the other hand, therapeutics that directly target the virus itself would hold the potential to prevent people infected with SARS-CoV-2 from developing potentially damaging symptoms.
These treatments typically fall into the broad category of antivirals.
@@ -1644,44 +1645,44 @@
[371].
+Trials data are from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [372].
5.4 Small Molecule Drugs
-
Small molecules are synthesized compounds of low molecular weight, typically less than 1 kilodalton (kDa) [372].
-Small-molecule pharmaceutical agents have been a backbone of drug development since the discovery of penicillin in the early twentieth century [373].
-It and other antibiotics have long been among the best known applications of small molecules to therapeutics, but biotechnological developments such as the prediction of protein-protein interactions have facilitated advances in precise targeting of specific structures using small molecules [373].
+
Small molecules are synthesized compounds of low molecular weight, typically less than 1 kilodalton (kDa) [373].
+Small-molecule pharmaceutical agents have been a backbone of drug development since the discovery of penicillin in the early twentieth century [374].
+It and other antibiotics have long been among the best known applications of small molecules to therapeutics, but biotechnological developments such as the prediction of protein-protein interactions have facilitated advances in precise targeting of specific structures using small molecules [374].
Small molecule drugs today encompass a wide range of therapeutics beyond antibiotics, including antivirals, protein inhibitors, and many broad-spectrum pharmaceuticals.
5.4.1 Small Molecule Antivirals
Antiviral drugs against SARS-CoV-2 are designed to inhibit replication of a virus within an epithelial host cell.
-This process requires inhibiting the replication cycle of a virus by disrupting one of six fundamental steps [374].
+This process requires inhibiting the replication cycle of a virus by disrupting one of six fundamental steps [375].
In the first of these steps, the virus attaches to and enters the host cell through endocytosis.
Then the virus undergoes uncoating, which is classically defined as the release of viral contents into the host cell.
Next, the viral genetic material enters the nucleus where it gets replicated during the biosynthesis stage.
During the assembly stage, viral proteins are translated, allowing new viral particles to be assembled.
In the final step new viruses are released into the extracellular environment.
Many antiviral drugs are designed to inhibit the replication of viral genetic material during the biosynthesis step.
-Unlike DNA viruses, which can use the host enzymes to propagate themselves, RNA viruses like SARS-CoV-2 depend on their own polymerase, the RNA-dependent RNA polymerase (RdRP), for replication [375,376].
-Targeting RdRP is therefore an effective strategy for antivirals against RNA viruses and is the proposed mechanism underlying the treatment of SARS and MERS with Ribavirin [377].
+Unlike DNA viruses, which can use the host enzymes to propagate themselves, RNA viruses like SARS-CoV-2 depend on their own polymerase, the RNA-dependent RNA polymerase (RdRP), for replication [376,377].
+Targeting RdRP is therefore an effective strategy for antivirals against RNA viruses and is the proposed mechanism underlying the treatment of SARS and MERS with Ribavirin [378].
However, although antivirals are designed to target a virus, they can also impact other processes in the host and may have unintended effects.
Therefore, these therapeutics must be evaluated for both efficacy and safety.
5.4.1.1 Nucleoside and Nucleotide Analogs
5.4.1.1.1 Favipiravir
-Favipiravir (Avigan), also known as T-705, was discovered by Toyama Chemical Co., Ltd. [378].
-The drug was found to be effective at blocking viral amplification in several influenza subtypes as well as other RNA viruses, such as Flaviviridae and Picornaviridae, through a reduction in plaque formation [379] and viral replication in Madin-Darby canine kidney cells [380].
-Furthermore, inoculation of mice with favipiravir was shown to increase survival of influenza infections [379,380].
-In 2014, the drug was approved in Japan for the treatment of influenza that was resistant to conventional treatments like neuraminidase inhibitors [381].
-Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) acts as a purine and purine nucleoside analogue that inhibits viral RNA polymerase in a dose-dependent manner across a range of RNA viruses, including influenza viruses [382,383,384,385,386].
+
Favipiravir (Avigan), also known as T-705, was discovered by Toyama Chemical Co., Ltd. [379].
+The drug was found to be effective at blocking viral amplification in several influenza subtypes as well as other RNA viruses, such as Flaviviridae and Picornaviridae, through a reduction in plaque formation [380] and viral replication in Madin-Darby canine kidney cells [381].
+Furthermore, inoculation of mice with favipiravir was shown to increase survival of influenza infections [380,381].
+In 2014, the drug was approved in Japan for the treatment of influenza that was resistant to conventional treatments like neuraminidase inhibitors [382].
+Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) acts as a purine and purine nucleoside analogue that inhibits viral RNA polymerase in a dose-dependent manner across a range of RNA viruses, including influenza viruses [383,384,385,386,387].
Nucleotides and nucleosides are the natural building blocks for RNA synthesis.
-Because of this, modifications to nucleotides and nucleosides can disrupt key processes including replication [387].
+Because of this, modifications to nucleotides and nucleosides can disrupt key processes including replication [388].
Biochemical experiments showed that favipiravir was recognized as a purine nucleoside analogue and incorporated into the viral RNA template.
-A single incorporation does not influence RNA transcription; however, multiple events of incorporation lead to the arrest of RNA synthesis [388].
-Evidence for T-705 inhibiting viral RNA polymerase are based on time-of-drug addition studies that found that viral loads were reduced with the addition of favipiravir in early times post-infection [382,385,386].
+A single incorporation does not influence RNA transcription; however, multiple events of incorporation lead to the arrest of RNA synthesis [389].
+Evidence for T-705 inhibiting viral RNA polymerase are based on time-of-drug addition studies that found that viral loads were reduced with the addition of favipiravir in early times post-infection [383,386,387].
The effectiveness of favipiravir for treating patients with COVID-19 is currently under investigation.
-An open-label, nonrandomized, before-after controlled study was recently conducted [389].
+An open-label, nonrandomized, before-after controlled study was recently conducted [390].
The study included 80 COVID-19 patients (35 treated with favipiravir, 45 control) from the isolation ward of the National Clinical Research Center for Infectious Diseases (The Third People’s Hospital of Shenzhen), Shenzhen, China.
The patients in the control group were treated with other antivirals, such as lopinavir and ritonavir.
-It should be noted that although the control patients received antivirals, two subsequent large-scale analyses, the WHO Solidarity trial and the RECOVERY trial, identified no effect of lopinavir or of a lopinavir-ritonavir combination, respectively, on the metrics of COVID-19-related mortality that each assessed [390,391,392].
+It should be noted that although the control patients received antivirals, two subsequent large-scale analyses, the WHO Solidarity trial and the RECOVERY trial, identified no effect of lopinavir or of a lopinavir-ritonavir combination, respectively, on the metrics of COVID-19-related mortality that each assessed [391,392,393].
Treatment was applied on days 2-14; treatment stopped either when viral clearance was confirmed or at day 14.
The efficacy of the treatment was measured by, first, the time until viral clearance using Kaplan-Meier survival curves, and, second, the improvement rate of chest computed tomography (CT) scans on day 14 after treatment.
The study found that favipiravir increased the speed of recovery, measured as viral clearance from the patient by RT-PCR, with patients receiving favipiravir recovering in four days compared to 11 days for patients receiving antivirals such as lopinavir and ritonavir.
@@ -1692,33 +1693,32 @@
[393].
-
In late 2020 and early 2021, the first randomized controlled trials of favipiravir for the treatment of COVID-19 released results [394,395,396].
-The first [394] used a randomized, controlled, open-label design to compare two drugs, favipiravir and baloxavir marboxil, to SOC alone.
+Additionally, it should be noted that this study was temporarily retracted and then restored without an explanation [394].
+In late 2020 and early 2021, the first randomized controlled trials of favipiravir for the treatment of COVID-19 released results [395,396,397].
+The first [395] used a randomized, controlled, open-label design to compare two drugs, favipiravir and baloxavir marboxil, to standard of care (SOC) alone.
Here, SOC included antivirals such as lopinavir/ritonavir and was administered to all patients.
The primary endpoint analyzed was viral clearance at day 14.
The sample size for this study was very small, with 29 total patients enrolled, and no significant effect of the treatments was found for the primary or any of the secondary outcomes analyzed, which included mortality.
The second study was larger, with 96 patients enrolled, and also utilized a randomized design.
-This study enrolled only patients with mild to moderate symptoms and randomized them into two groups: one receiving CQ in addition to SOC, and the other receiving favipiravir in addition to SOC.
+This study enrolled only patients with mild to moderate symptoms and randomized them into two groups: one receiving chloroquine (CQ) in addition to SOC, and the other receiving favipiravir in addition to SOC.
This study reported a non-significant trend for patients receiving favipiravir to have a shorter hospital stay and less likelihood of progressing to mechanical ventilation or to an oxygen saturation < 90%.
However, given the fact that favipiravir was being compared to CQ, which is now widely understood to be ineffective for treating COVID-19, these results do not suggest that favipiravir was likely to have had a strong effect on these outcomes.
-On the other hand, another trial of 60 patients reported a significant effect of favipiravir on viral clearance at four days (a secondary endpoint), but not at 10 days (the primary endpoint) [396].
-This study, as well as a prior study of favipiravir [397], also reported that the drug was generally well-tolerated.
+On the other hand, another trial of 60 patients reported a significant effect of favipiravir on viral clearance at four days (a secondary endpoint), but not at 10 days (the primary endpoint) [397].
+This study, as well as a prior study of favipiravir [398], also reported that the drug was generally well-tolerated.
Thus, in combination, these small studies suggest that the effects of favipiravir as a treatment for COVID-19 cannot be determined based on the available evidence, but additionally, none raise major concerns about the safety profile of the drug.
5.4.1.1.2 Remdesivir
Remdesivir (GS-5734) is an intravenous antiviral that was developed by Gilead Sciences to treat Ebola Virus Disease (EVD).
At the outset of the COVID-19 pandemic, it did not have any have any FDA-approved use.
-However, on May 1, 2020, the FDA issued an Emergency Use Authorization (EUA) for remdesivir for the treatment of hospitalized COVID-19 patients [398].
-The EUA was based on information from two clinical trials, NCT04280705 and NCT04292899 [399,400,401,402].
-Remdesivir is metabolized to GS-441524, an adenosine analog that inhibits a broad range of polymerases and then evades exonuclease repair, causing chain termination [403,404,405].
-A clinical trial in the Democratic Republic of Congo found some evidence of effectiveness against EVD, but two antibody preparations were found to be more effective, and remdesivir was not pursued [406].
-Although it was developed against EVD, remdesivir also inhibits polymerase and replication of the coronaviruses MERS-CoV and SARS-CoV-1 in cell culture assays with submicromolar IC50s [407].
-It has also been found to inhibit SARS-CoV-2, showing synergy with chloroquine in vitro [405].
-The effectiveness of remdesivir for treating patients with COVID-19 is currently under investigation.
-Remdesivir was first used on some COVID-19 patients under compassionate use guidelines [408,409].
+However, on May 1, 2020, the FDA issued an Emergency Use Authorization (EUA) for remdesivir for the treatment of hospitalized COVID-19 patients [399].
+The EUA was based on information from two clinical trials, NCT04280705 and NCT04292899 [400,401,402,403].
+Remdesivir is metabolized to GS-441524, an adenosine analog that inhibits a broad range of polymerases and then evades exonuclease repair, causing chain termination [404,405,406].
+A clinical trial in the Democratic Republic of Congo found some evidence of effectiveness against EVD, but two antibody preparations were found to be more effective, and remdesivir was not pursued [407].
+Although it was developed against EVD, remdesivir also inhibits polymerase and replication of the coronaviruses MERS-CoV and SARS-CoV-1 in cell culture assays with submicromolar IC50s [408].
+It has also been found to inhibit SARS-CoV-2, showing synergy with CQ in vitro [406].
+Remdesivir was first used on some COVID-19 patients under compassionate use guidelines [409,410].
All were in late stages of COVID-19 infection, and initial reports were inconclusive about the drug’s efficacy.
Gilead Sciences, the maker of remdesivir, led a recent publication that reported outcomes for compassionate use of the drug in 61 patients hospitalized with confirmed COVID-19.
-Here, 200 mg of remdesivir was administered intravenously on day 1, followed by a further 100 mg/day for 9 days [402].
+Here, 200 mg of remdesivir was administered intravenously on day 1, followed by a further 100 mg/day for 9 days [403].
There were significant issues with the study design, or lack thereof.
There was no randomized control group.
The inclusion criteria were variable: some patients only required low doses of oxygen, while others required ventilation.
@@ -1727,49 +1727,48 @@
There was a short follow-up period of investigation.
Some patients worsened, some patients died, and eight were excluded from the analysis mainly due to missing post-baseline information; thus, their health was unaccounted for.
Therefore, even though the study reported clinical improvement in 68% of the 53 patients ultimately evaluated, due to the significant issues with study design, it could not be determined whether treatment with remdesivir had an effect or whether these patients would have recovered regardless of treatment.
-Another study comparing 5- and 10-day treatment regimens reported similar results but was also limited because of the lack of a placebo control [411].
+Another study comparing 5- and 10-day treatment regimens reported similar results but was also limited because of the lack of a placebo control [412].
These studies did not alter the understanding of the efficacy of remdesivir in treating COVID-19, but the encouraging results provided motivation for placebo-controlled studies.
-Remdesivir was later tested in a double-blind placebo-controlled phase 3 clinical trial performed at 60 trial sites, 45 of which were in the United States [400,401].
+
Remdesivir was later tested in a double-blind placebo-controlled phase 3 clinical trial performed at 60 trial sites, 45 of which were in the United States [401,402].
The trial recruited 1,062 patients and randomly assigned them to placebo treatment or treatment with remdesivir.
-Patients were stratified for randomization based on site and the severity of disease presentation at baseline [401].
+Patients were stratified for randomization based on site and the severity of disease presentation at baseline [402].
The treatment was 200 mg on day 1, followed by 100 mg on days 2 through 10.
-Data was analyzed from a total of 1,059 patients who completed the 29-day course of the trial, with 517 assigned to remdesivir and 508 to placebo [401].
+Data was analyzed from a total of 1,059 patients who completed the 29-day course of the trial, with 517 assigned to remdesivir and 508 to placebo [402].
The two groups were well matched demographically and clinically at baseline.
Those who received remdesivir had a median recovery time of 10 days, as compared with 15 days in those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; p < 0.001).
The Kaplan-Meier estimates of mortality by 14 days were 6.7% with remdesivir and 11.9% with placebo, with a hazard ratio (HR) for death of 0.55 and a 95% CI of 0.36 to 0.83, and at day 29, remdesivir corresponded to 11.4% and the placebo to 15.2% (HR: 0.73; 95% CI: 0.52 to 1.03).
Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients in the placebo group (31.6%).
-This study also reported an association between remdesivir administration and both clinical improvement and a lack of progression to more invasive respiratory intervention in patients receiving non-invasive and invasive ventilation at randomization [401].
-Largely on the results of this trial, the FDA reissued and expanded the EUA for remdesivir for the treatment of hospitalized COVID-19 patients ages twelve and older [398].
-Additional clinical trials are currently underway to evaluate the use of remdesivir to treat COVID-19 patients at both early and late stages of infection and in combination with other drugs (Figure 3).
-These trials include [405,412,413,414,415].
-As of October 22, 2020, remdesivir received FDA approval based on three clinical trials [416].
-However, results suggesting no effect of remdesivir on survival were reported by the WHO Solidarity trial [390].
-This large-scale, open-label trial enrolled 11,330 adult in-patients at 405 hospitals in 30 countries around the world [390].
+This study also reported an association between remdesivir administration and both clinical improvement and a lack of progression to more invasive respiratory intervention in patients receiving non-invasive and invasive ventilation at randomization [402].
+Largely on the results of this trial, the FDA reissued and expanded the EUA for remdesivir for the treatment of hospitalized COVID-19 patients ages twelve and older [399].
+Additional clinical trials [406,413,414,415,416] are currently underway to evaluate the use of remdesivir to treat COVID-19 patients at both early and late stages of infection and in combination with other drugs (Figure 3).
+As of October 22, 2020, remdesivir received FDA approval based on three clinical trials [417].
+However, results suggesting no effect of remdesivir on survival were reported by the WHO Solidarity trial [391].
+This large-scale, open-label trial enrolled 11,330 adult in-patients at 405 hospitals in 30 countries around the world [391].
Patients were randomized in equal proportions into four experimental and a control conditions, corresponding to four candidate treatments for COVID-19 and SOC, respectively; no placebo was administered.
The 2,750 patients in the remdesivir group were administered 200 mg intravenously on the first day and 100 mg on each subsequent day until day 10 and assessed for in-hospital death (primary endpoint), duration of hospitalization, and progression to mechanical ventilation.
There were also 2,708 control patients who would have been eligible and able to receive remdesivir were they not assigned to the control group.
A total of 604 patients among these two cohorts deceased during initial hospitalization, with 301 in the remdesivir group and 303 in the control group.
The rate ratio of death between these two groups was therefore not significant (p = 0.50), suggesting that the administration of remdesivir did not affect survival.
The two secondary analyses similarly did not find any effect of remdesivir.
-Additionally, the authors compared data from their study with data from three other studies of remdesivir (including [401]) stratified by supplemental oxygen status.
+Additionally, the authors compared data from their study with data from three other studies of remdesivir (including [402]) stratified by supplemental oxygen status.
The adjusted rate ratio for death based on this meta-analysis was 0.91.
These results thus do not support the previous findings that remdesivir reduced median recovery time and mortality risk in COVID-19 patients.
-In response to the results of the Solidarity trial, Gilead, which manufactures remdesivir, released a statement pointing to the fact that the Solidarity trial was not placebo-controlled or double-blind and at the time of the statement had not been peer reviewed [417]; these sentiments have been echoed elsewhere [418].
-Other critiques of this study have noted that antivirals are not typically targeted at patients with severe illness, and therefore remdesivir could be more beneficial for patients with mild rather than severe cases [392,419].
-However, the publication associated with the trial sponsored by Gilead did purport an effect of remdesivir on patients with severe disease, identifying an 11 versus 18 day recovery period (rate ratio for recovery: 1.31, 95% CI 1.12 to 1.52), although the results of a significance test were not provided [401].
-Additionally, a smaller analysis of 598 patients, of whom two-thirds were randomized to receive remdesivir for either 5 or 10 days, reported a small effect of treatment with remdesivir for five days relative to standard of care in patients with moderate COVID-19 [420].
+
In response to the results of the Solidarity trial, Gilead, which manufactures remdesivir, released a statement pointing to the fact that the Solidarity trial was not placebo-controlled or double-blind and at the time of the statement had not been peer reviewed [418]; these sentiments have been echoed elsewhere [419].
+Other critiques of this study have noted that antivirals are not typically targeted at patients with severe illness, and therefore remdesivir could be more beneficial for patients with mild rather than severe cases [393,420].
+However, the publication associated with the trial sponsored by Gilead did purport an effect of remdesivir on patients with severe disease, identifying an 11 versus 18 day recovery period (rate ratio for recovery: 1.31, 95% CI 1.12 to 1.52), although the results of a significance test were not provided [402].
+Additionally, a smaller analysis of 598 patients, of whom two-thirds were randomized to receive remdesivir for either 5 or 10 days, reported a small effect of treatment with remdesivir for five days relative to standard of care in patients with moderate COVID-19 [421].
These results suggest that remdesivir could improve outcomes for patients with moderate COVID-19, but that additional information would be needed to understand the effects of different durations of treatment.
-Therefore, the arguments put forward in defense of remdesivir do not necessarily seem robust in light of the large sample size used in the Solidarity trial, especially since the broad international nature of the Solidarity clinical trial, which included countries with a wide range of economic profiles and a variety of healthcare systems, provides a much-needed global perspective in a pandemic [392].
-On the other hand, only 62% of patients in the Solidarity trial were randomized on the day of admission or one day afterwards [390], and concerns have been raised that differences in disease progression could influence the effectiveness of remdesivir [392].
+Therefore, the arguments put forward in defense of remdesivir do not necessarily seem robust in light of the large sample size used in the Solidarity trial, especially since the broad international nature of the Solidarity clinical trial, which included countries with a wide range of economic profiles and a variety of healthcare systems, provides a much-needed global perspective in a pandemic [393].
+On the other hand, only 62% of patients in the Solidarity trial were randomized on the day of admission or one day afterwards [391], and concerns have been raised that differences in disease progression could influence the effectiveness of remdesivir [393].
Despite the findings of the Solidarity trial, remdesivir remains available for the treatment of COVID-19 in many places.
-Follow-up studies are needed and, in many cases, are underway to further investigate remdesivir-related outcomes, with possibilities including combinations of remdesivir with other drugs such as baricitinib, which is an inhibitor of Janus kinase 1 and 2 [421].
+Follow-up studies are needed and, in many cases, are underway to further investigate remdesivir-related outcomes, with possibilities including combinations of remdesivir with other drugs such as baricitinib, which is an inhibitor of Janus kinase 1 and 2 [422].
Similarly, the extent to which the remdesivir dosing regimen could influence outcomes continues to be under consideration.
-In complement to the study that found that a 5-day course of remdesivir improved outcomes for patients with moderate COVID-19 but a 10-day course did not [420], a randomized, open-label trial compared the effect of remdesivir on 397 patients with severe COVID-19 over 5 versus 10 days [399,411].
+A randomized, open-label trial compared the effect of remdesivir on 397 patients with severe COVID-19 over 5 versus 10 days [400,412], complementing the study that found that a 5-day course of remdesivir improved outcomes for patients with moderate COVID-19 but a 10-day course did not [421].
Patients in the two groups were administered 200 mg of remdesivir intravenously on the first day, followed by 100 mg on the subsequent four or nine days, respectively.
The two groups differed significantly in their clinical status, with patients assigned to the 10-day group having more severe illness.
This study also differed from most because it included not only adults, but also pediatric patients as young as 12 years old.
It reported no significant differences across several outcomes for patients receiving a 5-day or 10-day course, when correcting for baseline clinical status.
-The data did suggest that the 10-day course might reduce mortality in the most severe patients at day 14, but the representation of this group in the study population was too low to justify any conclusions [411].
+The data did suggest that the 10-day course might reduce mortality in the most severe patients at day 14, but the representation of this group in the study population was too low to justify any conclusions [412].
Thus, additional research is also required to determine whether the dosage and duration of remdesivir administration influences outcomes.
In summary, remdesivir is a first in class drug due to its FDA approval.
Early investigations of this drug established proof of principle that drugs targeting the virus can benefit COVID-19 patients.
@@ -1781,43 +1780,43 @@
They are typically combined with protease inhibitors, integrase inhibitors, and even other polymerase inhibitors.
Additional clinical trials of remdesivir in different patient pools and in combination with other therapies will refine its use in the clinic.
5.4.1.2 Protease Inhibitors
-Several studies showed that viral proteases play an important role in the life cycle of viruses, including coronaviruses, by modulating the cleavage of viral polyprotein precursors [422].
+
Several studies showed that viral proteases play an important role in the life cycle of viruses, including coronaviruses, by modulating the cleavage of viral polyprotein precursors [423].
Several FDA-approved drugs target proteases, including lopinavir and ritonavir for HIV infection and simeprevir for hepatitis C virus infection.
-In particular, serine protease inhibitors were suggested for the treatment of SARS and MERS viruses [423].
-Recently, a study [67] suggested that camostat mesylate, an FDA-approved protease inhibitor (PI) could block the entry of SARS-CoV-2 into lung cells in vitro.
+In particular, serine protease inhibitors were suggested for the treatment of SARS and MERS viruses [424].
+Recently, a study [69] suggested that camostat mesylate, an FDA-approved protease inhibitor (PI) could block the entry of SARS-CoV-2 into lung cells in vitro.
Thus far, investigation of possible PIs that could work against SARS-CoV-2 has been driven by computational predictions.
Computer-aided design allowed for the development of a Michael acceptor inhibitor, now known as N3, to target a protease critical to SARS-CoV-2 replication.
-Discovery of the N3 mechanism arose from interest in the two polyproteins encoded by the SARS-CoV-2 replicase gene, pp1a and pp1ab, that are critical for viral replication and transcription [424].
+Discovery of the N3 mechanism arose from interest in the two polyproteins encoded by the SARS-CoV-2 replicase gene, pp1a and pp1ab, that are critical for viral replication and transcription [425].
These polyproteins must undergo proteolytic processing.
This processing is usually conducted by Mpro, a 33.8-kDa SARS-CoV-2 protease that is therefore fundamental to viral replication and transcription.
-N3 was designed computationally [425] to bind in the substrate binding pocket of the Mpro protease of SARS-like coronaviruses [426], therefore inhibiting proteolytic processing.
-Subsequently, the structure of N3-bound SARS-CoV-2 Mpro was solved [424], confirming the computational prediction.
-N3 was tested in vitro on SARS-CoV-2-infected Vero cells, which belong to a line of cells established from the kidney epithelial cells of an African green monkey, and was found to inhibit SARS-CoV-2 [424].
+N3 was designed computationally [426] to bind in the substrate binding pocket of the Mpro protease of SARS-like coronaviruses [427], therefore inhibiting proteolytic processing.
+Subsequently, the structure of N3-bound SARS-CoV-2 Mpro was solved [425], confirming the computational prediction.
+N3 was tested in vitro on SARS-CoV-2-infected Vero cells, which belong to a line of cells established from the kidney epithelial cells of an African green monkey, and was found to inhibit SARS-CoV-2 [425].
Although N3 is a strong inhibitor of SARS-CoV-2 in vitro, its safety and efficacy still need to be tested in healthy volunteers and patients.
-After the design and confirmation of N3 as a highly potent Michael acceptor inhibitor and the identification of Mpro’s structure [424,427], 10,000 compounds were screened for their in vitro anti-Mpro activity.
+After the design and confirmation of N3 as a highly potent Michael acceptor inhibitor and the identification of Mpro’s structure [425,428], 10,000 compounds were screened for their in vitro anti-Mpro activity.
The six leads that were identified were ebselen, disulfiram, tideglusib, carmofur, and PX-12.
-In vitro analysis revealed that Ebselen had the strongest potency in reducing the viral load in SARS-CoV-2-infected Vero cells [424].
-Ebselen is an organoselenium compound with anti-inflammatory and antioxidant properties [428].
-It has been proposed as a possible treatment for conditions ranging from bipolar disorder to diabetes to heart disease [428], and a preliminary investigation of ebselen as a treatment for noise-induced hearing loss provided promising reports of its safety [429].
-For COVID-19, the NSP5 in SARS-CoV-2 contains a cysteine at the active site of Mpro, and ebselen is able to inactivate the protease by bonding covalently with this cysteine to form a selenosulfide [428,430].
-Interestingly there has been some argument that selenium deficiency may be associated with more severe COVID-19 outcomes [431,432,433], possibly indicating that its antioxidative properties are protective [430].
-On the other hand, ebselen and the other compounds identified are likely to be promiscuous binders, which could diminish their therapeutic potential [424].
+In vitro analysis revealed that ebselen had the strongest potency in reducing the viral load in SARS-CoV-2-infected Vero cells [425].
+Ebselen is an organoselenium compound with anti-inflammatory and antioxidant properties [429].
+It has been proposed as a possible treatment for conditions ranging from bipolar disorder to diabetes to heart disease [429], and a preliminary investigation of ebselen as a treatment for noise-induced hearing loss provided promising reports of its safety [430].
+For COVID-19, the NSP5 in SARS-CoV-2 contains a cysteine at the active site of Mpro, and ebselen is able to inactivate the protease by bonding covalently with this cysteine to form a selenosulfide [429,431].
+Interestingly there has been some argument that selenium deficiency may be associated with more severe COVID-19 outcomes [432,433,434], possibly indicating that its antioxidative properties are protective [431].
+On the other hand, ebselen and the other compounds identified are likely to be promiscuous binders, which could diminish their therapeutic potential [425].
While there is clear computational and in vitro support for ebselen’s potential as a COVID-19 therapeutic, results from clinical trials are not yet available for this compound.
-However, as of July 2020, phase II clinical trials commenced to assess the effects of SPI-1005, an investigational drug from Sound Pharmaceuticals that contains ebselen [434], on 60 adults presenting with each of moderate [435] and severe [436] COVID-19.
+However, as of July 2020, phase II clinical trials commenced to assess the effects of SPI-1005, an investigational drug from Sound Pharmaceuticals that contains ebselen [435], on 60 adults presenting with each of moderate [436] and severe [437] COVID-19.
In summary, N3 is a computationally designed molecule that inhibits the viral transcription through inhibiting Mpro.
Ebselen is both a strong Mpro inhibitor and strong inhibitor of viral replication in vitro that was found to reduce SARS-CoV-2 viral load even more effectively than N3.
-Ebselen is a very promising compound since its safety has been demonstrated in other indications.
-However, ebselen may be a false positive, since it is a promiscuous compound that can have many targets [437].
+Ebselen is a promising compound since its safety has been demonstrated in other indications.
+However, ebselen may be a false positive, since it is a promiscuous compound that can have many targets [438].
Therefore, the results of ongoing clinical trials are expected to help establish whether compounds with higher specificity are required.
5.4.2 Broad-Spectrum Pharmaceuticals
-When a virus enters a host, the host becomes the virus’ environment.
+
When a virus enters a host, the host becomes the virus’s environment.
Therefore, the state of the host can also influence the virus’s ability to replicate and spread.
-Traditionally, viral targets have been favored for pharmaceutical interventions because altering host processes is likely to be less specific than targeting the virus directly [438].
-On the other hand, targeting the host offers potential for a complementary strategy to antivirals that could broadly limit the ability of viruses to replicate [438].
+Traditionally, viral targets have been favored for pharmaceutical interventions because altering host processes is likely to be less specific than targeting the virus directly [439].
+On the other hand, targeting the host offers potential for a complementary strategy to antivirals that could broadly limit the ability of viruses to replicate [439].
As a result, therapeutic approaches that target host proteins have become an area of interest for SARS-CoV-2.
Viral entry receptors in particular have been identified as a potential target.
-Entry of SARS-CoV-2 into the cell depends on binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which is catalyzed by the enzyme encoded by TMPRSS2 [67].
+Entry of SARS-CoV-2 into the cell depends on binding to angiotensin-converting enzyme 2 (ACE2), which is catalyzed by the enzyme encoded by TMPRSS2 [69].
In principle, drugs that reduce the expression of these proteins or sterically hinder viral interactions with them might reduce viral entry into cells.
Due to the urgent nature of the COVID-19 pandemic, many of the pharmaceutical agents that have been widely publicized as having possible therapeutic or prophylactic effects are broad-spectrum pharmaceuticals that pre-date the COVID-19 pandemic.
These treatments are not specifically targeted at the virus itself or at the host receptors it relies on, but rather induce broad shifts in host biology that are hypothesized to be potential inhibitors of the virus.
@@ -1825,56 +1824,56 @@
5.4.2.1 ACEi and ARB
4.4.2 Current Approaches
-5 Identification and Development of Prophylactics and Therapeutics for COVID-19
5.1 Abstract
@@ -1566,7 +1567,7 @@5.1
5.2 Importance
@@ -1578,54 +1579,54 @@ 5.2<
This rapidly changing area of research provides important insight into how the ongoing pandemic can be managed and also demonstrates the power of interdisciplinary collaboration to rapidly understand a virus and match its characteristics with existing or novel pharmaceuticals.
5.3 Introduction
The novel coronavirus Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) emerged in late 2019 and quickly precipitated the worldwide spread of novel coronavirus disease 2019 (COVID-19).
-COVID-19 is associated with symptoms ranging from none (asymptomatic) to mild to severe, with approximately 2% of patients dying from COVID-19-related complications, such as acute respiratory disease syndrome (ARDS) [367].
-The virus is likely spread between people primarily by droplets, with the role of contact and aerosol transmission still in question [194,195].
+COVID-19 is associated with symptoms ranging from none (asymptomatic) to mild to severe, with approximately 2% of patients dying from COVID-19-related complications, such as acute respiratory disease syndrome (ARDS) [1].
+The virus is likely spread between people primarily by droplets, with the role of contact and aerosol transmission still in question [196,197].
As a result, public health guidelines have been critical to efforts to control the spread of the virus.
However, as of early 2021, COVID-19 remains a significant worldwide concern (Figure 2), with cases in some places surging far above the numbers reported during the initial outbreak in early 2020.
Due to the continued threat of the virus and the severity of the disease, the identification and development of prophylactic and therapeutic interventions have emerged as significant international priorities.
Both approaches hold valuable potential for controlling the impact of the disease.
Prophylactics bolster immunity to prevent an individual from contracting a disease, whereas therapeutics treat a disease in individuals who have already been infected.
While vaccine development programs have attracted significant attention and produced a number of promising candidates, there is also an immediate need for treatments that palliate symptoms and prevent the most severe outcomes from infection.
-Fortunately, prior developments during other recent pandemics, especially those caused by human coronaviruses (HCoV), has provided a number of hypotheses guiding a biomedical approach to the novel coronavirus infection.
+Fortunately, prior developments during other recent pandemics, especially those caused by human coronaviruses (HCoV), have provided a number of hypotheses guiding a biomedical approach to the novel coronavirus infection.
2,354,561 COVID-19 deaths had been reported worldwide as of February 10, 2021 (Figure 2).
Figure 2: Cumulative global COVID-19 deaths since January 22, 2020.
-Data are from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [368].
+Data are from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [369].
5.3.1 Lessons from Prior HCoV Outbreaks
SARS-CoV-2’s rapid shift from an unknown virus to a significant worldwide threat closely parallels the emergence of Severe acute respiratory syndrome-related coronavirus (SARS-CoV-1).
The first documented case of COVID-19 was reported in Wuhan, China in November 2019, and the disease quickly spread worldwide during the early months of 2020.
-Similarly, the first case of SARS was reported in November 2002 in the Guangdong Province of China, and it spread within China and then into several countries across continents over the following months [28,30].
-In fact, genome sequencing quickly revealed the virus causing COVID-19 to be a novel betacoronavirus closely related to SARS-CoV-1 [10].
+Similarly, the first case of SARS was reported in November 2002 in the Guangdong Province of China, and it spread within China and then into several countries across continents over the following months [30,32].
+In fact, genome sequencing quickly revealed the virus causing COVID-19 to be a novel betacoronavirus closely related to SARS-CoV-1 [12].
There are many similarities but also some differences in the characteristics of the two viruses that determine how they spread.
-SARS infection is severe, with an estimated death rate of 9.5% [30], while estimates of the death rate associated with COVID-19 are much lower, at approximately 2% [367].
-SARS-CoV-1 is highly contagious via droplet transmission and has a basic reproduction number (R0) of 4 (i.e., each person infected was estimated to infect four other people) [30].
-SARS-CoV-2 also appears to be spread primarily by droplet transmission [194,195], and most estimates of its R0 fall between 2.5 and 3 [367].
+SARS infection is severe, with an estimated death rate of 9.5% [32], while estimates of the death rate associated with COVID-19 are much lower, at approximately 2% [1].
+SARS-CoV-1 is highly contagious via droplet transmission and has a basic reproduction number (R0) of 4 (i.e., each person infected was estimated to infect four other people) [32].
+SARS-CoV-2 also appears to be spread primarily by droplet transmission [196,197], and most estimates of its R0 fall between 2.5 and 3 [1].
Furthermore, the 17-year difference in the timing of these two outbreaks has led to some major differences in the tools available for the international community’s response.
-At the time that SARS-CoV-1 emerged, no new HCoV had been identified in almost 40 years [28].
-The identity of the virus underlying the SARS disease remained unknown until April of 2003, when the SARS-CoV-1 virus was characterized through a worldwide scientific effort spearheaded by the WHO [28].
-In contrast, the SARS-CoV-2 genomic sequence was released on January 3, 2020 [10], only days after the international community became aware of the novel pneumonia-like illness now known as COVID-19.
-While SARS-CoV-1 belonged to a distinct lineage from the two other HCoV known at the time of its discovery [30], SARS-CoV-2 is closely related to SARS-CoV-1 and a more distant relative of another HCoV characterized in 2012, Middle East respiratory syndrome-related coronavirus [13,369].
-Thus, despite their phylogenetic similarity, SARS-CoV-2 emerged under very different circumstances than SARS-CoV-1 in terms of scientific knowledge about HCoV.
+At the time that SARS-CoV-1 emerged, no new HCoV had been identified in almost 40 years [30].
+The identity of the virus underlying the SARS disease remained unknown until April of 2003, when the SARS-CoV-1 virus was characterized through a worldwide scientific effort spearheaded by the World Health Organization (WHO) [30].
+In contrast, the SARS-CoV-2 genomic sequence was released on January 3, 2020 [12], only days after the international community became aware of the novel pneumonia-like illness now known as COVID-19.
+While SARS-CoV-1 belonged to a distinct lineage from the two other HCoV known at the time of its discovery [32], SARS-CoV-2 is closely related to SARS-CoV-1 and a more distant relative of another HCoV characterized in 2012, Middle East respiratory syndrome-related coronavirus [15,370].
+Despite their phylogenetic similarity, SARS-CoV-2 emerged under very different circumstances than SARS-CoV-1 in terms of scientific knowledge about HCoV.
The trajectories of the pandemics associated with each of the viruses have also diverged significantly.
-By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices such as mask wearing [28].
-In contrast, MERS is still circulating and remains a concern; although the fatality rate is very high at almost 35%, the disease is much less easily transmitted, as its R0 has been estimated to be 1 [30].
-The low R0 in combination with public health practices allowed for its spread to be contained [30].
+By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices such as mask wearing [30].
+In contrast, MERS is still circulating and remains a concern; although the fatality rate is very high at almost 35%, the disease is much less easily transmitted, as its R0 has been estimated to be 1 [32].
+The low R0 in combination with public health practices allowed for its spread to be contained [32].
Neither of these trajectories are comparable to that of SARS-CoV-2, which remains a serious threat worldwide more than a year after the first cases of COVID-19 emerged.
Early results suggest that pharmaceutical interventions for COVID-19 may be more successful than efforts to develop prophylactics and therapeutics for SARS and MERS were.
-Care for SARS and MERS patients prioritized supportive care and symptom management [30].
+Care for SARS and MERS patients prioritized supportive care and symptom management [32].
To the extent that clinical treatments for SARS and MERS were explored, there is generally a lack of evidence supporting their efficacy.
-For example, Ribavirin is an antiviral that was often used in combination with corticosteroids and sometimes interferon (IFN) medications to treat SARS and MERS [28], but its effects have been found to be inconclusive in retrospective and in vitro analyses of SARS and the SARS-CoV-1 virus, respectively [28].
-IFNs and Ribavirin have shown promise in in vitro analyses of MERS, but their clinical effectiveness remains unknown [28].
+For example, Ribavirin is an antiviral that was often used in combination with corticosteroids and sometimes interferon (IFN) medications to treat SARS and MERS [30], but its effects have been found to be inconclusive in retrospective and in vitro analyses of SARS and the SARS-CoV-1 virus, respectively [30].
+IFNs and Ribavirin have shown promise in in vitro analyses of MERS, but their clinical effectiveness remains unknown [30].
Therefore, only limited pharmaceutical advances from prior HCoV outbreaks can be adopted to COVID-19.
Importantly, though, prior analyses of the virological and pathogenic properties of SARS-CoV-1 and MERS-CoV provide a strong foundation for the development of hypotheses about SARS-CoV-2 that have served to accelerated the development and identification of potential prophylactic and therapeutic approaches.
5.3.2 Therapeutic Approaches
Therapeutic approaches to the current pandemic can utilize two potential avenues: they can reduce the symptoms that are harmful to COVID-19 patients, or they can directly target the virus to hinder the spread of infection.
The goal of the former is to reduce the severity and risks of an active infection, while for the latter, it is to inhibit the replication of the virus once an individual is infected.
A variety of symptom profiles with a range of severity are associated with COVID-19, many of which are not life-threatening.
-A study of COVID-19 patients in a hospital in Berlin, Germany found that the symptoms associated with the highest risk of death included infection-related symptoms, such as sepsis, respiratory symptoms such as ARDS, and cardiovascular failure or pulmonary embolism [370].
+A study of COVID-19 patients in a hospital in Berlin, Germany found that the symptoms associated with the highest risk of death included infection-related symptoms, such as sepsis, respiratory symptoms such as ARDS, and cardiovascular failure or pulmonary embolism [371].
Therapeutics that reduce the risks associated with these severe outcomes hold particular potential to reduce the pandemic death toll.
On the other hand, therapeutics that directly target the virus itself would hold the potential to prevent people infected with SARS-CoV-2 from developing potentially damaging symptoms.
These treatments typically fall into the broad category of antivirals.
@@ -1644,44 +1645,44 @@
[371].
+Trials data are from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [372].
5.4 Small Molecule Drugs
-
Small molecules are synthesized compounds of low molecular weight, typically less than 1 kilodalton (kDa) [372].
-Small-molecule pharmaceutical agents have been a backbone of drug development since the discovery of penicillin in the early twentieth century [373].
-It and other antibiotics have long been among the best known applications of small molecules to therapeutics, but biotechnological developments such as the prediction of protein-protein interactions have facilitated advances in precise targeting of specific structures using small molecules [373].
+
Small molecules are synthesized compounds of low molecular weight, typically less than 1 kilodalton (kDa) [373].
+Small-molecule pharmaceutical agents have been a backbone of drug development since the discovery of penicillin in the early twentieth century [374].
+It and other antibiotics have long been among the best known applications of small molecules to therapeutics, but biotechnological developments such as the prediction of protein-protein interactions have facilitated advances in precise targeting of specific structures using small molecules [374].
Small molecule drugs today encompass a wide range of therapeutics beyond antibiotics, including antivirals, protein inhibitors, and many broad-spectrum pharmaceuticals.
5.4.1 Small Molecule Antivirals
Antiviral drugs against SARS-CoV-2 are designed to inhibit replication of a virus within an epithelial host cell.
-This process requires inhibiting the replication cycle of a virus by disrupting one of six fundamental steps [374].
+This process requires inhibiting the replication cycle of a virus by disrupting one of six fundamental steps [375].
In the first of these steps, the virus attaches to and enters the host cell through endocytosis.
Then the virus undergoes uncoating, which is classically defined as the release of viral contents into the host cell.
Next, the viral genetic material enters the nucleus where it gets replicated during the biosynthesis stage.
During the assembly stage, viral proteins are translated, allowing new viral particles to be assembled.
In the final step new viruses are released into the extracellular environment.
Many antiviral drugs are designed to inhibit the replication of viral genetic material during the biosynthesis step.
-Unlike DNA viruses, which can use the host enzymes to propagate themselves, RNA viruses like SARS-CoV-2 depend on their own polymerase, the RNA-dependent RNA polymerase (RdRP), for replication [375,376].
-Targeting RdRP is therefore an effective strategy for antivirals against RNA viruses and is the proposed mechanism underlying the treatment of SARS and MERS with Ribavirin [377].
+Unlike DNA viruses, which can use the host enzymes to propagate themselves, RNA viruses like SARS-CoV-2 depend on their own polymerase, the RNA-dependent RNA polymerase (RdRP), for replication [376,377].
+Targeting RdRP is therefore an effective strategy for antivirals against RNA viruses and is the proposed mechanism underlying the treatment of SARS and MERS with Ribavirin [378].
However, although antivirals are designed to target a virus, they can also impact other processes in the host and may have unintended effects.
Therefore, these therapeutics must be evaluated for both efficacy and safety.
5.4.1.1 Nucleoside and Nucleotide Analogs
5.4.1.1.1 Favipiravir
-Favipiravir (Avigan), also known as T-705, was discovered by Toyama Chemical Co., Ltd. [378].
-The drug was found to be effective at blocking viral amplification in several influenza subtypes as well as other RNA viruses, such as Flaviviridae and Picornaviridae, through a reduction in plaque formation [379] and viral replication in Madin-Darby canine kidney cells [380].
-Furthermore, inoculation of mice with favipiravir was shown to increase survival of influenza infections [379,380].
-In 2014, the drug was approved in Japan for the treatment of influenza that was resistant to conventional treatments like neuraminidase inhibitors [381].
-Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) acts as a purine and purine nucleoside analogue that inhibits viral RNA polymerase in a dose-dependent manner across a range of RNA viruses, including influenza viruses [382,383,384,385,386].
+
Favipiravir (Avigan), also known as T-705, was discovered by Toyama Chemical Co., Ltd. [379].
+The drug was found to be effective at blocking viral amplification in several influenza subtypes as well as other RNA viruses, such as Flaviviridae and Picornaviridae, through a reduction in plaque formation [380] and viral replication in Madin-Darby canine kidney cells [381].
+Furthermore, inoculation of mice with favipiravir was shown to increase survival of influenza infections [380,381].
+In 2014, the drug was approved in Japan for the treatment of influenza that was resistant to conventional treatments like neuraminidase inhibitors [382].
+Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) acts as a purine and purine nucleoside analogue that inhibits viral RNA polymerase in a dose-dependent manner across a range of RNA viruses, including influenza viruses [383,384,385,386,387].
Nucleotides and nucleosides are the natural building blocks for RNA synthesis.
-Because of this, modifications to nucleotides and nucleosides can disrupt key processes including replication [387].
+Because of this, modifications to nucleotides and nucleosides can disrupt key processes including replication [388].
Biochemical experiments showed that favipiravir was recognized as a purine nucleoside analogue and incorporated into the viral RNA template.
-A single incorporation does not influence RNA transcription; however, multiple events of incorporation lead to the arrest of RNA synthesis [388].
-Evidence for T-705 inhibiting viral RNA polymerase are based on time-of-drug addition studies that found that viral loads were reduced with the addition of favipiravir in early times post-infection [382,385,386].
+A single incorporation does not influence RNA transcription; however, multiple events of incorporation lead to the arrest of RNA synthesis [389].
+Evidence for T-705 inhibiting viral RNA polymerase are based on time-of-drug addition studies that found that viral loads were reduced with the addition of favipiravir in early times post-infection [383,386,387].
The effectiveness of favipiravir for treating patients with COVID-19 is currently under investigation.
-An open-label, nonrandomized, before-after controlled study was recently conducted [389].
+An open-label, nonrandomized, before-after controlled study was recently conducted [390].
The study included 80 COVID-19 patients (35 treated with favipiravir, 45 control) from the isolation ward of the National Clinical Research Center for Infectious Diseases (The Third People’s Hospital of Shenzhen), Shenzhen, China.
The patients in the control group were treated with other antivirals, such as lopinavir and ritonavir.
-It should be noted that although the control patients received antivirals, two subsequent large-scale analyses, the WHO Solidarity trial and the RECOVERY trial, identified no effect of lopinavir or of a lopinavir-ritonavir combination, respectively, on the metrics of COVID-19-related mortality that each assessed [390,391,392].
+It should be noted that although the control patients received antivirals, two subsequent large-scale analyses, the WHO Solidarity trial and the RECOVERY trial, identified no effect of lopinavir or of a lopinavir-ritonavir combination, respectively, on the metrics of COVID-19-related mortality that each assessed [391,392,393].
Treatment was applied on days 2-14; treatment stopped either when viral clearance was confirmed or at day 14.
The efficacy of the treatment was measured by, first, the time until viral clearance using Kaplan-Meier survival curves, and, second, the improvement rate of chest computed tomography (CT) scans on day 14 after treatment.
The study found that favipiravir increased the speed of recovery, measured as viral clearance from the patient by RT-PCR, with patients receiving favipiravir recovering in four days compared to 11 days for patients receiving antivirals such as lopinavir and ritonavir.
@@ -1692,33 +1693,32 @@
[393].
-
In late 2020 and early 2021, the first randomized controlled trials of favipiravir for the treatment of COVID-19 released results [394,395,396].
-The first [394] used a randomized, controlled, open-label design to compare two drugs, favipiravir and baloxavir marboxil, to SOC alone.
+Additionally, it should be noted that this study was temporarily retracted and then restored without an explanation [394].
+In late 2020 and early 2021, the first randomized controlled trials of favipiravir for the treatment of COVID-19 released results [395,396,397].
+The first [395] used a randomized, controlled, open-label design to compare two drugs, favipiravir and baloxavir marboxil, to standard of care (SOC) alone.
Here, SOC included antivirals such as lopinavir/ritonavir and was administered to all patients.
The primary endpoint analyzed was viral clearance at day 14.
The sample size for this study was very small, with 29 total patients enrolled, and no significant effect of the treatments was found for the primary or any of the secondary outcomes analyzed, which included mortality.
The second study was larger, with 96 patients enrolled, and also utilized a randomized design.
-This study enrolled only patients with mild to moderate symptoms and randomized them into two groups: one receiving CQ in addition to SOC, and the other receiving favipiravir in addition to SOC.
+This study enrolled only patients with mild to moderate symptoms and randomized them into two groups: one receiving chloroquine (CQ) in addition to SOC, and the other receiving favipiravir in addition to SOC.
This study reported a non-significant trend for patients receiving favipiravir to have a shorter hospital stay and less likelihood of progressing to mechanical ventilation or to an oxygen saturation < 90%.
However, given the fact that favipiravir was being compared to CQ, which is now widely understood to be ineffective for treating COVID-19, these results do not suggest that favipiravir was likely to have had a strong effect on these outcomes.
-On the other hand, another trial of 60 patients reported a significant effect of favipiravir on viral clearance at four days (a secondary endpoint), but not at 10 days (the primary endpoint) [396].
-This study, as well as a prior study of favipiravir [397], also reported that the drug was generally well-tolerated.
+On the other hand, another trial of 60 patients reported a significant effect of favipiravir on viral clearance at four days (a secondary endpoint), but not at 10 days (the primary endpoint) [397].
+This study, as well as a prior study of favipiravir [398], also reported that the drug was generally well-tolerated.
Thus, in combination, these small studies suggest that the effects of favipiravir as a treatment for COVID-19 cannot be determined based on the available evidence, but additionally, none raise major concerns about the safety profile of the drug.
5.4.1.1.2 Remdesivir
Remdesivir (GS-5734) is an intravenous antiviral that was developed by Gilead Sciences to treat Ebola Virus Disease (EVD).
At the outset of the COVID-19 pandemic, it did not have any have any FDA-approved use.
-However, on May 1, 2020, the FDA issued an Emergency Use Authorization (EUA) for remdesivir for the treatment of hospitalized COVID-19 patients [398].
-The EUA was based on information from two clinical trials, NCT04280705 and NCT04292899 [399,400,401,402].
-Remdesivir is metabolized to GS-441524, an adenosine analog that inhibits a broad range of polymerases and then evades exonuclease repair, causing chain termination [403,404,405].
-A clinical trial in the Democratic Republic of Congo found some evidence of effectiveness against EVD, but two antibody preparations were found to be more effective, and remdesivir was not pursued [406].
-Although it was developed against EVD, remdesivir also inhibits polymerase and replication of the coronaviruses MERS-CoV and SARS-CoV-1 in cell culture assays with submicromolar IC50s [407].
-It has also been found to inhibit SARS-CoV-2, showing synergy with chloroquine in vitro [405].
-The effectiveness of remdesivir for treating patients with COVID-19 is currently under investigation.
-Remdesivir was first used on some COVID-19 patients under compassionate use guidelines [408,409].
+However, on May 1, 2020, the FDA issued an Emergency Use Authorization (EUA) for remdesivir for the treatment of hospitalized COVID-19 patients [399].
+The EUA was based on information from two clinical trials, NCT04280705 and NCT04292899 [400,401,402,403].
+Remdesivir is metabolized to GS-441524, an adenosine analog that inhibits a broad range of polymerases and then evades exonuclease repair, causing chain termination [404,405,406].
+A clinical trial in the Democratic Republic of Congo found some evidence of effectiveness against EVD, but two antibody preparations were found to be more effective, and remdesivir was not pursued [407].
+Although it was developed against EVD, remdesivir also inhibits polymerase and replication of the coronaviruses MERS-CoV and SARS-CoV-1 in cell culture assays with submicromolar IC50s [408].
+It has also been found to inhibit SARS-CoV-2, showing synergy with CQ in vitro [406].
+Remdesivir was first used on some COVID-19 patients under compassionate use guidelines [409,410].
All were in late stages of COVID-19 infection, and initial reports were inconclusive about the drug’s efficacy.
Gilead Sciences, the maker of remdesivir, led a recent publication that reported outcomes for compassionate use of the drug in 61 patients hospitalized with confirmed COVID-19.
-Here, 200 mg of remdesivir was administered intravenously on day 1, followed by a further 100 mg/day for 9 days [402].
+Here, 200 mg of remdesivir was administered intravenously on day 1, followed by a further 100 mg/day for 9 days [403].
There were significant issues with the study design, or lack thereof.
There was no randomized control group.
The inclusion criteria were variable: some patients only required low doses of oxygen, while others required ventilation.
@@ -1727,49 +1727,48 @@
There was a short follow-up period of investigation.
Some patients worsened, some patients died, and eight were excluded from the analysis mainly due to missing post-baseline information; thus, their health was unaccounted for.
Therefore, even though the study reported clinical improvement in 68% of the 53 patients ultimately evaluated, due to the significant issues with study design, it could not be determined whether treatment with remdesivir had an effect or whether these patients would have recovered regardless of treatment.
-Another study comparing 5- and 10-day treatment regimens reported similar results but was also limited because of the lack of a placebo control [411].
+Another study comparing 5- and 10-day treatment regimens reported similar results but was also limited because of the lack of a placebo control [412].
These studies did not alter the understanding of the efficacy of remdesivir in treating COVID-19, but the encouraging results provided motivation for placebo-controlled studies.
-Remdesivir was later tested in a double-blind placebo-controlled phase 3 clinical trial performed at 60 trial sites, 45 of which were in the United States [400,401].
+
Remdesivir was later tested in a double-blind placebo-controlled phase 3 clinical trial performed at 60 trial sites, 45 of which were in the United States [401,402].
The trial recruited 1,062 patients and randomly assigned them to placebo treatment or treatment with remdesivir.
-Patients were stratified for randomization based on site and the severity of disease presentation at baseline [401].
+Patients were stratified for randomization based on site and the severity of disease presentation at baseline [402].
The treatment was 200 mg on day 1, followed by 100 mg on days 2 through 10.
-Data was analyzed from a total of 1,059 patients who completed the 29-day course of the trial, with 517 assigned to remdesivir and 508 to placebo [401].
+Data was analyzed from a total of 1,059 patients who completed the 29-day course of the trial, with 517 assigned to remdesivir and 508 to placebo [402].
The two groups were well matched demographically and clinically at baseline.
Those who received remdesivir had a median recovery time of 10 days, as compared with 15 days in those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; p < 0.001).
The Kaplan-Meier estimates of mortality by 14 days were 6.7% with remdesivir and 11.9% with placebo, with a hazard ratio (HR) for death of 0.55 and a 95% CI of 0.36 to 0.83, and at day 29, remdesivir corresponded to 11.4% and the placebo to 15.2% (HR: 0.73; 95% CI: 0.52 to 1.03).
Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients in the placebo group (31.6%).
-This study also reported an association between remdesivir administration and both clinical improvement and a lack of progression to more invasive respiratory intervention in patients receiving non-invasive and invasive ventilation at randomization [401].
-Largely on the results of this trial, the FDA reissued and expanded the EUA for remdesivir for the treatment of hospitalized COVID-19 patients ages twelve and older [398].
-Additional clinical trials are currently underway to evaluate the use of remdesivir to treat COVID-19 patients at both early and late stages of infection and in combination with other drugs (Figure 3).
-These trials include [405,412,413,414,415].
-As of October 22, 2020, remdesivir received FDA approval based on three clinical trials [416].
-However, results suggesting no effect of remdesivir on survival were reported by the WHO Solidarity trial [390].
-This large-scale, open-label trial enrolled 11,330 adult in-patients at 405 hospitals in 30 countries around the world [390].
+This study also reported an association between remdesivir administration and both clinical improvement and a lack of progression to more invasive respiratory intervention in patients receiving non-invasive and invasive ventilation at randomization [402].
+Largely on the results of this trial, the FDA reissued and expanded the EUA for remdesivir for the treatment of hospitalized COVID-19 patients ages twelve and older [399].
+Additional clinical trials [406,413,414,415,416] are currently underway to evaluate the use of remdesivir to treat COVID-19 patients at both early and late stages of infection and in combination with other drugs (Figure 3).
+As of October 22, 2020, remdesivir received FDA approval based on three clinical trials [417].
+However, results suggesting no effect of remdesivir on survival were reported by the WHO Solidarity trial [391].
+This large-scale, open-label trial enrolled 11,330 adult in-patients at 405 hospitals in 30 countries around the world [391].
Patients were randomized in equal proportions into four experimental and a control conditions, corresponding to four candidate treatments for COVID-19 and SOC, respectively; no placebo was administered.
The 2,750 patients in the remdesivir group were administered 200 mg intravenously on the first day and 100 mg on each subsequent day until day 10 and assessed for in-hospital death (primary endpoint), duration of hospitalization, and progression to mechanical ventilation.
There were also 2,708 control patients who would have been eligible and able to receive remdesivir were they not assigned to the control group.
A total of 604 patients among these two cohorts deceased during initial hospitalization, with 301 in the remdesivir group and 303 in the control group.
The rate ratio of death between these two groups was therefore not significant (p = 0.50), suggesting that the administration of remdesivir did not affect survival.
The two secondary analyses similarly did not find any effect of remdesivir.
-Additionally, the authors compared data from their study with data from three other studies of remdesivir (including [401]) stratified by supplemental oxygen status.
+Additionally, the authors compared data from their study with data from three other studies of remdesivir (including [402]) stratified by supplemental oxygen status.
The adjusted rate ratio for death based on this meta-analysis was 0.91.
These results thus do not support the previous findings that remdesivir reduced median recovery time and mortality risk in COVID-19 patients.
-In response to the results of the Solidarity trial, Gilead, which manufactures remdesivir, released a statement pointing to the fact that the Solidarity trial was not placebo-controlled or double-blind and at the time of the statement had not been peer reviewed [417]; these sentiments have been echoed elsewhere [418].
-Other critiques of this study have noted that antivirals are not typically targeted at patients with severe illness, and therefore remdesivir could be more beneficial for patients with mild rather than severe cases [392,419].
-However, the publication associated with the trial sponsored by Gilead did purport an effect of remdesivir on patients with severe disease, identifying an 11 versus 18 day recovery period (rate ratio for recovery: 1.31, 95% CI 1.12 to 1.52), although the results of a significance test were not provided [401].
-Additionally, a smaller analysis of 598 patients, of whom two-thirds were randomized to receive remdesivir for either 5 or 10 days, reported a small effect of treatment with remdesivir for five days relative to standard of care in patients with moderate COVID-19 [420].
+
In response to the results of the Solidarity trial, Gilead, which manufactures remdesivir, released a statement pointing to the fact that the Solidarity trial was not placebo-controlled or double-blind and at the time of the statement had not been peer reviewed [418]; these sentiments have been echoed elsewhere [419].
+Other critiques of this study have noted that antivirals are not typically targeted at patients with severe illness, and therefore remdesivir could be more beneficial for patients with mild rather than severe cases [393,420].
+However, the publication associated with the trial sponsored by Gilead did purport an effect of remdesivir on patients with severe disease, identifying an 11 versus 18 day recovery period (rate ratio for recovery: 1.31, 95% CI 1.12 to 1.52), although the results of a significance test were not provided [402].
+Additionally, a smaller analysis of 598 patients, of whom two-thirds were randomized to receive remdesivir for either 5 or 10 days, reported a small effect of treatment with remdesivir for five days relative to standard of care in patients with moderate COVID-19 [421].
These results suggest that remdesivir could improve outcomes for patients with moderate COVID-19, but that additional information would be needed to understand the effects of different durations of treatment.
-Therefore, the arguments put forward in defense of remdesivir do not necessarily seem robust in light of the large sample size used in the Solidarity trial, especially since the broad international nature of the Solidarity clinical trial, which included countries with a wide range of economic profiles and a variety of healthcare systems, provides a much-needed global perspective in a pandemic [392].
-On the other hand, only 62% of patients in the Solidarity trial were randomized on the day of admission or one day afterwards [390], and concerns have been raised that differences in disease progression could influence the effectiveness of remdesivir [392].
+Therefore, the arguments put forward in defense of remdesivir do not necessarily seem robust in light of the large sample size used in the Solidarity trial, especially since the broad international nature of the Solidarity clinical trial, which included countries with a wide range of economic profiles and a variety of healthcare systems, provides a much-needed global perspective in a pandemic [393].
+On the other hand, only 62% of patients in the Solidarity trial were randomized on the day of admission or one day afterwards [391], and concerns have been raised that differences in disease progression could influence the effectiveness of remdesivir [393].
Despite the findings of the Solidarity trial, remdesivir remains available for the treatment of COVID-19 in many places.
-Follow-up studies are needed and, in many cases, are underway to further investigate remdesivir-related outcomes, with possibilities including combinations of remdesivir with other drugs such as baricitinib, which is an inhibitor of Janus kinase 1 and 2 [421].
+Follow-up studies are needed and, in many cases, are underway to further investigate remdesivir-related outcomes, with possibilities including combinations of remdesivir with other drugs such as baricitinib, which is an inhibitor of Janus kinase 1 and 2 [422].
Similarly, the extent to which the remdesivir dosing regimen could influence outcomes continues to be under consideration.
-In complement to the study that found that a 5-day course of remdesivir improved outcomes for patients with moderate COVID-19 but a 10-day course did not [420], a randomized, open-label trial compared the effect of remdesivir on 397 patients with severe COVID-19 over 5 versus 10 days [399,411].
+A randomized, open-label trial compared the effect of remdesivir on 397 patients with severe COVID-19 over 5 versus 10 days [400,412], complementing the study that found that a 5-day course of remdesivir improved outcomes for patients with moderate COVID-19 but a 10-day course did not [421].
Patients in the two groups were administered 200 mg of remdesivir intravenously on the first day, followed by 100 mg on the subsequent four or nine days, respectively.
The two groups differed significantly in their clinical status, with patients assigned to the 10-day group having more severe illness.
This study also differed from most because it included not only adults, but also pediatric patients as young as 12 years old.
It reported no significant differences across several outcomes for patients receiving a 5-day or 10-day course, when correcting for baseline clinical status.
-The data did suggest that the 10-day course might reduce mortality in the most severe patients at day 14, but the representation of this group in the study population was too low to justify any conclusions [411].
+The data did suggest that the 10-day course might reduce mortality in the most severe patients at day 14, but the representation of this group in the study population was too low to justify any conclusions [412].
Thus, additional research is also required to determine whether the dosage and duration of remdesivir administration influences outcomes.
In summary, remdesivir is a first in class drug due to its FDA approval.
Early investigations of this drug established proof of principle that drugs targeting the virus can benefit COVID-19 patients.
@@ -1781,43 +1780,43 @@
They are typically combined with protease inhibitors, integrase inhibitors, and even other polymerase inhibitors.
Additional clinical trials of remdesivir in different patient pools and in combination with other therapies will refine its use in the clinic.
5.4.1.2 Protease Inhibitors
-Several studies showed that viral proteases play an important role in the life cycle of viruses, including coronaviruses, by modulating the cleavage of viral polyprotein precursors [422].
+
Several studies showed that viral proteases play an important role in the life cycle of viruses, including coronaviruses, by modulating the cleavage of viral polyprotein precursors [423].
Several FDA-approved drugs target proteases, including lopinavir and ritonavir for HIV infection and simeprevir for hepatitis C virus infection.
-In particular, serine protease inhibitors were suggested for the treatment of SARS and MERS viruses [423].
-Recently, a study [67] suggested that camostat mesylate, an FDA-approved protease inhibitor (PI) could block the entry of SARS-CoV-2 into lung cells in vitro.
+In particular, serine protease inhibitors were suggested for the treatment of SARS and MERS viruses [424].
+Recently, a study [69] suggested that camostat mesylate, an FDA-approved protease inhibitor (PI) could block the entry of SARS-CoV-2 into lung cells in vitro.
Thus far, investigation of possible PIs that could work against SARS-CoV-2 has been driven by computational predictions.
Computer-aided design allowed for the development of a Michael acceptor inhibitor, now known as N3, to target a protease critical to SARS-CoV-2 replication.
-Discovery of the N3 mechanism arose from interest in the two polyproteins encoded by the SARS-CoV-2 replicase gene, pp1a and pp1ab, that are critical for viral replication and transcription [424].
+Discovery of the N3 mechanism arose from interest in the two polyproteins encoded by the SARS-CoV-2 replicase gene, pp1a and pp1ab, that are critical for viral replication and transcription [425].
These polyproteins must undergo proteolytic processing.
This processing is usually conducted by Mpro, a 33.8-kDa SARS-CoV-2 protease that is therefore fundamental to viral replication and transcription.
-N3 was designed computationally [425] to bind in the substrate binding pocket of the Mpro protease of SARS-like coronaviruses [426], therefore inhibiting proteolytic processing.
-Subsequently, the structure of N3-bound SARS-CoV-2 Mpro was solved [424], confirming the computational prediction.
-N3 was tested in vitro on SARS-CoV-2-infected Vero cells, which belong to a line of cells established from the kidney epithelial cells of an African green monkey, and was found to inhibit SARS-CoV-2 [424].
+N3 was designed computationally [426] to bind in the substrate binding pocket of the Mpro protease of SARS-like coronaviruses [427], therefore inhibiting proteolytic processing.
+Subsequently, the structure of N3-bound SARS-CoV-2 Mpro was solved [425], confirming the computational prediction.
+N3 was tested in vitro on SARS-CoV-2-infected Vero cells, which belong to a line of cells established from the kidney epithelial cells of an African green monkey, and was found to inhibit SARS-CoV-2 [425].
Although N3 is a strong inhibitor of SARS-CoV-2 in vitro, its safety and efficacy still need to be tested in healthy volunteers and patients.
-After the design and confirmation of N3 as a highly potent Michael acceptor inhibitor and the identification of Mpro’s structure [424,427], 10,000 compounds were screened for their in vitro anti-Mpro activity.
+After the design and confirmation of N3 as a highly potent Michael acceptor inhibitor and the identification of Mpro’s structure [425,428], 10,000 compounds were screened for their in vitro anti-Mpro activity.
The six leads that were identified were ebselen, disulfiram, tideglusib, carmofur, and PX-12.
-In vitro analysis revealed that Ebselen had the strongest potency in reducing the viral load in SARS-CoV-2-infected Vero cells [424].
-Ebselen is an organoselenium compound with anti-inflammatory and antioxidant properties [428].
-It has been proposed as a possible treatment for conditions ranging from bipolar disorder to diabetes to heart disease [428], and a preliminary investigation of ebselen as a treatment for noise-induced hearing loss provided promising reports of its safety [429].
-For COVID-19, the NSP5 in SARS-CoV-2 contains a cysteine at the active site of Mpro, and ebselen is able to inactivate the protease by bonding covalently with this cysteine to form a selenosulfide [428,430].
-Interestingly there has been some argument that selenium deficiency may be associated with more severe COVID-19 outcomes [431,432,433], possibly indicating that its antioxidative properties are protective [430].
-On the other hand, ebselen and the other compounds identified are likely to be promiscuous binders, which could diminish their therapeutic potential [424].
+In vitro analysis revealed that ebselen had the strongest potency in reducing the viral load in SARS-CoV-2-infected Vero cells [425].
+Ebselen is an organoselenium compound with anti-inflammatory and antioxidant properties [429].
+It has been proposed as a possible treatment for conditions ranging from bipolar disorder to diabetes to heart disease [429], and a preliminary investigation of ebselen as a treatment for noise-induced hearing loss provided promising reports of its safety [430].
+For COVID-19, the NSP5 in SARS-CoV-2 contains a cysteine at the active site of Mpro, and ebselen is able to inactivate the protease by bonding covalently with this cysteine to form a selenosulfide [429,431].
+Interestingly there has been some argument that selenium deficiency may be associated with more severe COVID-19 outcomes [432,433,434], possibly indicating that its antioxidative properties are protective [431].
+On the other hand, ebselen and the other compounds identified are likely to be promiscuous binders, which could diminish their therapeutic potential [425].
While there is clear computational and in vitro support for ebselen’s potential as a COVID-19 therapeutic, results from clinical trials are not yet available for this compound.
-However, as of July 2020, phase II clinical trials commenced to assess the effects of SPI-1005, an investigational drug from Sound Pharmaceuticals that contains ebselen [434], on 60 adults presenting with each of moderate [435] and severe [436] COVID-19.
+However, as of July 2020, phase II clinical trials commenced to assess the effects of SPI-1005, an investigational drug from Sound Pharmaceuticals that contains ebselen [435], on 60 adults presenting with each of moderate [436] and severe [437] COVID-19.
In summary, N3 is a computationally designed molecule that inhibits the viral transcription through inhibiting Mpro.
Ebselen is both a strong Mpro inhibitor and strong inhibitor of viral replication in vitro that was found to reduce SARS-CoV-2 viral load even more effectively than N3.
-Ebselen is a very promising compound since its safety has been demonstrated in other indications.
-However, ebselen may be a false positive, since it is a promiscuous compound that can have many targets [437].
+Ebselen is a promising compound since its safety has been demonstrated in other indications.
+However, ebselen may be a false positive, since it is a promiscuous compound that can have many targets [438].
Therefore, the results of ongoing clinical trials are expected to help establish whether compounds with higher specificity are required.
5.4.2 Broad-Spectrum Pharmaceuticals
-When a virus enters a host, the host becomes the virus’ environment.
+
When a virus enters a host, the host becomes the virus’s environment.
Therefore, the state of the host can also influence the virus’s ability to replicate and spread.
-Traditionally, viral targets have been favored for pharmaceutical interventions because altering host processes is likely to be less specific than targeting the virus directly [438].
-On the other hand, targeting the host offers potential for a complementary strategy to antivirals that could broadly limit the ability of viruses to replicate [438].
+Traditionally, viral targets have been favored for pharmaceutical interventions because altering host processes is likely to be less specific than targeting the virus directly [439].
+On the other hand, targeting the host offers potential for a complementary strategy to antivirals that could broadly limit the ability of viruses to replicate [439].
As a result, therapeutic approaches that target host proteins have become an area of interest for SARS-CoV-2.
Viral entry receptors in particular have been identified as a potential target.
-Entry of SARS-CoV-2 into the cell depends on binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which is catalyzed by the enzyme encoded by TMPRSS2 [67].
+Entry of SARS-CoV-2 into the cell depends on binding to angiotensin-converting enzyme 2 (ACE2), which is catalyzed by the enzyme encoded by TMPRSS2 [69].
In principle, drugs that reduce the expression of these proteins or sterically hinder viral interactions with them might reduce viral entry into cells.
Due to the urgent nature of the COVID-19 pandemic, many of the pharmaceutical agents that have been widely publicized as having possible therapeutic or prophylactic effects are broad-spectrum pharmaceuticals that pre-date the COVID-19 pandemic.
These treatments are not specifically targeted at the virus itself or at the host receptors it relies on, but rather induce broad shifts in host biology that are hypothesized to be potential inhibitors of the virus.
@@ -1825,56 +1824,56 @@
5.4.2.1 ACEi and ARB
5.3 Introduction
The novel coronavirus Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) emerged in late 2019 and quickly precipitated the worldwide spread of novel coronavirus disease 2019 (COVID-19). -COVID-19 is associated with symptoms ranging from none (asymptomatic) to mild to severe, with approximately 2% of patients dying from COVID-19-related complications, such as acute respiratory disease syndrome (ARDS) [367]. -The virus is likely spread between people primarily by droplets, with the role of contact and aerosol transmission still in question [194,195]. +COVID-19 is associated with symptoms ranging from none (asymptomatic) to mild to severe, with approximately 2% of patients dying from COVID-19-related complications, such as acute respiratory disease syndrome (ARDS) [1]. +The virus is likely spread between people primarily by droplets, with the role of contact and aerosol transmission still in question [196,197]. As a result, public health guidelines have been critical to efforts to control the spread of the virus. However, as of early 2021, COVID-19 remains a significant worldwide concern (Figure 2), with cases in some places surging far above the numbers reported during the initial outbreak in early 2020. Due to the continued threat of the virus and the severity of the disease, the identification and development of prophylactic and therapeutic interventions have emerged as significant international priorities. Both approaches hold valuable potential for controlling the impact of the disease. Prophylactics bolster immunity to prevent an individual from contracting a disease, whereas therapeutics treat a disease in individuals who have already been infected. While vaccine development programs have attracted significant attention and produced a number of promising candidates, there is also an immediate need for treatments that palliate symptoms and prevent the most severe outcomes from infection. -Fortunately, prior developments during other recent pandemics, especially those caused by human coronaviruses (HCoV), has provided a number of hypotheses guiding a biomedical approach to the novel coronavirus infection.
+Fortunately, prior developments during other recent pandemics, especially those caused by human coronaviruses (HCoV), have provided a number of hypotheses guiding a biomedical approach to the novel coronavirus infection.2,354,561 COVID-19 deaths had been reported worldwide as of February 10, 2021 (Figure 2).
5.3.1 Lessons from Prior HCoV Outbreaks
SARS-CoV-2’s rapid shift from an unknown virus to a significant worldwide threat closely parallels the emergence of Severe acute respiratory syndrome-related coronavirus (SARS-CoV-1). The first documented case of COVID-19 was reported in Wuhan, China in November 2019, and the disease quickly spread worldwide during the early months of 2020. -Similarly, the first case of SARS was reported in November 2002 in the Guangdong Province of China, and it spread within China and then into several countries across continents over the following months [28,30]. -In fact, genome sequencing quickly revealed the virus causing COVID-19 to be a novel betacoronavirus closely related to SARS-CoV-1 [10].
+Similarly, the first case of SARS was reported in November 2002 in the Guangdong Province of China, and it spread within China and then into several countries across continents over the following months [30,32]. +In fact, genome sequencing quickly revealed the virus causing COVID-19 to be a novel betacoronavirus closely related to SARS-CoV-1 [12].There are many similarities but also some differences in the characteristics of the two viruses that determine how they spread. -SARS infection is severe, with an estimated death rate of 9.5% [30], while estimates of the death rate associated with COVID-19 are much lower, at approximately 2% [367]. -SARS-CoV-1 is highly contagious via droplet transmission and has a basic reproduction number (R0) of 4 (i.e., each person infected was estimated to infect four other people) [30]. -SARS-CoV-2 also appears to be spread primarily by droplet transmission [194,195], and most estimates of its R0 fall between 2.5 and 3 [367]. +SARS infection is severe, with an estimated death rate of 9.5% [32], while estimates of the death rate associated with COVID-19 are much lower, at approximately 2% [1]. +SARS-CoV-1 is highly contagious via droplet transmission and has a basic reproduction number (R0) of 4 (i.e., each person infected was estimated to infect four other people) [32]. +SARS-CoV-2 also appears to be spread primarily by droplet transmission [196,197], and most estimates of its R0 fall between 2.5 and 3 [1]. Furthermore, the 17-year difference in the timing of these two outbreaks has led to some major differences in the tools available for the international community’s response. -At the time that SARS-CoV-1 emerged, no new HCoV had been identified in almost 40 years [28]. -The identity of the virus underlying the SARS disease remained unknown until April of 2003, when the SARS-CoV-1 virus was characterized through a worldwide scientific effort spearheaded by the WHO [28]. -In contrast, the SARS-CoV-2 genomic sequence was released on January 3, 2020 [10], only days after the international community became aware of the novel pneumonia-like illness now known as COVID-19. -While SARS-CoV-1 belonged to a distinct lineage from the two other HCoV known at the time of its discovery [30], SARS-CoV-2 is closely related to SARS-CoV-1 and a more distant relative of another HCoV characterized in 2012, Middle East respiratory syndrome-related coronavirus [13,369].
-Thus, despite their phylogenetic similarity, SARS-CoV-2 emerged under very different circumstances than SARS-CoV-1 in terms of scientific knowledge about HCoV. +At the time that SARS-CoV-1 emerged, no new HCoV had been identified in almost 40 years [30]. +The identity of the virus underlying the SARS disease remained unknown until April of 2003, when the SARS-CoV-1 virus was characterized through a worldwide scientific effort spearheaded by the World Health Organization (WHO) [30]. +In contrast, the SARS-CoV-2 genomic sequence was released on January 3, 2020 [12], only days after the international community became aware of the novel pneumonia-like illness now known as COVID-19. +While SARS-CoV-1 belonged to a distinct lineage from the two other HCoV known at the time of its discovery [32], SARS-CoV-2 is closely related to SARS-CoV-1 and a more distant relative of another HCoV characterized in 2012, Middle East respiratory syndrome-related coronavirus [15,370].
+Despite their phylogenetic similarity, SARS-CoV-2 emerged under very different circumstances than SARS-CoV-1 in terms of scientific knowledge about HCoV. The trajectories of the pandemics associated with each of the viruses have also diverged significantly. -By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices such as mask wearing [28]. -In contrast, MERS is still circulating and remains a concern; although the fatality rate is very high at almost 35%, the disease is much less easily transmitted, as its R0 has been estimated to be 1 [30]. -The low R0 in combination with public health practices allowed for its spread to be contained [30]. +By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices such as mask wearing [30]. +In contrast, MERS is still circulating and remains a concern; although the fatality rate is very high at almost 35%, the disease is much less easily transmitted, as its R0 has been estimated to be 1 [32]. +The low R0 in combination with public health practices allowed for its spread to be contained [32]. Neither of these trajectories are comparable to that of SARS-CoV-2, which remains a serious threat worldwide more than a year after the first cases of COVID-19 emerged.
Early results suggest that pharmaceutical interventions for COVID-19 may be more successful than efforts to develop prophylactics and therapeutics for SARS and MERS were. -Care for SARS and MERS patients prioritized supportive care and symptom management [30]. +Care for SARS and MERS patients prioritized supportive care and symptom management [32]. To the extent that clinical treatments for SARS and MERS were explored, there is generally a lack of evidence supporting their efficacy. -For example, Ribavirin is an antiviral that was often used in combination with corticosteroids and sometimes interferon (IFN) medications to treat SARS and MERS [28], but its effects have been found to be inconclusive in retrospective and in vitro analyses of SARS and the SARS-CoV-1 virus, respectively [28]. -IFNs and Ribavirin have shown promise in in vitro analyses of MERS, but their clinical effectiveness remains unknown [28]. +For example, Ribavirin is an antiviral that was often used in combination with corticosteroids and sometimes interferon (IFN) medications to treat SARS and MERS [30], but its effects have been found to be inconclusive in retrospective and in vitro analyses of SARS and the SARS-CoV-1 virus, respectively [30]. +IFNs and Ribavirin have shown promise in in vitro analyses of MERS, but their clinical effectiveness remains unknown [30]. Therefore, only limited pharmaceutical advances from prior HCoV outbreaks can be adopted to COVID-19. Importantly, though, prior analyses of the virological and pathogenic properties of SARS-CoV-1 and MERS-CoV provide a strong foundation for the development of hypotheses about SARS-CoV-2 that have served to accelerated the development and identification of potential prophylactic and therapeutic approaches.
5.3.2 Therapeutic Approaches
Therapeutic approaches to the current pandemic can utilize two potential avenues: they can reduce the symptoms that are harmful to COVID-19 patients, or they can directly target the virus to hinder the spread of infection. The goal of the former is to reduce the severity and risks of an active infection, while for the latter, it is to inhibit the replication of the virus once an individual is infected. A variety of symptom profiles with a range of severity are associated with COVID-19, many of which are not life-threatening. -A study of COVID-19 patients in a hospital in Berlin, Germany found that the symptoms associated with the highest risk of death included infection-related symptoms, such as sepsis, respiratory symptoms such as ARDS, and cardiovascular failure or pulmonary embolism [370]. +A study of COVID-19 patients in a hospital in Berlin, Germany found that the symptoms associated with the highest risk of death included infection-related symptoms, such as sepsis, respiratory symptoms such as ARDS, and cardiovascular failure or pulmonary embolism [371]. Therapeutics that reduce the risks associated with these severe outcomes hold particular potential to reduce the pandemic death toll. On the other hand, therapeutics that directly target the virus itself would hold the potential to prevent people infected with SARS-CoV-2 from developing potentially damaging symptoms. These treatments typically fall into the broad category of antivirals. @@ -1644,44 +1645,44 @@
[371].
+Trials data are from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [372].
5.4 Small Molecule Drugs
-
Small molecules are synthesized compounds of low molecular weight, typically less than 1 kilodalton (kDa) [372]. -Small-molecule pharmaceutical agents have been a backbone of drug development since the discovery of penicillin in the early twentieth century [373]. -It and other antibiotics have long been among the best known applications of small molecules to therapeutics, but biotechnological developments such as the prediction of protein-protein interactions have facilitated advances in precise targeting of specific structures using small molecules [373]. +
Small molecules are synthesized compounds of low molecular weight, typically less than 1 kilodalton (kDa) [373]. +Small-molecule pharmaceutical agents have been a backbone of drug development since the discovery of penicillin in the early twentieth century [374]. +It and other antibiotics have long been among the best known applications of small molecules to therapeutics, but biotechnological developments such as the prediction of protein-protein interactions have facilitated advances in precise targeting of specific structures using small molecules [374]. Small molecule drugs today encompass a wide range of therapeutics beyond antibiotics, including antivirals, protein inhibitors, and many broad-spectrum pharmaceuticals.
5.4.1 Small Molecule Antivirals
Antiviral drugs against SARS-CoV-2 are designed to inhibit replication of a virus within an epithelial host cell. -This process requires inhibiting the replication cycle of a virus by disrupting one of six fundamental steps [374]. +This process requires inhibiting the replication cycle of a virus by disrupting one of six fundamental steps [375]. In the first of these steps, the virus attaches to and enters the host cell through endocytosis. Then the virus undergoes uncoating, which is classically defined as the release of viral contents into the host cell. Next, the viral genetic material enters the nucleus where it gets replicated during the biosynthesis stage. During the assembly stage, viral proteins are translated, allowing new viral particles to be assembled. In the final step new viruses are released into the extracellular environment. Many antiviral drugs are designed to inhibit the replication of viral genetic material during the biosynthesis step. -Unlike DNA viruses, which can use the host enzymes to propagate themselves, RNA viruses like SARS-CoV-2 depend on their own polymerase, the RNA-dependent RNA polymerase (RdRP), for replication [375,376]. -Targeting RdRP is therefore an effective strategy for antivirals against RNA viruses and is the proposed mechanism underlying the treatment of SARS and MERS with Ribavirin [377]. +Unlike DNA viruses, which can use the host enzymes to propagate themselves, RNA viruses like SARS-CoV-2 depend on their own polymerase, the RNA-dependent RNA polymerase (RdRP), for replication [376,377]. +Targeting RdRP is therefore an effective strategy for antivirals against RNA viruses and is the proposed mechanism underlying the treatment of SARS and MERS with Ribavirin [378]. However, although antivirals are designed to target a virus, they can also impact other processes in the host and may have unintended effects. Therefore, these therapeutics must be evaluated for both efficacy and safety.
5.4.1.1 Nucleoside and Nucleotide Analogs
5.4.1.1.1 Favipiravir
-Favipiravir (Avigan), also known as T-705, was discovered by Toyama Chemical Co., Ltd. [378]. -The drug was found to be effective at blocking viral amplification in several influenza subtypes as well as other RNA viruses, such as Flaviviridae and Picornaviridae, through a reduction in plaque formation [379] and viral replication in Madin-Darby canine kidney cells [380]. -Furthermore, inoculation of mice with favipiravir was shown to increase survival of influenza infections [379,380]. -In 2014, the drug was approved in Japan for the treatment of influenza that was resistant to conventional treatments like neuraminidase inhibitors [381]. -Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) acts as a purine and purine nucleoside analogue that inhibits viral RNA polymerase in a dose-dependent manner across a range of RNA viruses, including influenza viruses [382,383,384,385,386]. +
Favipiravir (Avigan), also known as T-705, was discovered by Toyama Chemical Co., Ltd. [379]. +The drug was found to be effective at blocking viral amplification in several influenza subtypes as well as other RNA viruses, such as Flaviviridae and Picornaviridae, through a reduction in plaque formation [380] and viral replication in Madin-Darby canine kidney cells [381]. +Furthermore, inoculation of mice with favipiravir was shown to increase survival of influenza infections [380,381]. +In 2014, the drug was approved in Japan for the treatment of influenza that was resistant to conventional treatments like neuraminidase inhibitors [382]. +Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) acts as a purine and purine nucleoside analogue that inhibits viral RNA polymerase in a dose-dependent manner across a range of RNA viruses, including influenza viruses [383,384,385,386,387]. Nucleotides and nucleosides are the natural building blocks for RNA synthesis. -Because of this, modifications to nucleotides and nucleosides can disrupt key processes including replication [387]. +Because of this, modifications to nucleotides and nucleosides can disrupt key processes including replication [388]. Biochemical experiments showed that favipiravir was recognized as a purine nucleoside analogue and incorporated into the viral RNA template. -A single incorporation does not influence RNA transcription; however, multiple events of incorporation lead to the arrest of RNA synthesis [388]. -Evidence for T-705 inhibiting viral RNA polymerase are based on time-of-drug addition studies that found that viral loads were reduced with the addition of favipiravir in early times post-infection [382,385,386].
+A single incorporation does not influence RNA transcription; however, multiple events of incorporation lead to the arrest of RNA synthesis [389]. +Evidence for T-705 inhibiting viral RNA polymerase are based on time-of-drug addition studies that found that viral loads were reduced with the addition of favipiravir in early times post-infection [383,386,387].The effectiveness of favipiravir for treating patients with COVID-19 is currently under investigation. -An open-label, nonrandomized, before-after controlled study was recently conducted [389]. +An open-label, nonrandomized, before-after controlled study was recently conducted [390]. The study included 80 COVID-19 patients (35 treated with favipiravir, 45 control) from the isolation ward of the National Clinical Research Center for Infectious Diseases (The Third People’s Hospital of Shenzhen), Shenzhen, China. The patients in the control group were treated with other antivirals, such as lopinavir and ritonavir. -It should be noted that although the control patients received antivirals, two subsequent large-scale analyses, the WHO Solidarity trial and the RECOVERY trial, identified no effect of lopinavir or of a lopinavir-ritonavir combination, respectively, on the metrics of COVID-19-related mortality that each assessed [390,391,392]. +It should be noted that although the control patients received antivirals, two subsequent large-scale analyses, the WHO Solidarity trial and the RECOVERY trial, identified no effect of lopinavir or of a lopinavir-ritonavir combination, respectively, on the metrics of COVID-19-related mortality that each assessed [391,392,393]. Treatment was applied on days 2-14; treatment stopped either when viral clearance was confirmed or at day 14. The efficacy of the treatment was measured by, first, the time until viral clearance using Kaplan-Meier survival curves, and, second, the improvement rate of chest computed tomography (CT) scans on day 14 after treatment. The study found that favipiravir increased the speed of recovery, measured as viral clearance from the patient by RT-PCR, with patients receiving favipiravir recovering in four days compared to 11 days for patients receiving antivirals such as lopinavir and ritonavir. @@ -1692,33 +1693,32 @@
[393]. -
In late 2020 and early 2021, the first randomized controlled trials of favipiravir for the treatment of COVID-19 released results [394,395,396]. -The first [394] used a randomized, controlled, open-label design to compare two drugs, favipiravir and baloxavir marboxil, to SOC alone. +Additionally, it should be noted that this study was temporarily retracted and then restored without an explanation [394].
+In late 2020 and early 2021, the first randomized controlled trials of favipiravir for the treatment of COVID-19 released results [395,396,397]. +The first [395] used a randomized, controlled, open-label design to compare two drugs, favipiravir and baloxavir marboxil, to standard of care (SOC) alone. Here, SOC included antivirals such as lopinavir/ritonavir and was administered to all patients. The primary endpoint analyzed was viral clearance at day 14. The sample size for this study was very small, with 29 total patients enrolled, and no significant effect of the treatments was found for the primary or any of the secondary outcomes analyzed, which included mortality. The second study was larger, with 96 patients enrolled, and also utilized a randomized design. -This study enrolled only patients with mild to moderate symptoms and randomized them into two groups: one receiving CQ in addition to SOC, and the other receiving favipiravir in addition to SOC. +This study enrolled only patients with mild to moderate symptoms and randomized them into two groups: one receiving chloroquine (CQ) in addition to SOC, and the other receiving favipiravir in addition to SOC. This study reported a non-significant trend for patients receiving favipiravir to have a shorter hospital stay and less likelihood of progressing to mechanical ventilation or to an oxygen saturation < 90%. However, given the fact that favipiravir was being compared to CQ, which is now widely understood to be ineffective for treating COVID-19, these results do not suggest that favipiravir was likely to have had a strong effect on these outcomes. -On the other hand, another trial of 60 patients reported a significant effect of favipiravir on viral clearance at four days (a secondary endpoint), but not at 10 days (the primary endpoint) [396]. -This study, as well as a prior study of favipiravir [397], also reported that the drug was generally well-tolerated. +On the other hand, another trial of 60 patients reported a significant effect of favipiravir on viral clearance at four days (a secondary endpoint), but not at 10 days (the primary endpoint) [397]. +This study, as well as a prior study of favipiravir [398], also reported that the drug was generally well-tolerated. Thus, in combination, these small studies suggest that the effects of favipiravir as a treatment for COVID-19 cannot be determined based on the available evidence, but additionally, none raise major concerns about the safety profile of the drug.
5.4.1.1.2 Remdesivir
Remdesivir (GS-5734) is an intravenous antiviral that was developed by Gilead Sciences to treat Ebola Virus Disease (EVD). At the outset of the COVID-19 pandemic, it did not have any have any FDA-approved use. -However, on May 1, 2020, the FDA issued an Emergency Use Authorization (EUA) for remdesivir for the treatment of hospitalized COVID-19 patients [398]. -The EUA was based on information from two clinical trials, NCT04280705 and NCT04292899 [399,400,401,402]. -Remdesivir is metabolized to GS-441524, an adenosine analog that inhibits a broad range of polymerases and then evades exonuclease repair, causing chain termination [403,404,405]. -A clinical trial in the Democratic Republic of Congo found some evidence of effectiveness against EVD, but two antibody preparations were found to be more effective, and remdesivir was not pursued [406]. -Although it was developed against EVD, remdesivir also inhibits polymerase and replication of the coronaviruses MERS-CoV and SARS-CoV-1 in cell culture assays with submicromolar IC50s [407]. -It has also been found to inhibit SARS-CoV-2, showing synergy with chloroquine in vitro [405]. -The effectiveness of remdesivir for treating patients with COVID-19 is currently under investigation.
-Remdesivir was first used on some COVID-19 patients under compassionate use guidelines [408,409]. +However, on May 1, 2020, the FDA issued an Emergency Use Authorization (EUA) for remdesivir for the treatment of hospitalized COVID-19 patients [399]. +The EUA was based on information from two clinical trials, NCT04280705 and NCT04292899 [400,401,402,403]. +Remdesivir is metabolized to GS-441524, an adenosine analog that inhibits a broad range of polymerases and then evades exonuclease repair, causing chain termination [404,405,406]. +A clinical trial in the Democratic Republic of Congo found some evidence of effectiveness against EVD, but two antibody preparations were found to be more effective, and remdesivir was not pursued [407]. +Although it was developed against EVD, remdesivir also inhibits polymerase and replication of the coronaviruses MERS-CoV and SARS-CoV-1 in cell culture assays with submicromolar IC50s [408]. +It has also been found to inhibit SARS-CoV-2, showing synergy with CQ in vitro [406].
+Remdesivir was first used on some COVID-19 patients under compassionate use guidelines [409,410]. All were in late stages of COVID-19 infection, and initial reports were inconclusive about the drug’s efficacy. Gilead Sciences, the maker of remdesivir, led a recent publication that reported outcomes for compassionate use of the drug in 61 patients hospitalized with confirmed COVID-19. -Here, 200 mg of remdesivir was administered intravenously on day 1, followed by a further 100 mg/day for 9 days [402]. +Here, 200 mg of remdesivir was administered intravenously on day 1, followed by a further 100 mg/day for 9 days [403]. There were significant issues with the study design, or lack thereof. There was no randomized control group. The inclusion criteria were variable: some patients only required low doses of oxygen, while others required ventilation. @@ -1727,49 +1727,48 @@
There was a short follow-up period of investigation.
Some patients worsened, some patients died, and eight were excluded from the analysis mainly due to missing post-baseline information; thus, their health was unaccounted for.
Therefore, even though the study reported clinical improvement in 68% of the 53 patients ultimately evaluated, due to the significant issues with study design, it could not be determined whether treatment with remdesivir had an effect or whether these patients would have recovered regardless of treatment.
-Another study comparing 5- and 10-day treatment regimens reported similar results but was also limited because of the lack of a placebo control [411].
+Another study comparing 5- and 10-day treatment regimens reported similar results but was also limited because of the lack of a placebo control [412].
These studies did not alter the understanding of the efficacy of remdesivir in treating COVID-19, but the encouraging results provided motivation for placebo-controlled studies.
-Remdesivir was later tested in a double-blind placebo-controlled phase 3 clinical trial performed at 60 trial sites, 45 of which were in the United States [400,401].
+
Remdesivir was later tested in a double-blind placebo-controlled phase 3 clinical trial performed at 60 trial sites, 45 of which were in the United States [401,402].
The trial recruited 1,062 patients and randomly assigned them to placebo treatment or treatment with remdesivir.
-Patients were stratified for randomization based on site and the severity of disease presentation at baseline [401].
+Patients were stratified for randomization based on site and the severity of disease presentation at baseline [402].
The treatment was 200 mg on day 1, followed by 100 mg on days 2 through 10.
-Data was analyzed from a total of 1,059 patients who completed the 29-day course of the trial, with 517 assigned to remdesivir and 508 to placebo [401].
+Data was analyzed from a total of 1,059 patients who completed the 29-day course of the trial, with 517 assigned to remdesivir and 508 to placebo [402].
The two groups were well matched demographically and clinically at baseline.
Those who received remdesivir had a median recovery time of 10 days, as compared with 15 days in those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; p < 0.001).
The Kaplan-Meier estimates of mortality by 14 days were 6.7% with remdesivir and 11.9% with placebo, with a hazard ratio (HR) for death of 0.55 and a 95% CI of 0.36 to 0.83, and at day 29, remdesivir corresponded to 11.4% and the placebo to 15.2% (HR: 0.73; 95% CI: 0.52 to 1.03).
Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients in the placebo group (31.6%).
-This study also reported an association between remdesivir administration and both clinical improvement and a lack of progression to more invasive respiratory intervention in patients receiving non-invasive and invasive ventilation at randomization [401].
-Largely on the results of this trial, the FDA reissued and expanded the EUA for remdesivir for the treatment of hospitalized COVID-19 patients ages twelve and older [398].
-Additional clinical trials are currently underway to evaluate the use of remdesivir to treat COVID-19 patients at both early and late stages of infection and in combination with other drugs (Figure 3).
-These trials include [405,412,413,414,415].
-As of October 22, 2020, remdesivir received FDA approval based on three clinical trials [416].
-However, results suggesting no effect of remdesivir on survival were reported by the WHO Solidarity trial [390].
-This large-scale, open-label trial enrolled 11,330 adult in-patients at 405 hospitals in 30 countries around the world [390].
+This study also reported an association between remdesivir administration and both clinical improvement and a lack of progression to more invasive respiratory intervention in patients receiving non-invasive and invasive ventilation at randomization [402].
+Largely on the results of this trial, the FDA reissued and expanded the EUA for remdesivir for the treatment of hospitalized COVID-19 patients ages twelve and older [399].
+Additional clinical trials [406,413,414,415,416] are currently underway to evaluate the use of remdesivir to treat COVID-19 patients at both early and late stages of infection and in combination with other drugs (Figure 3).
+As of October 22, 2020, remdesivir received FDA approval based on three clinical trials [417].
+However, results suggesting no effect of remdesivir on survival were reported by the WHO Solidarity trial [391].
+This large-scale, open-label trial enrolled 11,330 adult in-patients at 405 hospitals in 30 countries around the world [391].
Patients were randomized in equal proportions into four experimental and a control conditions, corresponding to four candidate treatments for COVID-19 and SOC, respectively; no placebo was administered.
The 2,750 patients in the remdesivir group were administered 200 mg intravenously on the first day and 100 mg on each subsequent day until day 10 and assessed for in-hospital death (primary endpoint), duration of hospitalization, and progression to mechanical ventilation.
There were also 2,708 control patients who would have been eligible and able to receive remdesivir were they not assigned to the control group.
A total of 604 patients among these two cohorts deceased during initial hospitalization, with 301 in the remdesivir group and 303 in the control group.
The rate ratio of death between these two groups was therefore not significant (p = 0.50), suggesting that the administration of remdesivir did not affect survival.
The two secondary analyses similarly did not find any effect of remdesivir.
-Additionally, the authors compared data from their study with data from three other studies of remdesivir (including [401]) stratified by supplemental oxygen status.
+Additionally, the authors compared data from their study with data from three other studies of remdesivir (including [402]) stratified by supplemental oxygen status.
The adjusted rate ratio for death based on this meta-analysis was 0.91.
These results thus do not support the previous findings that remdesivir reduced median recovery time and mortality risk in COVID-19 patients.
-In response to the results of the Solidarity trial, Gilead, which manufactures remdesivir, released a statement pointing to the fact that the Solidarity trial was not placebo-controlled or double-blind and at the time of the statement had not been peer reviewed [417]; these sentiments have been echoed elsewhere [418].
-Other critiques of this study have noted that antivirals are not typically targeted at patients with severe illness, and therefore remdesivir could be more beneficial for patients with mild rather than severe cases [392,419].
-However, the publication associated with the trial sponsored by Gilead did purport an effect of remdesivir on patients with severe disease, identifying an 11 versus 18 day recovery period (rate ratio for recovery: 1.31, 95% CI 1.12 to 1.52), although the results of a significance test were not provided [401].
-Additionally, a smaller analysis of 598 patients, of whom two-thirds were randomized to receive remdesivir for either 5 or 10 days, reported a small effect of treatment with remdesivir for five days relative to standard of care in patients with moderate COVID-19 [420].
+
In response to the results of the Solidarity trial, Gilead, which manufactures remdesivir, released a statement pointing to the fact that the Solidarity trial was not placebo-controlled or double-blind and at the time of the statement had not been peer reviewed [418]; these sentiments have been echoed elsewhere [419].
+Other critiques of this study have noted that antivirals are not typically targeted at patients with severe illness, and therefore remdesivir could be more beneficial for patients with mild rather than severe cases [393,420].
+However, the publication associated with the trial sponsored by Gilead did purport an effect of remdesivir on patients with severe disease, identifying an 11 versus 18 day recovery period (rate ratio for recovery: 1.31, 95% CI 1.12 to 1.52), although the results of a significance test were not provided [402].
+Additionally, a smaller analysis of 598 patients, of whom two-thirds were randomized to receive remdesivir for either 5 or 10 days, reported a small effect of treatment with remdesivir for five days relative to standard of care in patients with moderate COVID-19 [421].
These results suggest that remdesivir could improve outcomes for patients with moderate COVID-19, but that additional information would be needed to understand the effects of different durations of treatment.
-Therefore, the arguments put forward in defense of remdesivir do not necessarily seem robust in light of the large sample size used in the Solidarity trial, especially since the broad international nature of the Solidarity clinical trial, which included countries with a wide range of economic profiles and a variety of healthcare systems, provides a much-needed global perspective in a pandemic [392].
-On the other hand, only 62% of patients in the Solidarity trial were randomized on the day of admission or one day afterwards [390], and concerns have been raised that differences in disease progression could influence the effectiveness of remdesivir [392].
+Therefore, the arguments put forward in defense of remdesivir do not necessarily seem robust in light of the large sample size used in the Solidarity trial, especially since the broad international nature of the Solidarity clinical trial, which included countries with a wide range of economic profiles and a variety of healthcare systems, provides a much-needed global perspective in a pandemic [393].
+On the other hand, only 62% of patients in the Solidarity trial were randomized on the day of admission or one day afterwards [391], and concerns have been raised that differences in disease progression could influence the effectiveness of remdesivir [393].
Despite the findings of the Solidarity trial, remdesivir remains available for the treatment of COVID-19 in many places.
-Follow-up studies are needed and, in many cases, are underway to further investigate remdesivir-related outcomes, with possibilities including combinations of remdesivir with other drugs such as baricitinib, which is an inhibitor of Janus kinase 1 and 2 [421].
+Follow-up studies are needed and, in many cases, are underway to further investigate remdesivir-related outcomes, with possibilities including combinations of remdesivir with other drugs such as baricitinib, which is an inhibitor of Janus kinase 1 and 2 [422].
Similarly, the extent to which the remdesivir dosing regimen could influence outcomes continues to be under consideration.
-In complement to the study that found that a 5-day course of remdesivir improved outcomes for patients with moderate COVID-19 but a 10-day course did not [420], a randomized, open-label trial compared the effect of remdesivir on 397 patients with severe COVID-19 over 5 versus 10 days [399,411].
+A randomized, open-label trial compared the effect of remdesivir on 397 patients with severe COVID-19 over 5 versus 10 days [400,412], complementing the study that found that a 5-day course of remdesivir improved outcomes for patients with moderate COVID-19 but a 10-day course did not [421].
Patients in the two groups were administered 200 mg of remdesivir intravenously on the first day, followed by 100 mg on the subsequent four or nine days, respectively.
The two groups differed significantly in their clinical status, with patients assigned to the 10-day group having more severe illness.
This study also differed from most because it included not only adults, but also pediatric patients as young as 12 years old.
It reported no significant differences across several outcomes for patients receiving a 5-day or 10-day course, when correcting for baseline clinical status.
-The data did suggest that the 10-day course might reduce mortality in the most severe patients at day 14, but the representation of this group in the study population was too low to justify any conclusions [411].
+The data did suggest that the 10-day course might reduce mortality in the most severe patients at day 14, but the representation of this group in the study population was too low to justify any conclusions [412].
Thus, additional research is also required to determine whether the dosage and duration of remdesivir administration influences outcomes.
In summary, remdesivir is a first in class drug due to its FDA approval.
Early investigations of this drug established proof of principle that drugs targeting the virus can benefit COVID-19 patients.
@@ -1781,43 +1780,43 @@
They are typically combined with protease inhibitors, integrase inhibitors, and even other polymerase inhibitors.
Additional clinical trials of remdesivir in different patient pools and in combination with other therapies will refine its use in the clinic.
5.4.1.2 Protease Inhibitors
-Several studies showed that viral proteases play an important role in the life cycle of viruses, including coronaviruses, by modulating the cleavage of viral polyprotein precursors [422].
+
Several studies showed that viral proteases play an important role in the life cycle of viruses, including coronaviruses, by modulating the cleavage of viral polyprotein precursors [423].
Several FDA-approved drugs target proteases, including lopinavir and ritonavir for HIV infection and simeprevir for hepatitis C virus infection.
-In particular, serine protease inhibitors were suggested for the treatment of SARS and MERS viruses [423].
-Recently, a study [67] suggested that camostat mesylate, an FDA-approved protease inhibitor (PI) could block the entry of SARS-CoV-2 into lung cells in vitro.
+In particular, serine protease inhibitors were suggested for the treatment of SARS and MERS viruses [424].
+Recently, a study [69] suggested that camostat mesylate, an FDA-approved protease inhibitor (PI) could block the entry of SARS-CoV-2 into lung cells in vitro.
Thus far, investigation of possible PIs that could work against SARS-CoV-2 has been driven by computational predictions.
Computer-aided design allowed for the development of a Michael acceptor inhibitor, now known as N3, to target a protease critical to SARS-CoV-2 replication.
-Discovery of the N3 mechanism arose from interest in the two polyproteins encoded by the SARS-CoV-2 replicase gene, pp1a and pp1ab, that are critical for viral replication and transcription [424].
+Discovery of the N3 mechanism arose from interest in the two polyproteins encoded by the SARS-CoV-2 replicase gene, pp1a and pp1ab, that are critical for viral replication and transcription [425].
These polyproteins must undergo proteolytic processing.
This processing is usually conducted by Mpro, a 33.8-kDa SARS-CoV-2 protease that is therefore fundamental to viral replication and transcription.
-N3 was designed computationally [425] to bind in the substrate binding pocket of the Mpro protease of SARS-like coronaviruses [426], therefore inhibiting proteolytic processing.
-Subsequently, the structure of N3-bound SARS-CoV-2 Mpro was solved [424], confirming the computational prediction.
-N3 was tested in vitro on SARS-CoV-2-infected Vero cells, which belong to a line of cells established from the kidney epithelial cells of an African green monkey, and was found to inhibit SARS-CoV-2 [424].
+N3 was designed computationally [426] to bind in the substrate binding pocket of the Mpro protease of SARS-like coronaviruses [427], therefore inhibiting proteolytic processing.
+Subsequently, the structure of N3-bound SARS-CoV-2 Mpro was solved [425], confirming the computational prediction.
+N3 was tested in vitro on SARS-CoV-2-infected Vero cells, which belong to a line of cells established from the kidney epithelial cells of an African green monkey, and was found to inhibit SARS-CoV-2 [425].
Although N3 is a strong inhibitor of SARS-CoV-2 in vitro, its safety and efficacy still need to be tested in healthy volunteers and patients.
-After the design and confirmation of N3 as a highly potent Michael acceptor inhibitor and the identification of Mpro’s structure [424,427], 10,000 compounds were screened for their in vitro anti-Mpro activity.
+After the design and confirmation of N3 as a highly potent Michael acceptor inhibitor and the identification of Mpro’s structure [425,428], 10,000 compounds were screened for their in vitro anti-Mpro activity.
The six leads that were identified were ebselen, disulfiram, tideglusib, carmofur, and PX-12.
-In vitro analysis revealed that Ebselen had the strongest potency in reducing the viral load in SARS-CoV-2-infected Vero cells [424].
-Ebselen is an organoselenium compound with anti-inflammatory and antioxidant properties [428].
-It has been proposed as a possible treatment for conditions ranging from bipolar disorder to diabetes to heart disease [428], and a preliminary investigation of ebselen as a treatment for noise-induced hearing loss provided promising reports of its safety [429].
-For COVID-19, the NSP5 in SARS-CoV-2 contains a cysteine at the active site of Mpro, and ebselen is able to inactivate the protease by bonding covalently with this cysteine to form a selenosulfide [428,430].
-Interestingly there has been some argument that selenium deficiency may be associated with more severe COVID-19 outcomes [431,432,433], possibly indicating that its antioxidative properties are protective [430].
-On the other hand, ebselen and the other compounds identified are likely to be promiscuous binders, which could diminish their therapeutic potential [424].
+In vitro analysis revealed that ebselen had the strongest potency in reducing the viral load in SARS-CoV-2-infected Vero cells [425].
+Ebselen is an organoselenium compound with anti-inflammatory and antioxidant properties [429].
+It has been proposed as a possible treatment for conditions ranging from bipolar disorder to diabetes to heart disease [429], and a preliminary investigation of ebselen as a treatment for noise-induced hearing loss provided promising reports of its safety [430].
+For COVID-19, the NSP5 in SARS-CoV-2 contains a cysteine at the active site of Mpro, and ebselen is able to inactivate the protease by bonding covalently with this cysteine to form a selenosulfide [429,431].
+Interestingly there has been some argument that selenium deficiency may be associated with more severe COVID-19 outcomes [432,433,434], possibly indicating that its antioxidative properties are protective [431].
+On the other hand, ebselen and the other compounds identified are likely to be promiscuous binders, which could diminish their therapeutic potential [425].
While there is clear computational and in vitro support for ebselen’s potential as a COVID-19 therapeutic, results from clinical trials are not yet available for this compound.
-However, as of July 2020, phase II clinical trials commenced to assess the effects of SPI-1005, an investigational drug from Sound Pharmaceuticals that contains ebselen [434], on 60 adults presenting with each of moderate [435] and severe [436] COVID-19.
+However, as of July 2020, phase II clinical trials commenced to assess the effects of SPI-1005, an investigational drug from Sound Pharmaceuticals that contains ebselen [435], on 60 adults presenting with each of moderate [436] and severe [437] COVID-19.
In summary, N3 is a computationally designed molecule that inhibits the viral transcription through inhibiting Mpro.
Ebselen is both a strong Mpro inhibitor and strong inhibitor of viral replication in vitro that was found to reduce SARS-CoV-2 viral load even more effectively than N3.
-Ebselen is a very promising compound since its safety has been demonstrated in other indications.
-However, ebselen may be a false positive, since it is a promiscuous compound that can have many targets [437].
+Ebselen is a promising compound since its safety has been demonstrated in other indications.
+However, ebselen may be a false positive, since it is a promiscuous compound that can have many targets [438].
Therefore, the results of ongoing clinical trials are expected to help establish whether compounds with higher specificity are required.
5.4.2 Broad-Spectrum Pharmaceuticals
-When a virus enters a host, the host becomes the virus’ environment.
+
When a virus enters a host, the host becomes the virus’s environment.
Therefore, the state of the host can also influence the virus’s ability to replicate and spread.
-Traditionally, viral targets have been favored for pharmaceutical interventions because altering host processes is likely to be less specific than targeting the virus directly [438].
-On the other hand, targeting the host offers potential for a complementary strategy to antivirals that could broadly limit the ability of viruses to replicate [438].
+Traditionally, viral targets have been favored for pharmaceutical interventions because altering host processes is likely to be less specific than targeting the virus directly [439].
+On the other hand, targeting the host offers potential for a complementary strategy to antivirals that could broadly limit the ability of viruses to replicate [439].
As a result, therapeutic approaches that target host proteins have become an area of interest for SARS-CoV-2.
Viral entry receptors in particular have been identified as a potential target.
-Entry of SARS-CoV-2 into the cell depends on binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which is catalyzed by the enzyme encoded by TMPRSS2 [67].
+Entry of SARS-CoV-2 into the cell depends on binding to angiotensin-converting enzyme 2 (ACE2), which is catalyzed by the enzyme encoded by TMPRSS2 [69].
In principle, drugs that reduce the expression of these proteins or sterically hinder viral interactions with them might reduce viral entry into cells.
Due to the urgent nature of the COVID-19 pandemic, many of the pharmaceutical agents that have been widely publicized as having possible therapeutic or prophylactic effects are broad-spectrum pharmaceuticals that pre-date the COVID-19 pandemic.
These treatments are not specifically targeted at the virus itself or at the host receptors it relies on, but rather induce broad shifts in host biology that are hypothesized to be potential inhibitors of the virus.
@@ -1825,56 +1824,56 @@
5.4.2.1 ACEi and ARB
5.4.1.2 Protease Inhibitors
-Several studies showed that viral proteases play an important role in the life cycle of viruses, including coronaviruses, by modulating the cleavage of viral polyprotein precursors [422]. +
Several studies showed that viral proteases play an important role in the life cycle of viruses, including coronaviruses, by modulating the cleavage of viral polyprotein precursors [423]. Several FDA-approved drugs target proteases, including lopinavir and ritonavir for HIV infection and simeprevir for hepatitis C virus infection. -In particular, serine protease inhibitors were suggested for the treatment of SARS and MERS viruses [423]. -Recently, a study [67] suggested that camostat mesylate, an FDA-approved protease inhibitor (PI) could block the entry of SARS-CoV-2 into lung cells in vitro. +In particular, serine protease inhibitors were suggested for the treatment of SARS and MERS viruses [424]. +Recently, a study [69] suggested that camostat mesylate, an FDA-approved protease inhibitor (PI) could block the entry of SARS-CoV-2 into lung cells in vitro. Thus far, investigation of possible PIs that could work against SARS-CoV-2 has been driven by computational predictions.
Computer-aided design allowed for the development of a Michael acceptor inhibitor, now known as N3, to target a protease critical to SARS-CoV-2 replication. -Discovery of the N3 mechanism arose from interest in the two polyproteins encoded by the SARS-CoV-2 replicase gene, pp1a and pp1ab, that are critical for viral replication and transcription [424]. +Discovery of the N3 mechanism arose from interest in the two polyproteins encoded by the SARS-CoV-2 replicase gene, pp1a and pp1ab, that are critical for viral replication and transcription [425]. These polyproteins must undergo proteolytic processing. This processing is usually conducted by Mpro, a 33.8-kDa SARS-CoV-2 protease that is therefore fundamental to viral replication and transcription. -N3 was designed computationally [425] to bind in the substrate binding pocket of the Mpro protease of SARS-like coronaviruses [426], therefore inhibiting proteolytic processing. -Subsequently, the structure of N3-bound SARS-CoV-2 Mpro was solved [424], confirming the computational prediction. -N3 was tested in vitro on SARS-CoV-2-infected Vero cells, which belong to a line of cells established from the kidney epithelial cells of an African green monkey, and was found to inhibit SARS-CoV-2 [424].
+N3 was designed computationally [426] to bind in the substrate binding pocket of the Mpro protease of SARS-like coronaviruses [427], therefore inhibiting proteolytic processing. +Subsequently, the structure of N3-bound SARS-CoV-2 Mpro was solved [425], confirming the computational prediction. +N3 was tested in vitro on SARS-CoV-2-infected Vero cells, which belong to a line of cells established from the kidney epithelial cells of an African green monkey, and was found to inhibit SARS-CoV-2 [425].Although N3 is a strong inhibitor of SARS-CoV-2 in vitro, its safety and efficacy still need to be tested in healthy volunteers and patients. -After the design and confirmation of N3 as a highly potent Michael acceptor inhibitor and the identification of Mpro’s structure [424,427], 10,000 compounds were screened for their in vitro anti-Mpro activity. +After the design and confirmation of N3 as a highly potent Michael acceptor inhibitor and the identification of Mpro’s structure [425,428], 10,000 compounds were screened for their in vitro anti-Mpro activity. The six leads that were identified were ebselen, disulfiram, tideglusib, carmofur, and PX-12. -In vitro analysis revealed that Ebselen had the strongest potency in reducing the viral load in SARS-CoV-2-infected Vero cells [424]. -Ebselen is an organoselenium compound with anti-inflammatory and antioxidant properties [428]. -It has been proposed as a possible treatment for conditions ranging from bipolar disorder to diabetes to heart disease [428], and a preliminary investigation of ebselen as a treatment for noise-induced hearing loss provided promising reports of its safety [429]. -For COVID-19, the NSP5 in SARS-CoV-2 contains a cysteine at the active site of Mpro, and ebselen is able to inactivate the protease by bonding covalently with this cysteine to form a selenosulfide [428,430]. -Interestingly there has been some argument that selenium deficiency may be associated with more severe COVID-19 outcomes [431,432,433], possibly indicating that its antioxidative properties are protective [430]. -On the other hand, ebselen and the other compounds identified are likely to be promiscuous binders, which could diminish their therapeutic potential [424]. +In vitro analysis revealed that ebselen had the strongest potency in reducing the viral load in SARS-CoV-2-infected Vero cells [425]. +Ebselen is an organoselenium compound with anti-inflammatory and antioxidant properties [429]. +It has been proposed as a possible treatment for conditions ranging from bipolar disorder to diabetes to heart disease [429], and a preliminary investigation of ebselen as a treatment for noise-induced hearing loss provided promising reports of its safety [430]. +For COVID-19, the NSP5 in SARS-CoV-2 contains a cysteine at the active site of Mpro, and ebselen is able to inactivate the protease by bonding covalently with this cysteine to form a selenosulfide [429,431]. +Interestingly there has been some argument that selenium deficiency may be associated with more severe COVID-19 outcomes [432,433,434], possibly indicating that its antioxidative properties are protective [431]. +On the other hand, ebselen and the other compounds identified are likely to be promiscuous binders, which could diminish their therapeutic potential [425]. While there is clear computational and in vitro support for ebselen’s potential as a COVID-19 therapeutic, results from clinical trials are not yet available for this compound. -However, as of July 2020, phase II clinical trials commenced to assess the effects of SPI-1005, an investigational drug from Sound Pharmaceuticals that contains ebselen [434], on 60 adults presenting with each of moderate [435] and severe [436] COVID-19.
+However, as of July 2020, phase II clinical trials commenced to assess the effects of SPI-1005, an investigational drug from Sound Pharmaceuticals that contains ebselen [435], on 60 adults presenting with each of moderate [436] and severe [437] COVID-19.In summary, N3 is a computationally designed molecule that inhibits the viral transcription through inhibiting Mpro. Ebselen is both a strong Mpro inhibitor and strong inhibitor of viral replication in vitro that was found to reduce SARS-CoV-2 viral load even more effectively than N3. -Ebselen is a very promising compound since its safety has been demonstrated in other indications. -However, ebselen may be a false positive, since it is a promiscuous compound that can have many targets [437]. +Ebselen is a promising compound since its safety has been demonstrated in other indications. +However, ebselen may be a false positive, since it is a promiscuous compound that can have many targets [438]. Therefore, the results of ongoing clinical trials are expected to help establish whether compounds with higher specificity are required.
5.4.2 Broad-Spectrum Pharmaceuticals
-When a virus enters a host, the host becomes the virus’ environment. +
When a virus enters a host, the host becomes the virus’s environment. Therefore, the state of the host can also influence the virus’s ability to replicate and spread. -Traditionally, viral targets have been favored for pharmaceutical interventions because altering host processes is likely to be less specific than targeting the virus directly [438]. -On the other hand, targeting the host offers potential for a complementary strategy to antivirals that could broadly limit the ability of viruses to replicate [438]. +Traditionally, viral targets have been favored for pharmaceutical interventions because altering host processes is likely to be less specific than targeting the virus directly [439]. +On the other hand, targeting the host offers potential for a complementary strategy to antivirals that could broadly limit the ability of viruses to replicate [439]. As a result, therapeutic approaches that target host proteins have become an area of interest for SARS-CoV-2. Viral entry receptors in particular have been identified as a potential target. -Entry of SARS-CoV-2 into the cell depends on binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which is catalyzed by the enzyme encoded by TMPRSS2 [67]. +Entry of SARS-CoV-2 into the cell depends on binding to angiotensin-converting enzyme 2 (ACE2), which is catalyzed by the enzyme encoded by TMPRSS2 [69]. In principle, drugs that reduce the expression of these proteins or sterically hinder viral interactions with them might reduce viral entry into cells.
Due to the urgent nature of the COVID-19 pandemic, many of the pharmaceutical agents that have been widely publicized as having possible therapeutic or prophylactic effects are broad-spectrum pharmaceuticals that pre-date the COVID-19 pandemic. These treatments are not specifically targeted at the virus itself or at the host receptors it relies on, but rather induce broad shifts in host biology that are hypothesized to be potential inhibitors of the virus. @@ -1825,56 +1824,56 @@
5.4.2.1 ACEi and ARB
A second randomized trial, conducted by the Shanghai Public Health Clinical Center, analyzed whether HCQ increased rates of virological clearance at day 7 in respiratory pharyngeal swabs compared to SOC [469]. This trial was published in Chinese along with an abstract in English, and only the English abstract was read and interpreted for this review. The trial found comparable outcomes in virological clearance rate, time to virological clearance, and time to body temperature normalization between the treatment and control groups. -A known weakness is small sample size, with only 30 patients enrolled and 15 in each arm. +The small sample size is one weakness, with only 30 patients enrolled and 15 in each arm. This problem suggests the study is underpowered to detect potentially useful differences and precludes interpretation of results. Additionally, because only the abstract could be read, other design and analysis issues could be present. Thus, though these studies added randomization to their assessment of HCQ, their conclusions should be interpreted very cautiously. These two studies assessed different outcomes and reached differing conclusions about the efficacy of HCQ for treating COVID-19; the designs of both studies, especially with respect to sample size, meant that no general conclusions can be made about the efficacy of the drug.
Several widely reported studies on HCQ also have issues with data integrity and/or provenance. -A Letter to the Editor published in BioScience Trends on March 16, 2020 claimed that numerous clinical trials have shown that HCQ is superior to control treatment in inhibiting the exacerbation of COVID-19 pneumonia [469]. -This letter has been cited by numerous primary literature, review articles, and media alike [470,471]. +A Letter to the Editor published in BioScience Trends on March 16, 2020 claimed that numerous clinical trials have shown that HCQ is superior to control treatment in inhibiting the exacerbation of COVID-19 pneumonia [470]. +This letter has been cited by numerous primary literature, review articles, and media alike [471,472]. However, the letter referred to 15 pre-registration identifiers from the Chinese Clinical Trial Registry. When these identifiers are followed back to the registry, most trials claim they are not yet recruiting patients or are currently recruiting patients. For all of these 15 identifiers, no data uploads or links to publications could be located on the pre-registrations. At the very least, the lack of availability of the primary data means the claim that HCQ is efficacious against COVID-19 pneumonia cannot be verified. -Similarly, a recent multinational registry analysis [472] analyzed the efficacy of CQ and HCQ with and without a macrolide, which is a class of antibiotics that includes Azithromycin, for the treatment of COVID-19. +Similarly, a recent multinational registry analysis [473] analyzed the efficacy of CQ and HCQ with and without a macrolide, which is a class of antibiotics that includes Azithromycin, for the treatment of COVID-19. The study observed 96,032 patients split into a control and four treatment conditions (CQ with and without a macrolide; HCQ with and without a macrolide). They concluded that treatment with CQ and HCQ was associated with increased risk of de novo ventricular arrhythmia during hospitalization. -However, this study has since been retracted by The Lancet due to an inability to validate the data used [473]. -These studies demonstrate that increased skepticism in evaluation of the HCQ/CQ and COVID-19 literature may be warranted, possible because of the significant attention HCQ and CQ have received as possible treatments for COVID-19 and the politicization of these drugs.
+However, this study has since been retracted by The Lancet due to an inability to validate the data used [474]. +These studies demonstrate that increased skepticism in evaluation of the HCQ/CQ and COVID-19 literature may be warranted, possibly because of the significant attention HCQ and CQ have received as possible treatments for COVID-19 and the politicization of these drugs.Despite the fact that the study suggesting that CQ/HCQ increased risk of ventricular arrhythmia in COVID-19 patients has now been retracted, previous studies have identified risks associated with HCQ/CQ. -A patient with systemic lupus erythematosus developed a prolonged QT interval that was likely exacerbated by use of HCQ in combination with renal failure [474]. -A prolonged QT interval is associated with ventricular arrhythmia [475]. -Furthermore, a separate study [476] investigated the safety associated with the use of HCQ with and without macrolides between 2000 and 2020. +A patient with systemic lupus erythematosus developed a prolonged QT interval that was likely exacerbated by use of HCQ in combination with renal failure [475]. +A prolonged QT interval is associated with ventricular arrhythmia [476]. +Furthermore, a separate study [477] investigated the safety associated with the use of HCQ with and without macrolides between 2000 and 2020. The study involved 900,000 cases treated with HCQ and 300,000 cases treated with HCQ + AZ. The results indicated that short-term use of HCQ was not associated with additional risk, but that HCQ + AZ was associated with an enhanced risk of cardiovascular complications (15-20% increased risk of chest pain) and a two-fold increased risk of mortality. Therefore, whether studies utilize HCQ alone or HCQ in combination with a macrolide may be an important consideration in assessing risk. -As results from initial investigations of these drug combinations have emerged, concerns about the efficacy and risks of treating COVID-19 with HCQ and CQ has led to the removal of CQ/HCQ from SOC practices in several countries [477,478]. -As of May 25, 2020, WHO had suspended administration of HCQ as part of the worldwide Solidarity Trial [479], and later the final results of this large-scale trial that compared 947 patients administered HCQ to 906 controls revealed no effect on the primary outcome, mortality during hospitalization (rate ratio: 1.19; p = 0.23)
+As results from initial investigations of these drug combinations have emerged, concerns about the efficacy and risks of treating COVID-19 with HCQ and CQ has led to the removal of CQ/HCQ from SOC practices in several countries [478,479]. +As of May 25, 2020, WHO had suspended administration of HCQ as part of the worldwide Solidarity Trial [480], and later the final results of this large-scale trial that compared 947 patients administered HCQ to 906 controls revealed no effect on the primary outcome, mortality during hospitalization (rate ratio: 1.19; p = 0.23)Additional research has emerged largely identifying HCQ/CQ to be ineffective against COVID-19 while simultaneously revealing a number of significant side effects. -A randomized, open-label, non-placebo trial of 150 COVID-19 patients was conducted in parallel at 16 government-designated COVID-19 centers in China to assess the safety and efficacy of HCQ [480]. +A randomized, open-label, non-placebo trial of 150 COVID-19 patients was conducted in parallel at 16 government-designated COVID-19 centers in China to assess the safety and efficacy of HCQ [481]. The trial compared treatment with HCQ in conjunction with SOC to SOC alone in 150 infected patients who were assigned randomly to the two groups (75 per group). The primary endpoint of the study was the negative conversion rate of SARS-CoV-2 in 28 days, and the investigators found no difference in this parameter between the groups. The secondary endpoints were an amelioration of the symptoms of the disease such as axillary temperature ≤36.6°C, SpO2 >94% on room air, and disappearance of symptoms like shortness of breath, cough, and sore throat. -The median time to symptom alleviation was similar across different conditions (19 days in HCQ+SOC vs. 21 days in SOC). -Additionally, 30% of the patients receiving SOC+HCQ reported adverse outcomes compared to 8.8% of patients receiving only SOC, with the most common adverse outcome in the SOC+HCQ group being diarrhea (10% vs. 0% in the SOC group, p=0.004). +The median time to symptom alleviation was similar across different conditions (19 days in HCQ + SOC versus 21 days in SOC). +Additionally, 30% of the patients receiving SOC+HCQ reported adverse outcomes compared to 8.8% of patients receiving only SOC, with the most common adverse outcome in the SOC+HCQ group being diarrhea (10% versus 0% in the SOC group, p = 0.004). However, there are several factors that limit the interpretability of this study. Most of the enrolled patients had mild-to-moderate symptoms (98%), and the average age was 46. SOC in this study included the use of antivirals (Lopinavir-Ritonavir, Arbidol, Oseltamivir, Virazole, Entecavir, Ganciclovir, and Interferon alfa), which appeared to introduce confounding effects. Thus, to isolate the effect of HCQ, SOC would need to exclude the use of antivirals. -In this trial, the samples used to test for the presence of the SARS-CoV-2 virus were collected from the upper respiratory tract, and the authors indicated that the use of upper respiratory samples may have introduced false negatives (e.g., [81]). +In this trial, the samples used to test for the presence of the SARS-CoV-2 virus were collected from the upper respiratory tract, and the authors indicated that the use of upper respiratory samples may have introduced false negatives (e.g., [83]). Another limitation of the study that the authors acknowledge was that the HCQ treatment began, on average, at a 16-day delay from the symptom onset. The fact that this study was open-label and lacked a placebo limits interpretation, and additional analysis is required to determine whether HCQ reduces inflammatory response. Therefore, despite some potential areas of investigation identified in post hoc analysis, this study cannot be interpreted as providing support for HCQ as a therapeutic against COVID-19.
-Additional evidence comes from a retrospective analysis [481] that examined data from 368 COVID-19 patients across all United States Veteran Health Administration medical centers. +
Additional evidence comes from a retrospective analysis [482] that examined data from 368 COVID-19 patients across all United States Veteran Health Administration medical centers. The study retrospectively investigated the effect of the administration of HCQ (n=97), HCQ + AZ (n=113), and no HCQ (n=158) on 368 patients. The primary outcomes assessed were death and the need for mechanical ventilation. Standard supportive care was rendered to all patients. Due to the low representation of women (N=17) in the available data, the analysis included only men, and the median age was 65 years. The rate of death in the HCQ-only treatment condition was 27.8% and in the HCQ + AZ treatment condition, it was 22.1%. -In comparison to the 14.1% rate of death in the no-HCQ cohort, these data indicated a statistically significant elevation in the risk of death for the HCQ-only group compared to the no-HCQ group (adjusted HR: 2.61, p=0.03), but not for the HCQ + AZ group compared to the no-HCQ group (adjusted HR: 1.14; p=0.72). +In comparison to the 14.1% rate of death in the no-HCQ cohort, these data indicated a statistically significant elevation in the risk of death for the HCQ-only group compared to the no-HCQ group (adjusted HR: 2.61, p = 0.03), but not for the HCQ + AZ group compared to the no-HCQ group (adjusted HR: 1.14; p = 0.72). Further, the risk of ventilation was similar across all three groups (adjusted HR: 1.43, p = 0.48 (HCQ) and 0.43, p = 0.09 (HCQ + AZ) compared to no HCQ). The study thus showed evidence of an association between increased mortality and HCQ in this cohort of COVID-19 patients but no change in rates of mechanical ventilation among the treatment conditions. The study had a few limitations: it was not randomized, and the baseline vital signs, laboratory tests, and prescription drug use were significantly different among the three groups. All of these factors could potentially influence treatment outcome. Furthermore, the authors acknowledge that the effect of the drugs might be different in females and pediatric subjects, since these subjects were not part of the study. -The reported result that HCQ + AZ is safer than HCQ contradicts the findings of the previous large-scale analysis of twenty years of records that found HCQ + AZ to be more frequently associated with cardiac arrhythmia than HCQ alone [476]; whether this discrepancy is caused by the pathology of COVID-19, is influenced by age or sex, or is a statistical artifact is not presently known.
+The reported result that HCQ + AZ is safer than HCQ contradicts the findings of the previous large-scale analysis of twenty years of records that found HCQ + AZ to be more frequently associated with cardiac arrhythmia than HCQ alone [477]; whether this discrepancy is caused by the pathology of COVID-19, is influenced by age or sex, or is a statistical artifact is not presently known.Finally, findings from the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial were released on October 8, 2020. -This study used a randomized, open-label design to study the effects of HCQ compared to SOC at 176 hospitals in the United Kingdom [482]. +This study used a randomized, open-label design to study the effects of HCQ compared to SOC at 176 hospitals in the United Kingdom [483]. This large study enrolled 11,197 hospitalized patients whose physicians believed it would not harm them to participate. Patients were randomized into either the control group or one of the treatment arms, with twice as many patients enrolled in the control group as any treatment group. Of the patients eligible to receive HCQ, 1,561 were randomized into the HCQ arm, and 3,155 were randomized into the control arm. @@ -1958,14 +1957,14 @@
5.4.2.2.2 HCQ for the Treatment of Mild Cases
One additional possible therapeutic application of HCQ considered was the treatment of mild COVID-19 cases in otherwise healthy individuals. -This possibility was assessed in a randomized, open-label, multi-center analysis conducted in Catalonia (Spain) [483]. +This possibility was assessed in a randomized, open-label, multi-center analysis conducted in Catalonia (Spain) [484]. This analysis enrolled adults 18 and older who had been experiencing mild symptoms of COVID-19 for fewer than five days. Participants were randomized into an HCQ arm (N=136) and a control arm (N=157), and those in the treatment arm were administered 800 mg of HCQ on the first day of treatment followed by 400 mg on each of the subsequent six days. The primary outcome assessed was viral clearance at days 3 and 7 following the onset of treatment, and secondary outcomes were clinical progression and time to complete resolution of symptoms. They found no significant differences between the two groups. This study thus suggests that HCQ does not improve recovery from COVID-19, even in otherwise healthy adult patients with mild symptoms.
5.4.2.2.3 Prophylactic Administration of HCQ
-An initial study of the possible prophylactic application of HCQ utilized a randomized, double-blind, placebo-controlled design to analyze the administration of HCQ prophylactically [484]. +
An initial study of the possible prophylactic application of HCQ utilized a randomized, double-blind, placebo-controlled design to analyze the administration of HCQ prophylactically [485]. Asymptomatic adults in the United States and Canada who had been exposed to SARS-CoV-2 within the past four days were enrolled in an online study to evaluate whether administration of HCQ over five days influenced the probability of developing COVID-19 symptoms over a 14-day period. Of the participants, 414 received HCQ and 407 received a placebo. No significant difference in the rate of symptomatic illness was observed between the two groups (11.8% HCQ, 14.3% placebo, p = 0.35). @@ -1979,7 +1978,7 @@
-A second study [485] examined the effect of administering HCQ to healthcare workers as a pre-exposure prophylactic.
+
A second study [486] examined the effect of administering HCQ to healthcare workers as a pre-exposure prophylactic.
The primary outcome assessed was the conversion from SARS-CoV-2 negative to SARS-CoV-2 positive status over the 8 week study period.
This study was also randomized, double-blind, and placebo-controlled, and it sought to address some of the limitations of the first prophylactic study.
They aimed to enroll 200 healthcare workers, preferentially those working with COVID-19 patients, at two hospitals within the University of Pennsylvania hospital system in Philadelphia, PA.
@@ -1990,117 +1989,117 @@
5.4.2.2.4 Summary of HCQ/CQ Research Findings
Early in vitro evidence indicated that HCQ could be an effective therapeutic against SARS-CoV-2 and COVID-19, leading to significant media attention and public interest in its potential as both a therapeutic and prophylactic.
-Initially it was hypothesized that CQ/HCQ might be effective against SARS-CoV-2 in part because CQ and HCQ have both been found to inhibit the expression of CD154 in T-cells and to reduce TLR signaling that leads to the production of pro-inflammatory cytokines [486].
+Initially it was hypothesized that CQ/HCQ might be effective against SARS-CoV-2 in part because CQ and HCQ have both been found to inhibit the expression of CD154 in T-cells and to reduce TLR signaling that leads to the production of pro-inflammatory cytokines [487].
Clinical trials for COVID-19 have more often used HCQ rather than CQ because it offers the advantages of being cheaper and having fewer side effects than CQ.
However, research has not found support for a positive effect of HCQ on COVID-19 patients.
Multiple clinical studies have already been carried out to assess HCQ as a therapeutic agent for COVID-19, and many more are in progress.
To date, none of these studies have used randomized, double-blind, placebo-controlled designs with a large sample size, which would be the gold standard.
Despite the design limitations (which would be more likely to produce false positives than false negatives), initial optimism about HCQ has largely dissipated.
-The most methodologically rigorous analysis of HCQ as a prophylactic [484] found no significant differences between the treatment and control groups, and the WHO’s global Solidarity trial similarly reported no effect of HCQ on mortality [390].
+The most methodologically rigorous analysis of HCQ as a prophylactic [485] found no significant differences between the treatment and control groups, and the WHO’s global Solidarity trial similarly reported no effect of HCQ on mortality [391].
Thus, HCQ/CQ are not likely to be effective therapeutic or prophylactic agents against COVID-19.
-Additionally, one study identified an increased risk of mortality in older men receiving HCQ, and administration of HCQ and HCQ+AZ did not decrease the use of mechanical ventilation in these patients [481].
+Additionally, one study identified an increased risk of mortality in older men receiving HCQ, and administration of HCQ and HCQ + AZ did not decrease the use of mechanical ventilation in these patients [482].
HCQ use for COVID-19 could also lead to shortages for anti-malarial or anti-rheumatic use, where it has documented efficacy.
Despite significant early attention, these drugs appear to be ineffective against COVID-19.
Several countries have now removed CQ/HCQ from their SOC for COVID-19 due to the lack of evidence of efficacy and the frequency of adverse effects.
5.4.2.3 Dexamethasone
-Dexamethasone (9α-fluoro-16α-methylprednisolone) is a synthetic corticosteroid that binds to glucocorticoid receptors [487,488].
-It was first synthesized in the late 1950s as an anti-inflammatory and has been used to treat RA and other inflammatory conditions [489,490].
-Steroids such as dexamethasone are widely available and affordable, and they are often used to treat community-acquired pneumonia [491].
-A clinical trial that began in 2012 recently reported that dexamethasone may improve outcomes for patients with ARDS [492].
-However, a meta-analysis of a small amount of available data about dexamethasone as a treatment for SARS suggested that it may, in fact, be associated with patient harm [493]; however, these findings may have been biased by the fact that all of the studies examined were observational and a large number of inconclusive studies were not included [494].
-Dexamethasone works as an anti-inflammatory agent by binding to glucocorticoid receptors with higher affinity than endogenous cortisol [495].
+
Dexamethasone (9α-fluoro-16α-methylprednisolone) is a synthetic corticosteroid that binds to glucocorticoid receptors [488,489].
+It was first synthesized in the late 1950s as an anti-inflammatory and has been used to treat RA and other inflammatory conditions [490,491].
+Steroids such as dexamethasone are widely available and affordable, and they are often used to treat community-acquired pneumonia [492].
+A clinical trial that began in 2012 recently reported that dexamethasone may improve outcomes for patients with ARDS [493].
+However, a meta-analysis of a small amount of available data about dexamethasone as a treatment for SARS suggested that it may, in fact, be associated with patient harm [494]; however, these findings may have been biased by the fact that all of the studies examined were observational and a large number of inconclusive studies were not included [495].
+Dexamethasone works as an anti-inflammatory agent by binding to glucocorticoid receptors with higher affinity than endogenous cortisol [496].
In order to understand how dexamethasone reduces inflammation, it is necessary to consider the stress response broadly.
-In response to stress, corticotropin‐releasing hormone stimulates the release of neurotransmitters known as catecholamines, such as epinephrine, and steroid hormones known as glucocorticoids, such as cortisol [496,497].
-While catecholamines are often associated with the fight-or-flight response, the specific role that glucocorticoids play is less clear, although they are thought to be important to restoring homeostasis [498].
+In response to stress, corticotropin‐releasing hormone stimulates the release of neurotransmitters known as catecholamines, such as epinephrine, and steroid hormones known as glucocorticoids, such as cortisol [497,498].
+While catecholamines are often associated with the fight-or-flight response, the specific role that glucocorticoids play is less clear, although they are thought to be important to restoring homeostasis [499].
Immune challenge is a stressor that is known to interact closely with the stress response.
-The immune system can therefore interact with the central nervous system; for example, macrophages can both respond to and produce catecholamines [496].
-Additionally, the production of both catecholamines and glucocorticoids is associated with inhibition of proinflammatory cytokines such as IL-6, IL-12, and tumor necrosis factor-α (TNF‐α) and the stimulation of anti-inflammatory cytokines such as IL-10, meaning that the stress response can regulate inflammatory immune activity [497].
-Administration of dexamethasone has been found to correspond to dose-dependent inhibition of IL-12 production, but not to affect IL-10 [499]; the fact that this relationship could be disrupted by administration of a glucocorticoid-receptor antagonist suggests that it is regulated by the receptor itself [499].
+The immune system can therefore interact with the central nervous system; for example, macrophages can both respond to and produce catecholamines [497].
+Additionally, the production of both catecholamines and glucocorticoids is associated with inhibition of proinflammatory cytokines such as IL-6, IL-12, and tumor necrosis factor-α (TNF‐α) and the stimulation of anti-inflammatory cytokines such as IL-10, meaning that the stress response can regulate inflammatory immune activity [498].
+Administration of dexamethasone has been found to correspond to dose-dependent inhibition of IL-12 production, but not to affect IL-10 [500]; the fact that this relationship could be disrupted by administration of a glucocorticoid-receptor antagonist suggests that it is regulated by the receptor itself [500].
Thus, the administration of dexamethasone for COVID-19 is likely to simulate the release of glucocorticoids endogenously during stress, resulting in binding of the synthetic steroid to the glucocorticoid receptor and the associated inhibition of the production of proinflammatory cytokines.
-In this model, dexamethasone reduces inflammation by stimulating the biological mechanism that reduces inflammation following a threat such as immune challenge.
-Immunosuppressive drugs such as steroids are typically contraindicated in the setting of infection [500], but because COVID-19 results in hyperinflammation that appears to contribute to mortality via lung damage, immunosuppression may be a helpful approach to treatment [127].
-The decision of whether and/or when to counter hyperinflammation with immunosuppression in the setting of COVID-19 was an area of intense debate, as the risks of inhibiting antiviral immunity needed to be weighed against the beneficial anti-inflammatory effects [501].
-As a result, guidelines early in the pandemic typically recommended avoiding treating COVID-19 patients with corticosteroids such as dexamethasone [493].
-The application of dexamethasone for the treatment of COVID-19 was evaluated as part of the multi-site RECOVERY trial in the United Kingdom [502].
+In this model, dexamethasone reduces inflammation by stimulating the biological mechanism that reduces inflammation following a threat such as immune challenge.
+Immunosuppressive drugs such as steroids are typically contraindicated in the setting of infection [501], but because COVID-19 results in hyperinflammation that appears to contribute to mortality via lung damage, immunosuppression may be a helpful approach to treatment [129].
+The decision of whether and/or when to counter hyperinflammation with immunosuppression in the setting of COVID-19 was an area of intense debate, as the risks of inhibiting antiviral immunity needed to be weighed against the beneficial anti-inflammatory effects [502].
+As a result, guidelines early in the pandemic typically recommended avoiding treating COVID-19 patients with corticosteroids such as dexamethasone [494].
+The application of dexamethasone for the treatment of COVID-19 was evaluated as part of the multi-site RECOVERY trial in the United Kingdom [503].
Over 6,000 hospitalized COVID-19 patients were assigned into the SOC or treatment (dexamethasone) arms of the trial with a 2:1 ratio.
At the time of randomization, some patients were ventilated (16%), others were on non-invasive oxygen (60%), and others were breathing independently (24%).
Patients in the treatment arm were administered dexamethasone either orally or intravenously at 6 mg per day for up to 10 days.
The primary end-point was the patient’s status at 28-days post-randomization (mortality, discharge, or continued hospitalization), and secondary outcomes analyzed included the progression to invasive mechanical ventilation over the same period.
The 28-day mortality rate was found to be lower in the treatment group than in the SOC group (21.6% vs 24.6%, p < 0.001).
However, this finding was driven by differences in mortality among patients who were receiving mechanical ventilation or supplementary oxygen at the start of the study.
-The report indicated that dexamethasone reduced 28-day mortality relative to SOC in patients who were ventilated (29.3% vs. 41.4%) and among those who were receiving oxygen supplementation (23.3% vs. 26.2%) at randomization, but not in patients who were breathing independently (17.8% vs. 14.0%).
+The report indicated that dexamethasone reduced 28-day mortality relative to SOC in patients who were ventilated (29.3% versus 41.4%) and among those who were receiving oxygen supplementation (23.3% versus 26.2%) at randomization, but not in patients who were breathing independently (17.8% versus 14.0%).
One possible confounder is that patients receiving mechanical ventilation tended to be younger than patients who were not receiving respiratory support (by 10 years on average) and to have had symptoms for a longer period.
However, adjusting for age did not change the conclusions, although the duration of symptoms was found to be significantly associated with the effect of dexamethasone administration.
These findings also suggested that dexamethasone may have reduced progression to mechanical ventilation, especially among patients who were receiving oxygen support at randomization.
Thus, this large, randomized, and multi-site, albeit not placebo-controlled, study suggests that administration of dexamethasone to patients who are unable to breathe independently may significantly improve survival outcomes.
Additionally, dexamethasone is a widely available and affordable medication, raising the hope that it could be made available to COVID-19 patients globally.
-The results of the RECOVERY trial’s analysis of dexamethasone suggest that this therapeutic is effective primarily in patients who had been experiencing symptoms for at least seven days and patients who were not breathing independently [503].
-A meta-analysis that evaluated the results of the RECOVERY trial alongside trials of other corticosteroids, such as hydrocortisone, similarly concluded that corticosteroids may be beneficial to patients with severe COVID-19 who are receiving oxygen supplementation [504].
-Thus, it seems likely that dexamethasone is useful for treating inflammation associated with immunopathy or cytokine release syndrome.
-In fact, corticosteroids such as dexamethasone are sometimes used to treat cytokine release syndrome (CRS) [505].
+
The results of the RECOVERY trial’s analysis of dexamethasone suggest that this therapeutic is effective primarily in patients who had been experiencing symptoms for at least seven days and patients who were not breathing independently [504].
+A meta-analysis that evaluated the results of the RECOVERY trial alongside trials of other corticosteroids, such as hydrocortisone, similarly concluded that corticosteroids may be beneficial to patients with severe COVID-19 who are receiving oxygen supplementation [505].
+Thus, it seems likely that dexamethasone is useful for treating inflammation associated with immunopathy or cytokine release syndrome (CRS).
+In fact, corticosteroids such as dexamethasone are sometimes used to treat CRS [506].
It is not surprising that administration of an immunosuppressant would be most beneficial when the immune system was dysregulated towards inflammation.
However, it is also unsurprising that care must be taken in administering an immunosuppressant to patients fighting a viral infection.
-In particular, the concern has been raised that treatment with dexamethasone might increase patient susceptibility to concurrent (e.g., nosocomial) infections [506].
-Additionally, the drug could potentially slow viral clearance and inhibit patients’ ability to develop antibodies to SARS-CoV-2 [493,506], and the lack of data about viral clearance has been put forward as a major limitation of the RECOVERY trial [507].
-Furthermore, dexamethasone has been associated with side effects that include psychosis, glucocorticoid-induced diabetes, and avascular necrosis [493], and the RECOVERY trial did not report outcomes with enough detail to be able to determine whether they observed similar complications.
-The effects of dexamethasone have also been found to differ among populations, especially in high-income versus middle- or low-income countries [508].
-However, since the RECOVERY trial’s results were released, strategies have been proposed for administering dexamethasone alongside more targeted treatments to minimize the likelihood of negative side effects [506].
+In particular, the concern has been raised that treatment with dexamethasone might increase patient susceptibility to concurrent (e.g., nosocomial) infections [507].
+Additionally, the drug could potentially slow viral clearance and inhibit patients’ ability to develop antibodies to SARS-CoV-2 [494,507], and the lack of data about viral clearance has been put forward as a major limitation of the RECOVERY trial [508].
+Furthermore, dexamethasone has been associated with side effects that include psychosis, glucocorticoid-induced diabetes, and avascular necrosis [494], and the RECOVERY trial did not report outcomes with enough detail to be able to determine whether they observed similar complications.
+The effects of dexamethasone have also been found to differ among populations, especially in high-income versus middle- or low-income countries [509].
+However, since the RECOVERY trial’s results were released, strategies have been proposed for administering dexamethasone alongside more targeted treatments to minimize the likelihood of negative side effects [507].
Given the available evidence, dexamethasone is currently the most promising treatment for severe COVID-19.
5.5 Biologics
Biologics are produced from components of living organisms or viruses.
-They include treatments such as humanized monoclonal antibodies (mAb) tocilizumab (TCZ), and neutralizing antibodies (nAbs), and can also include prophylactics such as vaccines.
-Historically produced from animal tissue, biologics have become increasingly feasible to produce as recombinant DNA technologies have advanced [509].
-Often, they are glycoproteins or peptides [510], but whole viruses can also be used therapeutically or prophylactically, not only for vaccines but also as vectors for gene therapy or therapeutic proteins or for oncolytic virotherapy [511].
-They are typically catabolized by the body to their amino acid components [510].
+They include treatments such as humanized monoclonal antibodies (mAb), tocilizumab (TCZ), and neutralizing antibodies (nAbs), and can also include prophylactics such as vaccines.
+Historically produced from animal tissue, biologics have become increasingly feasible to produce as recombinant DNA technologies have advanced [510].
+Often, they are glycoproteins or peptides [511], but whole viruses can also be used therapeutically or prophylactically, not only for vaccines but also as vectors for gene therapy or therapeutic proteins or for oncolytic virotherapy [512].
+They are typically catabolized by the body to their amino acid components [511].
There are many differences on the development side between biologics and synthesized pharmaceuticals, such as small molecule drugs.
-Biologics are typically orders of magnitude larger than small molecule drugs, and their physiochemical properties are often much less understood [510].
-They are often heat sensitive, and their toxicity can vary, as it is not directly associated with the primary effects of the drug [510].
+Biologics are typically orders of magnitude larger than small molecule drugs, and their physiochemical properties are often much less understood [511].
+They are often heat sensitive, and their toxicity can vary, as it is not directly associated with the primary effects of the drug [511].
However, this class includes some extremely significant medical breakthroughs, including insulin for the management of diabetes and the smallpox vaccine.
As a result, biologics are another possible avenue through which the pharmacological management of SARS-CoV-2 infection can be approached.
5.5.1 Tocilizumab
-TCZ is a receptor antibody that was developed to manage chronic inflammation caused by the continuous synthesis of the cytokine IL-6 [512].
+
TCZ is a receptor antibody that was developed to manage chronic inflammation caused by the continuous synthesis of the cytokine IL-6 [513].
IL-6 is a pro-inflammatory cytokine belonging to the interleukin family, which is comprised by immune system regulators that are primarily responsible for immune cell differentiation.
-Often used to treat conditions such as RA [512], TCZ has become a pharmaceutical of interest for the treatment of COVID-19 because of the role IL-6 plays in this disease.
-While secretion of IL-6 can be associated with chronic conditions, it is a key player in the innate immune response and is secreted by macrophages in response to the detection of pathogen-associated molecular patterns and damage-associated molecular patterns [512].
+Often used to treat conditions such as RA [513], TCZ has become a pharmaceutical of interest for the treatment of COVID-19 because of the role IL-6 plays in this disease.
+While secretion of IL-6 can be associated with chronic conditions, it is a key player in the innate immune response and is secreted by macrophages in response to the detection of pathogen-associated molecular patterns and damage-associated molecular patterns [513].
An analysis of 191 in-patients at two Wuhan hospitals revealed that blood concentrations of IL-6 differed between patients who did and did not recover from COVID-19.
-Patients who ultimately deceased had higher IL-6 levels at admission than those who recovered [35].
-Additionally, IL-6 levels remained higher throughout the course of hospitalization in the patients who ultimately deceased [35].
-This finding provided some early evidence that COVID-19 deaths may be induced by the hyperactive immune response, often referred to as CRS or cytokine storm syndrome (CSS), as IL-6 plays a key role in this response [114].
+Patients who ultimately deceased had higher IL-6 levels at admission than those who recovered [37].
+Additionally, IL-6 levels remained higher throughout the course of hospitalization in the patients who ultimately deceased [37].
+This finding provided some early evidence that COVID-19 deaths may be induced by the hyperactive immune response, often referred to as CRS or cytokine storm syndrome (CSS), as IL-6 plays a key role in this response [116].
In this context, the observation of elevated IL-6 in patients who died may reflect an over-production of proinflammatory interleukins, suggesting that TCZ could potentially palliate some of the most severe symptoms of COVID-19 associated with increased cytokine production.
Human IL-6 is a 26-kDa glycoprotein that consists of 184 amino acids and contains two potential N-glycosylation sites and four cysteine residues.
-It binds to a type I cytokine receptor (IL-6Rα or glycoprotein 80) that exists in both membrane-bound (IL-6Rα) and soluble (sIL-6Rα) forms [513].
-It is not the binding of IL-6 to the receptor that initiates pro- and/or anti-inflammatory signaling, but rather the binding of the complex to another subunit, known as IL-6Rβ or glycoprotein 130 (gp13) [513,514].
-Unlike membrane-bound IL-6Rα, which is only found on hepatocytes and some types of leukocytes, gp130 is found on most cells [515].
-When IL-6 binds to sIL-6Rα, the complex can then bind to a gp130 protein on any cell [515].
-The binding of IL-6 to IL-6Rα is termed classical signaling, while its binding to sIL-6Rα is termed trans-signaling [515,516,517].
+It binds to a type I cytokine receptor (IL-6Rα or glycoprotein 80) that exists in both membrane-bound (IL-6Rα) and soluble (sIL-6Rα) forms [514].
+It is not the binding of IL-6 to the receptor that initiates pro- and/or anti-inflammatory signaling, but rather the binding of the complex to another subunit, known as IL-6Rβ or glycoprotein 130 (gp13) [514,515].
+Unlike membrane-bound IL-6Rα, which is only found on hepatocytes and some types of leukocytes, gp130 is found on most cells [516].
+When IL-6 binds to sIL-6Rα, the complex can then bind to a gp130 protein on any cell [516].
+The binding of IL-6 to IL-6Rα is termed classical signaling, while its binding to sIL-6Rα is termed trans-signaling [516,517,518].
These two signaling processes are thought to play different roles in health and illness.
-For example, trans-signaling may play a role in the proliferation of mucosal T-helper TH2 cells associated with asthma, while an earlier step in this proliferation process may be regulated by classical signaling [515].
-Similarly, IL-6 is known to play a role in Crohn’s Disease via trans-, but not classical, signaling [515].
-Both classical and trans-signaling can occur through three independent pathways: the Janus-activated kinase-STAT3 pathway, the Ras/Mitogen-Activated Protein Kinases (MAPK) pathway and the Phosphoinositol-3 Kinase/Akt pathway [513].
-These signaling pathways are involved in a variety of different functions, including cell type differentiation, immunoglobulin synthesis, and cellular survival signaling pathways, respectively [513].
-The ultimate result of the IL-6 cascade is to direct transcriptional activity of various promoters of pro-inflammatory cytokines, such as IL-1, TFN, and even IL-6 itself, through the activity of NF-κB [513].
-IL-6 synthesis is tightly regulated both transcriptionally and post-transcriptionally, and it has been shown that viral proteins can enhance transcription of the IL-6 gene by strengthening the DNA-binding activity between several transcription factors and IL-6 gene-cis-regulatory elements [518].
+For example, trans-signaling may play a role in the proliferation of mucosal T-helper TH2 cells associated with asthma, while an earlier step in this proliferation process may be regulated by classical signaling [516].
+Similarly, IL-6 is known to play a role in Crohn’s Disease via trans-, but not classical, signaling [516].
+Both classical and trans-signaling can occur through three independent pathways: the Janus-activated kinase-STAT3 pathway, the Ras/Mitogen-Activated Protein Kinases (MAPK) pathway and the Phosphoinositol-3 Kinase/Akt pathway [514].
+These signaling pathways are involved in a variety of different functions, including cell type differentiation, immunoglobulin synthesis, and cellular survival signaling pathways, respectively [514].
+The ultimate result of the IL-6 cascade is to direct transcriptional activity of various promoters of pro-inflammatory cytokines, such as IL-1, TFN, and even IL-6 itself, through the activity of NF-κB [514].
+IL-6 synthesis is tightly regulated both transcriptionally and post-transcriptionally, and it has been shown that viral proteins can enhance transcription of the IL-6 gene by strengthening the DNA-binding activity between several transcription factors and IL-6 gene-cis-regulatory elements [519].
Therefore, drugs inhibiting the binding of IL-6 to IL-6Rα or sIL-6Rα are of interest for combating the hyperactive inflammatory response characteristic of CRS and CSS.
TCZ is a humanized monoclonal antibody that binds both to the insoluble and soluble receptor of IL-6, providing de facto inhibition of the IL-6 immune cascade.
Tocilizumab is being administered either as an intervention or as concomitant medication in 84 COVID-19 clinical trials (Figure 3).
No randomized, placebo-controlled studies of TCZ have currently released results.
Therefore, no conclusions can be drawn about its efficacy for the treatment of COVID-19.
-However, early interest in TCZ as a possible treatment for COVID-19 emerged from a very small retrospective study in China that examined 20 patients with severe symptoms in early February 2020 and reported rapid improvement in symptoms following treatment with TCZ [519].
+However, early interest in TCZ as a possible treatment for COVID-19 emerged from a very small retrospective study in China that examined 20 patients with severe symptoms in early February 2020 and reported rapid improvement in symptoms following treatment with TCZ [520].
Subsequently, a number of retrospective studies have been conducted in several countries.
Many studies use a retrospective, observational design, where they compare outcomes for COVID-19 patients who received TCZ to those who did not over a set period of time.
-For example, one of the largest retrospective, observational analysis released to date [520] compared the rates at which patients who received TCZ deceased or progressed to invasive medical ventilation over a 14-day period compared to patients receiving only SOC.
+For example, one of the largest retrospective, observational analysis released to date [521] compared the rates at which patients who received TCZ deceased or progressed to invasive medical ventilation over a 14-day period compared to patients receiving only SOC.
Under this definition, SOC could include other drugs such as HCQ, azithromycin, lopinavir-ritonavir or darunavir-cobicistat, or heparin.
While this study was not randomized, a subset of patients who were eligible to receive TCZ were unable to obtain it due to shortages; however, these groups were not directly compared in the analysis.
After adjusting for variables such as age, sex, and SOFA (sequential organ failure assessment) score, they found that patients treated with TCZ were less likely to progress to invasive medical ventilation and/or death (adjusted HR = 0.61, CI 0.40-0.92, p = 0.020), although analysis of death and ventilation separately suggests that this effect may have been driven by differences in the death rate (20% of control versus 7% of TCZ-treated patients).
They reported particular benefits for patients whose PaO2/FiO2 ratio, also known as the Horowitz Index for Lung Function, fell below a 150 mm Hg threshold.
They found no differences between groups administered subcutaneous versus intravenous TCZ.
-Another retrospective observational analysis of interest examined the charts of patients at a hospital in Connecticut, USA where 64% of all 239 COVID-19 patients in the study period were administered TCZ based on assignment by a standardized algorithm [521].
+
Another retrospective observational analysis of interest examined the charts of patients at a hospital in Connecticut, USA where 64% of all 239 COVID-19 patients in the study period were administered TCZ based on assignment by a standardized algorithm [522].
They found that TCZ administration was associated with more similar rates of survivorship in patients with severe versus nonsevere COVID-19 at intake, defined based on the amount of supplemental oxygen needed.
They therefore proposed that their algorithm was able to identify patients presenting with or likely to develop CRS as good candidates for TCZ.
This study also reported higher survivorship in Black and Hispanic patients compared to white patients when adjusted for age.
The major limitation with interpretation for these studies is that there may be clinical characteristics that influenced medical practitioners decisions to administer TCZ to some patients and not others.
-One interesting example therefore comes from an analysis of patients at a single hospital in Brescia, Italy, where TCZ was not available for a period of time [522].
+One interesting example therefore comes from an analysis of patients at a single hospital in Brescia, Italy, where TCZ was not available for a period of time [523].
This study compared COVID-19 patients admitted to the hospital before and after March 13, 2020, when the hospital received TCZ.
Therefore, patients who would have been eligible for TCZ prior to this arbitrary date did not receive it as treatment, making this retrospective analysis something of a natural experiment.
Despite this design, demographic factors did not appear to be consistent between the two groups, and the average age of the control group was older than the TCZ group.
@@ -2111,113 +2110,114 @@
5.5
However, this study also holds a significant limitation: the time delay between the two groups means that knowledge about how to treat the disease likely improved over this timeframe as well.
All the same, the results of these observational retrospective studies provide support for TCZ as a pharmaceutical of interest for follow-up in clinical trials.
In addition to the retrospective observational studies, other analysis have utilized a retrospective case-control design to match pairs of patients with similar baseline characteristics, only one of whom received TCZ for COVID-19.
-In one such study, TCZ was significantly associated with a reduced risk of progression to ICU admission or death [523].
+In one such study, TCZ was significantly associated with a reduced risk of progression to ICU admission or death [524].
This study examined only 20 patients treated with TCZ (all but one of the patients treated with TCZ in the hospital during the study period) and compared them to 25 patients receiving SOC.
For the combined primary endpoint of death and/or ICU admission, only 25% of patients receiving TCZ progressed to an endpoint compared to 72% in the SOC group (p = 0.002, presumably based on a chi-square test based on the information provided in the text).
When the two endpoints were examined separately, progression to invasive medical ventilation remained significant (32% SOC compared to 0% TCZ, p = 0.006) but not for mortality (48% SOC compared to 25% TCZ, p = 0.066).
-In contrast, a study that compared 96 patients treated with TCZ to 97 patients treated with SOC only in New York City found that differences in mortality did not differ between the two groups, but that this difference did become significant when intubated patients were excluded from the analysis [524].
+In contrast, a study that compared 96 patients treated with TCZ to 97 patients treated with SOC only in New York City found that differences in mortality did not differ between the two groups, but that this difference did become significant when intubated patients were excluded from the analysis [525].
Taken together, these findings suggest that future clinical trials of TCZ may want to include intubation as an endpoint.
However, these studies should be approached with caution, not only because of the small number of patients enrolled and the retrospective design, but also because they performed a large number of statistical tests and did not account for multiple hypothesis testing.
These last findings highlight the need to search for a balance between impairing a harmful immune response, such as the one generated during CRS and CSS, and preventing the worsening of the clinical picture of the patients by potential new viral infections.
Though data about TCZ for COVID-19 is still only just emerging, some meta-analyses and systematic reviews have investigated the available data.
-One meta-analysis [525] evaluated 19 studies published or released as preprints prior to July 1, 2020 and found that the overall trends were supportive of the frequent conclusion that TCZ does improve survivorship, with a significant HR of 0.41 (p < 0.001).
+One meta-analysis [526] evaluated 19 studies published or released as preprints prior to July 1, 2020 and found that the overall trends were supportive of the frequent conclusion that TCZ does improve survivorship, with a significant HR of 0.41 (p < 0.001).
This trend improved when they excluded studies that administered a steroid alongside TCZ, with a significant HR of 0.04 (p < 0.001).
They also found some evidence for reduced invasive ventilation or ICU admission, but only when excluding all studies except a small number whose estimates were adjusted for the possible bias introduced by the challenges of stringency during the enrollment process.
-A systematic analysis of sixteen case-control studies of TCZ estimated an odds ratio of 0.453 (95% CI 0.376–0.547, p < 0.001), suggesting possible benefits associated with TCZ treatment [526].
+A systematic analysis of sixteen case-control studies of TCZ estimated an odds ratio of 0.453 (95% CI 0.376–0.547, p < 0.001), suggesting possible benefits associated with TCZ treatment [527].
Although these estimates are similar, it is important to note that they are drawing from the same literature and are therefore likely to be affected by the same biases in publication.
-A second systematic review of studies investigating TCZ treatment for COVID-19 analyzed 31 studies that had been published or released as pre-prints and reported that none carried a low risk of bias (RoB) [527].
+A second systematic review of studies investigating TCZ treatment for COVID-19 analyzed 31 studies that had been published or released as pre-prints and reported that none carried a low risk of bias [528].
Therefore, the present evidence is not likely to be sufficient for conclusions about the efficacy of TCZ.
Additionally, there are possible risks associated with the administration of TCZ for COVID-19.
-TCZ has been used for over a decade to treat RA [528], and a recent study found the drug to be safe for pregnant and breastfeeding women [529].
-However, TCZ may increase the risk of developing infections [528], and RA patients with chronic hepatitis B infections had a high risk of hepatitis B virus reactivation when TCZ was administered in combination with other RA drugs [530].
-As a result, TCZ is contraindicated in patients with active infections such as tuberculosis [531].
-Previous studies have investigated, with varying results, a possible increased risk of infection in RA patients administered TCZ [532,533], although another study reported that the incidence rate of infections was higher in clinical practice RA patients treated with TCZ than in the rates reported by clinical trials [534].
-In the investigation of 544 Italian COVID-19 patients, the group treated with TCZ was found to be more likely to develop secondary infections, with 24% compared to 4% in the control group [520].
+TCZ has been used for over a decade to treat RA [529], and a recent study found the drug to be safe for pregnant and breastfeeding women [530].
+However, TCZ may increase the risk of developing infections [529], and RA patients with chronic hepatitis B infections had a high risk of hepatitis B virus reactivation when TCZ was administered in combination with other RA drugs [531].
+As a result, TCZ is contraindicated in patients with active infections such as tuberculosis [532].
+Previous studies have investigated, with varying results, a possible increased risk of infection in RA patients administered TCZ [533,534], although another study reported that the incidence rate of infections was higher in clinical practice RA patients treated with TCZ than in the rates reported by clinical trials [535].
+In the investigation of 544 Italian COVID-19 patients, the group treated with TCZ was found to be more likely to develop secondary infections, with 24% compared to 4% in the control group [521].
Reactivation of hepatitis B and herpes simplex virus 1 was also reported in a small number of patients in this study, all of whom were receiving TCZ.
-A July 2020 case report described negative outcomes of two COVID-19 patients after receiving TCZ, including one death; however, both patients were intubated and had entered septic shock prior to receiving TCZ [535], likely indicating a severe level of cytokine production.
-Additionally, D-dimer and sIL2R levels were reported by one study to increase in patients treated with TCZ, which raised concerns because of the potential association between elevated D-dimer levels and thrombosis and between sIL2R and diseases where T-cell regulation is compromised [521].
-An increased risk of bacterial infection was also identified in a systematic review of the literature, based on the unadjusted estimates reported [525].
-In summary, TCZ administration to COVID-19 patients is not without risks, may introduce additional risk of developing secondary infections, and should be approached especially cautiously for patients who have latent viral infections.
-In summary, approximately 25% of coronavirus patients develop ARDS, which is caused by an excessive early response of the immune system which can be a component of cytokine release syndrome [521] and cytokine storm syndrome [531].
+A July 2020 case report described negative outcomes of two COVID-19 patients after receiving TCZ, including one death; however, both patients were intubated and had entered septic shock prior to receiving TCZ [536], likely indicating a severe level of cytokine production.
+Additionally, D-dimer and sIL2R levels were reported by one study to increase in patients treated with TCZ, which raised concerns because of the potential association between elevated D-dimer levels and thrombosis and between sIL2R and diseases where T-cell regulation is compromised [522].
+An increased risk of bacterial infection was also identified in a systematic review of the literature, based on the unadjusted estimates reported [526].
+TCZ administration to COVID-19 patients is not without risks, may introduce additional risk of developing secondary infections, and should be approached especially cautiously for patients who have latent viral infections.
+In summary, approximately 25% of coronavirus patients develop ARDS, which is caused by an excessive early response of the immune system which can be a component of CRS [522] and CSS [532].
This overwhelming inflammation is triggered by IL-6.
TCZ is an inhibitor of IL-6 and therefore may neutralize the inflammatory pathway that leads to the cytokine storm.
While the mechanism suggests TCZ could be beneficial for the treatment of COVID-19 patients experiencing excessive immune activity, no randomized controlled trials are available assessing its effect.
However, small initial studies have found preliminary indications that TCZ may reduce progression to invasive medical ventilation and/or death.
It should be noted that SOC varied widely across retrospective studies, with one study administering HCQ, lopinavir-ritonavir, antibiotics, and/or heparin as part of SOC.
-Interest in TCZ as a treatment for COVID-19 was supported by two meta-analyses [525,536], but a third meta-analysis found that all of the available literature carries a risk of bias, with even the largest available TCZ studies to date carrying a moderate risk of bias under the ROBINS-I criteria [527].
-Additionally, different studies used different dosages, number of doses, and methods of administration; ongoing research may be needed to optimize administration of TCZ [537], although similar results were reported by one study for intravenous and subcutaneous administration [520].
+Interest in TCZ as a treatment for COVID-19 was supported by two meta-analyses [526,537], but a third meta-analysis found that all of the available literature carries a risk of bias, with even the largest available TCZ studies to date carrying a moderate risk of bias under the ROBINS-I criteria [528].
+Additionally, different studies used different dosages, number of doses, and methods of administration.
+Ongoing research may be needed to optimize administration of TCZ [538], although similar results were reported by one study for intravenous and subcutaneous administration [521].
Clinical trials that are in progress are likely to provide additional insight into the effectiveness of this drug for the treatment of COVID-19 along with how it should be administered.
5.5.2 Neutralizing Antibodies
Monoclonal antibodies have revolutionized the way we treat human diseases.
-They have become some of the best-selling drugs in the pharmaceutical market in recent years [538].
-There are currently 79 FDA approved mAbs on the market, including antibodies for viral infections (e.g. Ibalizumab for HIV and Palivizumab for RSV) [538,539].
-Virus-specific neutralizing antibodies commonly target viral surface glycoproteins or host structures, thereby inhibiting viral entry through receptor binding interference [540,541].
-This section discusses current efforts in developing neutralizing antibodies against SARS-CoV-2 and how expertise gained from previous approaches for MERS-CoV and SARS-CoV-1 may benefit antibody development.
+They have become some of the best-selling drugs in the pharmaceutical market in recent years [539].
+There are currently 79 FDA approved mAbs on the market, including antibodies for viral infections (e.g. Ibalizumab for HIV and Palivizumab for RSV) [539,540].
+Virus-specific nAbs commonly target viral surface glycoproteins or host structures, thereby inhibiting viral entry through receptor binding interference [541,542].
+This section discusses current efforts in developing nAbs against SARS-CoV-2 and how expertise gained from previous approaches for MERS-CoV and SARS-CoV-1 may benefit antibody development.
5.5.2.1 Spike (S) Neutralizing Antibody
-During the first SARS epidemic in 2002, nAbs were found in SARS-CoV-1-infected patients [542,543].
-Several studies following up on these findings identified various S-glycoprotein epitopes as the major targets of neutralizing antibodies against SARS-CoV-1 [544].
-The passive transfer of immune serum containing nAbs from SARS-CoV-1-infected mice resulted in protection of naïve mice from viral lower respiratory tract infection upon intranasal challenge [545].
-Similarly, a meta-analysis suggested that administration of plasma from recovered SARS-CoV-1 patients reduced mortality upon SARS-CoV-1 infection [546].
+
During the first SARS epidemic in 2002, nAbs were found in SARS-CoV-1-infected patients [543,544].
+Several studies following up on these findings identified various S-glycoprotein epitopes as the major targets of nAbs against SARS-CoV-1 [545].
+The passive transfer of immune serum containing nAbs from SARS-CoV-1-infected mice resulted in protection of naïve mice from viral lower respiratory tract infection upon intranasal challenge [546].
+Similarly, a meta-analysis suggested that administration of plasma from recovered SARS-CoV-1 patients reduced mortality upon SARS-CoV-1 infection [547].
Similar results were observed in MERS-CoV infection during the second coronavirus-related epidemic of the 21st century.
-In these cases, neutralizing antibodies were identified against various epitopes of the receptor binding domain (RBD) of the S glycoprotein [547,548].
-Coronaviruses use trimeric spike (S) glycoproteins on their surface to bind to the host cell, allowing for cell entry [64,67].
+In these cases, nAbs were identified against various epitopes of the receptor binding domain (RBD) of the S glycoprotein [548,549].
+Coronaviruses use trimeric spike (S) glycoproteins on their surface to bind to the host cell, allowing for cell entry [66,69].
Each S glycoprotein protomer is comprised of an S1 domain, also called the RBD, and an S2 domain.
-The S1 domain binds to the host cell while the S2 domain facilitates the fusion between the viral envelope and host cell membranes [544].
-Although targeting of the host cell enzyme ACE2 shows efficacy in inhibiting SARS-CoV-2 infection [75], given the physiological relevance of ACE2 [549], it would be favorable to target virus-specific structures rather than host receptors.
-This concern underlies the rationale for developing neutralizing antibodies against the S glycoprotein, disrupting its interaction with ACE2 and other potential entry points and thereby inhibiting viral entry.
-The first human neutralizing antibody against SARS-CoV-2 targeting the S glycoproteins was developed using hybridoma technology [550], where antibody-producing B-cells developed by mice can be inserted into myeloma cells to produce a hybrid cell line (the hybridoma) that is grown in culture.
+The S1 domain binds to the host cell while the S2 domain facilitates the fusion between the viral envelope and host cell membranes [545].
+Although targeting of the host cell enzyme ACE2 shows efficacy in inhibiting SARS-CoV-2 infection [77], given the physiological relevance of ACE2 [550], it would be favorable to target virus-specific structures rather than host receptors.
+This concern underlies the rationale for developing nAbs against the S glycoprotein, disrupting its interaction with ACE2 and other potential entry points and thereby inhibiting viral entry.
+The first human nAb against SARS-CoV-2 targeting the S glycoproteins was developed using hybridoma technology [551], where antibody-producing B-cells developed by mice can be inserted into myeloma cells to produce a hybrid cell line (the hybridoma) that is grown in culture.
The 47D11 clone was able to cross-neutralize SARS-CoV-1 and SARS-CoV-2 by a mechanism that is different from receptor binding interference.
-The exact mechanism of how this clone neutralizes SARS-CoV-2 and inhibits infection in vitro remains unknown, but a potential mechanism might be antibody-induced destabilization of the membrane prefusion structure [550,551].
-The ability of this antibody to prevent infection at a feasible dose needs to be validated in vivo, especially since in vitro neutralization effects have been shown to not be reflective of in vivo efficacy [552].
-Only a week later, a different group successfully isolated multiple nAbs targeting the RBD of the S glycoprotein from blood samples taken from COVID-19 patients in China [154].
+The exact mechanism of how this clone neutralizes SARS-CoV-2 and inhibits infection in vitro remains unknown, but a potential mechanism might be antibody-induced destabilization of the membrane prefusion structure [551,552].
+The ability of this antibody to prevent infection at a feasible dose needs to be validated in vivo, especially since in vitro neutralization effects have been shown to not be reflective of in vivo efficacy [553].
+Only a week later, a different group successfully isolated multiple nAbs targeting the RBD of the S glycoprotein from blood samples taken from COVID-19 patients in China [156].
Interestingly, the patient-isolated antibodies did not cross-react with RBDs from SARS-CoV-1 and MERS-CoV, although cross-reactivity to the trimeric spike proteins of SARS-CoV-1 and MERS-CoV was observed.
This finding suggests that the RBDs between the three coronavirus species are immunologically distinct and that the isolated nAbs targeting the RBD of SARS-CoV-2 are species specific.
While this specificity is desirable, it also raises the question of whether these antibodies are more susceptible to viral escape mechanisms.
-Viral escape is a common resistance mechanism to nAb therapy due to selective pressure from neutralizing antibodies [553,554].
-For HIV, broadly neutralizing antibodies (bnAbs) targeting the CD4 binding site (CD4bs) show greater neutralization breadth than monoclonal antibodies, which target only specific HIV strains [555].
-For MERS-CoV, a combination of multiple neutralizing antibodies targeting different antigenic sites prevented neutralization escape [556].
-It was found that the different antibody isolates did not target the same epitopes, suggesting that using them in combination might produce a synergistic effect that prevents viral escape [154].
+Viral escape is a common resistance mechanism to nAb therapy due to selective pressure from nAbs [554,555].
+For HIV, broadly neutralizing antibodies (bnAbs) targeting the CD4 binding site (CD4bs) show greater neutralization breadth than monoclonal antibodies, which target only specific HIV strains [556].
+For MERS-CoV, a combination of multiple nAbs targeting different antigenic sites prevented neutralization escape [557].
+It was found that the different antibody isolates did not target the same epitopes, suggesting that using them in combination might produce a synergistic effect that prevents viral escape [156].
It was also demonstrated that binding affinity of the antibodies does not reflect their capability to compete with ACE2 binding.
-Furthermore, no conclusions about correlations between the severity of disease and the ability to produce neutralizing antibodies can be drawn at this point.
-Rather, higher neutralizing antibody titers were more frequently found in patients with severe disease.
-Correspondingly, higher levels of anti-spike IgG were observed in patients that deceased from infection compared to patient that recovered [557].
-Results from the SARS and MERS epidemics thus provide valuable lessons for the design of neutralizing antibodies for the current outbreak.
+Furthermore, no conclusions about correlations between the severity of disease and the ability to produce nAbs can be drawn at this point.
+Rather, higher nAb titers were more frequently found in patients with severe disease.
+Correspondingly, higher levels of anti-spike IgG were observed in patients that deceased from infection compared to patient that recovered [558].
+Results from the SARS and MERS epidemics thus provide valuable lessons for the design of nAbs for the current outbreak.
The findings for SARS-CoV-1 and MERS-CoV can aid in identifying which structures constitute suitable targets for nAbs, despite the fact that the RBD appears to be distinct between the three coronavirus species.
-These studies also suggest that a combination of nAbs targeting distinct antigens might be necessary to provide protection [556].
+These studies also suggest that a combination of nAbs targeting distinct antigens might be necessary to provide protection [557].
The biggest challenge remains identifying antibodies that not only bind to their target, but also prove to be beneficial for disease management.
-On that note, a recently published study indicates that anti-spike antibodies could make the disease worse rather than eliminating the virus [557].
+On that note, a recently published study indicates that anti-spike antibodies could make the disease worse rather than eliminating the virus [558].
These findings underscores our current lack of understanding the full immune response to SARS-CoV-2.
5.5.3 Interferons
IFNs are a family of cytokines critical to activating the innate immune response against viral infections.
-Interferons are classified into three categories based on their receptor specificity: types I, II and III [114].
-Specifically, IFNs I (IFN-𝛼 and 𝛽) and II (IFN-𝛾) induce the expression of antiviral proteins [558].
-Among these IFNs, IFN-𝛽 has already been found to strongly inhibit the replication of other coronaviruses, such as SARS-CoV-1, in cell culture, while IFN-𝛼 and 𝛾 were shown to be less effective in this context [558].
+Interferons are classified into three categories based on their receptor specificity: types I, II and III [116].
+Specifically, IFNs I (IFN-𝛼 and 𝛽) and II (IFN-𝛾) induce the expression of antiviral proteins [559].
+Among these IFNs, IFN-𝛽 has already been found to strongly inhibit the replication of other coronaviruses, such as SARS-CoV-1, in cell culture, while IFN-𝛼 and 𝛾 were shown to be less effective in this context [559].
There is evidence that patients with higher susceptibility to ARDS indeed show deficiency in IFN-𝛽.
-For instance, infection with other coronaviruses impairs IFN-𝛽 expression and synthesis, allowing the virus to escape the innate immune response [559].
-On March 18 2020, Synairgen plc received approval to start a phase II trial for SNG001, an IFN-𝛽-1a formulation to be delivered to the lungs via inhalation [560].
-SNG001, which contains recombinant interferon beta-1a, was previously shown to be effective in reducing viral load in an in vivo model of swine flu and in vitro models of other coronavirus infections [561].
-In July, a press release from Synairgen stated that SNG001 reduced progression to ventilation in a double-blind, placebo-controlled, multi-center study of 101 patients with an average age in the late 50s [562].
-These results were subsequently published in November 2020 [563].
+For instance, infection with other coronaviruses impairs IFN-𝛽 expression and synthesis, allowing the virus to escape the innate immune response [560].
+On March 18 2020, Synairgen plc received approval to start a phase II trial for SNG001, an IFN-𝛽-1a formulation to be delivered to the lungs via inhalation [561].
+SNG001, which contains recombinant interferon beta-1a, was previously shown to be effective in reducing viral load in an in vivo model of swine flu and in vitro models of other coronavirus infections [562].
+In July, a press release from Synairgen stated that SNG001 reduced progression to ventilation in a double-blind, placebo-controlled, multi-center study of 101 patients with an average age in the late 50s [563].
+These results were subsequently published in November 2020 [564].
The study reports that the participants were assigned at a ratio of 1:1 to receive either SNG001 or a placebo that lacked the active compound, by inhalation for up to 14 days.
The primary outcome they assessed was the change in patients’ score on the WHO Ordinal Scale for Clinical Improvement (OSCI) at trial day 15 or 16.
SNG001 was associated with an odds ratio (OR) of 2.32 (95% CI 1.07 – 5.04, p = 0.033) in the intention-to-treat analysis and 2.80 (95% CI 1.21 – 6.52, p = 0.017) in the per-protocol analysis, corresponding to significant improvement in the SNG001 group on the OSCI at day 15/16.
Some of the secondary endpoints analyzed also showed differences: at day 28, the OR for clinical improvement on the OSCI was 3.15 (95% CI 1.39 – 7.14, p = 0.006), and the odds of recovery at day 15/16 and at day 28 were also significant between the two groups.
Thus, this study suggested that IFN-𝛽1 administered via SNG001 may improve clinical outcomes.
-In contrast, the WHO Solidarity trial reported no significant effect of IFN-𝛽1a on patient survival during hospitalization [390].
-Here, the primary outcome analyzed was in-hospital mortality, and the rate ratio for the two groups was 1.16 (95% CI, 0.96 to 1.39; p = 0.11) administering IFN-𝛽-1a to 2050 patients and comparing their response to 2050 controls..
+
In contrast, the WHO Solidarity trial reported no significant effect of IFN-𝛽1a on patient survival during hospitalization [391].
+Here, the primary outcome analyzed was in-hospital mortality, and the rate ratio for the two groups was 1.16 (95% CI, 0.96 to 1.39; p = 0.11) administering IFN-𝛽-1a to 2050 patients and comparing their response to 2,050 controls.
However, there are a few reasons that the different findings of the two trials might not speak to the underlying efficacy of this treatment strategy.
One important consideration is the stage of COVID-19 infection analyzed in each study.
-The Synairgen trial enrolled only patients who were not receiving invasive ventilation, corresponding to a less severe stage of disease than many patients enrolled in the SOLIDARITY trial, as well as a lower overall rate of mortality [564].
-Additionally, the methods of administration differed between the two trials, with the SOLIDARITY trial administering IFN-𝛽-1a subcutaneously [564].
+The Synairgen trial enrolled only patients who were not receiving invasive ventilation, corresponding to a less severe stage of disease than many patients enrolled in the SOLIDARITY trial, as well as a lower overall rate of mortality [565].
+Additionally, the methods of administration differed between the two trials, with the SOLIDARITY trial administering IFN-𝛽-1a subcutaneously [565].
The differences in findings between the studies suggests that the method of administration might be relevant to outcomes, with nebulized IFN-𝛽-1a more directly targeting receptors in the lungs.
-A trial that analyzed the effect of subcutaneously administered IFN-β-1a on patients with ARDS between 2015 and 2017 had also reported no effect on 28-day mortality [565], while a smaller study analyzing the effect of subcutaneous IFN administration did find a significant improvement in 28-day mortality for COVID-19 [566].
-At present, several ongoing clinical trials are investigating the potential effects of IFN-𝛽-1a, including in combination with therapeutics such as remdesivir [567] and administered via inhalation [560].
+A trial that analyzed the effect of subcutaneously administered IFN-β-1a on patients with ARDS between 2015 and 2017 had also reported no effect on 28-day mortality [566], while a smaller study analyzing the effect of subcutaneous IFN administration did find a significant improvement in 28-day mortality for COVID-19 [567].
+At present, several ongoing clinical trials are investigating the potential effects of IFN-𝛽-1a, including in combination with therapeutics such as remdesivir [568] and administered via inhalation [561].
Thus, as additional information becomes available, a more detailed understanding of whether and under which circumstances IFN-𝛽-1a is beneficial to COVID-19 patients should develop.
5.6 Discussion
-With the emergence of the COVID-19 pandemic caused by the coronavirus SARS-CoV-2, the development and/or identification of therapeutic and prophylactic interventions became an issue of international urgency.
+
With the emergence of the COVID-19 pandemic caused by the coronavirus SARS-CoV-2, the development and identification of therapeutic and prophylactic interventions became issues of international urgency.
In previous outbreaks of HCoV, namely SARS and MERS, the development of these interventions was very limited.
-As research has progressed, several potential approaches to treatment have emerged (Figure 4)..
+As research has progressed, several potential approaches to treatment have emerged (Figure 4).
Most notably, remdesivir has been approved by the FDA for the treatment of COVID-19, and dexamethasone, which was approved by the FDA in 1958, has been found to improve outcomes for patients with severe COVID-19.
Other potential therapies are being still being explored and require additional data (Figure 3).
As more evidence becomes available, the potential for existing and novel therapies to improve outcomes for COVID-19 patients will become better understood.
@@ -2228,12 +2228,12 @@ 5.6
-Insights into the pathogenesis of and immune response to SARS-CoV-2 (see [367]) have also guided the identification of potential prophylactics and therapeutics.
+
Insights into the pathogenesis of and immune response to SARS-CoV-2 (see [1]) have also guided the identification of potential prophylactics and therapeutics.
As cases have become better characterized, it has become evident that many patients experience an initial immune response to the virus that is typically characterized by fever, cough, dyspnea, and related symptoms.
-However, the most serious concern is cytokine release syndrome, when the body’s immune response becomes dysregulated, resulting in an extreme inflammatory response.
-The RECOVERY trial, a large-scale, multi-arm trial enrolling about 15% of all COVID-19 patients in the United Kingdom, was the first to identify that the widely available steroid dexamethasone seems to be beneficial for patients suffering from this immune dysregulation [502].
+However, the most serious concern is CRS, when the body’s immune response becomes dysregulated, resulting in an extreme inflammatory response.
+The RECOVERY trial, a large-scale, multi-arm trial enrolling about 15% of all COVID-19 patients in the United Kingdom, was the first to identify that the widely available steroid dexamethasone seems to be beneficial for patients suffering from this immune dysregulation [503].
The results of efforts to identify therapeutic treatments to treat patients early in the course of infection have been more ambiguous.
-Early interest in the drugs hydroxychloroquine and chloroquine yielded no promising results from studies with robust experimental designs.
+Early interest in the drugs HCQ and CQ yielded no promising results from studies with robust experimental designs.
On the other hand, the experimental drug remdesivir, which was developed as a candidate therapeutic for EVD, has received enough support from early analyses to receive FDA approval, although results have been mixed.
The potential for other drugs, such as tocilizumab, to reduce recovery time remains unclear, but some early results were promising.
One additional concern is that the presentation of COVID-19 appears to be heterogeneous across the lifespan.
@@ -2245,33 +2245,33 @@
[568]
.
-Several other anti-inflammatory agents used for the treatment of autoimmune diseases may also be able to counter the effects of the cytokine storm induced by the virus, and some of these, such as cyclosporine, are likely to be more cost-effective and readily available than biologics [569].
+At the doses used for RA patients, the cost for tocilizumab ranges from $179.20 to $896 per dose for the IV form and $355 for the pre-filled syringe [569].
+Several other anti-inflammatory agents used for the treatment of autoimmune diseases may also be able to counter the effects of the cytokine storm induced by the virus, and some of these, such as cyclosporine, are likely to be more cost-effective and readily available than biologics [570].
While tocilizumab targets IL-6, several other inflammatory markers could be potential targets, including TNF-α.
-Inhibition of TNF-α by a compound such as Etanercept was previously suggested for treatment of SARS-CoV-1 [570] and may be relevant for SARS-CoV-2 as well.
-Another anti-IL-6 antibody, sarilumab, is also being investigated [571,572].
-Baricitinib and other small molecule inhibitors of the Janus-activated kinase pathway also curtail the inflammatory response and have been suggested as potential options for SARS-CoV-2 infections [573].
-Baricitinib, in particular, may be able to reduce the ability of SARS-CoV-2 to infect lung cells [574].
-Clinical trials studying baricitinib in COVID-19 have already begun in the US and in Italy [575,576].
+Inhibition of TNF-α by a compound such as Etanercept was previously suggested for treatment of SARS-CoV-1 [571] and may be relevant for SARS-CoV-2 as well.
+Another anti-IL-6 antibody, sarilumab, is also being investigated [572,573].
+Baricitinib and other small molecule inhibitors of the Janus-activated kinase pathway also curtail the inflammatory response and have been suggested as potential options for SARS-CoV-2 infections [574].
+Baricitinib, in particular, may be able to reduce the ability of SARS-CoV-2 to infect lung cells [575].
+Clinical trials studying baricitinib in COVID-19 have already begun in the US and in Italy [576,577].
Identification and targeting of further inflammatory markers that are relevant in SARS-CoV-2 infection may be of value for curtailing the inflammatory response and lung damage.
In addition to immunosuppressive treatments, which are most beneficial late in disease progression, much research is focused on identifying therapeutics for early-stage patients.
-For example, although studies of hydroxychloroquine have not supported the early theory-driven interest in this antiviral treatment, alternative compounds with related mechanisms may still have potential.
-Hydroxyferroquine derivatives of HCQ have been described as a class of bioorganometallic compounds that exert antiviral effects with some selectivity for SARS-CoV-1 in vitro [577].
+For example, although studies of HCQ have not supported the early theory-driven interest in this antiviral treatment, alternative compounds with related mechanisms may still have potential.
+Hydroxyferroquine derivatives of HCQ have been described as a class of bioorganometallic compounds that exert antiviral effects with some selectivity for SARS-CoV-1 in vitro [578].
Future work could explore whether such compounds exert antiviral effects against SARS-CoV-2 and whether they would be safer for use in COVID-19.
Another potential approach is the development of antivirals, which could be broad-spectrum, specific to coronaviruses, or targeted to SARS-CoV-2.
Development of new antivirals is complicated by the fact that none have yet been approved for human coronaviruses.
Intriguing new options are emerging, however.
-Beta-D-N4-hydroxycytidine (NHC) is an orally bioavailable ribonucleotide analog showing broad-spectrum activity against RNA viruses, which may inhibit SARS-CoV-2 replication in vitro and in vivo in mouse models of HCoVs [578].
+Beta-D-N4-hydroxycytidine (NHC) is an orally bioavailable ribonucleotide analog showing broad-spectrum activity against RNA viruses, which may inhibit SARS-CoV-2 replication in vitro and in vivo in mouse models of HCoVs [579].
A range of other antivirals are also in development.
Development of antivirals will be further facilitated as research reveals more information about the interaction of SARS-CoV-2 with the host cell and host cell genome, mechanisms of viral replication, mechanisms of viral assembly, and mechanisms of viral release to other cells; this can allow researchers to target specific stages and structures of the viral life cycle.
Finally, antibodies against viruses, also known as antiviral monoclonal antibodies, could be an alternative as well and are described in detail in an above section.
-The goal of antiviral antibodies is to neutralize viruses through either cell-killing activity or blocking of viral replication [579].
+The goal of antiviral antibodies is to neutralize viruses through either cell-killing activity or blocking of viral replication [580].
They may also engage the host immune response, encouraging the immune system to hone in on the virus.
-Given the cytokine storm that results from immune system activation in response to the virus, which has been implicated in worsening of the disease, a neutralizing antibody (nAb) may be preferable.
+Given the cytokine storm that results from immune system activation in response to the virus, which has been implicated in worsening of the disease, an nAb may be preferable.
Upcoming work may explore the specificity of nAbs for their target, mechanisms by which the nAbs impede the virus, and improvements to antibody structure that may enhance the ability of the antibody to block viral activity.
Some research is also investigating potential therapeutics and prophylactics that would interact with components of the innate immune response.
-For example, TLRs are PRRs that recognize pathogen- and damage-associated molecular patterns and contribute to innate immune recognition and, more generally, promotion of both the innate and adaptive immune responses [110].
-In mouse models, poly(I:C) and CpG, which are agonists of Toll-like receptors TLR3 and TLR9, respectively, showed protective effects when administered prior to SARS-CoV-1 infection [580].
+For example, TLRs are pattern recognition receptors that recognize pathogen- and damage-associated molecular patterns and contribute to innate immune recognition and, more generally, promotion of both the innate and adaptive immune responses [112].
+In mouse models, poly(I:C) and CpG, which are agonists of Toll-like receptors TLR3 and TLR9, respectively, showed protective effects when administered prior to SARS-CoV-1 infection [581].
Therefore, TLR agonists hold some potential for broad-spectrum prophylaxis.
Given that a large number of clinical trials are currently in progress, more information about the potential of these and other therapeutics should become available over time.
This information, combined with advances in understanding the molecular structure and viral pathogenesis of SARS-CoV-2, may lead to a more complete understanding of how the virus affects the human host and what strategies can improve outcomes.
@@ -2280,11 +2280,12 @@
[424,581]
, and efforts are already in place to perform screens for small molecule inhibitors of the main protease, which have yielded potential hits [424].
+Currently, crystal structures of the SARS-CoV-2 main protease have recently been resolved [425,582], and efforts are already in place to perform screens for small molecule inhibitors of the main protease, which have yielded potential hits [425].
Much work remains to be done to determine further crystal structures of other viral components, understand the relative utility of targeting different viral components, perform additional small molecule inhibitor screens, and determine the safety and efficacy of the potential inhibitors.
While still nascent, work in this area is promising.
-Over the longer term, this approach and others may lead to the development of novel therapeutics specifically for COVID-19 and SARS-CoV-2.
-5.6.2 Conclusions of the Present Analysis
+Over the longer term, this approach and others may lead to the development of novel therapeutics specifically for COVID-19 and SARS-CoV-2.
+
+5.6.2 Conclusions
Due to the large number of clinical trials currently under examination (Figure 3), not all candidates are examined here.
Instead, this review seeks to provide an overview of the range of mechanisms that have been explored and to examine some prominent candidates in the context of the pathogenesis of and immune response to SARS-CoV-2.
As more research becomes available, this review will be updated to include additional therapeutics that emerge and to include new findings that are released about those discussed here.
@@ -2315,140 +2316,140 @@
6.
This rapid effort led to the identification of some promising pharmaceutical therapies for hospitalized patients, such as remdesivir and dexamethasone.
Furthermore, most societies have adopted non-pharmacological preventative measures such as utilizing public health strategies that reduce the transmission of SARS-CoV-2.
However, during this time, many individuals sought additional protections via the consumption of various dietary supplements and nutraceuticals that they believed to confer beneficial effects.
-While a patient’s nutritional status does seem to play a role in COVID-19 susceptibility and outcomes [582,583,584,585,586], the beginning of the pandemic saw sales of vitamins and other supplements to soar despite a lack of any evidence supporting their use against COVID-19.
-In the United States, for example, dietary supplement and nutraceutical sales have shown modest annual growth in recent years (approximately 5%, or a $345 million increase in 2019), but during the six-week period preceding April 5, 2020, they increased by 44% ($435 million) relative to the same period in 2019 [587].
-While growth subsequently leveled off, sales continued to boom, with a further 16% ($151 million) increase during the six weeks preceding May 17, 2020 relative to 2019 [587].
-In France, New Zealand, India, and China, similar trends in sales were reported [588,589,590,591].
-The increase in sales was driven by a consumer perception that dietary supplements and nutraceuticals would protect consumers from infection and/or mitigate the impact of infection due to the various “immune-boosting” claims of these products [592,593].
+While a patient’s nutritional status does seem to play a role in COVID-19 susceptibility and outcomes [583,584,585,586,587], the beginning of the pandemic saw sales of vitamins and other supplements to soar despite a lack of any evidence supporting their use against COVID-19.
+In the United States, for example, dietary supplement and nutraceutical sales have shown modest annual growth in recent years (approximately 5%, or a $345 million increase in 2019), but during the six-week period preceding April 5, 2020, they increased by 44% ($435 million) relative to the same period in 2019 [588].
+While growth subsequently leveled off, sales continued to boom, with a further 16% ($151 million) increase during the six weeks preceding May 17, 2020 relative to 2019 [588].
+In France, New Zealand, India, and China, similar trends in sales were reported [589,590,591,592].
+The increase in sales was driven by a consumer perception that dietary supplements and nutraceuticals would protect consumers from infection and/or mitigate the impact of infection due to the various “immune-boosting” claims of these products [593,594].
Due to the significant interest from the general public in dietary additives, whether and to what extent nutraceuticals or dietary supplements can provide any prophylactic or therapeutic benefit remains a topic of interest for the scientific community.
Nutraceuticals and dietary supplements are related but distinct non-pharmaceutical products.
-Nutraceuticals are classified as supplements with health benefits beyond their basic nutritional value [594,595].
-The key difference between a dietary supplement and a nutraceutical is that nutraceuticals should not only supplement the diet, but also aid in the prophylaxis and/or treatment of a disorder or disease [596].
+Nutraceuticals are classified as supplements with health benefits beyond their basic nutritional value [595,596].
+The key difference between a dietary supplement and a nutraceutical is that nutraceuticals should not only supplement the diet, but also aid in the prophylaxis and/or treatment of a disorder or disease [597].
However, dietary supplements and nutraceuticals, unlike pharmaceuticals, are not subject to the same regulatory protocols that protect consumers of medicines.
-Indeed, nutraceuticals do not entirely fall under the responsibility of the Food and Drug Administration (FDA), but they are monitored as dietary supplements according to the Dietary Supplement, Health and Education Act 1994 (DSHEA) [597] and the Food and Drug Administration Modernization Act 1997 (FDAMA) [598].
+Indeed, nutraceuticals do not entirely fall under the responsibility of the Food and Drug Administration (FDA), but they are monitored as dietary supplements according to the Dietary Supplement, Health and Education Act 1994 (DSHEA) [598] and the Food and Drug Administration Modernization Act 1997 (FDAMA) [599].
Due to increases in sales of dietary supplements and nutraceuticals, in 1996 the FDA established the Office of Dietary Supplement Programs (ODSP) to increase surveillance.
Novel products or nutraceuticals must now submit a new dietary ingredient notification to the ODSP for review.
-There are significant concerns that these legislations do not adequately protect the consumer as they ascribe responsibility to the manufacturers to ensure the safety of the product before manufacturing or marketing [599].
+There are significant concerns that these legislations do not adequately protect the consumer as they ascribe responsibility to the manufacturers to ensure the safety of the product before manufacturing or marketing [600].
Manufacturers are not required to register or even seek approval from the FDA to produce or sell food supplements or nutraceuticals.
-Health or nutrient content claims for labeling purposes are approved based on an authoritative statement from the Academy of Sciences or relevant federal authorities once the FDA has been notified and on the basis that the information is known to be true and not deceptive [599].
+Health or nutrient content claims for labeling purposes are approved based on an authoritative statement from the Academy of Sciences or relevant federal authorities once the FDA has been notified and on the basis that the information is known to be true and not deceptive [600].
Therefore, there is often a gap between perceptions by the American public about a nutraceutical or dietary supplement and the actual clinical evidence surrounding its effects.
Despite differences in regulations, similar challenges exist outside of the United States.
-In Europe, where the safety of supplements are monitored by the European Union (EU) under Directive 2002/46/EC [600].
+In Europe, where the safety of supplements are monitored by the European Union (EU) under Directive 2002/46/EC [601].
However, nutraceuticals are not directly mentioned.
-Consequently, nutraceuticals can be generally described as either a medicinal product under Directive 2004/27/EC [601] or as a ‘foodstuff’ under Directive 2002/46/EC of the European council.
+Consequently, nutraceuticals can be generally described as either a medicinal product under Directive 2004/27/EC [602] or as a ‘foodstuff’ under Directive 2002/46/EC of the European council.
In order to synchronize the various existing legislations, Regulation EC 1924/2006 on nutrition and health claims was put into effect to assure customers of safety and efficacy of products and to deliver understandable information to consumers.
However, specific legislation for nutraceuticals is still elusive.
-Health claims are permitted on a product label only following compliance and authorization according to the European Food Safety Authority (EFSA) guidelines on nutrition and health claims [602].
-EFSA does not currently distinguish between food supplements and nutraceuticals for health claim applications of new products, as claim authorization is dependent on the availability of clinical data in order to substantiate efficacy [603].
-These guidelines seem to provide more protection to consumers than the FDA regulations but potentially at the cost of innovation in the sector [604].
-The situation becomes even more complicated when comparing regulations at a global level, as countries such as China and India have existing regulatory frameworks for traditional medicines and phytomedicines not commonly consumed in Western society [605].
-Currently, there is debate among scientists and regulatory authorities surrounding the development of a widespread regulatory framework to deal with the challenges of safety and health claim substantiation for nutraceuticals [599,603], as these products do not necessarily follow the same rigorous clinical trial frameworks used to approve the use of pharmaceuticals.
+Health claims are permitted on a product label only following compliance and authorization according to the European Food Safety Authority (EFSA) guidelines on nutrition and health claims [603].
+EFSA does not currently distinguish between food supplements and nutraceuticals for health claim applications of new products, as claim authorization is dependent on the availability of clinical data in order to substantiate efficacy [604].
+These guidelines seem to provide more protection to consumers than the FDA regulations but potentially at the cost of innovation in the sector [605].
+The situation becomes even more complicated when comparing regulations at a global level, as countries such as China and India have existing regulatory frameworks for traditional medicines and phytomedicines not commonly consumed in Western society [606].
+Currently, there is debate among scientists and regulatory authorities surrounding the development of a widespread regulatory framework to deal with the challenges of safety and health claim substantiation for nutraceuticals [600,604], as these products do not necessarily follow the same rigorous clinical trial frameworks used to approve the use of pharmaceuticals.
Such regulatory disparities have been highlighted by the pandemic, as many individuals and companies have attempted to profit from the vulnerabilities of others by overstating claims in relation to the treatment of COVID-19 using supplements and nutraceuticals.
-The FDA has written several letters to prevent companies marketing or selling products based on false hyperbolic promises about preventing SARS-CoV-2 infection or treating COVID-19 [606,607,608].
-These letters came in response to efforts to market nutraceutical prophylactics against COVID-19, some of which charged the consumer as much as $23,000 [609].
-There have even been some incidents highlighted in the media because of their potentially life threatening consequences; for example, the use of oleandrin was touted as a potential “cure” by individuals close to the former President of the United States despite its high toxicity [610].
+The FDA has written several letters to prevent companies marketing or selling products based on false hyperbolic promises about preventing SARS-CoV-2 infection or treating COVID-19 [607,608,609].
+These letters came in response to efforts to market nutraceutical prophylactics against COVID-19, some of which charged the consumer as much as $23,000 [610].
+There have even been some incidents highlighted in the media because of their potentially life threatening consequences; for example, the use of oleandrin was touted as a potential “cure” by individuals close to the former President of the United States despite its high toxicity [611].
Thus, heterogeneous and at times relaxed regulatory standards have permitted high-profile cases of the sale of nutraceuticals and dietary supplements that are purported to provide protection against COVID-19, despite a lack of research into these compounds.
Notwithstanding the issues of poor safety, efficacy, and regulatory oversight, some dietary supplements and nutraceuticals have exhibited therapeutic and prophylactic potential.
-Some have been linked with reduced immunopathology, antiviral and anti-inflammatory activities, or even the prevention of acute respiratory distress syndrome (ARDS) [592,611,612].
+Some have been linked with reduced immunopathology, antiviral and anti-inflammatory activities, or even the prevention of acute respiratory distress syndrome (ARDS) [593,612,613].
A host of potential candidates have been highlighted in the literature that target various aspects of the COVID-19 viral pathology, while others are thought to prime the host immune system.
-These candidates include vitamins and minerals along with extracts and omega-3 polyunsaturated fatty acids (n-3 PUFA) [613].
-In vitro and in vivo studies suggest that nutraceuticals containing phycocyanobilin, N-acetylcysteine, glucosamine, selenium or phase 2 inductive nutraceuticals (e.g. ferulic acid, lipoic acid, or sulforaphane) can prevent or modulate RNA virus infections via amplification of the signaling activity of mitochondrial antiviral-signaling protein (MAVS) and activation of Toll-like receptor 7 [614].
+These candidates include vitamins and minerals along with extracts and omega-3 polyunsaturated fatty acids (n-3 PUFA) [614].
+In vitro and in vivo studies suggest that nutraceuticals containing phycocyanobilin, N-acetylcysteine, glucosamine, selenium or phase 2 inductive nutraceuticals (e.g. ferulic acid, lipoic acid, or sulforaphane) can prevent or modulate RNA virus infections via amplification of the signaling activity of mitochondrial antiviral-signaling protein (MAVS) and activation of Toll-like receptor 7 [615].
While promising, further animal and human studies are required to assess the therapeutic potential of these various nutrients and nutraceuticals against COVID-19.
For the purpose of this review, we have highlighted some of the main dietary supplements and nutraceuticals that are currently under investigation for their potential prophylactic and therapeutic applications.
These include n-3 PUFA, zinc, vitamins C and D, and probiotics.
6.4 n-3 PUFA
-One category of supplements that has been explored for beneficial effects against various viral infections are the n-3 PUFAs [613], commonly referred to as omega-3 fatty acids, which include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
-EPA and DHA intake can come from a diet high in fish or through dietary supplementation with fish oils or purified oils [615].
-Other, more sustainable sources of EPA and DHA include algae [616,617], which can also be exploited for their rich abundance of other bioactive compounds such as angiotensin converting enzyme inhibitor peptides and antiviral agents including phycobiliproteins, sulfated polysaccharides, and calcium-spirulan [618].
-n-3 PUFAs have been investigated for many years for their therapeutic potential [619].
-Supplementation with fish oils is generally well tolerated [619], and intake of n-3 PUFAs through dietary sources or supplementation is specifically encouraged for vulnerable groups such as pregnant and lactating women [620,621].
+
One category of supplements that has been explored for beneficial effects against various viral infections are the n-3 PUFAs [614], commonly referred to as omega-3 fatty acids, which include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
+EPA and DHA intake can come from a diet high in fish or through dietary supplementation with fish oils or purified oils [616].
+Other, more sustainable sources of EPA and DHA include algae [617,618], which can also be exploited for their rich abundance of other bioactive compounds such as angiotensin converting enzyme inhibitor peptides and antiviral agents including phycobiliproteins, sulfated polysaccharides, and calcium-spirulan [619].
+n-3 PUFAs have been investigated for many years for their therapeutic potential [620].
+Supplementation with fish oils is generally well tolerated [620], and intake of n-3 PUFAs through dietary sources or supplementation is specifically encouraged for vulnerable groups such as pregnant and lactating women [621,622].
As a result, these well-established compounds have drawn significant interest for their potential immune effects and therapeutic potential.
Particular interest has arisen in n-3 PUFAs as potential therapeutics against diseases associated with inflammation.
-n-3 PUFAs have been found to mediate inflammation by influencing processes such as leukocyte chemotaxis, adhesion molecule expression, and the production of eicosanoids [622,623].
-This and other evidence indicates that n-3 PUFAs may have the capacity to modulate the adaptive immune response [595,615,622]; for example, they have been found to influence antigen presentation and the production of CD4(+) Th1 cells, among other relevant effects [624].
-Certainly, preliminary evidence from banked blood samples from 100 COVID-19 patients suggests that patients with a higher omega-3 index, a measure of n-3 and n-6 fatty acids in red blood cells, had a lower risk of death due to COVID-19 [625].
-Interest has also arisen as to whether nutritional status related to n-3 PUFAs can also affect inflammation associated with severe disease, such as ARDS or sepsis [626,627].
-ARDS and sepsis hold particular concern in the treatment of severe COVID-19; an analysis of 82 deceased COVID-19 patients in Wuhan during January to February 2020 reported that respiratory failure (associated with ARDS) was the cause of death in 69.5% of cases, and sepsis or multi-organ failure accounted for 28.0% of deaths [628].
+n-3 PUFAs have been found to mediate inflammation by influencing processes such as leukocyte chemotaxis, adhesion molecule expression, and the production of eicosanoids [623,624].
+This and other evidence indicates that n-3 PUFAs may have the capacity to modulate the adaptive immune response [596,616,623]; for example, they have been found to influence antigen presentation and the production of CD4(+) Th1 cells, among other relevant effects [625].
+Certainly, preliminary evidence from banked blood samples from 100 COVID-19 patients suggests that patients with a higher omega-3 index, a measure of n-3 and n-6 fatty acids in red blood cells, had a lower risk of death due to COVID-19 [626].
+Interest has also arisen as to whether nutritional status related to n-3 PUFAs can also affect inflammation associated with severe disease, such as ARDS or sepsis [627,628].
+ARDS and sepsis hold particular concern in the treatment of severe COVID-19; an analysis of 82 deceased COVID-19 patients in Wuhan during January to February 2020 reported that respiratory failure (associated with ARDS) was the cause of death in 69.5% of cases, and sepsis or multi-organ failure accounted for 28.0% of deaths [629].
Research in ARDS prior to current pandemic suggests that n-3 PUFAs may hold some therapeutic potential.
-One study randomized 16 consecutive ARDS patients to receive either a fish oil-enriched lipid emulsion or a control lipid emulsion (comprised of 100% long-chain triglycerides) under a double-blinded design [629].
+One study randomized 16 consecutive ARDS patients to receive either a fish oil-enriched lipid emulsion or a control lipid emulsion (comprised of 100% long-chain triglycerides) under a double-blinded design [630].
They reported a statistically significant reduction in leukotriene B4 levels in the group receiving the fish oil-enriched emulsion, suggesting that the fish oil supplementation may have reduced inflammation.
However, they also reported that most of their tests were not statistically significant, and therefore it seems that additional research using larger sample sizes is required.
-A recent meta-analysis of 10 randomized controlled trials (RCTs) examining the effects of n-3 PUFAs on ARDS patients did not find evidence of any effect on mortality, although the effect on secondary outcomes could not be determined due to a low quality of evidence [630].
-However, another meta-analysis that examined 24 RCTs studying the effects of n-3 fatty acids on sepsis, including ARDS-induced sepsis, did find support for an effect on mortality when n-3 fatty acids were administered via enteral nutrition, although a paucity of high-quality evidence again limited conclusions [631].
+A recent meta-analysis of 10 randomized controlled trials (RCTs) examining the effects of n-3 PUFAs on ARDS patients did not find evidence of any effect on mortality, although the effect on secondary outcomes could not be determined due to a low quality of evidence [631].
+However, another meta-analysis that examined 24 RCTs studying the effects of n-3 fatty acids on sepsis, including ARDS-induced sepsis, did find support for an effect on mortality when n-3 fatty acids were administered via enteral nutrition, although a paucity of high-quality evidence again limited conclusions [632].
Therefore, despite theoretical support for an immunomodulatory effect of n-3 PUFAs in COVID-19, evidence from existing RCTs is insufficient to determine whether supplementation offers an advantage in a clinical setting that would be relevant to COVID-19.
-Another potential mechanism that has led to interest in n-3 PUFAs as protective against viral infections including COVID-19 is its potential as a precursor molecule for the biosynthesis of endogenous specialized proresolving mediators (SPM), such as protectins and resolvins, that actively resolve inflammation and infection [632].
-SPM have exhibited beneficial effects against a variety of lung infections, including some caused by RNA viruses [633,634].
-Indeed, protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [635].
-Several mechanisms for SPM have been proposed, including preventing the release of pro-inflammatory cytokines and chemokines or increasing phagocytosis of cellular debris by macrophages [636].
-In influenza, SPM promote antiviral B lymphocytic activities [637], and protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [635].
-It has thus been hypothesized that SPM could aid in the resolution of the cytokine storm and pulmonary inflammation associated with COVID-19 [638,639].
-Another theory is that some comorbidities, such as obesity, could lead to deficiencies of SPM, which could in turn be related to the occurrence of adverse outcomes for COVID-19 [640].
-However, not all studies are in agreement that n-3 PUFAs or their resulting SPM are effective against infections [641].
-At a minimum, the effectiveness of n-3 PUFAs against infections would be dependent on the dosage, timing, and the specific pathogens responsible [642].
-On another level, there is still the question of whether fish oils can raise the levels of SPM levels upon ingestion and in response to acute inflammation in humans [643].
-Currently, Karolinska University Hospital is running a trial that will measure the levels of SPM as a secondary outcome following intravenous supplementation of n-3 PUFAs in hospitalized COVID-19 patients to determine whether n-3 PUFAs provides therapeutic value [644,645].
+
Another potential mechanism that has led to interest in n-3 PUFAs as protective against viral infections including COVID-19 is its potential as a precursor molecule for the biosynthesis of endogenous specialized proresolving mediators (SPM), such as protectins and resolvins, that actively resolve inflammation and infection [633].
+SPM have exhibited beneficial effects against a variety of lung infections, including some caused by RNA viruses [634,635].
+Indeed, protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [636].
+Several mechanisms for SPM have been proposed, including preventing the release of pro-inflammatory cytokines and chemokines or increasing phagocytosis of cellular debris by macrophages [637].
+In influenza, SPM promote antiviral B lymphocytic activities [638], and protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [636].
+It has thus been hypothesized that SPM could aid in the resolution of the cytokine storm and pulmonary inflammation associated with COVID-19 [639,640].
+Another theory is that some comorbidities, such as obesity, could lead to deficiencies of SPM, which could in turn be related to the occurrence of adverse outcomes for COVID-19 [641].
+However, not all studies are in agreement that n-3 PUFAs or their resulting SPM are effective against infections [642].
+At a minimum, the effectiveness of n-3 PUFAs against infections would be dependent on the dosage, timing, and the specific pathogens responsible [643].
+On another level, there is still the question of whether fish oils can raise the levels of SPM levels upon ingestion and in response to acute inflammation in humans [644].
+Currently, Karolinska University Hospital is running a trial that will measure the levels of SPM as a secondary outcome following intravenous supplementation of n-3 PUFAs in hospitalized COVID-19 patients to determine whether n-3 PUFAs provides therapeutic value [645,646].
Therefore, while this mechanism provides theoretical support for a role for n-3 PUFAs against COVID-19, experimental support is still needed.
-A third possible mechanism by which n-3 PUFAs could benefit COVID-19 patients arises from the fact that some COVID-19 patients, particularly those with comorbidities, are at a significant risk of thrombotic complications including arterial and venous thrombosis [107,646].
-Therefore, the use of prophylactic and therapeutic anticoagulants and antithrombotic agents is under consideration [647,648].
-Considering that there is significant evidence that n-3 fatty acids and other fish oil-derived lipids possess antithrombotic properties and anti-inflammatory properties [615,649,650], they may have therapeutic value against the prothrombotic complications of COVID-19.
-In particular, concerns have been raised within the medical community about using investigational therapeutics on COVID-19 patients who are already on antiplatelet therapies due to pre-existing comorbidities because the introduction of such therapeutics could lead to issues with dosing and drug choice and/or negative drug-drug interactions [647].
+
A third possible mechanism by which n-3 PUFAs could benefit COVID-19 patients arises from the fact that some COVID-19 patients, particularly those with comorbidities, are at a significant risk of thrombotic complications including arterial and venous thrombosis [109,647].
+Therefore, the use of prophylactic and therapeutic anticoagulants and antithrombotic agents is under consideration [648,649].
+Considering that there is significant evidence that n-3 fatty acids and other fish oil-derived lipids possess antithrombotic properties and anti-inflammatory properties [616,650,651], they may have therapeutic value against the prothrombotic complications of COVID-19.
+In particular, concerns have been raised within the medical community about using investigational therapeutics on COVID-19 patients who are already on antiplatelet therapies due to pre-existing comorbidities because the introduction of such therapeutics could lead to issues with dosing and drug choice and/or negative drug-drug interactions [648].
In such cases, dietary sources of n-3 fatty acids or other nutraceuticals with antiplatelet activities could hold particular value for reducing the risk of thrombotic complications in patients already receiving pharmaceutical antiplatelet therapies.
-A new clinical trial [651] is currently recruiting COVID-19 positive patients to investigate the anti-inflammatory activity of a recently developed, highly purified nutraceutical derivative of EPA known as icosapent ethyl (VascepaTM) [652].
-Other randomized controlled trials that are in the preparatory stages intend to investigate the administration of EPA and other bioactive compounds to COVID-19 positive patients in order to observe whether anti-inflammatory effects or disease state improvements occur [653,654].
-Finally, while there have been studies investigating the therapeutic value of n-3 fatty acids against ARDS in humans, there is still limited evidence of their effectiveness [655].
+A new clinical trial [652] is currently recruiting COVID-19 positive patients to investigate the anti-inflammatory activity of a recently developed, highly purified nutraceutical derivative of EPA known as icosapent ethyl (VascepaTM) [653].
+Other randomized controlled trials that are in the preparatory stages intend to investigate the administration of EPA and other bioactive compounds to COVID-19 positive patients in order to observe whether anti-inflammatory effects or disease state improvements occur [654,655].
+Finally, while there have been studies investigating the therapeutic value of n-3 fatty acids against ARDS in humans, there is still limited evidence of their effectiveness [656].
It should be noted that the overall lack of human studies in this area means there is limited evidence as to whether these supplements could affect COVID-19 infection.
Consequently, the clinical trials that are underway and those that have been proposed will provide valuable insight into whether the anti-inflammatory potential of n-3 PUFAs and their derivatives can be beneficial to the treatment of COVID-19.
All the same, while the evidence is not present to draw conclusions about whether n-3 PUFAs will be useful in treating COVID-19, there is likely little harm associated with a diet rich in fish oils, and interest in n-3 PUFA supplementation by the general public is unlikely to have negative effects.
6.5 Zinc
Zinc is nutrient supplement that may exhibit some benefits against RNA viral infections.
-Zinc is a trace metal obtained from dietary sources or supplementation and is important for the maintenance of immune cells involved in adaptive and innate immunity [656].
+Zinc is a trace metal obtained from dietary sources or supplementation and is important for the maintenance of immune cells involved in adaptive and innate immunity [657].
Supplements can be administered orally as a tablet or as a lozenge and are available in many forms, such as zinc picolinate, zinc acetate, and zinc citrate.
Zinc is also available from dietary sources including meat, seafood, nuts, seeds, legumes, and dairy.
-The role of zinc in immune function has been extensively reviewed [656].
+The role of zinc in immune function has been extensively reviewed [657].
Zinc is an important signaling molecule, and zinc levels can alter host defense systems.
-In inflammatory situations such as an infection, zinc can regulate leukocyte immune responses and activate the nuclear factor kappa-light-chain-enhancer of activated B cells, thus altering cytokine production [657,658].
-In particular, zinc supplementation can increase natural killer cell levels, which are important cells for host defense against viral infections [656,659].
+In inflammatory situations such as an infection, zinc can regulate leukocyte immune responses and activate the nuclear factor kappa-light-chain-enhancer of activated B cells, thus altering cytokine production [658,659].
+In particular, zinc supplementation can increase natural killer cell levels, which are important cells for host defense against viral infections [657,660].
As a result of these immune-related functions, zinc is also under consideration for possible benefits against COVID-19.
-Adequate zinc intake has been associated with reduced incidence of infection [660] and antiviral immunity [661].
-A randomized, double-blind, placebo-controlled trial that administered zinc supplementation to elderly subjects over the course of a year found zinc deficiency to be associated with increased susceptibility to infection and that zinc deficiency could be prevented through supplementation [660].
-Clinical trial data supports the utility of zinc to diminish the duration and severity of symptoms associated with common colds when it is provided within 24 hours of the onset of symptoms [662,663].
-An observational study showed that COVID-19 patients had significantly lower zinc levels in comparison to healthy controls and that zinc-deficient COVID-19 patients (those with levels less than 80 μg/dl) tended to have more complications (70.4% vs 30.0%, p = 0.009) and potentially prolonged hospital stays (7.9 vs 5.7 days, p = 0.048) relative to patients who were not zinc deficient [664].
-In coronaviruses specifically, in vitro evidence has demonstrated that the combination of zinc (Zn2+) and zinc ionophores (pyrithione) can interrupt the replication mechanisms of SARS-CoV-GFP (a fluorescently tagged SARS-CoV-1) and a variety of other RNA viruses [665,666].
+
Adequate zinc intake has been associated with reduced incidence of infection [661] and antiviral immunity [662].
+A randomized, double-blind, placebo-controlled trial that administered zinc supplementation to elderly subjects over the course of a year found zinc deficiency to be associated with increased susceptibility to infection and that zinc deficiency could be prevented through supplementation [661].
+Clinical trial data supports the utility of zinc to diminish the duration and severity of symptoms associated with common colds when it is provided within 24 hours of the onset of symptoms [663,664].
+An observational study showed that COVID-19 patients had significantly lower zinc levels in comparison to healthy controls and that zinc-deficient COVID-19 patients (those with levels less than 80 μg/dl) tended to have more complications (70.4% vs 30.0%, p = 0.009) and potentially prolonged hospital stays (7.9 vs 5.7 days, p = 0.048) relative to patients who were not zinc deficient [665].
+In coronaviruses specifically, in vitro evidence has demonstrated that the combination of zinc (Zn2+) and zinc ionophores (pyrithione) can interrupt the replication mechanisms of SARS-CoV-GFP (a fluorescently tagged SARS-CoV-1) and a variety of other RNA viruses [666,667].
Currently, there are over twenty clinical trials registered with the intention to use zinc in a preventative or therapeutic manner for COVID-19.
-However, many of these trials proposed the use of zinc in conjunction with hydroxychloroquine and azithromycin [667,668,669,670], and it is not known how the lack of evidence supporting the use of hydroxychloroquine will affect investigation of zinc.
+However, many of these trials proposed the use of zinc in conjunction with hydroxychloroquine and azithromycin [668,669,670,671], and it is not known how the lack of evidence supporting the use of hydroxychloroquine will affect investigation of zinc.
One retrospective observational study of New York University Langone hospitals in New York compared outcomes among hospitalized COVID-19 patients administered hydroxychloroquine and azithromycin with zinc sulfate (n = 411) versus hydroxychloroquine and azithromycin alone (n = 521).
-Notably, zinc is the only treatment that was used in this trial that is still under consideration as a therapeutic agent due to the lack of efficacy and potential adverse events associated with hydroxychloroquine and azithromycin against COVID-19 [671,672,673].
-While the addition of zinc sulfate did not affect the duration of hospitalization, the length of ICU stays or patient ventilation duration, univariate analyses indicated that zinc did increase the frequency of patients discharged and decreased the requirement for ventilation, referrals to the ICU, mortality [674].
-However, a smaller retrospective study at Hoboken University Medical Center New Jersey failed to find an association between zinc supplementation and survival of hospitalized patients [675].
+Notably, zinc is the only treatment that was used in this trial that is still under consideration as a therapeutic agent due to the lack of efficacy and potential adverse events associated with hydroxychloroquine and azithromycin against COVID-19 [672,673,674].
+While the addition of zinc sulfate did not affect the duration of hospitalization, the length of ICU stays or patient ventilation duration, univariate analyses indicated that zinc did increase the frequency of patients discharged and decreased the requirement for ventilation, referrals to the ICU, mortality [675].
+However, a smaller retrospective study at Hoboken University Medical Center New Jersey failed to find an association between zinc supplementation and survival of hospitalized patients [676].
Therefore, whether zinc contributes to COVID-19 recovery remains unclear.
-Other trials are now investigating zinc in conjunction with other supplements such as vitamin C or n-3 PUFA [654,676].
+Other trials are now investigating zinc in conjunction with other supplements such as vitamin C or n-3 PUFA [655,677].
Though there is, overall, encouraging data for zinc supplementation against the common cold and viral infections, there is currently limited evidence to suggest zinc supplementation has any beneficial effects against the current novel COVID-19; thus, the clinical trials that are currently underway will provide vital information on the efficacious use of zinc in COVID-19 prevention and/or treatment.
However, given the limited risk and the potential association between zinc deficiency and illness, maintaining a healthy diet to ensure an adequate zinc status may be advisable for individuals seeking to reduce their likelihood of infection.
6.6 Vitamin C
-Vitamins B, C, D, and E have also been suggested as potential nutrient supplement interventions for COVID-19 [613,677].
-In particular vitamin C has been proposed as a potential therapeutic agent against COVID-19 due to its long history of use against the common cold and other respiratory infections [678,679].
+
Vitamins B, C, D, and E have also been suggested as potential nutrient supplement interventions for COVID-19 [614,678].
+In particular vitamin C has been proposed as a potential therapeutic agent against COVID-19 due to its long history of use against the common cold and other respiratory infections [679,680].
Vitamin C can be obtained via dietary sources such as fruits and vegetables or via supplementation.
Vitamin C plays a significant role in promoting immune function due to its effects on various immune cells.
-It affects inflammation by modulating cytokine production, decreasing histamine levels, enhancing the differentiation and proliferation of T- and B-lymphocytes, increasing antibody levels, and protecting against the negative effects of reactive oxygen species, among other effects related to COVID-19 pathology [680,681,682].
+It affects inflammation by modulating cytokine production, decreasing histamine levels, enhancing the differentiation and proliferation of T- and B-lymphocytes, increasing antibody levels, and protecting against the negative effects of reactive oxygen species, among other effects related to COVID-19 pathology [681,682,683].
Vitamin C is utilized by the body during viral infections, as evinced by lower concentrations in leukocytes and lower concentrations of urinary vitamin C.
-Post-infection, these levels return to baseline ranges [683,684,685,686,687].
-It has been shown that as little as 0.1 g/d of vitamin C can maintain normal plasma levels of vitamin C in healthy individuals, but higher doses of at least 1-3 g/d are required for critically ill patients in ICUs [688].
-Indeed, vitamin C deficiency appears to be common among COVID-19 patients [689,690].
-COVID-19 is also associated with the formation of microthrombi and coagulopathy [109] that contribute to its characteristic lung pathology [691], but these symptoms can be ameliorated by early infusions of vitamin C to inhibit endothelial surface P-selectin expression and platelet-endothelial adhesion [692].
-Intravenous vitamin C also reduced D-dimer levels, which are notably elevated in COVID-19 patients [105,106], in a case study of 17 COVID-19 patients [693].
+Post-infection, these levels return to baseline ranges [684,685,686,687,688].
+It has been shown that as little as 0.1 g/d of vitamin C can maintain normal plasma levels of vitamin C in healthy individuals, but higher doses of at least 1-3 g/d are required for critically ill patients in ICUs [689].
+Indeed, vitamin C deficiency appears to be common among COVID-19 patients [690,691].
+COVID-19 is also associated with the formation of microthrombi and coagulopathy [111] that contribute to its characteristic lung pathology [692], but these symptoms can be ameliorated by early infusions of vitamin C to inhibit endothelial surface P-selectin expression and platelet-endothelial adhesion [693].
+Intravenous vitamin C also reduced D-dimer levels, which are notably elevated in COVID-19 patients [107,108], in a case study of 17 COVID-19 patients [694].
There is therefore preliminary evidence suggesting that vitamin C status and vitamin C administration may be relevant to COVID-19 outcomes.
Larger-scale studies of vitamin C, however, have provided mixed results.
-A recent meta-analysis found consistent support for regular vitamin C supplementation reducing the duration of the common cold, but that supplementation with vitamin C (> 200 mg) failed to reduce the incidence of colds [694].
-Individual studies have found Vitamin C to reduce the susceptibility of patients to lower respiratory tract infections, such as pneumonia [695].
+A recent meta-analysis found consistent support for regular vitamin C supplementation reducing the duration of the common cold, but that supplementation with vitamin C (> 200 mg) failed to reduce the incidence of colds [695].
+Individual studies have found Vitamin C to reduce the susceptibility of patients to lower respiratory tract infections, such as pneumonia [696].
Another meta-analysis demonstrated that in twelve trials, vitamin C supplementation reduced the length of stay of patients in intensive care units (ICUs) by 7.8% (95% CI: 4.2% to 11.2%; p = 0.00003).
Furthermore, high doses (1-3 g/day) significantly reduced the length of an ICU stay by 8.6% in six trials (p = 0.003).
-Vitamin C also shortened the duration of mechanical ventilation by 18.2% in three trials in which patients required intervention for over 24 hours (95% CI 7.7% to 27%; p = 0.001) [688].
-Despite these findings, an RCT of 167 patients known as CITRUS ALI failed to show a benefit of a 96-hour infusion of vitamin C to treat ARDS [696].
-Clinical trials specifically investigating vitamin C in the context of COVID-19 have now begun, as highlighted by Carr et al. [679].
+Vitamin C also shortened the duration of mechanical ventilation by 18.2% in three trials in which patients required intervention for over 24 hours (95% CI 7.7% to 27%; p = 0.001) [689].
+Despite these findings, an RCT of 167 patients known as CITRUS ALI failed to show a benefit of a 96-hour infusion of vitamin C to treat ARDS [697].
+Clinical trials specifically investigating vitamin C in the context of COVID-19 have now begun, as highlighted by Carr et al. [680].
These trials intend to investigate the use of intravenous vitamin C in hospitalized COVID-19 patients.
-The first trial to report initial results took place in Wuhan, China [697].
-These initial results indicated that the administration of 12 g/12 hr of intravenous vitamin C for 7 days in 56 critically ill COVID-19 patients resulted in a promising reduction of 28-day mortality (p = 0.06) in univariate survival analysis [698].
-Indeed, the same study reported a significant decrease in IL-6 levels by day 7 of vitamin C infusion (p = 0.04) [699].
+The first trial to report initial results took place in Wuhan, China [698].
+These initial results indicated that the administration of 12 g/12 hr of intravenous vitamin C for 7 days in 56 critically ill COVID-19 patients resulted in a promising reduction of 28-day mortality (p = 0.06) in univariate survival analysis [699].
+Indeed, the same study reported a significant decrease in IL-6 levels by day 7 of vitamin C infusion (p = 0.04) [700].
Additional studies that are being conducted in Canada, China, Iran, and the USA will provide additional insight into whether vitamin C supplementation affects COVID-19 outcomes on a larger scale.
Even though evidence supporting the use of vitamin C is beginning to emerge, we will not know how effective vitamin C is as a therapeutic for quite some time.
Currently (as of January 2021) over fifteen trials are registered with clinicaltrials.gov that are either recruiting, active or are currently in preparation.
@@ -2456,166 +2457,166 @@
6.6[582].
-The recommended dietary allowance according to the FDA is 75-90 mg/d, whereas EFSA recommends 110 mg/d [700].
+To maintain vitamin C status, it would be prudent for individuals to ensure that they consume the recommended dietary allowance of vitamin C to maintain a healthy immune system [583].
+The recommended dietary allowance according to the FDA is 75-90 mg/d, whereas EFSA recommends 110 mg/d [701].
6.7 Vitamin D
Of all of the supplements currently under investigation, vitamin D has become a leading prophylactic and therapeutic candidate against SARS-CoV-2.
-Vitamin D can modulate both the adaptive and innate immune system and is associated with various aspects of immune health and antiviral defense [701,702,703,704,705].
+Vitamin D can modulate both the adaptive and innate immune system and is associated with various aspects of immune health and antiviral defense [702,703,704,705,706].
Vitamin D can be sourced through diet or supplementation, but it is mainly biosynthesized by the body on exposure to ultraviolet light (UVB) from sunlight.
-Vitamin D deficiency is associated with an increased susceptibility to infection [706].
-In particular, vitamin D deficient patients are at risk of developing acute respiratory infections [707] and ARDS [707].
+Vitamin D deficiency is associated with an increased susceptibility to infection [707].
+In particular, vitamin D deficient patients are at risk of developing acute respiratory infections [708] and ARDS [708].
1,25-dihydroxyvitamin D3 is the active form of vitamin D that is involved in adaptive and innate responses; however, due to its low concentration and a short half life of a few hours, vitamin D levels are typically measured by the longer lasting and more abundant precursor 25-hydroxyvitamin D.
-The vitamin D receptor is expressed in various immune cells, and vitamin D is an immunomodulator of antigen presenting cells, dendritic cells, macrophages, monocytes, and T- and B-lymphocytes [706,708].
+The vitamin D receptor is expressed in various immune cells, and vitamin D is an immunomodulator of antigen presenting cells, dendritic cells, macrophages, monocytes, and T- and B-lymphocytes [707,709].
Due to its potential immunomodulating properties, vitamin D supplementation may be advantageous to maintain a healthy immune system.
-Early in the pandemic it was postulated that an individual’s vitamin D status could significantly affect their risk of developing COVID-19 [709].
+
Early in the pandemic it was postulated that an individual’s vitamin D status could significantly affect their risk of developing COVID-19 [710].
This hypothesis was derived from the fact that the current pandemic emerged in Wuhan China during winter, when 25-hydroxyvitamin D concentrations are at their lowest due to a lack of sunlight, whereas in the Southern Hemisphere, where it was nearing the end of the summer and higher 25-hydroxyvitamin D concentrations would be higher, the number of cases was low.
-This led researchers to question whether there was a seasonal component to the SARS-CoV-2 pandemic and whether vitamin D levels might play a role [709,710,711,712].
+This led researchers to question whether there was a seasonal component to the SARS-CoV-2 pandemic and whether vitamin D levels might play a role [710,711,712,713].
Though it is assumed that COVID-19 is seasonal, multiple other factors that can affect vitamin D levels should also be considered.
These factors include an individual’s nutritional status, their age, their occupation, skin pigmentation, potential comorbidities, and the variation of exposure to sunlight due to latitude amongst others.
-Indeed, it has been estimated that each degree of latitude north of 28 degrees corresponded to a 4.4% increase of COVID-19 mortality, indirectly linking a persons vitamin D levels via exposure to UVB light to COVID-19 mortality [710].
-As the pandemic has evolved, additional research of varying quality has investigated some of the potential links identified early in the pandemic [709] between vitamin D and COVID-19.
+Indeed, it has been estimated that each degree of latitude north of 28 degrees corresponded to a 4.4% increase of COVID-19 mortality, indirectly linking a persons vitamin D levels via exposure to UVB light to COVID-19 mortality [711].
+As the pandemic has evolved, additional research of varying quality has investigated some of the potential links identified early in the pandemic [710] between vitamin D and COVID-19.
Indeed, studies are beginning to investigate whether there is any prophylactic and/or therapeutic relationship between vitamin D and COVID-19.
-A study in Switzerland demonstrated that 27 SARS-CoV-2 positive patients exhibited 25-hydroxyvitamin D plasma concentrations that were significantly lower (11.1 ng/ml) than those of SARS-CoV-2 negative patients (24.6 ng/ml; p = 0.004), an association that held when stratifying patients greater than 70 years old [713].
-These findings seem to be supported by a Belgian observational study of 186 SARS-CoV-2 positive patients exhibiting symptoms of pneumonia, where 25-hydroxyvitamin D plasma concentrations were measured and CT scans of the lungs were obtained upon hospitalization [714].
+A study in Switzerland demonstrated that 27 SARS-CoV-2 positive patients exhibited 25-hydroxyvitamin D plasma concentrations that were significantly lower (11.1 ng/ml) than those of SARS-CoV-2 negative patients (24.6 ng/ml; p = 0.004), an association that held when stratifying patients greater than 70 years old [714].
+These findings seem to be supported by a Belgian observational study of 186 SARS-CoV-2 positive patients exhibiting symptoms of pneumonia, where 25-hydroxyvitamin D plasma concentrations were measured and CT scans of the lungs were obtained upon hospitalization [715].
A significant difference in 25-hydroxyvitamin D levels was observed between the SARS-CoV-2 patients and 2,717 season-matched diseased controls.
Both female and male patients possessed lower median 25-hydroxyvitamin D concentrations than the control group as a whole (18.6 ng/ml versus 21.5 ng/ml; p = 0.0016) and a higher rate of vitamin D deficiency (58.6% versus 42.5%).
However, when comparisons were stratified by sex, evidence of sexual dimorphism became apparent, as female patients had equivalent levels of 25-hydroxyvitamin D to females in the control group, whereas male patients were deficient in 25-hydroxyvitamin D relative to male controls (67% versus 49%; p = 0.0006).
Notably, vitamin D deficiency was progressively lower in males with advancing radiological disease stages (p = 0.001).
-These studies are supported by several others that indicate that vitamin D status may be an independent risk factor for the severity of COVID-19 [715,716,717,718] and in COVID-19 patients relative to population-based controls [719].
-Indeed, serum concentrations of 25-hydroxyvitamin D above 30 ng/ml, which indicate vitamin D sufficiency, seems to be associated with a reduction in serum C-reactive protein, an inflammatory marker, along with increased lymphocyte levels, which suggests that vitamin D levels may modulate the immune response by reducing risk for cytokine storm in response to SARS-CoV-2 infection [719].
-A study in India determined that COVID-19 fatality was higher in patients with severe COVID-19 and low serum 25-hydroxyvitamin D (mean level 6.2 ng/ml; 97% vitamin D deficient) levels versus asymptomatic non-severe patients with higher levels of vitamin D (mean level 27.9 ng/ml; 33% vitamin D deficient) [720].
+These studies are supported by several others that indicate that vitamin D status may be an independent risk factor for the severity of COVID-19 [716,717,718,719] and in COVID-19 patients relative to population-based controls [720].
+Indeed, serum concentrations of 25-hydroxyvitamin D above 30 ng/ml, which indicate vitamin D sufficiency, seems to be associated with a reduction in serum C-reactive protein, an inflammatory marker, along with increased lymphocyte levels, which suggests that vitamin D levels may modulate the immune response by reducing risk for cytokine storm in response to SARS-CoV-2 infection [720].
+A study in India determined that COVID-19 fatality was higher in patients with severe COVID-19 and low serum 25-hydroxyvitamin D (mean level 6.2 ng/ml; 97% vitamin D deficient) levels versus asymptomatic non-severe patients with higher levels of vitamin D (mean level 27.9 ng/ml; 33% vitamin D deficient) [721].
In the same study, vitamin D deficiency was associated with higher levels of inflammatory markers including IL-6, ferritin, and tumor necrosis factor α.
-Collectively, these studies add to a multitude of observational studies reporting potential associations between low levels of 25-hydroxyvitamin D and COVID-19 incidence and severity [713,718,719,721,722,723,724,725,726,727].
-Despite the large number of studies establishing a link between vitamin D status and COVID-19 severity, an examination of data from the UK Biobank did not support this thesis [728,729].
+Collectively, these studies add to a multitude of observational studies reporting potential associations between low levels of 25-hydroxyvitamin D and COVID-19 incidence and severity [714,719,720,722,723,724,725,726,727,728].
+Despite the large number of studies establishing a link between vitamin D status and COVID-19 severity, an examination of data from the UK Biobank did not support this thesis [729,730].
These analyses examined 25-hydroxyvitamin D concentrations alongside SARS-CoV-2 positivity and COVID-19 mortality in over 340,000 UK Biobank participants.
-However, these studies have caused considerable debate that will likely be settled following further studies [730,731].
-Overall, while the evidence suggests that there is likely an association between low serum 25-hydroxyvitamin D and COVID-19 incidence, these studies must be interpreted with caution, as there is the potential for reverse causality, bias, and other confounding factors including that vitamin D deficiency is also associated with numerous pre-existing conditions and risk factors that can increase the risk for severe COVID-19 [582,710,732,733].
+However, these studies have caused considerable debate that will likely be settled following further studies [731,732].
+Overall, while the evidence suggests that there is likely an association between low serum 25-hydroxyvitamin D and COVID-19 incidence, these studies must be interpreted with caution, as there is the potential for reverse causality, bias, and other confounding factors including that vitamin D deficiency is also associated with numerous pre-existing conditions and risk factors that can increase the risk for severe COVID-19 [583,711,733,734].
While these studies inform us of the potential importance of vitamin D sufficiency and the risk of SARS-CoV-2 infection and severe COVID-19, they fail to conclusively determine whether vitamin D supplementation can therapeutically affect the clinical course of COVID-19.
In one study, 40 vitamin D deficient asymptomatic or mildly symptomatic participants patients were either randomized to receive 60,000 IU of cholecalciferol daily for at least 7 days (n = 16) or a placebo (n = 24) with a target serum 25-hydroxyvitamin D level >50 ng/ml.
At day 7, 10 patients achieved >50 ng/ml, followed by another 2 by day 14.
-By the end of the study, the treatment group had a greater proportion of vitamin D-deficient participants that tested negative for SARS-CoV-2 RNA, and they had a significantly lower fibrinogen levels, potentially indicating a beneficial effect [734].
-A pilot study in Spain determined that early administration of high dose calcifediol (~21,000 IU days 1-2 and ~11,000 IU days 3-7 of hospital admission) with hydroxychloroquine and azithromycin to 50 hospitalized COVID-19 patients significantly reduced ICU admissions and may have reduced disease severity versus hydroxychloroquine and azithromycin alone [735].
-Although this study received significant criticism from the National Institute for Health and Care Excellence (NICE) in the UK [736], an independent follow-up statistical analysis supported the findings of the study with respect to the results of cholecalciferol treatment [737].
-Another trial of 986 patients hospitalized for COVID-19 in three UK hospitals administered cholecalciferol supplementation (≥ 280,000 IU in a time period of 7 weeks) to 151 patients and found an association with a reduced risk of COVID-19 mortality, regardless of baseline 25-hydroxyvitamin D levels [738].
+By the end of the study, the treatment group had a greater proportion of vitamin D-deficient participants that tested negative for SARS-CoV-2 RNA, and they had a significantly lower fibrinogen levels, potentially indicating a beneficial effect [735].
+A pilot study in Spain determined that early administration of high dose calcifediol (~21,000 IU days 1-2 and ~11,000 IU days 3-7 of hospital admission) with hydroxychloroquine and azithromycin to 50 hospitalized COVID-19 patients significantly reduced ICU admissions and may have reduced disease severity versus hydroxychloroquine and azithromycin alone [736].
+Although this study received significant criticism from the National Institute for Health and Care Excellence (NICE) in the UK [737], an independent follow-up statistical analysis supported the findings of the study with respect to the results of cholecalciferol treatment [738].
+Another trial of 986 patients hospitalized for COVID-19 in three UK hospitals administered cholecalciferol supplementation (≥ 280,000 IU in a time period of 7 weeks) to 151 patients and found an association with a reduced risk of COVID-19 mortality, regardless of baseline 25-hydroxyvitamin D levels [739].
However, a double-blind, randomized, placebo-controlled trial of 240 hospitalized COVID-19 patients in São Paulo, Brazil administered a single 200,000 IU oral dose of vitamin D.
-While levels of 25-hydroxyvitamin D did increase from 21% to ~27% (p = 0.001) and the supplementation was well tolerated, there was no reduction in the length of hospital stay or mortality and no change to any other relevant secondary outcomes [739].
+While levels of 25-hydroxyvitamin D did increase from 21% to ~27% (p = 0.001) and the supplementation was well tolerated, there was no reduction in the length of hospital stay or mortality and no change to any other relevant secondary outcomes [740].
These early findings are thus still inconclusive with regards to the therapeutic value of vitamin D supplementation.
-However, other trials are underway, including one trial that is investigating the utility of vitamin D as an immune-modulating agent by monitoring whether administration of vitamin D precipitates an improvement of health status in non-severe symptomatic COVID-19 patients and whether vitamin D prevents patient deterioration [740].
-Other trials are examining various factors including mortality, symptom recovery, severity of disease, rates of ventilation, inflammatory markers such as C-reactive protein and IL-6, blood cell counts, and the prophylactic capacity of vitamin D administration [740,741,742,743].
-Concomitant administration of vitamin D with pharmaceuticals such as aspirin [744] and bioactive molecules such as resveratrol [745] are also under investigation.
+However, other trials are underway, including one trial that is investigating the utility of vitamin D as an immune-modulating agent by monitoring whether administration of vitamin D precipitates an improvement of health status in non-severe symptomatic COVID-19 patients and whether vitamin D prevents patient deterioration [741].
+Other trials are examining various factors including mortality, symptom recovery, severity of disease, rates of ventilation, inflammatory markers such as C-reactive protein and IL-6, blood cell counts, and the prophylactic capacity of vitamin D administration [741,742,743,744].
+Concomitant administration of vitamin D with pharmaceuticals such as aspirin [745] and bioactive molecules such as resveratrol [746] are also under investigation.
The effectiveness of vitamin D supplementation against COVID-19 remains open for debate.
-All the same, there is no doubt that vitamin D deficiency is a widespread issue and should be addressed not only because of its potential link to SARS-CoV-2 incidence [746], but also due to its importance for overall health.
+All the same, there is no doubt that vitamin D deficiency is a widespread issue and should be addressed not only because of its potential link to SARS-CoV-2 incidence [747], but also due to its importance for overall health.
There is a possibility that safe exposure to sunlight could improve endogenous synthesis of vitamin D, potentially strengthening the immune system.
However, sun exposure is not sufficient on its own, particularly in the winter months.
Indeed, while the possible link between vitamin D status and COVID-19 is further investigated, preemptive supplementation of vitamin D and encouraging people to maintain a healthy diet for optimum vitamin D status is likely to raise serum levels of 25-hydroxyvitamin D while being unlikely to carry major health risks.
These principles seem to be the basis of a number of guidelines issued by some countries and scientific organizations that have advised supplementation of vitamin D during the pandemic.
The Académie Nationale de Médecine in France recommends rapid testing of 25-hydroxyvitamin D for people over 60 years old to identify those most at risk of vitamin D deficiency and advises them to obtain a bolus dose of 50,000 to 100,000 IU vitamin D to limit respiratory complications.
-It has also recommended that those under 60 years old should take 800 to 1,000 IU daily if they receive a SARS-CoV-2 positive test [747].
-In Slovenia, doctors have been advised to provide nursing home patients with vitamin D [748].
-Both Public Health England and Public Health Scotland have advised members of the Black, Asian, and minority ethnic communities to supplement for vitamin D in light of evidence that they may be at higher risk for vitamin D deficiency along with other COVID-19 risk factors, a trend that has also been observed in the United States [749,750].
+It has also recommended that those under 60 years old should take 800 to 1,000 IU daily if they receive a SARS-CoV-2 positive test [748].
+In Slovenia, doctors have been advised to provide nursing home patients with vitamin D [749].
+Both Public Health England and Public Health Scotland have advised members of the Black, Asian, and minority ethnic communities to supplement for vitamin D in light of evidence that they may be at higher risk for vitamin D deficiency along with other COVID-19 risk factors, a trend that has also been observed in the United States [750,751].
However, other UK scientific bodies including the NICE recommend that individuals supplement for vitamin D as per usual UK government advice but warn that people should not supplement for vitamin D solely to prevent COVID-19.
-All the same, the NICE has provided guidelines for research to investigate the supplementation of vitamin D in the context of COVID-19 [751].
-Despite vitamin D deficiency being a widespread issue in the United States [752], the National Institutes of Health have stated that there is “insufficient data to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19” [753].
+All the same, the NICE has provided guidelines for research to investigate the supplementation of vitamin D in the context of COVID-19 [752].
+Despite vitamin D deficiency being a widespread issue in the United States [753], the National Institutes of Health have stated that there is “insufficient data to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19” [754].
These are just some examples of how public health guidance has responded to the emerging evidence regarding vitamin D and COVID-19.
-Outside of official recommendations, there is also evidence that individuals may be paying increased attention to their vitamin D levels, as a survey of Polish consumers showed that 56% of respondents used vitamin D during the pandemic [754].
-However, some companies have used the emerging evidence surrounding vitamin D to sell products that claim to prevent and treat COVID-19, which in one incident required a federal court to intervene and issue an injunction barring the sale of vitamin-D-related products due to the lack of clinical data supporting these claims [755].
+Outside of official recommendations, there is also evidence that individuals may be paying increased attention to their vitamin D levels, as a survey of Polish consumers showed that 56% of respondents used vitamin D during the pandemic [755].
+However, some companies have used the emerging evidence surrounding vitamin D to sell products that claim to prevent and treat COVID-19, which in one incident required a federal court to intervene and issue an injunction barring the sale of vitamin-D-related products due to the lack of clinical data supporting these claims [756].
It is clear that further studies and clinical trials are required to conclusively determine the prophylactic and therapeutic potential of vitamin D supplementation against COVID-19.
Until such time that sufficient evidence emerges, individuals should follow their national guidelines surrounding vitamin D intake to achieve vitamin D sufficiency.
6.8 Probiotics
-Probiotics are “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” [756].
-Some studies suggest that probiotics are beneficial against common viral infections, and there is modest evidence to suggest that they can modulate the immune response [757,758].
-As a result, it has been hypothesized that probiotics may have therapeutic value worthy of investigation against SARS-CoV-2 [759].
-Probiotics and next-generation probiotics, which are more akin to pharmacological-grade supplements, have been associated with multiple potential beneficial effects for allergies, digestive tract disorders, and even metabolic diseases through their anti-inflammatory and immunomodulatory effects [760,761].
-However, the mechanisms by which probiotics affect these various conditions would likely differ among strains, with the ultimate effect of the probiotic depending on the heterogeneous set of bacteria present [761].
-Some of the beneficial effects of probiotics include reducing inflammation by promoting the expression of anti-inflammatory mediators, inhibiting Toll-like receptors 2 and 4, competing directly with pathogens, synthesizing antimicrobial substances or other metabolites, improving intestinal barrier function, and/or favorably altering the gut microbiota and the brain-gut axis [761,762,763].
-It is also thought that lactobacilli such as Lactobacillus paracasei, Lactobacillus plantarum and Lactobacillus rhamnosus have the capacity to bind to and inactivate some viruses via adsorptive and/or trapping mechanisms [764].
-Other probiotic lactobacilli and even non-viable bacterium-like particles have been shown to reduce both viral attachment to host cells and viral titers, along with reducing cytokine synthesis, enhancing the antiviral IFN-α response, and inducing various other antiviral mechanisms [764,765,766,767,768,769,770,771,772].
-These antiviral and immunobiotic mechanisms and others have been reviewed in detail elsewhere [612,759,773].
-However, there is also a bi-directional relationship between the lungs and gut microbiota known as the gut-lung axis [774], whereby gut microbial metabolites and endotoxins may affect the lungs via the circulatory system and the lung microbiota in return may affect the gut [775].
-Therefore, the gut-lung axis may play role in our future understanding of COVID-19 pathogenesis and become a target for probiotic treatments [776].
-Moreover, as microbial dysbiosis of the respiratory tract and gut may play a role in some viral infections, it has been suggested that SARS-CoV-2 may interact with our commensal microbiota [612; 777; 10.3389/fmicb.2020.01840] and that the lung microbiome could play a role in developing immunity to viral infections [778].
+
Probiotics are “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” [757].
+Some studies suggest that probiotics are beneficial against common viral infections, and there is modest evidence to suggest that they can modulate the immune response [758,759].
+As a result, it has been hypothesized that probiotics may have therapeutic value worthy of investigation against SARS-CoV-2 [760].
+Probiotics and next-generation probiotics, which are more akin to pharmacological-grade supplements, have been associated with multiple potential beneficial effects for allergies, digestive tract disorders, and even metabolic diseases through their anti-inflammatory and immunomodulatory effects [761,762].
+However, the mechanisms by which probiotics affect these various conditions would likely differ among strains, with the ultimate effect of the probiotic depending on the heterogeneous set of bacteria present [762].
+Some of the beneficial effects of probiotics include reducing inflammation by promoting the expression of anti-inflammatory mediators, inhibiting Toll-like receptors 2 and 4, competing directly with pathogens, synthesizing antimicrobial substances or other metabolites, improving intestinal barrier function, and/or favorably altering the gut microbiota and the brain-gut axis [762,763,764].
+It is also thought that lactobacilli such as Lactobacillus paracasei, Lactobacillus plantarum and Lactobacillus rhamnosus have the capacity to bind to and inactivate some viruses via adsorptive and/or trapping mechanisms [765].
+Other probiotic lactobacilli and even non-viable bacterium-like particles have been shown to reduce both viral attachment to host cells and viral titers, along with reducing cytokine synthesis, enhancing the antiviral IFN-α response, and inducing various other antiviral mechanisms [765,766,767,768,769,770,771,772,773].
+These antiviral and immunobiotic mechanisms and others have been reviewed in detail elsewhere [613,760,774].
+However, there is also a bi-directional relationship between the lungs and gut microbiota known as the gut-lung axis [775], whereby gut microbial metabolites and endotoxins may affect the lungs via the circulatory system and the lung microbiota in return may affect the gut [776].
+Therefore, the gut-lung axis may play role in our future understanding of COVID-19 pathogenesis and become a target for probiotic treatments [777].
+Moreover, as microbial dysbiosis of the respiratory tract and gut may play a role in some viral infections, it has been suggested that SARS-CoV-2 may interact with our commensal microbiota [613; 778; 10.3389/fmicb.2020.01840] and that the lung microbiome could play a role in developing immunity to viral infections [779].
These postulations, if correct, could lead to the development of novel probiotic and prebiotic treatments.
However, significant research is required to confirm these associations and their relevance to patient care, if any.
Probiotic therapies and prophylactics may also confer some advantages for managing symptoms of COVID-19 or risks associated with its treatment.
-Probiotics have tentatively been associated with the reduction of risk and duration of viral upper respiratory tract infections [779,780,781].
-Some meta-analyses that have assessed the efficacy of probiotics in viral respiratory infections have reported moderate reductions in the incidence and duration of infection [780,782].
-Indeed, randomized controlled trials have shown that administering Bacillus subtilis and Enterococcus faecalis [783], Lactobacillus rhamnosus GG [784], or Lactobacillus casei and Bifidobacterium breve with galactooligosaccharides [785] via the nasogastric tube to ventilated patients reduced the occurrence of ventilator-associated pneumonia in comparison to the respective control groups in studies of viral infections and sepsis.
-These findings were also supported by a recent meta-analysis [786].
-Additionally, COVID-19 patients carry a significant risk of ventilator-associated bacterial pneumonia [787], but it can be challenging for clinicians to diagnose this infection due to the fact that severe COVID-19 infection presents with the symptoms of pneumonia [788].
+Probiotics have tentatively been associated with the reduction of risk and duration of viral upper respiratory tract infections [780,781,782].
+Some meta-analyses that have assessed the efficacy of probiotics in viral respiratory infections have reported moderate reductions in the incidence and duration of infection [781,783].
+Indeed, randomized controlled trials have shown that administering Bacillus subtilis and Enterococcus faecalis [784], Lactobacillus rhamnosus GG [785], or Lactobacillus casei and Bifidobacterium breve with galactooligosaccharides [786] via the nasogastric tube to ventilated patients reduced the occurrence of ventilator-associated pneumonia in comparison to the respective control groups in studies of viral infections and sepsis.
+These findings were also supported by a recent meta-analysis [787].
+Additionally, COVID-19 patients carry a significant risk of ventilator-associated bacterial pneumonia [788], but it can be challenging for clinicians to diagnose this infection due to the fact that severe COVID-19 infection presents with the symptoms of pneumonia [789].
Therefore, an effective prophylactic therapy for ventilator-associated pneumonia in severe COVID-19 patients would carry significant therapeutic value.
-Additionally, in recent years, probiotics have become almost synonymous with the treatment of gastrointestinal issues due to their supposed anti-inflammatory and immunomodulatory effects [789].
-Notably, gastrointestinal symptoms commonly occur in COVID-19 patients [790], and angiotensin-converting enzyme 2, the portal by which SARS-CoV-2 enters human cells, is highly expressed in enterocytes of the ileum and colon, suggesting that these organs may be a potential route of infection [791,792].
-Indeed, SARS-CoV-2 viral RNA has been detected in human feces [89,793], and fecal-oral transmission of the virus has not yet been ruled out [794].
-Rectal swabs of some SARS-CoV-2 positive pediatric patients persistently tested positive for several days despite negative nasopharyngeal tests, indicating the potential for fecal viral shedding [795].
-However, there is conflicting evidence for the therapeutic value of various probiotics against the incidence or severity of gastrointestinal symptoms in viral or bacterial infections such as gastroenteritis [796,797].
-Nevertheless, it has been proposed that the administration of probiotics to COVID-19 patients and healthcare workers may prevent or ameliorate the gastrointestinal symptoms of COVID-19, a hypothesis that several clinical trials are now preparing to investigate [798,799].
-Other studies are investigating whether probiotics may affect patient outcomes following SARS-CoV-2 infection [800].
+Additionally, in recent years, probiotics have become almost synonymous with the treatment of gastrointestinal issues due to their supposed anti-inflammatory and immunomodulatory effects [790].
+Notably, gastrointestinal symptoms commonly occur in COVID-19 patients [791], and angiotensin-converting enzyme 2, the portal by which SARS-CoV-2 enters human cells, is highly expressed in enterocytes of the ileum and colon, suggesting that these organs may be a potential route of infection [792,793].
+Indeed, SARS-CoV-2 viral RNA has been detected in human feces [91,794], and fecal-oral transmission of the virus has not yet been ruled out [795].
+Rectal swabs of some SARS-CoV-2 positive pediatric patients persistently tested positive for several days despite negative nasopharyngeal tests, indicating the potential for fecal viral shedding [796].
+However, there is conflicting evidence for the therapeutic value of various probiotics against the incidence or severity of gastrointestinal symptoms in viral or bacterial infections such as gastroenteritis [797,798].
+Nevertheless, it has been proposed that the administration of probiotics to COVID-19 patients and healthcare workers may prevent or ameliorate the gastrointestinal symptoms of COVID-19, a hypothesis that several clinical trials are now preparing to investigate [799,800].
+Other studies are investigating whether probiotics may affect patient outcomes following SARS-CoV-2 infection [801].
Generally, the efficacy of probiotic use is a controversial topic among scientists.
-In Europe, EFSA has banned the term probiotics on products labels, which has elicited either criticism for EFSA or support for probiotics from researchers in the field [756,801,802].
+In Europe, EFSA has banned the term probiotics on products labels, which has elicited either criticism for EFSA or support for probiotics from researchers in the field [757,802,803].
This regulation is due to the hyperbolic claims placed on the labels of various probiotic products, which lack rigorous scientific data to support their efficacy.
-Overall, the data supporting probiotics in the treatment or prevention of many different disorders and diseases is not conclusive, as the quality of the evidence is generally considered low [779].
+Overall, the data supporting probiotics in the treatment or prevention of many different disorders and diseases is not conclusive, as the quality of the evidence is generally considered low [780].
However, in the case of probiotics and respiratory infections, the evidence seems to be supportive of their potential therapeutic value.
Consequently, several investigations are underway to investigate the prophylactic and therapeutic potential of probiotics for COVID-19.
-The blind use of conventional probiotics for COVID-19 is currently cautioned against until the pathogenesis of SARS-CoV-2 can be further established [803].
+The blind use of conventional probiotics for COVID-19 is currently cautioned against until the pathogenesis of SARS-CoV-2 can be further established [804].
Until clinical trials investigating the prophylactic and therapeutic potential of probiotics for COVID-19 are complete, it is not possible to provide an evidence-based recommendation for their use.
-Despite these concerns, complementary use of probiotics as an adjuvant therapeutic has been proposed by the Chinese National Health Commission and National Administration of Traditional Chinese Medicine [90].
-While supply issues prevented the probiotics market from showing the same rapid response to the COVID-19 as some other supplements, many suppliers are reporting growth during the pandemic [804].
+Despite these concerns, complementary use of probiotics as an adjuvant therapeutic has been proposed by the Chinese National Health Commission and National Administration of Traditional Chinese Medicine [92].
+While supply issues prevented the probiotics market from showing the same rapid response to the COVID-19 as some other supplements, many suppliers are reporting growth during the pandemic [805].
Therefore, the public response once again seems to have adopted supplements promoted as bolstering the immune response despite a lack of evidence suggesting they are beneficial for preventing or mitigating COVID-19.
6.9 Discussion
In this review, we report the findings to date of analyses of several dietary supplements and nutraceuticals.
While existing evidence suggests potential benefits of n-3 PUFA and probiotic supplementation for COVID-19 treatment and prophylaxis, clinical data is still lacking, although trials are underway.
Both zinc and vitamin C supplementation in hospitalized patients seem to be associated with positive outcomes; however, further clinical trials are required.
In any case, both vitamin C and zinc intake are part of a healthy diet and both likely presents minimal risk when supplemented for, though their potential prophylactic or therapeutic effects against COVID-19 are yet to be determined.
-On the other hand, mounting evidence from observational studies indicates that there is an association between vitamin D deficiency and COVID-19 incidence has also been supported by meta-analysis [805].
+On the other hand, mounting evidence from observational studies indicates that there is an association between vitamin D deficiency and COVID-19 incidence has also been supported by meta-analysis [806].
Indeed, scientists are working to confirm these findings and to determine whether a patient’s serum 25-hydroxyvitamin D levels are also associated with COVID-19 severity.
Clinical trials are required to determine whether preemptive vitamin D supplementation may mitigate against severe COVID-19.
-In terms of the therapeutic potential of vitamin D, initial evidence from clinical trials are conflicting, but seem to indicate that vitamin D supplementation may reduce COVID-19 severity [735].
+In terms of the therapeutic potential of vitamin D, initial evidence from clinical trials are conflicting, but seem to indicate that vitamin D supplementation may reduce COVID-19 severity [736].
The various clinical trials currently underway will be imperative to provide information on the efficacious use of vitamin D supplementation for COVID-19 prevention and/or treatment.
The purported prophylactic and therapeutic benefits of dietary supplements and nutraceuticals for multiple disorders, diseases, and infections has been the subject of significant research and debate for the last few decades.
Inevitably, scientists are also investigating the potential for these various products to treat or prevent COVID-19.
This interest also extends to consumers, which led to a remarkable increase of sales of dietary supplements and nutraceuticals throughout the pandemic due to a desire to obtain additional protections from infection and disease.
The nutraceuticals discussed in this review, namely vitamin C, vitamin D, n-3 PUFA, zinc, and probiotics, were selected because of potential biological mechanisms that could beneficially affect viral and respiratory infections and because they are currently under clinical investigation.
Specifically, these compounds have all been found to influence cellular processes related to inflammation.
-Inflammation is particularly relevant to COVID-19 because of the negative outcomes (often death) observed in a large number of patients whose immune response becomes hyperactive in response to SARS-CoV-2, leading to severe outcomes such as ARDS and sepsis [806].
-Additionally, there is a well-established link between diet and inflammation [807], potentially mediated in part by the microbiome [808].
+Inflammation is particularly relevant to COVID-19 because of the negative outcomes (often death) observed in a large number of patients whose immune response becomes hyperactive in response to SARS-CoV-2, leading to severe outcomes such as ARDS and sepsis [807].
+Additionally, there is a well-established link between diet and inflammation [808], potentially mediated in part by the microbiome [809].
Thus, the idea that dietary modifications or supplementation could be used to modify the inflammatory response is tied to a broader view of how diet and the immune system are interconnected.
-The supplements and nutraceuticals discussed here therefore lie in sharp contrast to other alleged nutraceutical or dietary supplements that have attracted during the pandemic, such as colloidal silver [809], which have no known nutritional function and can be harmful.
+The supplements and nutraceuticals discussed here therefore lie in sharp contrast to other alleged nutraceutical or dietary supplements that have attracted during the pandemic, such as colloidal silver [810], which have no known nutritional function and can be harmful.
Importantly, while little clinical evidence is available about the effects of any supplements against COVID-19, the risks associated with those discussed above are likely to be low, and in some cases, they can be obtained from dietary sources alone.
There are various other products and molecules that have garnered scientific interest and could merit further investigation.
-These include polyphenols, lipid extracts, and tomato-based nutraceuticals, all of which have been suggested for the potential prevention of cardiovascular complications of COVID-19 such as thrombosis [612,648].
-Melatonin is another supplement that has been identified as a potential antiviral agent against SARS-CoV-2 using computational methods [810], and it has also been highlighted as a potential therapeutic agent for COVID-19 due to its documented antioxidant, anti-apoptotic, immunomodulatory, and anti-inflammatory effects [648,811,812].
-Notably, melatonin, vitamin D and zinc have attracted public attention because they were included in the treatment plan of the former President of the United States upon his hospitalization due to COVID-19 [813].
+These include polyphenols, lipid extracts, and tomato-based nutraceuticals, all of which have been suggested for the potential prevention of cardiovascular complications of COVID-19 such as thrombosis [613,649].
+Melatonin is another supplement that has been identified as a potential antiviral agent against SARS-CoV-2 using computational methods [811], and it has also been highlighted as a potential therapeutic agent for COVID-19 due to its documented antioxidant, anti-apoptotic, immunomodulatory, and anti-inflammatory effects [649,812,813].
+Notably, melatonin, vitamin D and zinc have attracted public attention because they were included in the treatment plan of the former President of the United States upon his hospitalization due to COVID-19 [814].
These are just some of the many substances and supplements that are currently under investigation but as of yet lack evidence to support their use for the prevention or treatment of COVID-19.
-While there is plenty of skepticism put forward by physicians and scientists surrounding the use of supplements, these statements have not stopped consumers from purchasing these products, with one study reporting that online searches for dietary supplements in Poland began trending with the start of the pandemic [754].
+While there is plenty of skepticism put forward by physicians and scientists surrounding the use of supplements, these statements have not stopped consumers from purchasing these products, with one study reporting that online searches for dietary supplements in Poland began trending with the start of the pandemic [755].
Additionally, supplement usage increased between the first and second wave of the pandemic.
Participants reported various reasons for their use of supplements, including to improve immunity (60%), to improve overall health (57%), and to fill nutrient gaps in their diet (53%).
Other efforts to collect large datasets regarding such behavior have also sought to explore a possible association between vitamin or supplement consumption and COVID-19.
-An observational analysis of survey responses from 327,720 users of the COVID Symptom Study App found that the consumption of n-3 PUFA supplements, probiotics, multivitamins, and vitamin D was associated with a lower risk of SARS-CoV-2 infection in women but not men after adjusting for potential confounders [814].
-According to the authors, the sexual dimorphism observed may in part be because supplements may better support females due to known differences between the male and female immune systems, or it could be due to behavioral and health consciousness differences between the sexes [814].
+An observational analysis of survey responses from 327,720 users of the COVID Symptom Study App found that the consumption of n-3 PUFA supplements, probiotics, multivitamins, and vitamin D was associated with a lower risk of SARS-CoV-2 infection in women but not men after adjusting for potential confounders [815].
+According to the authors, the sexual dimorphism observed may in part be because supplements may better support females due to known differences between the male and female immune systems, or it could be due to behavioral and health consciousness differences between the sexes [815].
Certainly, randomized controlled trials are required to investigate these findings further.
-Finally, it is known that a patient’s nutritional status affects health outcomes in various infectious diseases [586], and COVID-19 is no different [584,815,816].
-Some of the main risk factors for severe COVID-19, which also happen to be linked to poor nutritional status, include obesity, hypertension, cardiovascular diseases, type II diabetes mellitus, and indeed age-related malnutrition [582,584,817].
+
Finally, it is known that a patient’s nutritional status affects health outcomes in various infectious diseases [587], and COVID-19 is no different [585,816,817].
+Some of the main risk factors for severe COVID-19, which also happen to be linked to poor nutritional status, include obesity, hypertension, cardiovascular diseases, type II diabetes mellitus, and indeed age-related malnutrition [583,585,818].
Although not the main focus of this review, it is important to consider the nutritional challenges associated with severe COVID-19 patients.
-Hospitalized COVID-19 patients tend to report an unusually high loss of appetite preceding admission, some suffer diarrhea and gastrointestinal symptoms that result in significantly lower food intake, and patients with poorer nutritional status were more likely to have worse outcomes and require nutrition therapy [818].
-Dysphagia also seems to be a significant problem in pediatric patients that suffered multisystem inflammatory syndrome [819] and rehabilitating COVID-19 patients, potentially contributing to poor nutritional status [820].
-Almost two-thirds of discharged COVID-19 ICU patients exhibit significant weight loss, of which 26% had weight loss greater than 10% [816].
-As investigated in this review, hospitalized patients also tend to exhibit vitamin D deficiency or insufficiency, which may be associated with greater disease severity [805].
+Hospitalized COVID-19 patients tend to report an unusually high loss of appetite preceding admission, some suffer diarrhea and gastrointestinal symptoms that result in significantly lower food intake, and patients with poorer nutritional status were more likely to have worse outcomes and require nutrition therapy [819].
+Dysphagia also seems to be a significant problem in pediatric patients that suffered multisystem inflammatory syndrome [820] and rehabilitating COVID-19 patients, potentially contributing to poor nutritional status [821].
+Almost two-thirds of discharged COVID-19 ICU patients exhibit significant weight loss, of which 26% had weight loss greater than 10% [817].
+As investigated in this review, hospitalized patients also tend to exhibit vitamin D deficiency or insufficiency, which may be associated with greater disease severity [806].
Therefore, further research is required to determine how dietary supplements and nutraceuticals may contribute to the treatment of severely ill and rehabilitating patients, who often rely on enteral nutrition.
-6.10 Conclusions
+6.10 Conclusions
Despite all the potential benefits of nutraceutical and dietary supplement interventions presented, currently there is a paucity of clinical evidence to support their use for the prevention or mitigation of COVID-19 infection.
-Nevertheless, optimal nutritional status can prime an individual’s immune system to protect against the effects of acute respiratory viral infections by supporting normal maintenance of the immune system [582,586].
-Nutritional strategies can also play a role in the treatment of hospitalized patients, as malnutrition is a risk to COVID-19 patients [820].
+Nevertheless, optimal nutritional status can prime an individual’s immune system to protect against the effects of acute respiratory viral infections by supporting normal maintenance of the immune system [583,587].
+Nutritional strategies can also play a role in the treatment of hospitalized patients, as malnutrition is a risk to COVID-19 patients [821].
Overall, supplementation of vitamin C, vitamin D, and zinc may be an effective method of ensuring their adequate intake to maintain optimal immune function, which may also convey beneficial effects against viral infections due to their immunomodulatory effects.
Individuals should pay attention to their nutritional status, particularly their intake of vitamin D, considering that vitamin D deficiency is widespread.
-The prevailing evidence seems to indicate an association between vitamin D deficiency with COVID-19 incidence and, potentially, severity [710].
+The prevailing evidence seems to indicate an association between vitamin D deficiency with COVID-19 incidence and, potentially, severity [711].
As a result, some international authorities have advised the general public, particularly those at high risk of infection, to consider vitamin D supplementation.
However, further well-controlled clinical trials are required to confirm these observations.
-Many supplements and nutraceuticals designed for various ailments that are available in the United States and beyond are not strictly regulated [821].
+
Many supplements and nutraceuticals designed for various ailments that are available in the United States and beyond are not strictly regulated [822].
Consequently, there can be safety and efficacy concerns associated with many of these products.
Often, the vulnerable members of society can be exploited in this regard and, unfortunately, the COVID-19 pandemic has proven no different.
-As mentioned above, the FDA has issued warnings to several companies for advertising falsified claims in relation to the preventative and therapeutic capabilities of their products against COVID-19 [822].
+As mentioned above, the FDA has issued warnings to several companies for advertising falsified claims in relation to the preventative and therapeutic capabilities of their products against COVID-19 [823].
Further intensive investigation is required to establish the effects of these nutraceuticals, if any, against COVID-19.
-Until more effective therapeutics are established, the most effective mitigation strategies consist of encouraging standard public health practices such as regular hand washing with soap, wearing a face mask, and covering a cough with your elbow [823], along with following social distancing measures, “stay at home” guidelines, expansive testing, and contact tracing [824,825].
+Until more effective therapeutics are established, the most effective mitigation strategies consist of encouraging standard public health practices such as regular hand washing with soap, wearing a face mask, and covering a cough with your elbow [824], along with following social distancing measures, “stay at home” guidelines, expansive testing, and contact tracing [825,826].
Indeed, in light of this review, it would also be pertinent to adopt a healthy diet and lifestyle following national guidelines in order to maintain optimal immune health.
Because of the broad public appeal of dietary supplements and nutraceuticals, it is important to evaluate the evidence regarding the use of such products.
We will continue to update this review as more findings become available.
@@ -2624,21 +2625,21 @@ 7.17.2 Importance
7.3 Introduction
For a highly infectious virus like SARS-CoV-2, a vaccine would hold particular value because it could bolster the immune response to the virus of the population broadly, thereby driving a lower rate of infection and likely significantly reducing fatalities.
-However, the vaccine development process has historically been slow, and vaccines fail to provide immediate prophylactic protection or treat ongoing infections [826].
+However, the vaccine development process has historically been slow, and vaccines fail to provide immediate prophylactic protection or treat ongoing infections [827].
Flu-like illnesses caused by viruses are a common target of vaccine development programs, and influenza vaccine technology in particular has made many strides.
During the H1N1 influenza outbreak, vaccine development was accelerated because of the existing infrastructure, along with the fact that regulatory agencies had already decided that vaccines produced using egg- and cell-based platforms could be licensed under the regulations used for a strain change.
Critiques of the production and distribution of the H1N1 vaccine have stressed the need for alternative development-and-manufacturing platforms that can be readily adapted to new pathogens.
-Although a monovalent H1N1 vaccine was not available before the pandemic peaked in the United States and Europe, it was available soon afterward as a stand-alone vaccine that was eventually incorporated into commercially available seasonal influenza vaccines [827].
+Although a monovalent H1N1 vaccine was not available before the pandemic peaked in the United States and Europe, it was available soon afterward as a stand-alone vaccine that was eventually incorporated into commercially available seasonal influenza vaccines [828].
If H1N1 vaccine development provides any indication, considering developing and manufacturing platforms for promising COVID-19 vaccine trials early could hasten the emergence of an effective prophylactic vaccine against SARS-CoV-2.
-The first critical step towards developing a vaccine against SARS-CoV-2 was characterizing the target, which fortunately happened early in the COVID-19 outbreak with the sequencing and dissemination of the viral genome [828].
+
The first critical step towards developing a vaccine against SARS-CoV-2 was characterizing the target, which fortunately happened early in the COVID-19 outbreak with the sequencing and dissemination of the viral genome [829].
The Coalition for Epidemic Preparedness Innovations (CEPI) is coordinating global health agencies and pharmaceutical companies to develop vaccines against SARS-CoV-2.
-As of September 2020, there were over 180 vaccine candidates against SARS-CoV-2 in development [829].
+As of September 2020, there were over 180 vaccine candidates against SARS-CoV-2 in development [830].
Unlike many global vaccine development programs previously, such as with H1N1, the vaccine development landscape for COVID-19 includes vaccines produced by a wide array of technologies.
-Experience in the field of oncology is encouraging COVID-19 vaccine developers to use next-generation approaches to vaccine development, which have led to the great diversity of vaccine development programs [830].
+Experience in the field of oncology is encouraging COVID-19 vaccine developers to use next-generation approaches to vaccine development, which have led to the great diversity of vaccine development programs [831].
These diverse technology platforms include DNA, RNA, virus-like particle, recombinant protein, both replicating and non-replicating viral vectors, live attenuated virus, and inactivated virus approaches (Figure 5).
Given the wide range of vaccines under development, it is possible that some vaccine products may eventually be shown to be more effective in certain subpopulations, such as children, pregnant women, immunocompromised patients, the elderly, etc.
-The requirements for a successful vaccine trial and deployment are complex and may require coordination between government, industry, academia, and philanthropic entities [831].
-While little is currently known about immunity to SARS-CoV-2, vaccine development typically tests for serum neutralizing activity, as this has been established as a biomarker for adaptive immunity in other respiratory illnesses [832].
+The requirements for a successful vaccine trial and deployment are complex and may require coordination between government, industry, academia, and philanthropic entities [832].
+While little is currently known about immunity to SARS-CoV-2, vaccine development typically tests for serum neutralizing activity, as this has been established as a biomarker for adaptive immunity in other respiratory illnesses [833].
Figure 5: Vaccine Development Strategies.
@@ -2647,13 +2648,13 @@ 7.
7.4 DNA Vaccines
-This vaccination method involves the direct introduction of a plasmid containing a DNA sequence encoding the antigen(s) against which an immune response is sought into appropriate tissues [833].
+
This vaccination method involves the direct introduction of a plasmid containing a DNA sequence encoding the antigen(s) against which an immune response is sought into appropriate tissues [834].
This approach may offer several advantages over traditional vaccination approaches, such as the stimulation of both B- as well as T-cell responses and the absence of any infectious agent.
-Currently, a Phase I safety and immunogenicity clinical trial of INO-4800, a prophylactic vaccine against SARS-CoV-2, is underway [834].
+Currently, a Phase I safety and immunogenicity clinical trial of INO-4800, a prophylactic vaccine against SARS-CoV-2, is underway [835].
The vaccine developer Inovio Pharmaceuticals Technology is overseeing administration of INO-4800 by intradermal injection followed by electroporation with the CELLECTRA® device to healthy volunteers.
Electroporation is the application of brief electric pulses to tissues in order to permeabilize cell membranes in a transient and reversible manner.
-It has been shown that electroporation can enhance vaccine efficacy by up to 100-fold, as measured by increases in antigen-specific antibody titers [835].
-The safety of the CELLECTRA® device has been studied for over seven years, and these studies support the further development of electroporation as a safe vaccine delivery method [836].
+It has been shown that electroporation can enhance vaccine efficacy by up to 100-fold, as measured by increases in antigen-specific antibody titers [836].
+The safety of the CELLECTRA® device has been studied for over seven years, and these studies support the further development of electroporation as a safe vaccine delivery method [837].
The temporary formation of pores through electroporation facilitates the successful transportation of macromolecules into cells, allowing cells to robustly take up INO-4800 for the production of an antibody response.
Approved by the U.S. FDA on April 6, 2020, the Phase I study is enrolling up to 40 healthy adult volunteers in Philadelphia, PA at the Perelman School of Medicine and at the Center for Pharmaceutical Research in Kansas City, MO.
The trial has two experimental arms corresponding to the two locations.
@@ -2664,98 +2665,98 @@
7.4<
Although exciting, the cost of vaccine manufacturing and electroporation may make scaling the use of this technology for prophylactic use for the general public difficult.
7.5 RNA Vaccines
RNA vaccines are nucleic-acid based modalities that code for viral antigens against which the human body elicits a humoral and cellular immune response.
-The mRNA technology is transcribed in vitro and delivered to cells via lipid nanoparticles (LNP) [837].
-They are recognized by ribosomes in vivo and then translated and modified into functional proteins [838].
-The resulting intracellular viral proteins are displayed on surface MHC proteins, provoking a strong CD8+ T cell response as well as a CD4+ T cell and B cell-associated antibody responses [838].
+The mRNA technology is transcribed in vitro and delivered to cells via lipid nanoparticles (LNP) [838].
+They are recognized by ribosomes in vivo and then translated and modified into functional proteins [839].
+The resulting intracellular viral proteins are displayed on surface MHC proteins, provoking a strong CD8+ T cell response as well as a CD4+ T cell and B cell-associated antibody responses [839].
Naturally, mRNA is not very stable and can degrade quickly in the extracellular environment or the cytoplasm.
-The LNP covering protects the mRNA from enzymatic degradation outside of the cell [839].
+The LNP covering protects the mRNA from enzymatic degradation outside of the cell [840].
Codon optimization to prevent secondary structure formation and modifications of the poly-A tail as well as the 5’ untranslated region to promote ribosomal complex binding can increase mRNA expression in cells.
-Furthermore, purifying out double-stranded RNA and immature RNA with FPLC (fast performance liquid chromatography) and HPLC (high performance liquid chromatography) technology will improve translation of the mRNA in the cell [838,840].
+Furthermore, purifying out double-stranded RNA and immature RNA with FPLC (fast performance liquid chromatography) and HPLC (high performance liquid chromatography) technology will improve translation of the mRNA in the cell [839,841].
Vaccines based on mRNA delivery confer many advantages over traditional viral vectored vaccines and DNA vaccines.
-In comparison to live attenuated viruses, mRNA vaccines are non-infectious and can be synthetically produced in an egg-free, cell-free environment, thereby reducing the risk of a detrimental immune response in the host [841].
-Unlike DNA vaccines, mRNA technologies are naturally degradable and non-integrating, and they do not need to cross the nuclear membrane in addition to the plasma membrane for their effects to be seen [838].
+In comparison to live attenuated viruses, mRNA vaccines are non-infectious and can be synthetically produced in an egg-free, cell-free environment, thereby reducing the risk of a detrimental immune response in the host [842].
+Unlike DNA vaccines, mRNA technologies are naturally degradable and non-integrating, and they do not need to cross the nuclear membrane in addition to the plasma membrane for their effects to be seen [839].
Furthermore, mRNA vaccines are easily, affordably, and rapidly scalable.
Although mRNA vaccines have been developed for therapeutic and prophylactic purposes, none have previously been licensed or commercialized.
-Nevertheless, they have shown promise in animal models and preliminary clinical trials for several indications, including rabies, coronavirus, influenza, and cytomegalovirus [842].
-Preclinical data previously identified effective antibody generation against full-length FPLC-purified influenza hemagglutinin stalk-encoding mRNA in mice, rabbits, and ferrets [843].
-Similar immunological responses for mRNA vaccines were observed in humans in Phase I and II clinical trials operated by the pharmaceutical-development companies Curevac and Moderna for rabies, flu, and zika [840].
-Positively charged bilayer LNPs carrying the mRNA attract negatively charged cell membranes, endocytose into the cytoplasm [839], and facilitate endosomal escape.
-LNPs can be coated with modalities recognized and engulfed by specific cell types, and LNPs that are 150 nm or less effectively enter into lymphatic vessels [839,844].
+Nevertheless, they have shown promise in animal models and preliminary clinical trials for several indications, including rabies, coronavirus, influenza, and cytomegalovirus [843].
+Preclinical data previously identified effective antibody generation against full-length FPLC-purified influenza hemagglutinin stalk-encoding mRNA in mice, rabbits, and ferrets [844].
+Similar immunological responses for mRNA vaccines were observed in humans in Phase I and II clinical trials operated by the pharmaceutical-development companies Curevac and Moderna for rabies, flu, and zika [841].
+Positively charged bilayer LNPs carrying the mRNA attract negatively charged cell membranes, endocytose into the cytoplasm [840], and facilitate endosomal escape.
+LNPs can be coated with modalities recognized and engulfed by specific cell types, and LNPs that are 150 nm or less effectively enter into lymphatic vessels [840,845].
Therefore, this technology holds great potential for targeted delivery of modified mRNA.
-There are three types of RNA vaccines: non-replicating, in vivo self-replicating, and in vitro dendritic cell non-replicating [845].
+
There are three types of RNA vaccines: non-replicating, in vivo self-replicating, and in vitro dendritic cell non-replicating [846].
Non-replicating mRNA vaccines consist of a simple open reading frame (ORF) for the viral antigen flanked by the 5’ UTR and 3’ poly-A tail.
-In vivo self-replicating vaccines encode a modified viral genome derived from single-stranded, positive sense RNA alphaviruses [838,840].
+In vivo self-replicating vaccines encode a modified viral genome derived from single-stranded, positive sense RNA alphaviruses [839,841].
The RNA genome encodes the viral antigen along with proteins of the genome replication machinery, including an RNA polymerase.
-Structural proteins required for viral assembly are not included in the engineered genome [838].
-Self-replicating vaccines produce more viral antigens over a longer period of time, thereby evoking a more robust immune response [845].
+Structural proteins required for viral assembly are not included in the engineered genome [839].
+Self-replicating vaccines produce more viral antigens over a longer period of time, thereby evoking a more robust immune response [846].
Finally, in vitro dendritic cell non-replicating RNA vaccines limit transfection to dendritic cells.
Dendritic cells are potent antigen-presenting immune cells that easily take up mRNA and present fragments of the translated peptide on their MHC proteins, which can then interact with T cell receptors.
-Ultimately, primed T follicular helper cells can stimulate germinal center B cells that also present the viral antigen to produce antibodies against the virus [846].
-These cells are isolated from the patient, grown and transfected ex vivo, and reintroduced to the patient [847].
+Ultimately, primed T follicular helper cells can stimulate germinal center B cells that also present the viral antigen to produce antibodies against the virus [847].
+These cells are isolated from the patient, grown and transfected ex vivo, and reintroduced to the patient [848].
Given the potential for this technology to be quickly adapted for a new pathogen, it has held significant interest for the treatment of COVID-19.
-In the vaccines developed under this approach, the spike protein, which is immunogenic [39], can be furnished to the immune system in order to train its response.
-The vaccine candidates developed against SARS-CoV-2 using mRNA vectors utilize similar principles and technologies, although there are slight differences in implementation among candidates such as the formulation of the platform and the specific components of the spike protein encapsulated (e.g., the full Spike protein vs. the RBD alone) [848].
+In the vaccines developed under this approach, the spike protein, which is immunogenic [41], can be furnished to the immune system in order to train its response.
+The vaccine candidates developed against SARS-CoV-2 using mRNA vectors utilize similar principles and technologies, although there are slight differences in implementation among candidates such as the formulation of the platform and the specific components of the spike protein encapsulated (e.g., the full Spike protein vs. the RBD alone) [849].
The results of the interim analyses of two mRNA vaccine candidates became available at the end of 2020 and provided strong support for this emerging approach to vaccination.
Below we describe the results available as of February 2021 for two such candidates, mRNA-1273 produced by ModernaTX and BNT162b2 produced by Pfizer, Inc. and BioNTech.
7.5.1 ModernaTX mRNA Vaccine
ModernaTX’s mRNA-1273 vaccine, which is an was the first COVID-19 vaccine to enter a phase I clinical trial in the United States.
-In this trial, Moderna spearheaded an investigation on the immunogenicity and reactogenicity of mRNA-1273, a conventional lipid nanoparticle encapsulated RNA encoding a full-length prefusion stabilized S protein for SARS-CoV-2 [849].
-An initial report described the results of enrolling forty-five participants who were administered intramuscular injections of mRNA-1273 in their deltoid muscle on day 1 and day 29, and then followed for the next twelve months [832].
+In this trial, Moderna spearheaded an investigation on the immunogenicity and reactogenicity of mRNA-1273, a conventional lipid nanoparticle encapsulated RNA encoding a full-length prefusion stabilized S protein for SARS-CoV-2 [850].
+An initial report described the results of enrolling forty-five participants who were administered intramuscular injections of mRNA-1273 in their deltoid muscle on day 1 and day 29, and then followed for the next twelve months [833].
Healthy males and non-pregnant females aged 18-55 years were recruited for this study and divided into three groups receiving 25, 100, or 250 micrograms (μg) of mRNA-1273.
-IgG ELISA assays on patient serology samples were used to examine the immunogenicity of the vaccine [849].
+IgG ELISA assays on patient serology samples were used to examine the immunogenicity of the vaccine [850].
Binding antibodies were observed at two weeks after the first dose at all concentrations.
At the time point one week after the second dose was administered on day 29, the pseudotyped lentivirus reporter single-round-of-infection neutralization assay (PsVNA), which was used to assess neutralizing activity, reached a median level similar to the median observed in convalescent plasma samples.
Participants reported mild and moderate systemic adverse events after the day 1 injection, and one severe local event was observed in each of the two highest dose levels.
The second injection led to severe systemic adverse events for three of the participants at the highest dose levels, with one participant in the group being evaluated at an urgent care center on the day after the second dose.
The reported localized adverse events from the second dose were similar to those from the first.
-Several months later, a press release from ModernaTX described the results of the first interim analysis of the vaccine [850].
-On November 16, 2020, a report was released describing the initial results from Phase III testing, corresponding to the first 95 cases of COVID-19 in the 30,000 enrolled participants [850], with additional data released to the FDA on December 17, 2020 [851].
-These results were subsequently published in a peer-reviewed journal (The New England Journal of Medicine) on December 30, 2020 [852].
-The first group of 30,420 study participants were randomized to receive the vaccine or a placebo at a ratio of 1:1 [852].
-Administration occurred at 99 sites within the United States in two sessions, spaced 28 days apart [852,853].
-Patients reporting COVID-19 symptoms upon follow-up were tested for SARS-CoV-2 using a nasopharyngeal swab that was evaluated with RT-PCR [853].
+
Several months later, a press release from ModernaTX described the results of the first interim analysis of the vaccine [851].
+On November 16, 2020, a report was released describing the initial results from Phase III testing, corresponding to the first 95 cases of COVID-19 in the 30,000 enrolled participants [851], with additional data released to the FDA on December 17, 2020 [852].
+These results were subsequently published in a peer-reviewed journal (The New England Journal of Medicine) on December 30, 2020 [853].
+The first group of 30,420 study participants were randomized to receive the vaccine or a placebo at a ratio of 1:1 [853].
+Administration occurred at 99 sites within the United States in two sessions, spaced 28 days apart [853,854].
+Patients reporting COVID-19 symptoms upon follow-up were tested for SARS-CoV-2 using a nasopharyngeal swab that was evaluated with RT-PCR [854].
The initial preliminary analysis reported the results of the cases observed up until a cut-off date of November 11, 2020.
-Of these first 95 cases reported, 90 occurred in participants receiving the placebo compared to 5 cases in the group receiving the vaccine [850].
+Of these first 95 cases reported, 90 occurred in participants receiving the placebo compared to 5 cases in the group receiving the vaccine [851].
These results suggested the vaccine is 94.5% effective in preventing COVID-19.
Additionally, eleven severe cases of COVID-19 were observed, and all eleven occurred in participants receiving the placebo.
-The publication reported the results through an extended cut-off date of November 21, 2020, corresponding to 196 cases [852].
+The publication reported the results through an extended cut-off date of November 21, 2020, corresponding to 196 cases [853].
Of these, 11 occurred in the vaccine group and 185 in the placebo group, corresponding to an efficacy of 94.1%.
Once again, all of the severe cases of COVID-19 observed (n=30) occurred in the placebo group, including one death.
Thus, as more cases are reported, the efficacy of the vaccine has remained above 90%, and no cases of severe COVID-19 have yet been reported in participants receiving the vaccine.
These findings suggest the possibility that the vaccine might bolster immune defenses even for subjects who do still develop a SARS-CoV-2 infection.
-The study was designed with an explicit goal of including individuals at high risk for COVID-19, including older adults, people with underlying health conditions, and people of color [854].
-The Phase III trial population was comprised by approximately 25.3% adults over age 65 in the initial report and 24.8% in the publication [853].
-Among the cases reported by both interim analyses, 16-17% occurred in older adults [850,852]..
-Additionally, approximately 10% of participants identified a Black or African-American background and 20% identified Hispanic or Latino ethnicity [852,853].
-Among the first 95 cases, 12.6% occurred in participants identifying a Hispanic or Latino background and 4% in participants reporting a Black or African-American background [850]; in the publication, they indicated only that 41 of the cases reported in the placebo group and 1 case in the treatment group occurred in “communities of color”, corresponding to 21.4% of all cases [852].
+The study was designed with an explicit goal of including individuals at high risk for COVID-19, including older adults, people with underlying health conditions, and people of color [855].
+The Phase III trial population was comprised by approximately 25.3% adults over age 65 in the initial report and 24.8% in the publication [854].
+Among the cases reported by both interim analyses, 16-17% occurred in older adults [851,853]..
+Additionally, approximately 10% of participants identified a Black or African-American background and 20% identified Hispanic or Latino ethnicity [853,854].
+Among the first 95 cases, 12.6% occurred in participants identifying a Hispanic or Latino background and 4% in participants reporting a Black or African-American background [851]; in the publication, they indicated only that 41 of the cases reported in the placebo group and 1 case in the treatment group occurred in “communities of color”, corresponding to 21.4% of all cases [853].
While the sample size in both analyses is small relative to the study population of over 30,000, these results suggest that the vaccine is likely to be effective in people from a variety of backgrounds.
By all indications, this vaccine is likely to be highly useful in mitigating the damage of SARS-CoV-2.
-In-depth safety data was released by ModernaTX as part of their application for an EUA from the FDA and summarized in the associated publication [852,853].
+
In-depth safety data was released by ModernaTX as part of their application for an EUA from the FDA and summarized in the associated publication [853,854].
Because the detail provided in the report is greater than that provided in the publication, here we emphasize the results observed at the time of the first analysis.
-Overall, a large percentage of participants reported adverse effects when solicited, and these reports were higher in the vaccine group than in the placebo group (94.5% versus 59.5%, respectively, at the time of the initial analysis) [853].
-Some of these events met the criteria for grade 3 (local or systemic) or grade 4 (systemic only) toxicity [853], but most were grade 1 or grade 2 and lasted 2-3 days [852].
-The most common local adverse reaction was pain at the injection site, reported by 83.7% of participants receiving the first dose of the vaccine and 88.4% upon receiving the second dose, compared to 19.8% and 19.8% and 17.0%, respectively, of patients in the placebo condition [853].
+Overall, a large percentage of participants reported adverse effects when solicited, and these reports were higher in the vaccine group than in the placebo group (94.5% versus 59.5%, respectively, at the time of the initial analysis) [854].
+Some of these events met the criteria for grade 3 (local or systemic) or grade 4 (systemic only) toxicity [854], but most were grade 1 or grade 2 and lasted 2-3 days [853].
+The most common local adverse reaction was pain at the injection site, reported by 83.7% of participants receiving the first dose of the vaccine and 88.4% upon receiving the second dose, compared to 19.8% and 19.8% and 17.0%, respectively, of patients in the placebo condition [854].
Fewer than 5% of vaccine recipients reported grade 3 pain at either administration.
-Other frequent local reactions included erythema, swelling, and lymphadenopathy [853].
-For systemic adverse reactions, fatigue was the most common [853].
-Among participants receiving either dose of the vaccine, 68.5% reported fatigue compared to 36.1% participants receiving the placebo [853].
-The level of fatigue experienced was usually fairly mild, with only 9.6% and 1.3% of participants in the vaccine and placebo conditions, respectively, reporting grade 3 fatigue [853], which corresponds to significant interference with daily activity [855].
-Based on the results of the report, an EUA was issued on December 18, 2020 to allow distribution of this vaccine in the United States [856], and it was shortly followed by an Interim Order authorizing distribution of the vaccine in Canada [857] and a conditional marketing authorization by the European Medicines Agency to facilitate distribution in the European Union [858].
+Other frequent local reactions included erythema, swelling, and lymphadenopathy [854].
+For systemic adverse reactions, fatigue was the most common [854].
+Among participants receiving either dose of the vaccine, 68.5% reported fatigue compared to 36.1% participants receiving the placebo [854].
+The level of fatigue experienced was usually fairly mild, with only 9.6% and 1.3% of participants in the vaccine and placebo conditions, respectively, reporting grade 3 fatigue [854], which corresponds to significant interference with daily activity [856].
+Based on the results of the report, an EUA was issued on December 18, 2020 to allow distribution of this vaccine in the United States [857], and it was shortly followed by an Interim Order authorizing distribution of the vaccine in Canada [858] and a conditional marketing authorization by the European Medicines Agency to facilitate distribution in the European Union [859].
7.5.2 Pfizer/BioNTech BNT162b2
ModernaTX was, in fact, the second company to release news of a successful interim analysis of an mRNA vaccine and receive an EUA.
-The first report came from Pfizer and BioNTech’s mRNA vaccine BNT162b2 on November 9, 2020 [859], and a preliminary report was published in the New England Journal of Medicine one month later [304].
-The vaccine candidate is contains the full prefusion stabilized, membrane-anchored SARS-CoV-2 spike protein in a vaccine formulation based on modified mRNA (modRNA) technology [860,861].
-This vaccine candidate should not be confused with a similar candidate from Pfizer/BioNTech, BNT162b1, that delivered only the RBD of the spike protein [862,863], which was not advanced to a stage III trial because of the improved reactogenicity/immunogenicity profile of BNT162b2 [305].
-During the Phase III trial of BNT162b2, 43,538 participants were enrolled 1:1 in the placebo and the vaccine candidate and received two 30-μg doses 21 days apart [304].
-Of these enrolled participants, 21,720 received BNT162b2 and 21,728 received a placebo [304].
+The first report came from Pfizer and BioNTech’s mRNA vaccine BNT162b2 on November 9, 2020 [860], and a preliminary report was published in the New England Journal of Medicine one month later [306].
+The vaccine candidate is contains the full prefusion stabilized, membrane-anchored SARS-CoV-2 spike protein in a vaccine formulation based on modified mRNA (modRNA) technology [861,862].
+This vaccine candidate should not be confused with a similar candidate from Pfizer/BioNTech, BNT162b1, that delivered only the RBD of the spike protein [863,864], which was not advanced to a stage III trial because of the improved reactogenicity/immunogenicity profile of BNT162b2 [307].
+During the Phase III trial of BNT162b2, 43,538 participants were enrolled 1:1 in the placebo and the vaccine candidate and received two 30-μg doses 21 days apart [306].
+Of these enrolled participants, 21,720 received BNT162b2 and 21,728 received a placebo [306].
Recruitment occurred at 135 sites across six countries: Argentina, Brazil, Germany, South Africa, Turkey, and the United States.
-An initial press release described the first 94 cases, which were consistent with 90% efficacy of the vaccine at 7 days following the second dose [859].
+An initial press release described the first 94 cases, which were consistent with 90% efficacy of the vaccine at 7 days following the second dose [860].
The release of the full trial information covered a longer period and analyzed the first 170 cases occurring at least 7 days after the second dose, 8 of which occurred in patients who had received BNT162b2.
-The press release characterized the study population as diverse, reporting that 42% of the participants worldwide came from non-white backgrounds, including 10% Black and 26% Hispanic or Latino [864].
-Within the United States, 10% and 13% of participants, respectively, identified themselves as having Black or Hispanic/Latino backgrounds [864].
-Additionally, 41% of participants worldwide were 56 years of age or older [864], and they reported that the efficacy of the vaccine in adults over 65 was 94% [865].
-The primary efficacy analysis of the Phase III study was concluded on November 18, 2020 [865], and the final results indicted 94.6% efficacy of the vaccine [304]v.
-The safety profile of the vaccine was also assessed [304].
+The press release characterized the study population as diverse, reporting that 42% of the participants worldwide came from non-white backgrounds, including 10% Black and 26% Hispanic or Latino [865].
+Within the United States, 10% and 13% of participants, respectively, identified themselves as having Black or Hispanic/Latino backgrounds [865].
+Additionally, 41% of participants worldwide were 56 years of age or older [865], and they reported that the efficacy of the vaccine in adults over 65 was 94% [866].
+The primary efficacy analysis of the Phase III study was concluded on November 18, 2020 [866], and the final results indicted 94.6% efficacy of the vaccine [306]v.
+The safety profile of the vaccine was also assessed [306].
A subset of patients were followed for reactogenicity using electronic diaries, with the data collected from these 8,183 participants comprising the solicited safety events analyzed.
Much like those who received the ModernaTX vaccine candidate, a large proportion of participants reported experiencing site injection pain within 7 days of vaccination.
While percentages are broken down by age group in the publication, these proportions correspond to approximately 78% and 73% of all participants after the first and second doses, respectively, overall.
@@ -2764,8 +2765,8 @@
[866,867].
-As of December 11, 2020, the United States FDA approved this vaccine under an emergency use authorization [868].
+Based on the efficacy and safety information released, the vaccine was approved in early December by the United Kingdom’s Medicines and Healthcare Products Regulatory Agency with administration outside of a clinical trial beginning on December 8, 2020 [867,868].
+As of December 11, 2020, the United States FDA approved this vaccine under an emergency use authorization [869].
7.6 Viral Vector Vaccines
7.6.1 COVID-19 Vaccine AstraZeneca
7.6.2 Sputnik-V
@@ -2784,121 +2785,121 @@ also included a brief summary of the potential of adjuvants for these vaccines, including a brief description of some already commonly used adjuvants.
+A review on the development of SARS-CoV-2 vaccines [870] also included a brief summary of the potential of adjuvants for these vaccines, including a brief description of some already commonly used adjuvants.
Different adjuvants can regulate different types of immune responses, so the type or combination of adjuvants used in a vaccine will depend on both the type of vaccine and concern related to efficacy and safety.
-A variety of possible mechanisms for adjuvants have been researched [870,871,872], including the following: induction of DAMPs that can be recognized by certain PRRs of the innate immune system; functioning as PAMP that can also be recognized by certain PRRs; and more generally enhancing the humoral or cellular immune responses.
+A variety of possible mechanisms for adjuvants have been researched [871,872,873], including the following: induction of DAMPs that can be recognized by certain PRRs of the innate immune system; functioning as PAMP that can also be recognized by certain PRRs; and more generally enhancing the humoral or cellular immune responses.
Selection of one or more adjuvants requires considering how to promote the advantageous effects of the components and/or immune response and, likewise, to inhibit possible deleterious effects.
There are also considerations related to the method of delivering (or co-delivering) the adjuvant and antigen components of a vaccine.
7.10.2 Trained Immunity
Another approach that is being investigated explores the potential for vaccines that are not made from the SARS-CoV-2 virus to confer what has been termed trained immunity.
-In a recent review [873], trained immunity was defined as forms of memory that are temporary (e.g., months or years) and reversible.
+In a recent review [874], trained immunity was defined as forms of memory that are temporary (e.g., months or years) and reversible.
It is induced by exposure to whole-microorganism vaccines or other microbial stimuli that generates heterologous protective effects.
Trained immunity can be displayed by innate immune cells or innate immune features of other cells, and it is characterized by alterations to immune responsiveness to future immune challenges due to epigenetic and metabolic mechanisms.
These alterations can take the form of either an increased or decreased response to immune challenge by a pathogen.
-Trained immunity elicited by non-SARS-CoV-2 whole-microorganism vaccines could potentially improve SARS-CoV-2 susceptibility or severity [874].
+Trained immunity elicited by non-SARS-CoV-2 whole-microorganism vaccines could potentially improve SARS-CoV-2 susceptibility or severity [875].
One type of stimulus which research indicates can induce trained immunity is bacillus Calmette-Guerin (BCG) vaccination.
BCG is an attenuated form of bacteria Mycobacterium bovis.
The vaccine is most commonly administered for the prevention of tuberculosis in humans.
Clinical trials in non-SARS-CoV-2-infected adults have been designed to assess whether BCG vaccination could have prophylactic effects against SARS-CoV-2 by reducing susceptibility, preventing infection, or reducing disease severity.
-A number of trials are now evaluating the effects of the BCG vaccine or the related vaccine VPM1002 [874,875,876,877,878,879,880,881,882,883,884,885,886,887,888].
+A number of trials are now evaluating the effects of the BCG vaccine or the related vaccine VPM1002 [875,876,877,878,879,880,881,882,883,884,885,886,887,888,889].
The ongoing trials are using a number of different approaches.
Some trials enroll healthcare workers, other trials hospitalized elderly adults without immunosuppression who get vaccinated with placebo or BCG at hospital discharge, and yet another set of trials older adults (>50 years) under chronic care for conditions like hypertension and diabetes.
One set of trials, for example, uses time until first infection as the primary study endpoint; more generally, outcomes measured in some of these trials are related to incidence of disease and disease severity or symptoms.
-Some analyses have suggested a possible correlation at the country level between the frequency of BCG vaccination (or BCG vaccination policies) and the severity of COVID-19 [874].
+Some analyses have suggested a possible correlation at the country level between the frequency of BCG vaccination (or BCG vaccination policies) and the severity of COVID-19 [875].
Currently it is unclear whether this correlation has any connection to trained immunity.
Many possible confounding factors are also likely to vary among countries, such as age distribution, detection efficiency, stochastic epidemic dynamic effects, differences in healthcare capacity over time in relation to epidemic dynamics, and these have not been adequately accounted for in current analyses.
It is unclear whether there is an effect of the timing of BCG vaccination, both during an individual’s life cycle and relative to the COVID-19 pandemic.
-Additionally, given that severe SARS-CoV-2 may be associated with a dysregulated immune response, it is unclear what alterations to the immune response would be most likely to be protective versus pathogenic (e.g., [112,874,889,890]).
-The article [874] proposes that trained immunity might lead to an earlier and stronger response, which could in turn reduce viremia and the risk of later, detrimental immunopathology.
+Additionally, given that severe SARS-CoV-2 may be associated with a dysregulated immune response, it is unclear what alterations to the immune response would be most likely to be protective versus pathogenic (e.g., [114,875,890,891]).
+The article [875] proposes that trained immunity might lead to an earlier and stronger response, which could in turn reduce viremia and the risk of later, detrimental immunopathology.
While trained immunity is an interesting possible avenue to complement vaccine development efforts through the use of an existing vaccine, additional research is required to assess whether the BCG vaccine is likely to confer trained immunity in the case of SARS-CoV-2.
7.11 Discussion
Additionally, major advances in vaccines using mRNA and adenoviruses that have led to three vaccines becoming available or close to becoming available in late 2020 (Figure 4).
Though some concerns remain about the duration of sustained immunity for convalescents, vaccine development efforts are ongoing and show initial promising results.
The Moderna trial, for example, reported that the neutralizing activity in participants who received two doses of the vaccine was similar to that observed in convalescent plasma.
-One of the two mRNA vaccines, Pfizer and BioNTech’s BNT162b2, has been issued an EUA for patients as young as 16 [891], while ModernaTX has begun a clinical trial to assess its mRNA vaccine in adolescents ages 12 to 18 [892].
+One of the two mRNA vaccines, Pfizer and BioNTech’s BNT162b2, has been issued an EUA for patients as young as 16 [892], while ModernaTX has begun a clinical trial to assess its mRNA vaccine in adolescents ages 12 to 18 [893].
8 Social Factors Influencing COVID-19 Exposure and Outcomes
8.1 Social Factors Influencing COVID-19 Outcomes
In addition to understanding the fundamental biology of the SARS-CoV-2 virus and COVID-19, it is critical to consider how the broader environment can influence both COVID-19 outcomes and efforts to develop and implement treatments for the disease.
The evidence clearly indicates that social environmental factors are critical determinants of individuals’ and communities’ risks related to COVID-19.
There are distinct components to COVID-19 susceptibility, and an individual’s risk can be elevated at one or all stages from exposure to recovery/mortality: an individual may be more likely to be exposed to the virus, more likely to get infected once exposed, more likely to have serious complications once infected, and be less likely to receive adequate care once they are seriously ill.
-The fact that differences in survival between Black and white patients were no longer significant after controlling for comorbidities and socioeconomic status (type of insurance, neighborhood deprivation score, and hospital where treatment was received) in addition to sex and age [893] underscores the relevance of social factors to understanding mortality differences between racial and ethnic groups.
-Moreover, the Black patients were younger and more likely to be female than white patients, yet still had a higher mortality rate without correction for the other variables [893].
+The fact that differences in survival between Black and white patients were no longer significant after controlling for comorbidities and socioeconomic status (type of insurance, neighborhood deprivation score, and hospital where treatment was received) in addition to sex and age [894] underscores the relevance of social factors to understanding mortality differences between racial and ethnic groups.
+Moreover, the Black patients were younger and more likely to be female than white patients, yet still had a higher mortality rate without correction for the other variables [894].
Here, we outline a few systemic reasons that may exacerbate the COVID-19 pandemic in communities of color.
8.2 Factors Observed to be Associated with Susceptibility
As COVID-19 has spread into communities around the globe, it has become clear that the risks associated with this disease are not equally shared by all individuals or all communities.
Significant disparities in outcomes have led to interest in the demographic, biomedical, and social factors that influence COVID-19 severity.
Untangling the factors influencing COVID-19 susceptibility is a complex undertaking.
-Among patients who are admitted to the hospital, outcomes have generally been poor, with rates of admission to the intensive care unit (ICU) upwards of 15% in both Wuhan, China and Italy [34,894,895].
-However, hospitalization rates vary by location [896].
+Among patients who are admitted to the hospital, outcomes have generally been poor, with rates of admission to the intensive care unit (ICU) upwards of 15% in both Wuhan, China and Italy [36,895,896].
+However, hospitalization rates vary by location [897].
This variation may be influenced by demographic (e.g., average age in the area), medical (e.g., the prevalence of comorbid conditions such as diabetes), and social (e.g., income or healthcare availability) factors that vary geographically.
Additionally, some of the same factors may influence an individual’s probability of exposure to SARS-CoV-2, their risk of developing a more serious case of COVID-19 that would require hospitalization, and their access to medical support.
As a result, quantifying or comparing susceptibility among individuals, communities, or other groups requires consideration of a number of complex phenomena that intersect across many disciplines of research.
In this section, the term “risk factor” is used to refer to variables that are statistically associated with more severe COVID-19 outcomes.
Some are intrinsic characteristics that have been observed to carry an association with variation in outcomes, whereas others may be more functionally linked to the pathophysiology of COVID-19.
8.2.1 Patient Traits Associated with Increased Risk
-Two traits that have been consistently associated with more severe COVID-19 outcomes are male sex and advanced age (typically defined as 60 or older, with the greatest risk among those 85 and older [897]).
-In the United States, males and older individuals diagnosed with COVID-19 were found to be more likely to require hospitalization [898,899].
-A retrospective study of hospitalized Chinese patients [35] found that a higher probability of mortality was associated with older age, and world-wide, population age structure has been found to be an important variable for explaining differences in outbreak severity [900].
-The CFR for adults over 80 has been estimated upwards of 14% or even 20% [901].
-Male sex has also been identified as a risk factor for severe COVID-19 outcomes, including death [902,903,904].
-Early reports from China and Europe indicated that even though the case rates were similar across males and females, males were at elevated risk for hospital admission, ICU admission, and death [903], although data from some US states indicates more cases among females, potentially due to gender representation in care-taking professions [905].
-In older age groups (e.g., age 60 and older), comparable absolute numbers of male and female cases actually suggests a higher rate of occurrence in males, due to increased skew in the sex ratio [903].
-Current estimates based on worldwide data suggest that, compared to females, males may be 30% more likely to be hospitalized, 80% more likely to be admitted to the ICU, and 40% more likely to die as a result of COVID-19 [904].
-There also may be a compounding effect of advanced age and male sex, with differences time to recovery worst for males over 60 years old relative to female members of their age cohort [906].
+Two traits that have been consistently associated with more severe COVID-19 outcomes are male sex and advanced age (typically defined as 60 or older, with the greatest risk among those 85 and older [898]).
+In the United States, males and older individuals diagnosed with COVID-19 were found to be more likely to require hospitalization [899,900].
+A retrospective study of hospitalized Chinese patients [37] found that a higher probability of mortality was associated with older age, and world-wide, population age structure has been found to be an important variable for explaining differences in outbreak severity [901].
+The CFR for adults over 80 has been estimated upwards of 14% or even 20% [902].
+Male sex has also been identified as a risk factor for severe COVID-19 outcomes, including death [903,904,905].
+Early reports from China and Europe indicated that even though the case rates were similar across males and females, males were at elevated risk for hospital admission, ICU admission, and death [904], although data from some US states indicates more cases among females, potentially due to gender representation in care-taking professions [906].
+In older age groups (e.g., age 60 and older), comparable absolute numbers of male and female cases actually suggests a higher rate of occurrence in males, due to increased skew in the sex ratio [904].
+Current estimates based on worldwide data suggest that, compared to females, males may be 30% more likely to be hospitalized, 80% more likely to be admitted to the ICU, and 40% more likely to die as a result of COVID-19 [905].
+There also may be a compounding effect of advanced age and male sex, with differences time to recovery worst for males over 60 years old relative to female members of their age cohort [907].
Both of these risk factors can be approached through the lens of biology.
-The biological basis for greater susceptibility with age is likely linked to the prevalence of extenuating health conditions such as heart failure or diabetes [901].
+The biological basis for greater susceptibility with age is likely linked to the prevalence of extenuating health conditions such as heart failure or diabetes [902].
Several hypotheses have been proposed to account for differences in severity between males and females.
-For example, some evidence suggests that female sex hormones may be protective [903,905].
-ACE2 expression in the kidneys of male mice was observed to be twice as high as that of females, and a regulatory effect of estradiol on ACE2 expression was demonstrated by removing the gonads and then supplementing with estradiol [905,907].
-Other work in mice has shown an inverse association between mortality due to SARS-CoV-1 and estradiol, suggesting a protective role for the sex hormone [905].
+For example, some evidence suggests that female sex hormones may be protective [904,906].
+ACE2 expression in the kidneys of male mice was observed to be twice as high as that of females, and a regulatory effect of estradiol on ACE2 expression was demonstrated by removing the gonads and then supplementing with estradiol [906,908].
+Other work in mice has shown an inverse association between mortality due to SARS-CoV-1 and estradiol, suggesting a protective role for the sex hormone [906].
Similarly, evidence suggests that similar patterns might be found in other tissues.
-A preliminary analysis identified higher levels of ACE2 expression in the myocardium of male patients with aortic valve stenosis showed than female patients, although this pattern was not found in controls [903].
-Additionally, research has indicated that females respond to lower doses than males of heart medications that act on the Renin angiotensin aldosterone system (RAAS) pathway, which is shared with ACE2 [903].
-Additionally, several components of the immune response, including the inflammatory response, may differ in intensity and timing between males and females [905,907].
-This hypothesis is supported by some preliminary evidence showing that female patients who recovered from severe COVID-19 had higher antibody titers than males [905].
-Sex steroids can also bind to immune cell receptors to influence cytokine production [903].
-Additionally, social factors may influence risks related to both age and sex: for example, older adults are more likely to live in care facilities, which have been a source for a large number of outbreaks [908], and gender roles may also influence exposure and/or susceptibility due to differences in care-taking and/or risky behaviors (e.g., caring for elder relatives and smoking, respectively) [903] among men and women (however, it should be noted that both transgender men and women are suspected to be at heightened risk [909].)
+A preliminary analysis identified higher levels of ACE2 expression in the myocardium of male patients with aortic valve stenosis showed than female patients, although this pattern was not found in controls [904].
+Additionally, research has indicated that females respond to lower doses than males of heart medications that act on the Renin angiotensin aldosterone system (RAAS) pathway, which is shared with ACE2 [904].
+Additionally, several components of the immune response, including the inflammatory response, may differ in intensity and timing between males and females [906,908].
+This hypothesis is supported by some preliminary evidence showing that female patients who recovered from severe COVID-19 had higher antibody titers than males [906].
+Sex steroids can also bind to immune cell receptors to influence cytokine production [904].
+Additionally, social factors may influence risks related to both age and sex: for example, older adults are more likely to live in care facilities, which have been a source for a large number of outbreaks [909], and gender roles may also influence exposure and/or susceptibility due to differences in care-taking and/or risky behaviors (e.g., caring for elder relatives and smoking, respectively) [904] among men and women (however, it should be noted that both transgender men and women are suspected to be at heightened risk [910].)
8.2.2 Comorbid Health Conditions
A number of pre-existing or comorbid conditions have repeatedly been identified as risk factors for more severe COVID-19 outcomes.
-Several underlying health conditions were identified at high prevalence among hospitalized patients, including obesity, diabetes, hypertension, lung disease, and cardiovascular disease [896].
-Higher Sequential Organ Failure Assessment (SOFA) scores have been associated with a higher probability of mortality [35], and comorbid conditions such as cardiovascular and lung disease as well as obesity were also associated with an increased risk of hospitalization and death, even when correcting for age and sex [902].
-Diabetes may increase the risk of lengthy hospitalization [910] or of death [910,911].
-[912] and [913] discuss possible ways in which COVID-19 and diabetes may interact.
-Obesity also appears to be associated with higher risk of severe outcomes from SARS-CoV-2 [914,915].
-Obesity is considered an underlying risk factor for other health problems, and the mechanism for its contributions to COVID-19 hospitalization or mortality is not yet clear [916].
-Dementia and cancer were also associated with the risk of death in an analysis of a large number (more than 20,000) COVID-19 patients in the United Kingdom [902].
-It should be noted that comorbid conditions are inextricably tied to age, as conditions tend to be accumulated over time, but that the prevalence of individual comorbidities or of population health overall can vary regionally [917].
-Several comorbidities that are highly prevalent in older adults, such as COPD, hypertension, cardiovascular disease, and diabetes, have been associated with CFRs upwards of 8% compared to an estimate of 1.4% in people without comorbidities [901,918].
-Therefore, both age and health are important considerations when predicting the impact of COVID-19 on a population [917].
-However, other associations may exist, such as patients with sepsis having higher SOFA scores – in fact, SOFA was developed for the assessment of organ failure in the context of sepsis, and the acronym originally stood for Sepsis-Related Organ Failure Assessment [919,920].
+Several underlying health conditions were identified at high prevalence among hospitalized patients, including obesity, diabetes, hypertension, lung disease, and cardiovascular disease [897].
+Higher Sequential Organ Failure Assessment (SOFA) scores have been associated with a higher probability of mortality [37], and comorbid conditions such as cardiovascular and lung disease as well as obesity were also associated with an increased risk of hospitalization and death, even when correcting for age and sex [903].
+Diabetes may increase the risk of lengthy hospitalization [911] or of death [911,912].
+[913] and [914] discuss possible ways in which COVID-19 and diabetes may interact.
+Obesity also appears to be associated with higher risk of severe outcomes from SARS-CoV-2 [915,916].
+Obesity is considered an underlying risk factor for other health problems, and the mechanism for its contributions to COVID-19 hospitalization or mortality is not yet clear [917].
+Dementia and cancer were also associated with the risk of death in an analysis of a large number (more than 20,000) COVID-19 patients in the United Kingdom [903].
+It should be noted that comorbid conditions are inextricably tied to age, as conditions tend to be accumulated over time, but that the prevalence of individual comorbidities or of population health overall can vary regionally [918].
+Several comorbidities that are highly prevalent in older adults, such as COPD, hypertension, cardiovascular disease, and diabetes, have been associated with CFRs upwards of 8% compared to an estimate of 1.4% in people without comorbidities [902,919].
+Therefore, both age and health are important considerations when predicting the impact of COVID-19 on a population [918].
+However, other associations may exist, such as patients with sepsis having higher SOFA scores – in fact, SOFA was developed for the assessment of organ failure in the context of sepsis, and the acronym originally stood for Sepsis-Related Organ Failure Assessment [920,921].
Additionally, certain conditions are likely to be more prevalent under or exacerbated by social conditions, especially poverty, as is discussed further below.
8.2.3 Ancestry
A number of studies have suggested associations between individuals’ racial and ethnic backgrounds and their COVID-19 risk.
-In particular, Black Americans are consistently identified as carrying a higher burden of COVID-19 than white Americans [898,899], with differences in the rates of kidney complications from COVID-19 particularly pronounced [94].
-Statistics from a number of cities indicate significant discrepancies between the proportion of COVID-19 cases and deaths in Black Americans relative to their representation in the general population [921].
-In addition to Black Americans, disproportionate harm and mortality from COVID-19 has also been noted in Latino/Hispanic Americans and in Native American and Alaskan Native communities, including the Navajo nation [922,923,924,925,926,927].
-In Brazil, indigenous communities likewise carry an increased burden of COVID-19 [928].
-In the United Kingdom, nonwhite ethnicity (principally Black or South Asian) was one of several factors found to be associated with a higher risk of death from COVID-19 [929].
+In particular, Black Americans are consistently identified as carrying a higher burden of COVID-19 than white Americans [899,900], with differences in the rates of kidney complications from COVID-19 particularly pronounced [96].
+Statistics from a number of cities indicate significant discrepancies between the proportion of COVID-19 cases and deaths in Black Americans relative to their representation in the general population [922].
+In addition to Black Americans, disproportionate harm and mortality from COVID-19 has also been noted in Latino/Hispanic Americans and in Native American and Alaskan Native communities, including the Navajo nation [923,924,925,926,927,928].
+In Brazil, indigenous communities likewise carry an increased burden of COVID-19 [929].
+In the United Kingdom, nonwhite ethnicity (principally Black or South Asian) was one of several factors found to be associated with a higher risk of death from COVID-19 [930].
From a genetic standpoint, it is highly unlikely that ancestry itself predisposes individuals to contracting COVID-19 or to experiencing severe COVID-19 outcomes.
-Examining human genetic diversity indicates variation over a geographic continuum, and that most human genetic variation is associated with the African continent [930].
-African-Americans are also a more genetically diverse group relative to European-Americans, with a large number of rare alleles and a much smaller fraction of common alleles identified in African-Americans [931].
-Therefore, the idea that African ancestry (at the continent level) might convey some sort of genetic risk for severe COVID-19 contrasts with what is known about worldwide human genetic diversity [932].
+Examining human genetic diversity indicates variation over a geographic continuum, and that most human genetic variation is associated with the African continent [931].
+African-Americans are also a more genetically diverse group relative to European-Americans, with a large number of rare alleles and a much smaller fraction of common alleles identified in African-Americans [932].
+Therefore, the idea that African ancestry (at the continent level) might convey some sort of genetic risk for severe COVID-19 contrasts with what is known about worldwide human genetic diversity [933].
The possibility for genetic variants that confer some risk or some protection remains possible, but has not been widely explored, especially at a global level.
-Research in Beijing of a small number (n=80) hospitalized COVID-19 patients revealed an association between severe COVID-19 outcomes and homozygosity for an allele in the interferon-induced transmembrane protein 3 (IFITM3) gene, which was selected as a candidate because it was previously found to be associated with influenza outcomes in Chinese patients [933].
-Genetic factors may also play a role in the risk of respiratory failure for COVID-19 [934,935,936].
+Research in Beijing of a small number (n=80) hospitalized COVID-19 patients revealed an association between severe COVID-19 outcomes and homozygosity for an allele in the interferon-induced transmembrane protein 3 (IFITM3) gene, which was selected as a candidate because it was previously found to be associated with influenza outcomes in Chinese patients [934].
+Genetic factors may also play a role in the risk of respiratory failure for COVID-19 [935,936,937].
However, genetic variants associated with outcomes within ancestral groups are far less surprising than genetic variants explaining outcomes between groups.
-Alleles in ACE2 and TMPRSS2 have been identified that vary in frequency among ancestral groups [937], but whether these variants are associated with COVID-19 susceptibility has not been explored.
+Alleles in ACE2 and TMPRSS2 have been identified that vary in frequency among ancestral groups [938], but whether these variants are associated with COVID-19 susceptibility has not been explored.
Instead, examining patterns of COVID-19 susceptibility on a global scale that suggest that social factors are of primary importance in predicting mortality.
Reports from several sub-Saharan African countries have indicated that the effects of the COVID-19 pandemic have been less severe than expected based on the outbreaks in China and Italy.
-In Kenya, for example, estimates of national prevalence based on testing blood donors for SARS-CoV-2 antibodies were consistent with 5% of Kenyan adults having recovered from COVID-19 [938].
-This high seroprevalence of antibodies lies in sharp contrast to the low number of COVID-19 fatalities in Kenya, which at the time was 71 out of 2093 known cases [938].
-Likewise, a serosurvey of health care workers in Blantyre City, Malawi reported an adjusted antibody prevalence of 12.3%, suggesting that the virus had been circulating more widely than thought and that the death rate was up eight times lower than models had predicted [939].
-While several possible hypotheses for the apparent reduced impact of COVID-19 on the African continent are being explored, such as young demographics in many places [940], these reports present a stark contrast to the severity of COVID-19 in Americans and Europeans of African descent.
-Additionally, ethnic minorities in the United Kingdom also tend to be younger than white British living in the same areas, yet the burden of COVID-19 is still more serious for minorities, especially people of Black Caribbean ancestry, both in absolute numbers and when controlling for age and location [941].
+In Kenya, for example, estimates of national prevalence based on testing blood donors for SARS-CoV-2 antibodies were consistent with 5% of Kenyan adults having recovered from COVID-19 [939].
+This high seroprevalence of antibodies lies in sharp contrast to the low number of COVID-19 fatalities in Kenya, which at the time was 71 out of 2093 known cases [939].
+Likewise, a serosurvey of health care workers in Blantyre City, Malawi reported an adjusted antibody prevalence of 12.3%, suggesting that the virus had been circulating more widely than thought and that the death rate was up eight times lower than models had predicted [940].
+While several possible hypotheses for the apparent reduced impact of COVID-19 on the African continent are being explored, such as young demographics in many places [941], these reports present a stark contrast to the severity of COVID-19 in Americans and Europeans of African descent.
+Additionally, ethnic minorities in the United Kingdom also tend to be younger than white British living in the same areas, yet the burden of COVID-19 is still more serious for minorities, especially people of Black Caribbean ancestry, both in absolute numbers and when controlling for age and location [942].
Furthermore, the groups in the United States and United Kingdom that have been identified as carrying elevated COVID-19 burden, namely Black American, indigenous American, and Black and South Asian British, are quite distinct in their position on the human ancestral tree.
What is shared across these groups is instead a history of disenfranchisement under colonialism and ongoing systematic racism.
-A large analysis of over 11,000 COVID-19 patients hospitalized in 92 hospitals across U.S. states revealed that Black patients were younger, more often female, more likely to be on Medicaid, more likely to have comorbidities, and came from neighborhoods identified as more economically deprived than white patients [893].
+A large analysis of over 11,000 COVID-19 patients hospitalized in 92 hospitals across U.S. states revealed that Black patients were younger, more often female, more likely to be on Medicaid, more likely to have comorbidities, and came from neighborhoods identified as more economically deprived than white patients [894].
This study reported that when these factors were accounted for, the differences in mortality between Black and white patients were no longer significant.
Thus, the current evidence suggests that the apparent correlations between ancestry and health outcomes must be examined in the appropriate social context.
8.3 Environmental Influences on Susceptibility
@@ -2906,83 +2907,83 @@ .
-A linear relationship was observed between counties’ reduction in mobility and their wealth and health, as measured by access to health care, food security, income, space, and other factors [942].
-Counties with greater reductions in mobility were also found to have much lower child poverty and household crowding and to be more racially segregated, and to have fewer youth and more elderly residents [942].
-Similar associations between wealth and decreased mobility were observed in cellphone GPS data from Colombia, Indonesia, and Mexico collected between January and May 2020 [943], as well as in a very large data set from several US cities [944].
+In U.S. counties with and without stay-at-home orders, smartphone tracking indicated a significant decrease in the general population’s mobility in April relative to February through March of 2020 (-52.3% and -60.8%, respectively) [943].
+A linear relationship was observed between counties’ reduction in mobility and their wealth and health, as measured by access to health care, food security, income, space, and other factors [943].
+Counties with greater reductions in mobility were also found to have much lower child poverty and household crowding and to be more racially segregated, and to have fewer youth and more elderly residents [943].
+Similar associations between wealth and decreased mobility were observed in cellphone GPS data from Colombia, Indonesia, and Mexico collected between January and May 2020 [944], as well as in a very large data set from several US cities [945].
These disparities in mobility are likely to be related to the role that essential workers have played during the pandemic.
-Essential workers are disproportionately likely to be female, people of color, immigrants, and to have an income below 200% of the poverty line [945].
-Black Americans in particular are over-represented among front-line workers and in professions where social distancing is infeasible [946].
-Health care work in particular presents an increased risk of exposure to SARS-CoV-2 [946,947,948,949,950].
-In the United Kingdom, (South) Asians are more likely than their white counterparts to be medical professionals [941], although BAME medical professionals are still disproportionately represented in the proportion of National Health Service staff deaths [951].
-Similar trends have been reported for nurses, especially nurses of color, in the United States [952].
-Furthermore, beyond the risks associated with work itself, use of public transportation may also impact COVID-19 risk [953].
+Essential workers are disproportionately likely to be female, people of color, immigrants, and to have an income below 200% of the poverty line [946].
+Black Americans in particular are over-represented among front-line workers and in professions where social distancing is infeasible [947].
+Health care work in particular presents an increased risk of exposure to SARS-CoV-2 [947,948,949,950,951].
+In the United Kingdom, (South) Asians are more likely than their white counterparts to be medical professionals [942], although BAME medical professionals are still disproportionately represented in the proportion of National Health Service staff deaths [952].
+Similar trends have been reported for nurses, especially nurses of color, in the United States [953].
+Furthermore, beyond the risks associated with work itself, use of public transportation may also impact COVID-19 risk [954].
The socioeconomic and racial/ethnic gaps in who is working on the front lines of the pandemic make it clear that socioeconomic privilege is likely to decrease the probability of exposure to SARS-CoV-2.
Increased risk of exposure can also arise outside the workplace.
-Nursing homes and skilled nursing facilities received attention early on as high-risk locations for COVID-19 outbreaks [954].
-Prisons and detention centers also confer a high risk of exposure or infection [955,956].
-Populations in care facilities are largely older adults, and in the United States, incarcerated people are more likely to be male and persons of color, especially Black [957].
-Additionally, multi-generational households are less common among non-Hispanic white Americans than people of other racial and ethnic backgrounds [958], increasing the risk of exposure for more susceptible family members.
-Analysis suggests that household crowding may also be associated with increased risk of COVID-19 exposure [942], and household crowding is associated with poverty [959].
-Forms of economic insecurity like housing insecurity, which is associated with poverty and more pronounced in communities subjected to racism [960,961], would be likely to increase household crowding and other possible sources of exposure.
+Nursing homes and skilled nursing facilities received attention early on as high-risk locations for COVID-19 outbreaks [955].
+Prisons and detention centers also confer a high risk of exposure or infection [956,957].
+Populations in care facilities are largely older adults, and in the United States, incarcerated people are more likely to be male and persons of color, especially Black [958].
+Additionally, multi-generational households are less common among non-Hispanic white Americans than people of other racial and ethnic backgrounds [959], increasing the risk of exposure for more susceptible family members.
+Analysis suggests that household crowding may also be associated with increased risk of COVID-19 exposure [943], and household crowding is associated with poverty [960].
+Forms of economic insecurity like housing insecurity, which is associated with poverty and more pronounced in communities subjected to racism [961,962], would be likely to increase household crowding and other possible sources of exposure.
As a result, facets of systemic inequality such as mass incarceration of Black Americans and poverty are likely to increase the risk of exposure outside of the workplace.
8.3.2 Severity of COVID-19 Following Exposure
Following exposure to SARS-CoV-2, the likelihood that an individual develops COVID-19 and the severity of the disease presentation can be influenced by a number of social factors.
As discussed above, a number of patient characteristics are associated with the likelihood of severe COVID-19 symptoms.
-In some cases, these trends run counter to those expected given rates of exposure: for example, although women are more likely to be exposed, men are more likely to be diagnosed with, hospitalized from, or die from COVID-19 [905].
+In some cases, these trends run counter to those expected given rates of exposure: for example, although women are more likely to be exposed, men are more likely to be diagnosed with, hospitalized from, or die from COVID-19 [906].
In the case of comorbid conditions and racial/ethnic demographics, however, social factors are highly likely to modulate or at least influence the apparent association between these traits and the increased risk from COVID-19.
In particular, the comorbidities and racial/ethnic correlates of severe COVID-19 outcomes suggest that poverty confers additional risk for COVID-19.
In order to explore the relationship between poverty and COVID-19 outcomes, it is necessary to consider how poverty impacts biology.
In particular, we focus on the United States and the United Kingdom.
-Comorbidities that increase risk for COVID-19, including obesity, type II diabetes, hypertension, and cardiovascular disease, are known to be intercorrelated [962].
-Metabolic conditions related to heightened inflammation, like obesity, type II diabetes, and hypertension, are more strongly associated with negative COVID-19 outcomes than other comorbid conditions, such as chronic heart disease [963].
+Comorbidities that increase risk for COVID-19, including obesity, type II diabetes, hypertension, and cardiovascular disease, are known to be intercorrelated [963].
+Metabolic conditions related to heightened inflammation, like obesity, type II diabetes, and hypertension, are more strongly associated with negative COVID-19 outcomes than other comorbid conditions, such as chronic heart disease [964].
As discussed above, dysregulated inflammation characteristic of cytokine release syndrome is one of the greatest concerns for COVID-19-related death.
-Therefore, it is possible that chronic inflammation characteristic of these metabolic conditions predisposes patients to COVID-19-related death [963].
-The association between these diseases and severe COVID-19 outcomes is a concern from a health equity perspective because poverty exposes people to “obesogenic” conditions [964] and is therefore unsurprisingly associated with higher incidence of obesity and associated disorders [965].
-Furthermore, cell phone GPS data suggests that lower socioeconomic status may also be associated with decreased access to healthy food choices during the COVID-19 pandemic [966,967], suggesting that health-related risk factors for COVID-19 may be exacerbated as the pandemic continues [968].
-Chronic inflammation is a known outcome of chronic stress (e.g., [969,970,971,972]).
-Therefore, the chronic stress of poverty is likely to influence health broadly (as summarized in [973]) and especially during the stress of the ongoing pandemic.
-A preprint [974] provided observational evidence that geographical areas in the United States that suffer from worse air pollution by fine particulate matter have also suffered more COVID-19 deaths per capita, after adjusting for demographic covariates.
-Although lack of individual-level exposure data and the impossibility of randomization make it difficult to elucidate the exact causal mechanism, this finding would be consistent with similar findings for all-cause mortality (e.g., [975]).
-Exposure to air pollution is associated with both poverty (e.g., [976]) and chronic inflammation [977].
-Other outcomes of environmental racism, such as the proximity of abandoned uranium mines to Navajo land, can also cause respiratory illnesses and other health issues [927].
-Similarly, preliminary findings indicate that nutritional status (e.g., vitamin D deficiency [719]) may be associated with COVID-19 outcomes, and reduced access to grocery stores and fresh food often co-occurs with environmental racism [927,978].
+Therefore, it is possible that chronic inflammation characteristic of these metabolic conditions predisposes patients to COVID-19-related death [964].
+The association between these diseases and severe COVID-19 outcomes is a concern from a health equity perspective because poverty exposes people to “obesogenic” conditions [965] and is therefore unsurprisingly associated with higher incidence of obesity and associated disorders [966].
+Furthermore, cell phone GPS data suggests that lower socioeconomic status may also be associated with decreased access to healthy food choices during the COVID-19 pandemic [967,968], suggesting that health-related risk factors for COVID-19 may be exacerbated as the pandemic continues [969].
+Chronic inflammation is a known outcome of chronic stress (e.g., [970,971,972,973]).
+Therefore, the chronic stress of poverty is likely to influence health broadly (as summarized in [974]) and especially during the stress of the ongoing pandemic.
+A preprint [975] provided observational evidence that geographical areas in the United States that suffer from worse air pollution by fine particulate matter have also suffered more COVID-19 deaths per capita, after adjusting for demographic covariates.
+Although lack of individual-level exposure data and the impossibility of randomization make it difficult to elucidate the exact causal mechanism, this finding would be consistent with similar findings for all-cause mortality (e.g., [976]).
+Exposure to air pollution is associated with both poverty (e.g., [977]) and chronic inflammation [978].
+Other outcomes of environmental racism, such as the proximity of abandoned uranium mines to Navajo land, can also cause respiratory illnesses and other health issues [928].
+Similarly, preliminary findings indicate that nutritional status (e.g., vitamin D deficiency [720]) may be associated with COVID-19 outcomes, and reduced access to grocery stores and fresh food often co-occurs with environmental racism [928,979].
Taken together, the evidence suggests that low-income workers who face greater exposure to SARS-CoV-2 due to their home or work conditions are also more likely to face environmental and social stressors associated with increased inflammation, and therefore with increased risk from COVID-19.
In particular, structural racism can play an important role on disease severity after SARS-CoV-2 exposure, due to consequences of racism which include an increased likelihood of poverty and its associated food and housing instability.
-COVID-19 can thus be considered a “syndemic”, or a synergistic interaction between several epidemics [979].
+COVID-19 can thus be considered a “syndemic”, or a synergistic interaction between several epidemics [980].
As a result, it is not surprising that people from minoritized backgrounds and/or with certain pre-existing conditions are more likely to suffer severe effects of COVID-19, but these “risk factors” are likely to be causally linked to poverty.
8.3.3 Access to Treatment
Finally, COVID-19 outcomes can be influenced by access to healthcare.
Receiving care for COVID-19 can, but does not always, include receiving a positive test for the SARS-CoV-2 virus.
-For example, it is common to see treatment guidelines for suspected cases regardless of whether the presence of SARS-CoV-2 has been confirmed (e.g., [980]).
+For example, it is common to see treatment guidelines for suspected cases regardless of whether the presence of SARS-CoV-2 has been confirmed (e.g., [981]).
Whether and where a patient is diagnosed can depend on their access to testing, which can vary both between and within countries.
-In the United States, it is not always clear whether an individual will have access to free testing [981,982].
-The concern has been raised that more economic privilege is likely to correspond to increased access to testing, at least within the United States [983].
-This is supported by the fact that African Americans seem to be more likely to be diagnosed in the hospital, while individuals from other groups were more likely to have been diagnosed in ambulatory settings in the community [898].
-Any delays in treatment are a cause for concern [983], which could potentially be increased by an inability to acquire testing because in the United States, insurance coverage for care received can depend on a positive test [984].
+In the United States, it is not always clear whether an individual will have access to free testing [982,983].
+The concern has been raised that more economic privilege is likely to correspond to increased access to testing, at least within the United States [984].
+This is supported by the fact that African Americans seem to be more likely to be diagnosed in the hospital, while individuals from other groups were more likely to have been diagnosed in ambulatory settings in the community [899].
+Any delays in treatment are a cause for concern [984], which could potentially be increased by an inability to acquire testing because in the United States, insurance coverage for care received can depend on a positive test [985].
Another important question is whether patients with moderate to severe cases are able to access hospital facilities and treatments, to the extent that they have been identified.
-Early findings from China as of February 2020 suggested the COVID-19 mortality rate to be much lower in the most developed regions of the country [985], although reported mortality is generally an estimate of CFR, which is dependent on rates of testing.
-Efforts to make treatment accessible for all confirmed and suspected cases of COVID-19 in China are credited with expanding care to people with fewer economic resources [986].
-In the United States, access to healthcare varies widely, with certain sectors of the workforce less likely to have health insurance; many essential workers in transportation, food service, and other frontline fields are among those likely to be uninsured or underinsured [983].
-As of 2018, Hispanic Americans of all races were much less likely to have health insurance than people from non-Hispanic backgrounds [987].
+Early findings from China as of February 2020 suggested the COVID-19 mortality rate to be much lower in the most developed regions of the country [986], although reported mortality is generally an estimate of CFR, which is dependent on rates of testing.
+Efforts to make treatment accessible for all confirmed and suspected cases of COVID-19 in China are credited with expanding care to people with fewer economic resources [987].
+In the United States, access to healthcare varies widely, with certain sectors of the workforce less likely to have health insurance; many essential workers in transportation, food service, and other frontline fields are among those likely to be uninsured or underinsured [984].
+As of 2018, Hispanic Americans of all races were much less likely to have health insurance than people from non-Hispanic backgrounds [988].
Therefore, access to diagnostics and care prior to the development of severe COVID-19 is likely to vary depending on socioeconomic and social factors, many of which overlap with the risks of exposure and of developing more severe COVID-19 symptoms.
This discrepancy ties into concerns about broad infrastructural challenges imposed by COVID-19.
-A major concern in many countries has been the saturation of healthcare systems due to the volume of COVID-19 hospitalizations (e.g., [240]).
-Similarly, there have been shortages of supplies such as ventilators that are critical to the survival of many COVID-19 patients, leading to extensive ethical discussions about how to allocate limited resources among patients [988,989,990,991].
-Although it is generally considered unethical to consider demographic factors such as age, sex, race, or ethnicity while making such decisions, and ideally this information would not be shared with triage teams tasked with allocating limited resources among patients [992], there are substantial concerns about implicit and explicit biases against older adults [993], premature infants [994], and people with disabilities or comorbidities [992,995,996].
-Because of the greater burden of chronic disease in populations subjected to systemic racism, algorithms intended to be blind to race and ethnicity could, in fact, reinforce systemic inequalities caused by structural racism [997,998,999].
-Because of this inequality, it has been argued that groups facing health disparities should be prioritized by these algorithms [1000].
-This approach would carry its own ethical concerns, including the fact that many resources that need to be distributed do not have well-established risks and benefits [1000].
-As the pandemic has progressed, it has become clear that ICU beds and ventilators are not the only limited resources that needs to be allocated, and, in fact, the survival rate for patients who receive mechanical ventilation is lower than these discussions would suggest [1001].
-Allocation of interventions that may reduce suffering, including palliative care, has become critically important [1001,1002].
-The ambiguities surrounding the risks and benefits associated with therapeutics that have been approved under emergency use authorizations also present ethical concerns related to the distribution of resources [1000].
-For example, remdesivir, discussed above, is currently available for the treatment of COVID-19 under compassionate use guidelines and through expanded access programs, and in many cases has been donated to hospitals by Gilead [1003,1004].
-Regulations guiding the distribution of drugs in situations like these typically do not address how to determine which patients receive them [1004].
-Prioritizing marginalized groups for treatment with a drug like remdesivir would also be unethical because it would entail disproportionately exposing these groups to a therapeutic that may or not be beneficial [1000].
+A major concern in many countries has been the saturation of healthcare systems due to the volume of COVID-19 hospitalizations (e.g., [242]).
+Similarly, there have been shortages of supplies such as ventilators that are critical to the survival of many COVID-19 patients, leading to extensive ethical discussions about how to allocate limited resources among patients [989,990,991,992].
+Although it is generally considered unethical to consider demographic factors such as age, sex, race, or ethnicity while making such decisions, and ideally this information would not be shared with triage teams tasked with allocating limited resources among patients [993], there are substantial concerns about implicit and explicit biases against older adults [994], premature infants [995], and people with disabilities or comorbidities [993,996,997].
+Because of the greater burden of chronic disease in populations subjected to systemic racism, algorithms intended to be blind to race and ethnicity could, in fact, reinforce systemic inequalities caused by structural racism [998,999,1000].
+Because of this inequality, it has been argued that groups facing health disparities should be prioritized by these algorithms [1001].
+This approach would carry its own ethical concerns, including the fact that many resources that need to be distributed do not have well-established risks and benefits [1001].
+As the pandemic has progressed, it has become clear that ICU beds and ventilators are not the only limited resources that needs to be allocated, and, in fact, the survival rate for patients who receive mechanical ventilation is lower than these discussions would suggest [1002].
+Allocation of interventions that may reduce suffering, including palliative care, has become critically important [1002,1003].
+The ambiguities surrounding the risks and benefits associated with therapeutics that have been approved under emergency use authorizations also present ethical concerns related to the distribution of resources [1001].
+For example, remdesivir, discussed above, is currently available for the treatment of COVID-19 under compassionate use guidelines and through expanded access programs, and in many cases has been donated to hospitals by Gilead [1004,1005].
+Regulations guiding the distribution of drugs in situations like these typically do not address how to determine which patients receive them [1005].
+Prioritizing marginalized groups for treatment with a drug like remdesivir would also be unethical because it would entail disproportionately exposing these groups to a therapeutic that may or not be beneficial [1001].
On the other hand, given that the drug is one of the most promising treatments available for many patients, using a framework that tacitly feeds into structural biases would also be unethical.
-At present, the report prepared for the Director of the CDC by Ethics Subcommittee of the CDC fails to address the complexity of this ethical question given the state of structural racism in the United States, instead stating that “prioritizing individuals according to their chances for short-term survival also avoids ethically irrelevant considerations, such as race or socioeconomic status” [1005].
-In many cases, experimental therapeutics are made available only through participation in clinical trials [1006].
-However, given the history of medical trials abusing minority communities, especially Black Americans, there is a history of unequal representation in clinical trial enrollment [1006].
+At present, the report prepared for the Director of the CDC by Ethics Subcommittee of the CDC fails to address the complexity of this ethical question given the state of structural racism in the United States, instead stating that “prioritizing individuals according to their chances for short-term survival also avoids ethically irrelevant considerations, such as race or socioeconomic status” [1006].
+In many cases, experimental therapeutics are made available only through participation in clinical trials [1007].
+However, given the history of medical trials abusing minority communities, especially Black Americans, there is a history of unequal representation in clinical trial enrollment [1007].
As a result, the standard practice of requiring enrollment in a clinical trial in order to receive experimental treatment may also reinforce patterns established by systemic racism.
8.3.4 Access to and Representation in Clinical Trials
@@ -2999,7 +3000,7 @@ [1007]
.
+The WHO Director‐General Tedros Adhanom Ghebreyesus stated his condemnation of utilizing low and middle income countries as test subjects for clinical trials, yet having highly developed countries as the majority of clinical trial representation is also not the answer [1008].
Figure 6 showcases two choropleths detailing COVID-19 clinical trial recruitment by country.
China, the United States, and France are among the countries with the most clinical trial recruiting for trials with single-country enrollment.
Many countries have little to no clinical trial recruiting, with the continents of Africa and South America much less represented than Asia, Europe, and North America.
@@ -3008,46 +3009,46 @@
Figure 6: Geographic distribution of COVID-19 clinical trials.
The density of clinical trials is reported at the country level.
-As of November 9, 2020, there are 6,417 trials in the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [371].
+As of November 9, 2020, there are 6,417 trials in the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [372].
The top figure demonstrates the density of trials recruiting only from a singular country, while the bottom shows the distribution of recruitment for trials that involve more than one country.
A few different concerns arise from this skewed geographic representation in clinical trial recruitment.
First, treatments such as remdesivir that are promising but primarily available to clinical trial participants are unlikely to be accessible by people in many countries.
Second, it raises the concern that the findings of clinical trials will be based on participants from many of the wealthiest countries, which may lead to ambiguity in whether the findings can be extrapolated to COVID-19 patients elsewhere.
-Especially with the global nature of COVID-19, equitable access to therapeutics and vaccines has been a concern at the forefront of many discussions about policy (e.g., [1008], yet data like that shown in Figure 6 demonstrates that accessibility is likely to be a significant issue.
-Another concern with the heterogeneous international distribution of clinical trials is that the governments of countries leading these clinical trials might prioritize their own populations once vaccines are developed, causing unequal health outcomes [1009].
-Additionally, even within a single state in the United States (Maryland), geography was found to influence the likelihood of being recruited into or enrolled in a clinical trial, with patients in under-served rural areas less likely to enroll [1010].
+Especially with the global nature of COVID-19, equitable access to therapeutics and vaccines has been a concern at the forefront of many discussions about policy (e.g., [1009], yet data like that shown in Figure 6 demonstrates that accessibility is likely to be a significant issue.
+Another concern with the heterogeneous international distribution of clinical trials is that the governments of countries leading these clinical trials might prioritize their own populations once vaccines are developed, causing unequal health outcomes [1010].
+Additionally, even within a single state in the United States (Maryland), geography was found to influence the likelihood of being recruited into or enrolled in a clinical trial, with patients in under-served rural areas less likely to enroll [1011].
Thus, geography both on the global and local levels may influence when treatments and vaccines are available and who is able to access them.
-Efforts such as the African Union’s efforts to coordinate and promote vaccine development [1011] are therefore critical to promoting equity in the COVID-19 response.
+Efforts such as the African Union’s efforts to coordinate and promote vaccine development [1012] are therefore critical to promoting equity in the COVID-19 response.
Even when patients are located within the geographic recruitment area of clinical trials, however, there can still be demographic inequalities in enrollment.
-When efforts are made to ensure equal opportunity to participate in clinical trials, there is no significant difference in participation among racial/ethnic groups [1012].
-However, within the United States, real clinical trial recruitment numbers have indicated for many years that racial minorities, especially African-Americans, tend to be under-represented (e.g., [1013,1014,1015,1016]).
+When efforts are made to ensure equal opportunity to participate in clinical trials, there is no significant difference in participation among racial/ethnic groups [1013].
+However, within the United States, real clinical trial recruitment numbers have indicated for many years that racial minorities, especially African-Americans, tend to be under-represented (e.g., [1014,1015,1016,1017]).
This trend is especially concerning given the disproportionate impact of COVID-19 on African-Americans.
-Early evidence suggests that the proportion of Black, Latinx, and Native American participants in clinical trials for drugs such as remdesivir is much lower than the representation of these groups among COVID-19 patients [1017].
+Early evidence suggests that the proportion of Black, Latinx, and Native American participants in clinical trials for drugs such as remdesivir is much lower than the representation of these groups among COVID-19 patients [1018].
One proposed explanation for differences among racial and ethnic groups in clinical trial enrollment refers to different experiences in healthcare settings.
-While some plausible reasons for the disparity in communication between physicians and patients could be a lack of awareness and education, mistrust in healthcare professionals, and a lack of health insurance [1012], a major concern is that patients from certain racial and ethnic groups are marginalized even while seeking healthcare.
-In the United States, many patients experience “othering” from physicians and other medical professionals due to their race or other external characteristics such as gender (e.g., [1018]).
+While some plausible reasons for the disparity in communication between physicians and patients could be a lack of awareness and education, mistrust in healthcare professionals, and a lack of health insurance [1013], a major concern is that patients from certain racial and ethnic groups are marginalized even while seeking healthcare.
+In the United States, many patients experience “othering” from physicians and other medical professionals due to their race or other external characteristics such as gender (e.g., [1019]).
Many studies have sought to characterize implicit biases in healthcare providers and whether they affect their perceptions or treatment of patients.
-A systematic review that examined 37 such studies reported that most (31) identified racial and/or ethnic biases in healthcare providers in many different roles, although the evidence about whether these biases translated to different attitudes towards patients was mixed [1019], with similar findings reported by a second systematic review [1020].
-However, data about real-world patient outcomes are very limited, with most studies relying on clinical vignette-based exercises [1019], and other analyses suggest that physician implicit bias could impact the patient’s perception of the negativity/positivity of the interaction regardless of the physician’s explicit behavior towards the patient [1021].
-Because racism is a common factor in both, negative patient experiences with medical professionals are likely to compound other issues of systemic inequality, such as a lack of access to adequate care, a lack of insurance, or increased exposure to SARS-CoV-2 [1022].
+A systematic review that examined 37 such studies reported that most (31) identified racial and/or ethnic biases in healthcare providers in many different roles, although the evidence about whether these biases translated to different attitudes towards patients was mixed [1020], with similar findings reported by a second systematic review [1021].
+However, data about real-world patient outcomes are very limited, with most studies relying on clinical vignette-based exercises [1020], and other analyses suggest that physician implicit bias could impact the patient’s perception of the negativity/positivity of the interaction regardless of the physician’s explicit behavior towards the patient [1022].
+Because racism is a common factor in both, negative patient experiences with medical professionals are likely to compound other issues of systemic inequality, such as a lack of access to adequate care, a lack of insurance, or increased exposure to SARS-CoV-2 [1023].
Furthermore, the experience of being othered is not only expected to impact patients’ trust in and comfort with their provider, but also may directly impact whether or not the patient is offered the opportunity to participate in a clinical trial at all.
Some studies suggest communication between physicians and patients impacts whether or not a physician offers a patient participation in a clinical trial.
-For example, researchers utilized a linguistic analysis to assess mean word count of phrases related to clinical trial enrollment, such as voluntary participation, clinical trial, etc. [1012].
+For example, researchers utilized a linguistic analysis to assess mean word count of phrases related to clinical trial enrollment, such as voluntary participation, clinical trial, etc. [1013].
The data indicated that the mean word count of the entire visit was 1.5 times more for white patients in comparison to Black patients.
-In addition, the greatest disparity between white and Black patients’ experience was the discussion of risks, with over 2 times as many risk-related words spoken with white patients than Black patients [1012].
+In addition, the greatest disparity between white and Black patients’ experience was the discussion of risks, with over 2 times as many risk-related words spoken with white patients than Black patients [1013].
The trends observed for other clinical trials raise the concern that COVID-19 clinical trial information may not be discussed as thoroughly or as often with Black patients compared to white patients.
These discrepancies are especially concerning given that many COVID-19 treatments are being or are considered being made available to patients prior to FDA approval through Emergency Use Authorizations.
-In the past, African-Americans have been over-represented relative to national demographics in use of the FDA’s Exception From Informed Consent (EFIC) pathway [1023].
+In the past, African-Americans have been over-represented relative to national demographics in use of the FDA’s Exception From Informed Consent (EFIC) pathway [1024].
Through this pathway, people who are incapacitated can receive an experimental treatment even if they are not able to consent and there is not sufficient time to seek approval from an authorized representative.
-This pathway presents concerns, however, when it is considered in the context of a long history of systematic abuses in medical experimentation where informed consent was not obtained from people of color, such as the Tuskegee syphilis experiments [1024].
+This pathway presents concerns, however, when it is considered in the context of a long history of systematic abuses in medical experimentation where informed consent was not obtained from people of color, such as the Tuskegee syphilis experiments [1025].
While the goal of EFIC approval is to provide treatment to patients who urgently need it, the combination of the ongoing legacy of racism in medicine renders this trend concerning.
-With COVID-19, efforts to prioritize people who suffer from systemic racism are often designed with the goal of righting some of these inequalities (e.g., [1025]), but particular attention to informed consent will be imperative in ensuring these trials are ethical given that the benefits and risks of emerging treatments are still poorly characterized.
+With COVID-19, efforts to prioritize people who suffer from systemic racism are often designed with the goal of righting some of these inequalities (e.g., [1026]), but particular attention to informed consent will be imperative in ensuring these trials are ethical given that the benefits and risks of emerging treatments are still poorly characterized.
Making a substantial effort to run inclusive clinical trials is also important because of the possibility that racism could impact how a patient responds to a treatment.
For example, as discussed above, dexamethasone has been identified as a promising treatment for patients experiencing cytokine release syndrome, but the mechanism of action is tied to the stress response.
-A study from 2005 reported that Black asthma patients showed reduced responsiveness to dexamethasone in comparison to white patients and suggested Black patients might therefore require higher doses of the drug [1026].
-In the context of chronic stress caused by systemic racism, this result is not surprising: chronic stress is associated with dysregulated production of glucocorticoids [1027] and glucocorticoid receptor resistance [1028].
+A study from 2005 reported that Black asthma patients showed reduced responsiveness to dexamethasone in comparison to white patients and suggested Black patients might therefore require higher doses of the drug [1027].
+In the context of chronic stress caused by systemic racism, this result is not surprising: chronic stress is associated with dysregulated production of glucocorticoids [1028] and glucocorticoid receptor resistance [1029].
However, it underscores the critical need for treatment guidelines to take into account differences in life experience, which would be facilitated by the recruitment of patients from a wide range of backgrounds.
Attention to the social aspects of clinical trial enrollment must therefore be an essential component of the medical research community’s response to COVID-19.
-Our primary goal is to sort and distill informative content out of the overwhelming flood of information [5] and help the broader scientific community become more conversant on this critical subject.
+Our primary goal is to sort and distill informative content out of the overwhelming flood of information [7] and help the broader scientific community become more conversant on this critical subject.
Thus, our approach has been to develop a real-time, collaborative effort that welcomes submissions from scientists worldwide into this ongoing effort.
This document represents the first snapshot, which aims to reflect the state of the field as of October, 2020.
We plan to refine and expand this document until technologies to mitigate the pandemic are widely available.
-In an effort to keep pace as new information about COVID-19 and SARS-CoV-2 becomes available, this project is an open, collaborative effort that invited contributions from the scientific community broadly, similar to previous efforts to develop collaborative reviews [1029,1030].
+
In an effort to keep pace as new information about COVID-19 and SARS-CoV-2 becomes available, this project is an open, collaborative effort that invited contributions from the scientific community broadly, similar to previous efforts to develop collaborative reviews [1030,1031].
Contributors were recruited by word of mouth and on Twitter.
-Existing efforts to train early-career scientists were also integrated: Appendix A contains summaries written by the students, post-docs, and faculty of the Immunology Institute at the Mount Sinai School of Medicine [1031,1032], and two of the authors were recruited through the American Physician Scientist Association’s Virtual Summer Research Program [1033].
-The project was managed through GitHub [1034] using Manubot [6] to continuously generate a version of the manuscript online [1035].
+Existing efforts to train early-career scientists were also integrated: Appendix A contains summaries written by the students, post-docs, and faculty of the Immunology Institute at the Mount Sinai School of Medicine [1032,1033], and two of the authors were recruited through the American Physician Scientist Association’s Virtual Summer Research Program [1034].
+The project was managed through GitHub [1035] using Manubot [8] to continuously generate a version of the manuscript online [1036].
Contributors developed text that was proposed through GitHub’s pull request system and then reviewed and approved by at least one other author.
While this document reflects the current version of record, the online version will continue to be developed as information about the pandemic emerges.
Below, we will describe the processes used to synthesize the literature.
10.3 Technical Infrastructure
10.3.1 Collaborative Writing and Manuscript Generation
-Manubot [6] is a collaborative framework developed to adapt open-source software development techniques and version control for manuscript writing.
+
Manubot [8] is a collaborative framework developed to adapt open-source software development techniques and version control for manuscript writing.
Here, Manubot was used to generate a manuscript from text maintained using GitHub, a popular, online version control interface.
The GitHub implementation allowed users to contribute either using git on the command line or using the GitHub user interface, and we developed documentation for users with less experience with this platform.
Manubot also provides a functionality to create a bibliography using digital object identifiers (DOIs), website URLs, or other identifiers such as PubMed identifiers and arXiv IDs.
Due to the needs of this project, project contributors also implemented new features in Manubot and Zotero, which Manubot uses to extract metadata for some types of citations.
-These features support directly citing clinical trial identifiers such as clinicaltrials:NCT04292899 [399] and generating the complete review manuscript along with the individual manuscripts reviewing specific topics.
+These features support directly citing clinical trial identifiers such as clinicaltrials:NCT04292899 [400] and generating the complete review manuscript along with the individual manuscripts reviewing specific topics.
Finally, Manubot and GitHub Actions continuous integration allowed for scripted updates to be run each time the manuscript was generated.
These scripts were used to check that the manuscript was built correctly, run spellchecking, and cross-reference the manuscripts cited in this review, summarized in Appendix A, and discussed in the project’s issues and pull requests.
10.3.2 Data Analysis and Visualization
The combination of Manubot and GitHub Actions also made it possible to dynamically update information such as statistics and visualizations in the manuscript.
-Data about worldwide cases and deaths from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [368] were read using a Python script.
-Similarly, the clinical trials statistics and figure were generated based on data from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [371].
-In both cases, frequency data were plotted using Matplotlib [1036] in Python.
+Data about worldwide cases and deaths from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [369] were read using a Python script.
+Similarly, the clinical trials statistics and figure were generated based on data from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [372].
+In both cases, frequency data were plotted using Matplotlib [1037] in Python.
The figure showing the geographic distribution of COVID-19 clinical trials was generated using the countries associated with the trials listed in the COVID-19 TrialsTracker, converting the country names to 3-letter ISO codes using pycountry or manual adjustment when necessary, and visualizing the geographic distribution of trial recruitment using geopandas.
GitHub Actions runs a nightly workflow to update these external data and regenerate the statistics and figures for the manuscript.
The workflow uses the GitHub API to detect and save the latest commit of the external data sources, which are both GitHub repositories.
@@ -3202,7 +3203,7 @@
10.4 Article Selection and Evaluation
Relevant articles were identified and submitted as issues on GitHub for review.
Articles were classified as diagnostic, therapeutic, or other, and a template was developed to guide the review of papers and preprints in each category.
-Following a framework often used for assessing medical literature, the review consisted of examining methods used in each relevant article, assignment (whether the study was observational or randomized), assessment, results, interpretation, and how well the study extrapolates [1037].
+Following a framework often used for assessing medical literature, the review consisted of examining methods used in each relevant article, assignment (whether the study was observational or randomized), assessment, results, interpretation, and how well the study extrapolates [1038].
For examples of each template, please see Appendices B-D.
10.4.1 Diagnostic Papers
10.4.1.1 Methods
@@ -3245,15 +3246,15 @@ 10.4.2.6 Extrapolation
Reviewers describe how the study may extrapolate to a different species or population.
-10.5 Conclusions
+10.5 Conclusions
Figure 7: Summary of the relationships among topics covered in this review.
Several review articles on aspects of COVID-19 have already been published.
-These have included reviews on the disease epidemiology [38], immunological response [39], diagnostics [40], and pharmacological treatments [39,41].
-Others [42,43] provide narrative reviews of progress on some important ongoing COVID-19 research questions.
+These have included reviews on the disease epidemiology [40], immunological response [41], diagnostics [42], and pharmacological treatments [41,43].
+Others [44,45] provide narrative reviews of progress on some important ongoing COVID-19 research questions.
With the worldwide scientific community uniting during 2020 to investigate SARS-CoV-2 and COVID-19 from a wide range of perspectives, findings from many disciplines are relevant on a rapid timescale to a broad scientific audience.
Additionally, many findings are published as preprints, which are available prior to going through the peer review process.
As a result, centralizing, summarizing, and critiquing new literature broadly relevant to COVID-19 can help to expedite the interdisciplinary scientific process that is currently happening at an advanced pace.
@@ -3724,6631 +3725,6636 @@
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+arXiv (2021-02-03) https://arxiv.org/abs/2102.01521
+
+
+2. Dietary Supplements and Nutraceuticals Under Investigation for COVID-19 Prevention and Treatment
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Thiago Carvalho
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Zhila Maghbooli, Mohammad Ali Sahraian, Mehdi Ebrahimi, Marzieh Pazoki, Samira Kafan, Hedieh Moradi Tabriz, Azar Hadadi, Mahnaz Montazeri, Mehrad Nasiri, Arash Shirvani, Michael F. Holick
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718. Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: an Israeli population‐based study
Eugene Merzon, Dmitry Tworowski, Alessandro Gorohovski, Shlomo Vinker, Avivit Golan Cohen, Ilan Green, Milana Frenkel‐Morgenstern
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David O. Meltzer, Thomas J. Best, Hui Zhang, Tamara Vokes, Vineet Arora, Julian Solway
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José L Hernández, Daniel Nan, Marta Fernandez-Ayala, Mayte García-Unzueta, Miguel A Hernández-Hernández, Marcos López-Hoyos, Pedro Muñoz-Cacho, José M Olmos, Manuel Gutiérrez-Cuadra, Juan J Ruiz-Cubillán, … Víctor M Martínez-Taboada
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Aleksandar Radujkovic, Theresa Hippchen, Shilpa Tiwari-Heckler, Saida Dreher, Monica Boxberger, Uta Merle
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725. Impact of Vitamin D Deficiency on COVID-19—A Prospective Analysis from the CovILD Registry
Alex Pizzini, Magdalena Aichner, Sabina Sahanic, Anna Böhm, Alexander Egger, Gregor Hoermann, Katharina Kurz, Gerlig Widmann, Rosa Bellmann-Weiler, Günter Weiss, … Judith Löffler-Ragg
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726. Does Serum Vitamin D Level Affect COVID-19 Infection and Its Severity?-A Case-Control Study
Kun Ye, Fen Tang, Xin Liao, Benjamin A. Shaw, Meiqiu Deng, Guangyi Huang, Zhiqiang Qin, Xiaomei Peng, Hewei Xiao, Chunxia Chen, … Jianrong Yang
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727. Lower levels of vitamin D are associated with SARS-CoV-2 infection and mortality in the Indian population: An observational study
Sunali Padhi, Subham Suvankar, Venketesh K. Panda, Abhijit Pati, Aditya K. Panda
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728. Vitamin D Deficiency Is Associated with COVID-19 Incidence and Disease Severity in Chinese People
Xia Luo, Qing Liao, Ying Shen, Huijun Li, Liming Cheng
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729. Vitamin D concentrations and COVID-19 infection in UK Biobank
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730. Vitamin D and COVID-19 infection and mortality in UK Biobank
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731. Low serum 25‐hydroxyvitamin D (25[OH]D) levels in patients hospitalized with COVID‐19 are associated with greater disease severity
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733. Vitamin D deficiency in African Americans is associated with a high risk of severe disease and mortality by SARS-CoV-2
Virna Margarita Martín Giménez, Felipe Inserra, León Ferder, Joxel García, Walter Manucha
Journal of Human Hypertension (2020-08-13) https://doi.org/ghr933
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Ali Daneshkhah, Vasundhara Agrawal, Adam Eshein, Hariharan Subramanian, Hemant Kumar Roy, Vadim Backman
Aging Clinical and Experimental Research (2020-09-02) https://doi.org/ghr93q
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735. Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study)
Ashu Rastogi, Anil Bhansali, Niranjan Khare, Vikas Suri, Narayana Yaddanapudi, Naresh Sachdeva, GD Puri, Pankaj Malhotra
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Marta Entrenas Castillo, Luis Manuel Entrenas Costa, José Manuel Vaquero Barrios, Juan Francisco Alcalá Díaz, José López Miranda, Roger Bouillon, José Manuel Quesada Gomez
The Journal of Steroid Biochemistry and Molecular Biology (2020-10) https://doi.org/ghd79r
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738. Mathematical analysis of Córdoba calcifediol trial suggests strong role for Vitamin D in reducing ICU admissions of hospitalized COVID-19 patients
Irwin Jungreis, Manolis Kellis
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739. High-Dose Cholecalciferol Booster Therapy is Associated with a Reduced Risk of Mortality in Patients with COVID-19: A Cross-Sectional Multi-Centre Observational Study
Stephanie F. Ling, Eleanor Broad, Rebecca Murphy, Joseph M. Pappachan, Satveer Pardesi-Newton, Marie-France Kong, Edward B. Jude
Nutrients (2020-12-11) https://doi.org/ghr95f
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740. Effect of Vitamin D 3 Supplementation vs Placebo on Hospital Length of Stay in Patients with Severe COVID-19: A Multicenter, Double-blind, Randomized Controlled Trial
Igor H. Murai, Alan L. Fernandes, Lucas P. Sales, Ana J. Pinto, Karla F. Goessler, Camila S. C. Duran, Carla B. R. Silva, André S. Franco, Marina B. Macedo, Henrique H. H. Dalmolin, … Rosa M. R. Pereira
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741. Effect of Vitamin D Administration on Prevention and Treatment of Mild Forms of Suspected Covid-19
Manuel Castillo Garzón
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Aldo Montano-Loza
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745. The LEAD COVID-19 Trial: Low-risk, Early Aspirin and Vitamin D to Reduce COVID-19 Hospitalizations
Louisiana State University Health Sciences Center in New Orleans
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Marvin McCreary MD
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Paul Lips, Kevin D Cashman, Christel Lamberg-Allardt, Heike Annette Bischoff-Ferrari, Barbara Obermayer-Pietsch, Maria Luisa Bianchi, Jan Stepan, Ghada El-Hajj Fuleihan, Roger Bouillon
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Gareth Iacobucci
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Ingrid Torjesen
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Martin Kohlmeier
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Titilola Falasinnu, Yashaar Chaichian, Michelle B. Bass, Julia F. Simard
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Daniel B. Chastain, Sharmon P. Osae, Andrés F. Henao-Martínez, Carlos Franco-Paredes, Joeanna S. Chastain, Henry N. Young
New England Journal of Medicine (2020-08-27) https://doi.org/gg7vcf
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Joy L. Johnson, Joan L. Bottorff, Annette J. Browne, Sukhdev Grewal, B. Ann Hilton, Heather Clarke
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Ivy W. Maina, Tanisha D. Belton, Sara Ginzberg, Ajit Singh, Tiffani J. Johnson
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Erin Dehon, Nicole Weiss, Jonathan Jones, Whitney Faulconer, Elizabeth Hinton, Sarah Sterling
Academic Emergency Medicine (2017-08) https://doi.org/gbw5pk
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Louis A. Penner, John F. Dovidio, Tessa V. West, Samuel L. Gaertner, Terrance L. Albrecht, Rhonda K. Dailey, Tsveti Markova
Journal of Experimental Social Psychology (2010-03) https://doi.org/dc5342
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1023. Intersection of Bias, Structural Racism, and Social Determinants With Health Care Inequities
Tiffani J. Johnson
Pediatrics (2020-08) https://doi.org/ghjmqz
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1024. A Systematic Review Of The Food And Drug Administration’s “Exception From Informed Consent” Pathway
William B. Feldman, Spencer Phillips Hey, Aaron S. Kesselheim
Health Affairs (2018-10) https://doi.org/ghjmqw
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Terri A. Schmidt
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-1025. CDC officials are considering a plan to distribute COVID-19 vaccines to the most vulnerable first — including people of color
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1026. CDC officials are considering a plan to distribute COVID-19 vaccines to the most vulnerable first — including people of color
Sarah Al-Arshani
Business Insider https://www.businessinsider.com/cdc-official-considering-giving-covid-19-vaccine-most-vulnerable-first-2020-10
-1026. Racial Differences in T-Lymphocyte Response to Glucocorticoids
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1027. Racial Differences in T-Lymphocyte Response to Glucocorticoids
Monica J. Federico, Ronina A. Covar, Eleanor E. Brown, Donald Y. M. Leung, Joseph D. Spahn
Chest (2005-02) https://doi.org/bjfcf6
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-1027. ENDOCRINOLOGY OF THE STRESS RESPONSE
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Evangelia Charmandari, Constantine Tsigos, George Chrousos
Annual Review of Physiology (2005-03-17) https://doi.org/brcm9n
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1029. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk
S. Cohen, D. Janicki-Deverts, W. J. Doyle, G. E. Miller, E. Frank, B. S. Rabin, R. B. Turner
Proceedings of the National Academy of Sciences (2012-04-02) https://doi.org/f4n6r8
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-1029. Opportunities and obstacles for deep learning in biology and medicine
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1030. Opportunities and obstacles for deep learning in biology and medicine
Travers Ching, Daniel S. Himmelstein, Brett K. Beaulieu-Jones, Alexandr A. Kalinin, Brian T. Do, Gregory P. Way, Enrico Ferrero, Paul-Michael Agapow, Michael Zietz, Michael M. Hoffman, … Casey S. Greene
Journal of The Royal Society Interface (2018-04-04) https://doi.org/gddkhn
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-1030. Opportunities and obstacles for deep learning in biology and medicine [update in progress]
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1031. Opportunities and obstacles for deep learning in biology and medicine [update in progress]
Casey S. Greene, Daniel S. Himmelstein, Daniel C. Elton, Brock C. Christensen, Anthony Gitter, Alexander J. Titus, Joshua J. Levy
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1032. ismms-himc/covid-19_sinai_reviews
Human Immune Monitoring Center at Mount Sinai
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-1032. Advancing scientific knowledge in times of pandemics
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1033. Advancing scientific knowledge in times of pandemics
Nicolas Vabret, Robert Samstein, Nicolas Fernandez, Miriam Merad, The Sinai Immunology Review Project, Trainees, Faculty
Nature Reviews Immunology (2020-04-23) https://doi.org/ghjs79
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-1033. Undergraduate Mentoring - American Physician Scientists Association https://www.physicianscientists.org/page/summer-research-pilot-program
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-1034. greenelab/covid19-review
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1035. greenelab/covid19-review
Greene Laboratory
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-1035. SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics
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1036. SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics
Halie M. Rando, Casey S. Greene, Michael P. Robson, Simina M. Boca, Nils Wellhausen, Ronan Lordan, Christian Brueffer, Sandipan Ray, Lucy D\’Agostino McGowan, Anthony Gitter, … Rishi Raj Goel
Manubot (2021-02-08) https://greenelab.github.io/covid19-review/
-1036. Matplotlib: A 2D Graphics Environment
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John D. Hunter
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DOI: 10.1109/mcse.2007.55
-1037. Using the MAARIE Framework To Read the Research Literature
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1038. Using the MAARIE Framework To Read the Research Literature
M. Corcoran
American Journal of Occupational Therapy (2006-07-01) https://doi.org/bqh97x
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-1038. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody
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1039. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody
Xiaolong Tian, Cheng Li, Ailing Huang, Shuai Xia, Sicong Lu, Zhengli Shi, Lu Lu, Shibo Jiang, Zhenlin Yang, Yanling Wu, Tianlei Ying
Cold Spring Harbor Laboratory (2020-01-28) https://doi.org/ggjqfd
DOI: 10.1101/2020.01.28.923011
-1039. Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of 2019-nCoV
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1040. Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of 2019-nCoV
Xiang He, Lei Zhang, Qin Ran, Junyi Wang, Anying Xiong, Dehong Wu, Feng Chen, Guoping Li
Cold Spring Harbor Laboratory (2020-02-05) https://doi.org/ggrbd8
DOI: 10.1101/2020.02.03.20020206
-1040. Diarrhea may be underestimated: a missing link in 2019 novel coronavirus
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1041. Diarrhea may be underestimated: a missing link in 2019 novel coronavirus
Weicheng Liang, Zhijie Feng, Shitao Rao, Cuicui Xiao, Ze-Xiao Lin, Qi Zhang, Qi Wei
Cold Spring Harbor Laboratory (2020-02-17) https://doi.org/ggrbdw
DOI: 10.1101/2020.02.03.20020289
-1041. Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection
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1042. Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection
Xiaoqiang Chai, Longfei Hu, Yan Zhang, Weiyu Han, Zhou Lu, Aiwu Ke, Jian Zhou, Guoming Shi, Nan Fang, Jia Fan, … Fei Lan
Cold Spring Harbor Laboratory (2020-02-04) https://doi.org/ggq626
DOI: 10.1101/2020.02.03.931766
-1042. Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids
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1043. Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids
Bing Zhao, Chao Ni, Ran Gao, Yuyan Wang, Li Yang, Jinsong Wei, Ting Lv, Jianqing Liang, Qisheng Zhang, Wei Xu, … Xinhua Lin
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq648
DOI: 10.1101/2020.03.16.990317
-1043. ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism
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1044. ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism
Jun Wang, Shanmeizi Zhao, Ming Liu, Zhiyao Zhao, Yiping Xu, Ping Wang, Meng Lin, Yanhui Xu, Bing Huang, Xiaoyu Zuo, … Yuxia Zhang
Cold Spring Harbor Laboratory (2020-02-07) https://doi.org/ggrfbx
DOI: 10.1101/2020.02.05.20020545
-1044. The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice
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1045. The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice
Linlin Bao, Wei Deng, Baoying Huang, Hong Gao, Jiangning Liu, Lili Ren, Qiang Wei, Pin Yu, Yanfeng Xu, Feifei Qi, … Chuan Qin
Cold Spring Harbor Laboratory (2020-02-28) https://doi.org/dph2
DOI: 10.1101/2020.02.07.939389
-1045. Caution on Kidney Dysfunctions of COVID-19 Patients
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1046. Caution on Kidney Dysfunctions of COVID-19 Patients
Zhen Li, Ming Wu, Jiwei Yao, Jie Guo, Xiang Liao, Siji Song, Jiali Li, Guangjie Duan, Yuanxiu Zhou, Xiaojun Wu, … Junan Yan
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq627
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-1046. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome
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1047. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome
Kwok Hong Chu, Wai Kay Tsang, Colin S. Tang, Man Fai Lam, Fernand M. Lai, Ka Fai To, Ka Shun Fung, Hon Lok Tang, Wing Wa Yan, Hilda W. H. Chan, … Kar Neng Lai
Kidney International (2005-02) https://doi.org/b7tgtx
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-1047. Single-cell Analysis of ACE2 Expression in Human Kidneys and Bladders Reveals a Potential Route of 2019-nCoV Infection
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1048. Single-cell Analysis of ACE2 Expression in Human Kidneys and Bladders Reveals a Potential Route of 2019-nCoV Infection
Wei Lin, Longfei Hu, Yan Zhang, Joshua D. Ooi, Ting Meng, Peng Jin, Xiang Ding, Longkai Peng, Lei Song, Zhou Xiao, … Yong Zhong
Cold Spring Harbor Laboratory (2020-02-18) https://doi.org/ggq629
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-1048. The immune vulnerability landscape of the 2019 Novel Coronavirus, SARS-CoV-2
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1049. The immune vulnerability landscape of the 2019 Novel Coronavirus, SARS-CoV-2
James Zhu, Jiwoong Kim, Xue Xiao, Yunguan Wang, Danni Luo, Shuang Jiang, Ran Chen, Lin Xu, He Zhang, Lenny Moise, … Yang Xie
Cold Spring Harbor Laboratory (2020-09-04) https://doi.org/ggq628
DOI: 10.1101/2020.02.08.939553 · PMID: 32908981
-1049. Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection
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1050. Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection
Yaseen M. Arabi, Ahmed A. Arifi, Hanan H. Balkhy, Hani Najm, Abdulaziz S. Aldawood, Alaa Ghabashi, Hassan Hawa, Adel Alothman, Abdulaziz Khaldi, Basel Al Raiy
Annals of Internal Medicine (2014-03-18) https://doi.org/ggptxw
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-1050. Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage
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1051. Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage
Jingyuan Liu, Yao Liu, Pan Xiang, Lin Pu, Haofeng Xiong, Chuansheng Li, Ming Zhang, Jianbo Tan, Yanli Xu, Rui Song, … Xianbo Wang
Cold Spring Harbor Laboratory (2020-02-12) https://doi.org/ggrbdx
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-1051. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China
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1052. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China
Chuan Qin, Luoqi Zhou, Ziwei Hu, Shuoqi Zhang, Sheng Yang, Yu Tao, Cuihong Xie, Ke Ma, Ke Shang, Wei Wang, Dai-Shi Tian
Clinical Infectious Diseases (2020-08-01) https://doi.org/ggpxcf
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-1052. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)
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1053. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)
Suxin Wan, Qingjie Yi, Shibing Fan, Jinglong Lv, Xianxiang Zhang, Lian Guo, Chunhui Lang, Qing Xiao, Kaihu Xiao, Zhengjun Yi, … Yongping Chen
Cold Spring Harbor Laboratory (2020-02-12) https://doi.org/ggq63b
DOI: 10.1101/2020.02.10.20021832
-1053. Longitudinal Characteristics of Lymphocyte Responses and Cytokine Profiles in the Peripheral Blood of SARS-CoV-2 Infected Patients
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1054. Longitudinal Characteristics of Lymphocyte Responses and Cytokine Profiles in the Peripheral Blood of SARS-CoV-2 Infected Patients
Jing Liu, Sumeng Li, Jia Liu, Boyun Liang, Xiaobei Wang, Wei Li, Hua Wang, Qiaoxia Tong, Jianhua Yi, Lei Zhao, … Xin Zheng
SSRN Electronic Journal (2020) https://doi.org/ggq655
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-1054. Epidemiological and Clinical Characteristics of 17 Hospitalized Patients with 2019 Novel Coronavirus Infections Outside Wuhan, China
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1055. Epidemiological and Clinical Characteristics of 17 Hospitalized Patients with 2019 Novel Coronavirus Infections Outside Wuhan, China
Jie Li, Shilin Li, Yurui Cai, Qin Liu, Xue Li, Zhaoping Zeng, Yanpeng Chu, Fangcheng Zhu, Fanxin Zeng
Cold Spring Harbor Laboratory (2020-02-12) https://doi.org/ggq63c
DOI: 10.1101/2020.02.11.20022053
-1055. ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection
+
1056. ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection
Caibin Fan, Kai Li, Yanhong Ding, Wei Lu, Jianqing Wang
Cold Spring Harbor Laboratory (2020-02-13) https://doi.org/ggq63d
DOI: 10.1101/2020.02.12.20022418
-1056. Aberrant pathogenic GM-CSF + T cells and inflammatory CD14 + CD16 + monocytes in severe pulmonary syndrome patients of a new coronavirus
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1057. Aberrant pathogenic GM-CSF + T cells and inflammatory CD14 + CD16 + monocytes in severe pulmonary syndrome patients of a new coronavirus
Yonggang Zhou, Binqing Fu, Xiaohu Zheng, Dongsheng Wang, Changcheng Zhao, Yingjie qi, Rui Sun, Zhigang Tian, Xiaoling Xu, Haiming Wei
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggq63f
DOI: 10.1101/2020.02.12.945576
-1057. Clinical Characteristics of 2019 Novel Infected Coronavirus Pneumonia: A Systemic Review and Meta-analysis
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1058. Clinical Characteristics of 2019 Novel Infected Coronavirus Pneumonia: A Systemic Review and Meta-analysis
Kai Qian, Yi Deng, Yong-Hang Tai, Jun Peng, Hao Peng, Li-Hong Jiang
Cold Spring Harbor Laboratory (2020-02-17) https://doi.org/ggrgbq
DOI: 10.1101/2020.02.14.20021535
-1058. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients
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1059. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients
Jing Liu, Sumeng Li, Jia Liu, Boyun Liang, Xiaobei Wang, Hua Wang, Wei Li, Qiaoxia Tong, Jianhua Yi, Lei Zhao, … Xin Zheng
Cold Spring Harbor Laboratory (2020-02-22) https://doi.org/ggq63g
DOI: 10.1101/2020.02.16.20023671
-1059. Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019
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1060. Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019
Guang Chen, Di Wu, Wei Guo, Yong Cao, Da Huang, Hongwu Wang, Tao Wang, Xiaoyun Zhang, Huilong Chen, Haijing Yu, … Qin Ning
Cold Spring Harbor Laboratory (2020-02-19) https://doi.org/ggq63h
DOI: 10.1101/2020.02.16.20023903
-1060. SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development
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1061. SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development
Chunyun Sun, Long Chen, Ji Yang, Chunxia Luo, Yanjing Zhang, Jing Li, Jiahui Yang, Jie Zhang, Liangzhi Xie
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggq63j
DOI: 10.1101/2020.02.16.951723
-1061. Protection of Rhesus Macaque from SARS-Coronavirus challenge by recombinant adenovirus vaccine
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1062. Protection of Rhesus Macaque from SARS-Coronavirus challenge by recombinant adenovirus vaccine
Yiyou Chen, Qiang Wei, Ruobing Li, Hong Gao, Hua Zhu, Wei Deng, Linlin Bao, Wei Tong, Zhe Cong, Hong Jiang, Chuan Qin
Cold Spring Harbor Laboratory (2020-02-21) https://doi.org/ggq63k
DOI: 10.1101/2020.02.17.951939
-1062. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)
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1063. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)
Bo Diao, Chenhui Wang, Yingjun Tan, Xiewan Chen, Ying Liu, Lifen Ning, Li Chen, Min Li, Yueping Liu, Gang Wang, … Yongwen Chen
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggq63m
DOI: 10.1101/2020.02.18.20024364
-1063. Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China
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1064. Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China
Xun Li, Luwen Wang, Shaonan Yan, Fan Yang, Longkui Xiang, Jiling Zhu, Bo Shen, Zuojiong Gong
Cold Spring Harbor Laboratory (2020-02-25) https://doi.org/ggq63n
DOI: 10.1101/2020.02.19.20025239
-1064. SARS-CoV-2 infection does not significantly cause acute renal injury: an analysis of 116 hospitalized patients with COVID-19 in a single hospital, Wuhan, China
+
1065. SARS-CoV-2 infection does not significantly cause acute renal injury: an analysis of 116 hospitalized patients with COVID-19 in a single hospital, Wuhan, China
Luwen Wang, Xun Li, Hui Chen, Shaonan Yan, Yan Li, Dong Li, Zuojiong Gong
Cold Spring Harbor Laboratory (2020-02-23) https://doi.org/ggq63p
DOI: 10.1101/2020.02.19.20025288
-1065. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China
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1066. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China
Dawei Wang, Bo Hu, Chang Hu, Fangfang Zhu, Xing Liu, Jing Zhang, Binbin Wang, Hui Xiang, Zhenshun Cheng, Yong Xiong, … Zhiyong Peng
JAMA (2020-03-17) https://doi.org/ggkh48
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-1066. Clinical characteristics of 2019 novel coronavirus infection in China
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1067. Clinical characteristics of 2019 novel coronavirus infection in China
Wei-jie Guan, Zheng-yi Ni, Yu Hu, Wen-hua Liang, Chun-quan Ou, Jian-xing He, Lei Liu, Hong Shan, Chun-liang Lei, David S. C. Hui, … Nan-shan Zhong
Cold Spring Harbor Laboratory (2020-02-09) https://doi.org/ggkj9s
DOI: 10.1101/2020.02.06.20020974
-1067. Potential T-cell and B-cell Epitopes of 2019-nCoV
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1068. Potential T-cell and B-cell Epitopes of 2019-nCoV
Ethan Fast, Russ B. Altman, Binbin Chen
Cold Spring Harbor Laboratory (2020-03-18) https://doi.org/ggq63q
DOI: 10.1101/2020.02.19.955484
-1068. Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein
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1069. Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein
Alexandra C. Walls, Young-Jun Park, M. Alexandra Tortorici, Abigail Wall, Andrew T. McGuire, David Veesler
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggrgbr
DOI: 10.1101/2020.02.19.956581
-1069. Breadth of concomitant immune responses underpinning viral clearance and patient recovery in a non-severe case of COVID-19
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1070. Breadth of concomitant immune responses underpinning viral clearance and patient recovery in a non-severe case of COVID-19
Irani Thevarajan, Thi HO Nguyen, Marios Koutsakos, Julian Druce, Leon Caly, Carolien E van de Sandt, Xiaoxiao Jia, Suellen Nicholson, Mike Catton, Benjamin Cowie, … Katherine Kedzierska
Cold Spring Harbor Laboratory (2020-02-23) https://doi.org/ggq63r
DOI: 10.1101/2020.02.20.20025841
-1070. The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing
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1071. The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing
Minfeng Liao, Yang Liu, Jin Yuan, Yanling Wen, Gang Xu, Juanjuan Zhao, Lin Chen, Jinxiu Li, Xin Wang, Fuxiang Wang, … Zheng Zhang
Cold Spring Harbor Laboratory (2020-02-26) https://doi.org/ggq63s
DOI: 10.1101/2020.02.23.20026690
-1071. Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells
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1072. Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells
Marlena Scharenberg, Sindhu Vangeti, Eliisa Kekäläinen, Per Bergman, Mamdoh Al-Ameri, Niclas Johansson, Klara Sondén, Sara Falck-Jones, Anna Färnert, Hans-Gustaf Ljunggren, … Nicole Marquardt
Frontiers in Immunology (2019-05-17) https://doi.org/ggq656
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-1072. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
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1073. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
Chaolin Huang, Yeming Wang, Xingwang Li, Lili Ren, Jianping Zhao, Yi Hu, Li Zhang, Guohui Fan, Jiuyang Xu, Xiaoying Gu, … Bin Cao
The Lancet (2020-02) https://doi.org/ggjfnn
DOI: 10.1016/s0140-6736(20)30183-5
-1073. Alveolar Macrophages in the Resolution of Inflammation, Tissue Repair, and Tolerance to Infection
+
1074. Alveolar Macrophages in the Resolution of Inflammation, Tissue Repair, and Tolerance to Infection
Benoit Allard, Alice Panariti, James G. Martin
Frontiers in Immunology (2018-07-31) https://doi.org/gd3bnz
DOI: 10.3389/fimmu.2018.01777 · PMID: 30108592 · PMCID: PMC6079255
-1074. PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery following Respiratory Viral Infection
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1075. PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery following Respiratory Viral Infection
Su Huang, Bibo Zhu, In Su Cheon, Nick P. Goplen, Li Jiang, Ruixuan Zhang, R. Stokes Peebles, Matthias Mack, Mark H. Kaplan, Andrew H. Limper, Jie Sun
Journal of Virology (2019-04-17) https://doi.org/ggq652
DOI: 10.1128/jvi.00030-19 · PMID: 30787149 · PMCID: PMC6475778
-1075. Can routine laboratory tests discriminate 2019 novel coronavirus infected pneumonia from other community-acquired pneumonia?
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1076. Can routine laboratory tests discriminate 2019 novel coronavirus infected pneumonia from other community-acquired pneumonia?
Yunbao Pan, Guangming Ye, Xiantao Zeng, Guohong Liu, Xiaojiao Zeng, Xianghu Jiang, Jin Zhao, Liangjun Chen, Shuang Guo, Qiaoling Deng, … Xinghuan Wang
Cold Spring Harbor Laboratory (2020-02-25) https://doi.org/ggq63t
DOI: 10.1101/2020.02.25.20024711
-1076. Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia
+
1077. Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia
Jing Gong, Hui Dong, Qingsong Xia, Zhaoyi Huang, Dingkun Wang, Yan Zhao, Wenhua Liu, Shenghao Tu, Mingmin Zhang, Qi Wang, Fuer Lu
Cold Spring Harbor Laboratory (2020-02-26) https://doi.org/ggq63v
DOI: 10.1101/2020.02.25.20025643
-1077. An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors’ CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design
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1078. An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors’ CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design
CV Herst, S Burkholz, J Sidney, A Sette, PE Harris, S Massey, T Brasel, E Cunha-Neto, DS Rosa, WCH Chao, … R Rubsamen
Cold Spring Harbor Laboratory (2020-04-06) https://doi.org/ggq63x
DOI: 10.1101/2020.02.25.963546
-1078. Epitope-based peptide vaccine design and target site characterization against novel coronavirus disease caused by SARS-CoV-2
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1079. Epitope-based peptide vaccine design and target site characterization against novel coronavirus disease caused by SARS-CoV-2
Lin Li, Ting Sun, Yufei He, Wendong Li, Yubo Fan, Jing Zhang
Cold Spring Harbor Laboratory (2020-02-27) https://doi.org/ggnqwt
DOI: 10.1101/2020.02.25.965434
-1079. The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and Retrospective Analysis
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1080. The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and Retrospective Analysis
Wang Wenjun, Liu Xiaoqing, Wu Sipei, Lie Puyi, Huang Liyan, Li Yimin, Cheng Linling, Chen Sibei, Nong Lingbo, Lin Yongping, He Jianxing
Cold Spring Harbor Laboratory (2020-02-27) https://doi.org/ggrgbs
DOI: 10.1101/2020.02.26.20026989
-1080. Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China
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1081. Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China
Ying Huang, Rui Yang, Ying Xu, Ping Gong
Cold Spring Harbor Laboratory (2020-03-05) https://doi.org/ggq63z
DOI: 10.1101/2020.02.27.20029009
-1081. Risk factors related to hepatic injury in patients with corona virus disease 2019
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1082. Risk factors related to hepatic injury in patients with corona virus disease 2019
Lu Li, Shuang Li, Manman Xu, Pengfei Yu, Sujun Zheng, Zhongping Duan, Jing Liu, Yu Chen, Junfeng Li
Cold Spring Harbor Laboratory (2020-03-10) https://doi.org/ggq632
DOI: 10.1101/2020.02.28.20028514
-1082. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients
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1083. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients
Xiaohua Chen, Binghong Zhao, Yueming Qu, Yurou Chen, Jie Xiong, Yong Feng, Dong Men, Qianchuan Huang, Ying Liu, Bo Yang, … Feng Li
Cold Spring Harbor Laboratory (2020-03-03) https://doi.org/ggq633
DOI: 10.1101/2020.02.29.20029520
-1083. Prognostic factors in the acute respiratory distress syndrome
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1084. Prognostic factors in the acute respiratory distress syndrome
Wei Chen, Lorraine B Ware
Clinical and Translational Medicine (2015-07-02) https://doi.org/ggq653
DOI: 10.1186/s40169-015-0065-2 · PMID: 26162279 · PMCID: PMC4534483
-1084. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study
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1085. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study
Li Tan, Qi Wang, Duanyang Zhang, Jinya Ding, Qianchuan Huang, Yi-Quan Tang, Qiongshu Wang, Hongming Miao
Cold Spring Harbor Laboratory (2020-03-03) https://doi.org/ggq634
DOI: 10.1101/2020.03.01.20029074
-1085. The potential role of IL-6 in monitoring severe case of coronavirus disease 2019
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1086. The potential role of IL-6 in monitoring severe case of coronavirus disease 2019
Tao Liu, Jieying Zhang, Yuhui Yang, Hong Ma, Zhengyu Li, Jiaoyu Zhang, Ji Cheng, Xiaoyun Zhang, Yanxia Zhao, Zihan Xia, … Jianhua Yi
Cold Spring Harbor Laboratory (2020-03-10) https://doi.org/ggq635
DOI: 10.1101/2020.03.01.20029769
-1086. Clinical and Laboratory Profiles of 75 Hospitalized Patients with Novel Coronavirus Disease 2019 in Hefei, China
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1087. Clinical and Laboratory Profiles of 75 Hospitalized Patients with Novel Coronavirus Disease 2019 in Hefei, China
Zonghao Zhao, Jiajia Xie, Ming Yin, Yun Yang, Hongliang He, Tengchuan Jin, Wenting Li, Xiaowu Zhu, Jing Xu, Changcheng Zhao, … Xiaoling Ma
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq636
DOI: 10.1101/2020.03.01.20029785
-1087. Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome
+
1088. Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome
Yang Yang, Chenguang Shen, Jinxiu Li, Jing Yuan, Minghui Yang, Fuxiang Wang, Guobao Li, Yanjie Li, Li Xing, Ling Peng, … Yingxia Liu
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq637
DOI: 10.1101/2020.03.02.20029975
-1088. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019
+
1089. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019
Juanjuan Zhao, Quan Yuan, Haiyan Wang, Wei Liu, Xuejiao Liao, Yingying Su, Xin Wang, Jing Yuan, Tingdong Li, Jinxiu Li, … Zheng Zhang
Cold Spring Harbor Laboratory (2020-03-02) https://doi.org/ggrbj6
DOI: 10.1101/2020.03.02.20030189
-1089. Restoration of leukomonocyte counts is associated with viral clearance in COVID-19 hospitalized patients
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1090. Restoration of leukomonocyte counts is associated with viral clearance in COVID-19 hospitalized patients
Xiaoping Chen, Jiaxin Ling, Pingzheng Mo, Yongxi Zhang, Qunqun Jiang, Zhiyong Ma, Qian Cao, Wenjia Hu, Shi Zou, Liangjun Chen, … Yong Xiong
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq639
DOI: 10.1101/2020.03.03.20030437
-1090. Effects of Systemically Administered Hydrocortisone on the Human Immunome
+
1091. Effects of Systemically Administered Hydrocortisone on the Human Immunome
Matthew J. Olnes, Yuri Kotliarov, Angélique Biancotto, Foo Cheung, Jinguo Chen, Rongye Shi, Huizhi Zhou, Ena Wang, John S. Tsang, Robert Nussenblatt, The CHI Consortium
Scientific Reports (2016-03-14) https://doi.org/f8dmvw
DOI: 10.1038/srep23002 · PMID: 26972611 · PMCID: PMC4789739
-1091. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis
+
1092. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis
Giuseppe Lippi, Mario Plebani
Clinica Chimica Acta (2020-06) https://doi.org/ggpxp7
DOI: 10.1016/j.cca.2020.03.004 · PMID: 32145275 · PMCID: PMC7094472
-1092. Clinical findings in critically ill patients infected with SARS-CoV-2 in Guangdong Province, China: a multi-center, retrospective, observational study
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1093. Clinical findings in critically ill patients infected with SARS-CoV-2 in Guangdong Province, China: a multi-center, retrospective, observational study
Yonghao Xu, Zhiheng Xu, Xuesong Liu, Lihua Cai, Haichong Zheng, Yongbo Huang, Lixin Zhou, Linxi Huang, Yun Lin, Liehua Deng, … Yimin Li
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq64b
DOI: 10.1101/2020.03.03.20030668
-1093. Multi-epitope vaccine design using an immunoinformatics approach for 2019 novel coronavirus (SARS-CoV-2)
+
1094. Multi-epitope vaccine design using an immunoinformatics approach for 2019 novel coronavirus (SARS-CoV-2)
Ye Feng, Min Qiu, Liang Liu, Shengmei Zou, Yun Li, Kai Luo, Qianpeng Guo, Ning Han, Yingqiang Sun, Kui Wang, … Fan Mo
Cold Spring Harbor Laboratory (2020-06-30) https://doi.org/ggq64c
DOI: 10.1101/2020.03.03.962332
-1094. Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19) in Shanghai, China
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1095. Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19) in Shanghai, China
Min Cao, Dandan Zhang, Youhua Wang, Yunfei Lu, Xiangdong Zhu, Ying Li, Honghao Xue, Yunxiao Lin, Min Zhang, Yiguo Sun, … Hongzhou Lu
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq64d
DOI: 10.1101/2020.03.04.20030395 · PMID: 32511465
-1095. Serological detection of 2019-nCoV respond to the epidemic: A useful complement to nucleic acid testing
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1096. Serological detection of 2019-nCoV respond to the epidemic: A useful complement to nucleic acid testing
Jin Zhang, Jianhua Liu, Na Li, Yong Liu, Rui Ye, Xiaosong Qin, Rui Zheng
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq64f
DOI: 10.1101/2020.03.04.20030916
-1096. Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection
+
1097. Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection
Bo Diao, Chenhui Wang, Rongshuai Wang, Zeqing Feng, Yingjun Tan, Huiming Wang, Changsong Wang, Liang Liu, Ying Liu, Yueping Liu, … Yongwen Chen
Cold Spring Harbor Laboratory (2020-04-10) https://doi.org/ggq64g
DOI: 10.1101/2020.03.04.20031120
-1097. COVID-19 early warning score: a multi-parameter screening tool to identify highly suspected patients
+
1098. COVID-19 early warning score: a multi-parameter screening tool to identify highly suspected patients
Cong-Ying Song, Jia Xu, Jian-Qin He, Yuan-Qiang Lu
Cold Spring Harbor Laboratory (2020-03-08) https://doi.org/ggq64h
DOI: 10.1101/2020.03.05.20031906
-1098. LY6E impairs coronavirus fusion and confers immune control of viral disease
+
1099. LY6E impairs coronavirus fusion and confers immune control of viral disease
Stephanie Pfaender, Katrina B. Mar, Eleftherios Michailidis, Annika Kratzel, Dagny Hirt, Philip V’kovski, Wenchun Fan, Nadine Ebert, Hanspeter Stalder, Hannah Kleine-Weber, … Volker Thiel
Cold Spring Harbor Laboratory (2020-03-07) https://doi.org/dpvn
DOI: 10.1101/2020.03.05.979260 · PMID: 32511345
-1099. A preliminary study on serological assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 238 admitted hospital patients
+
1100. A preliminary study on serological assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 238 admitted hospital patients
Lei Liu, Wanbing Liu, Yaqiong Zheng, Xiaojing Jiang, Guomei Kou, Jinya Ding, Qiongshu Wang, Qianchuan Huang, Yinjuan Ding, Wenxu Ni, … Shangen Zheng
Cold Spring Harbor Laboratory (2020-03-08) https://doi.org/ggq64j
DOI: 10.1101/2020.03.06.20031856
-1100. Monoclonal antibodies for the S2 subunit of spike of SARS-CoV cross-react with the newly-emerged SARS-CoV-2
+
1101. Monoclonal antibodies for the S2 subunit of spike of SARS-CoV cross-react with the newly-emerged SARS-CoV-2
Zhiqiang Zheng, Vanessa M. Monteil, Sebastian Maurer-Stroh, Chow Wenn Yew, Carol Leong, Nur Khairiah Mohd-Ismail, Suganya Cheyyatraivendran Arularasu, Vincent Tak Kwong Chow, Raymond Lin Tzer Pin, Ali Mirazimi, … Yee-Joo Tan
Cold Spring Harbor Laboratory (2020-03-07) https://doi.org/ggrbj7
DOI: 10.1101/2020.03.06.980037
-1101. Mortality of COVID-19 is Associated with Cellular Immune Function Compared to Immune Function in Chinese Han Population
+
1102. Mortality of COVID-19 is Associated with Cellular Immune Function Compared to Immune Function in Chinese Han Population
Qiang Zeng, Yong-zhe Li, Gang Huang, Wei Wu, Sheng-yong Dong, Yang Xu
Cold Spring Harbor Laboratory (2020-03-13) https://doi.org/ggq64k
DOI: 10.1101/2020.03.08.20031229
-1102. Retrospective Analysis of Clinical Features in 101 Death Cases with COVID-19
+
1103. Retrospective Analysis of Clinical Features in 101 Death Cases with COVID-19
Hua Fan, Lin Zhang, Bin Huang, Muxin Zhu, Yong Zhou, Huan Zhang, Xiaogen Tao, Shaohui Cheng, Wenhu Yu, Liping Zhu, Jian Chen
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq64n
DOI: 10.1101/2020.03.09.20033068
-1103. Relationship between the ABO Blood Group and the COVID-19 Susceptibility
+
1104. Relationship between the ABO Blood Group and the COVID-19 Susceptibility
Jiao Zhao, Yan Yang, Hanping Huang, Dong Li, Dongfeng Gu, Xiangfeng Lu, Zheng Zhang, Lei Liu, Ting Liu, Yukun Liu, … Peng George Wang
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggpn3d
DOI: 10.1101/2020.03.11.20031096
-1104. The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15
+
1105. The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15
Shutoku Matsuyama, Miyuki Kawase, Naganori Nao, Kazuya Shirato, Makoto Ujike, Wataru Kamitani, Masayuki Shimojima, Shuetsu Fukushi
Cold Spring Harbor Laboratory (2020-03-12) https://doi.org/ggq64p
DOI: 10.1101/2020.03.11.987016
-1105. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19
+
1106. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19
Bicheng Zhang, Xiaoyang Zhou, Chengliang Zhu, Fan Feng, Yanru Qiu, Jia Feng, Qingzhu Jia, Qibin Song, Bo Zhu, Jun Wang
Cold Spring Harbor Laboratory (2020-03-16) https://doi.org/ggq64q
DOI: 10.1101/2020.03.12.20035048
-1106. Lack of Reinfection in Rhesus Macaques Infected with SARS-CoV-2
+
1107. Lack of Reinfection in Rhesus Macaques Infected with SARS-CoV-2
Linlin Bao, Wei Deng, Hong Gao, Chong Xiao, Jiayi Liu, Jing Xue, Qi Lv, Jiangning Liu, Pin Yu, Yanfeng Xu, … Chuan Qin
Cold Spring Harbor Laboratory (2020-05-01) https://doi.org/ggn8r8
DOI: 10.1101/2020.03.13.990226
-1107. A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV
+
1108. A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV
Meng Yuan, Nicholas C. Wu, Xueyong Zhu, Chang-Chun D. Lee, Ray T. Y. So, Huibin Lv, Chris K. P. Mok, Ian A. Wilson
Cold Spring Harbor Laboratory (2020-03-14) https://doi.org/ggq64s
DOI: 10.1101/2020.03.13.991570
-1108. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein
+
1109. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein
Ke Wang, Wei Chen, Yu-Sen Zhou, Jian-Qi Lian, Zheng Zhang, Peng Du, Li Gong, Yang Zhang, Hong-Yong Cui, Jie-Jie Geng, … Zhi-Nan Chen
Cold Spring Harbor Laboratory (2020-03-14) https://doi.org/ggq64t
DOI: 10.1101/2020.03.14.988345
-1109. CD147 (EMMPRIN/Basigin) in kidney diseases: from an inflammation and immune system viewpoint
+
1110. CD147 (EMMPRIN/Basigin) in kidney diseases: from an inflammation and immune system viewpoint
Tomoki Kosugi, Kayaho Maeda, Waichi Sato, Shoichi Maruyama, Kenji Kadomatsu
Nephrology Dialysis Transplantation (2015-07) https://doi.org/ggq624
DOI: 10.1093/ndt/gfu302 · PMID: 25248362
-1110. The roles of CyPA and CD147 in cardiac remodelling
+
1111. The roles of CyPA and CD147 in cardiac remodelling
Hongyan Su, Yi Yang
Experimental and Molecular Pathology (2018-06) https://doi.org/ggq622
DOI: 10.1016/j.yexmp.2018.05.001 · PMID: 29772453
-1111. Cancer-related issues of CD147.
+
1112. Cancer-related issues of CD147.
Ulrich H Weidle, Werner Scheuer, Daniela Eggle, Stefan Klostermann, Hannes Stockinger
Cancer genomics & proteomics https://www.ncbi.nlm.nih.gov/pubmed/20551248
PMID: 20551248
-1112. Blood single cell immune profiling reveals the interferon-MAPK pathway mediated adaptive immune response for COVID-19
+
1113. Blood single cell immune profiling reveals the interferon-MAPK pathway mediated adaptive immune response for COVID-19
Lulin Huang, Yi Shi, Bo Gong, Li Jiang, Xiaoqi Liu, Jialiang Yang, Juan Tang, Chunfang You, Qi Jiang, Bo Long, … Zhenglin Yang
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq64v
DOI: 10.1101/2020.03.15.20033472
-1113. Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections
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1114. Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections
Huibin Lv, Nicholas C. Wu, Owen Tak-Yin Tsang, Meng Yuan, Ranawaka A. P. M. Perera, Wai Shing Leung, Ray T. Y. So, Jacky Man Chun Chan, Garrick K. Yip, Thomas Shiu Hong Chik, … Chris K. P. Mok
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq64w
DOI: 10.1101/2020.03.15.993097 · PMID: 32511317
-1114. The feasibility of convalescent plasma therapy in severe COVID- 19 patients: a pilot study
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1115. The feasibility of convalescent plasma therapy in severe COVID- 19 patients: a pilot study
Kai Duan, Bende Liu, Cesheng Li, Huajun Zhang, Ting Yu, Jieming Qu, Min Zhou, Li Chen, Shengli Meng, Yong Hu, … Xiaoming Yang
Cold Spring Harbor Laboratory (2020-03-23) https://doi.org/dqrs
DOI: 10.1101/2020.03.16.20036145
-1115. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial
+
1116. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial
Philippe Gautret, Jean-Christophe Lagier, Philippe Parola, Van Thuan Hoang, Line Meddeb, Morgane Mailhe, Barbara Doudier, Johan Courjon, Valérie Giordanengo, Vera Esteves Vieira, … Didier Raoult
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/dqbv
DOI: 10.1101/2020.03.16.20037135
-1116. Chloroquine: Modes of action of an undervalued drug
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1117. Chloroquine: Modes of action of an undervalued drug
Rodolfo Thomé, Stefanie Costa Pinto Lopes, Fabio Trindade Maranhão Costa, Liana Verinaud
Immunology Letters (2013-06) https://doi.org/f5b5cr
DOI: 10.1016/j.imlet.2013.07.004 · PMID: 23891850
-1117. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy
+
1118. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy
B. Lo, K. Zhang, W. Lu, L. Zheng, Q. Zhang, C. Kanellopoulou, Y. Zhang, Z. Liu, J. M. Fritz, R. Marsh, … M. B. Jordan
Science (2015-07-23) https://doi.org/f7kc8d
DOI: 10.1126/science.aaa1663 · PMID: 26206937
-1118. The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2
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1119. The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2
Erik Procko
Cold Spring Harbor Laboratory (2020-05-11) https://doi.org/ggrbj8
DOI: 10.1101/2020.03.16.994236 · PMID: 32511321
-1119. Comparative Pathogenesis Of COVID-19, MERS And SARS In A Non-Human Primate Model
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1120. Comparative Pathogenesis Of COVID-19, MERS And SARS In A Non-Human Primate Model
Barry Rockx, Thijs Kuiken, Sander Herfst, Theo Bestebroer, Mart M. Lamers, Dennis de Meulder, Geert van Amerongen, Judith van den Brand, Nisreen M. A. Okba, Debby Schipper, … Bart L. Haagmans
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq649
DOI: 10.1101/2020.03.17.995639
-1120. Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus
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1121. Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus
Paul B. McCray, Lecia Pewe, Christine Wohlford-Lenane, Melissa Hickey, Lori Manzel, Lei Shi, Jason Netland, Hong Peng Jia, Carmen Halabi, Curt D. Sigmund, … Stanley Perlman
Journal of Virology (2007-01-15) https://doi.org/b2dr3s
DOI: 10.1128/jvi.02012-06 · PMID: 17079315 · PMCID: PMC1797474
-1121. Modeling the Impact of Asymptomatic Carriers on COVID-19 Transmission Dynamics During Lockdown
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1122. Modeling the Impact of Asymptomatic Carriers on COVID-19 Transmission Dynamics During Lockdown
Jacob B. Aguilar, Jeremy Samuel Faust, Lauren M. Westafer, Juan B. Gutierrez
Cold Spring Harbor Laboratory (2020-08-11) https://doi.org/ggqnvp
DOI: 10.1101/2020.03.18.20037994
-1122. Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice
+
1123. Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice
Quan-xin Long, Hai-jun Deng, Juan Chen, Jie-li Hu, Bei-zhong Liu, Pu Liao, Yong Lin, Li-hua Yu, Zhan Mo, Yin-yin Xu, … Ai-long Huang
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggpvz3
DOI: 10.1101/2020.03.18.20038018
-1123. Heat inactivation of serum interferes with the immunoanalysis of antibodies to SARS-CoV-2
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1124. Heat inactivation of serum interferes with the immunoanalysis of antibodies to SARS-CoV-2
Xiumei Hu, Taixue An, Bo Situ, Yuhai Hu, Zihao Ou, Qiang Li, Xiaojing He, Ye Zhang, Peifu Tian, Dehua Sun, … Lei Zheng
Cold Spring Harbor Laboratory (2020-03-16) https://doi.org/ggq646
DOI: 10.1101/2020.03.12.20034231
-1124. SARS-CoV-2 specific antibody responses in COVID-19 patients
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1125. SARS-CoV-2 specific antibody responses in COVID-19 patients
Nisreen M. A. Okba, Marcel A. Müller, Wentao Li, Chunyan Wang, Corine H. GeurtsvanKessel, Victor M. Corman, Mart M. Lamers, Reina S. Sikkema, Erwin de Bruin, Felicity D. Chandler, … Bart L. Haagmans
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggpvz2
DOI: 10.1101/2020.03.18.20038059
-1125. A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19
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1126. A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19
Drifa Belhadi, Nathan Peiffer-Smadja, François-Xavier Lescure, Yazdan Yazdanpanah, France Mentré, Cédric Laouénan
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65b
DOI: 10.1101/2020.03.18.20038190
-1126. ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19
+
1127. ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19
Janice M. Leung, Chen X. Yang, Anthony Tam, Tawimas Shaipanich, Tillie-Louise Hackett, Gurpreet K. Singhera, Delbert R. Dorscheid, Don D. Sin
Cold Spring Harbor Laboratory (2020-03-23) https://doi.org/dqx2
DOI: 10.1101/2020.03.18.20038455
-1127. Dynamic profile of severe or critical COVID-19 cases
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1128. Dynamic profile of severe or critical COVID-19 cases
Yang Xu
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggrbj9
DOI: 10.1101/2020.03.18.20038513
-1128. Association between Clinical, Laboratory and CT Characteristics and RT-PCR Results in the Follow-up of COVID-19 patients
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1129. Association between Clinical, Laboratory and CT Characteristics and RT-PCR Results in the Follow-up of COVID-19 patients
Hang Fu, Huayan Xu, Na Zhang, Hong Xu, Zhenlin Li, Huizhu Chen, Rong Xu, Ran Sun, Lingyi Wen, Linjun Xie, … Yingkun Guo
Cold Spring Harbor Laboratory (2020-03-23) https://doi.org/ggq65c
DOI: 10.1101/2020.03.19.20038315
-1129. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus
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1130. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus
Timothy P. Sheahan, Amy C. Sims, Shuntai Zhou, Rachel L. Graham, Collin S. Hill, Sarah R. Leist, Alexandra Schäfer, Kenneth H. Dinnon, Stephanie A. Montgomery, Maria L. Agostini, … Ralph S. Baric
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggrbkb
DOI: 10.1101/2020.03.19.997890
-1130. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs
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1131. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs
Sangeun Jeon, Meehyun Ko, Jihye Lee, Inhee Choi, Soo Young Byun, Soonju Park, David Shum, Seungtaek Kim
Cold Spring Harbor Laboratory (2020-03-28) https://doi.org/ggq65h
DOI: 10.1101/2020.03.20.999730
-1131. Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2
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1132. Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2
Vincent J. Munster, Friederike Feldmann, Brandi N. Williamson, Neeltje van Doremalen, Lizzette Pérez-Pérez, Jonathan Schulz, Kimberly Meade-White, Atsushi Okumura, Julie Callison, Beniah Brumbaugh, … Emmie de Wit
Cold Spring Harbor Laboratory (2020-03-21) https://doi.org/ggq65j
DOI: 10.1101/2020.03.21.001628 · PMID: 32511299
-1132. Ocular conjunctival inoculation of SARS-CoV-2 can cause mild COVID-19 in Rhesus macaques
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1133. Ocular conjunctival inoculation of SARS-CoV-2 can cause mild COVID-19 in Rhesus macaques
Wei Deng, Linlin Bao, Hong Gao, Zhiguang Xiang, Yajin Qu, Zhiqi Song, Shunran Gong, Jiayi Liu, Jiangning Liu, Pin Yu, … Chuan Qin
Cold Spring Harbor Laboratory (2020-03-30) https://doi.org/ggq64r
DOI: 10.1101/2020.03.13.990036
-1133. ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19
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1134. ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19
Bruna G. G. Pinto, Antonio E. R. Oliveira, Youvika Singh, Leandro Jimenez, Andre N A. Gonçalves, Rodrigo L. T. Ogava, Rachel Creighton, Jean Pierre Schatzmann Peron, Helder I. Nakaya
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65k
DOI: 10.1101/2020.03.21.20040261 · PMID: 32511627
-1134. Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial
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1135. Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial
Huijie Bian, Zhao-Hui Zheng, Ding Wei, Zheng Zhang, Wen-Zhen Kang, Chun-Qiu Hao, Ke Dong, Wen Kang, Jie-Lai Xia, Jin-Lin Miao, … Ping Zhu
Cold Spring Harbor Laboratory (2020-07-15) https://doi.org/ggq65m
DOI: 10.1101/2020.03.21.20040691
-1135. CD147 facilitates HIV-1 infection by interacting with virus-associated cyclophilin A
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1136. CD147 facilitates HIV-1 infection by interacting with virus-associated cyclophilin A
T. Pushkarsky, G. Zybarth, L. Dubrovsky, V. Yurchenko, H. Tang, H. Guo, B. Toole, B. Sherry, M. Bukrinsky
Proceedings of the National Academy of Sciences (2001-05-15) https://doi.org/cc4c7p
DOI: 10.1073/pnas.111583198 · PMID: 11353871 · PMCID: PMC33473
-1136. CD147/EMMPRIN Acts as a Functional Entry Receptor for Measles Virus on Epithelial Cells
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1137. CD147/EMMPRIN Acts as a Functional Entry Receptor for Measles Virus on Epithelial Cells
Akira Watanabe, Misako Yoneda, Fusako Ikeda, Yuri Terao-Muto, Hiroki Sato, Chieko Kai
Journal of Virology (2010-05-01) https://doi.org/dpcsqg
DOI: 10.1128/jvi.02168-09 · PMID: 20147391 · PMCID: PMC2863760
-1137. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum
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1138. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum
Cécile Crosnier, Leyla Y. Bustamante, S. Josefin Bartholdson, Amy K. Bei, Michel Theron, Makoto Uchikawa, Souleymane Mboup, Omar Ndir, Dominic P. Kwiatkowski, Manoj T. Duraisingh, … Gavin J. Wright
Nature (2011-11-09) https://doi.org/dm59hf
DOI: 10.1038/nature10606 · PMID: 22080952 · PMCID: PMC3245779
-1138. Function of HAb18G/CD147 in Invasion of Host Cells by Severe Acute Respiratory Syndrome Coronavirus
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1139. Function of HAb18G/CD147 in Invasion of Host Cells by Severe Acute Respiratory Syndrome Coronavirus
Zhinan Chen, Li Mi, Jing Xu, Jiyun Yu, Xianhui Wang, Jianli Jiang, Jinliang Xing, Peng Shang, Airong Qian, Yu Li, … Ping Zhu
The Journal of Infectious Diseases (2005-03) https://doi.org/cd8snd
DOI: 10.1086/427811 · PMID: 15688292 · PMCID: PMC7110046
-1139. CD147 mediates intrahepatic leukocyte aggregation and determines the extent of liver injury
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1140. CD147 mediates intrahepatic leukocyte aggregation and determines the extent of liver injury
Christine Yee, Nathan M. Main, Alexandra Terry, Igor Stevanovski, Annette Maczurek, Alison J. Morgan, Sarah Calabro, Alison J. Potter, Tina L. Iemma, David G. Bowen, … Nicholas A. Shackel
PLOS ONE (2019-07-10) https://doi.org/ggq654
DOI: 10.1371/journal.pone.0215557 · PMID: 31291257 · PMCID: PMC6619953
-1140. Characterisation of the transcriptome and proteome of SARS-CoV-2 using direct RNA sequencing and tandem mass spectrometry reveals evidence for a cell passage induced in-frame deletion in the spike glycoprotein that removes the furin-like cleavage site
+
1141. Characterisation of the transcriptome and proteome of SARS-CoV-2 using direct RNA sequencing and tandem mass spectrometry reveals evidence for a cell passage induced in-frame deletion in the spike glycoprotein that removes the furin-like cleavage site
Andrew D. Davidson, Maia Kavanagh Williamson, Sebastian Lewis, Deborah Shoemark, Miles W. Carroll, Kate Heesom, Maria Zambon, Joanna Ellis, Phillip A. Lewis, Julian A. Hiscox, David A. Matthews
Cold Spring Harbor Laboratory (2020-03-24) https://doi.org/ggq65n
DOI: 10.1101/2020.03.22.002204
-1141. Modifications to the Hemagglutinin Cleavage Site Control the Virulence of a Neurotropic H1N1 Influenza Virus
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1142. Modifications to the Hemagglutinin Cleavage Site Control the Virulence of a Neurotropic H1N1 Influenza Virus
Xiangjie Sun, Longping V. Tse, A Damon Ferguson, Gary R. Whittaker
Journal of Virology (2010-09-01) https://doi.org/drs2zt
DOI: 10.1128/jvi.00797-10 · PMID: 20554779 · PMCID: PMC2919019
-1142. The architecture of SARS-CoV-2 transcriptome
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1143. The architecture of SARS-CoV-2 transcriptome
Dongwan Kim, Joo-Yeon Lee, Jeong-Sun Yang, Jun Won Kim, V. Narry Kim, Hyeshik Chang
Cold Spring Harbor Laboratory (2020-03-14) https://doi.org/ggpx9q
DOI: 10.1101/2020.03.12.988865
-1143. First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naïve and Experienced COVID-19 Patients
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1144. First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naïve and Experienced COVID-19 Patients
Hongyi Chen, Zhicheng Zhang, Li Wang, Zhihua Huang, Fanghua Gong, Xiaodong Li, Yahong Chen, Jinzi J. Wu
Cold Spring Harbor Laboratory (2020-03-24) https://doi.org/ggrgbt
DOI: 10.1101/2020.03.22.20034041
-1144. Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)
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1145. Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)
Scott D. Seiwert, Steven W. Andrews, Yutong Jiang, Vladimir Serebryany, Hua Tan, Karl Kossen, P. T. Ravi Rajagopalan, Shawn Misialek, Sarah K. Stevens, Antitsa Stoycheva, … Lawrence M. Blatt
Antimicrobial Agents and Chemotherapy (2008-12) https://doi.org/btpg52
DOI: 10.1128/aac.00699-08 · PMID: 18824605 · PMCID: PMC2592891
-1145. Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China
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1146. Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China
Xiaoyuan Xu, Bo Feng, Yujuan Guan, Sujun Zheng, Jifang Sheng, Xingxiang Yang, Yuanji Ma, Yan Huang, Yi Kang, Xiaofeng Wen, … Lai Wei
Journal of Clinical and Translational Hepatology (2019-09-30) https://doi.org/ggrbkd
DOI: 10.14218/jcth.2019.00033 · PMID: 31608212 · PMCID: PMC6783683
-1146. Potentially highly potent drugs for 2019-nCoV
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1147. Potentially highly potent drugs for 2019-nCoV
Duc Duy Nguyen, Kaifu Gao, Jiahui Chen, Rui Wang, Guo-Wei Wei
Cold Spring Harbor Laboratory (2020-02-13) https://doi.org/ggrbj5
DOI: 10.1101/2020.02.05.936013 · PMID: 32511344
-1147. Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset
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1148. Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset
Bin Lou, Ting-Dong Li, Shu-Fa Zheng, Ying-Ying Su, Zhi-Yong Li, Wei Liu, Fei Yu, Sheng-Xiang Ge, Qian-Da Zou, Quan Yuan, … Yu Chen
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggrbkc
DOI: 10.1101/2020.03.23.20041707
-1148. SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems
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1149. SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems
Daniel Blanco-Melo, Benjamin E. Nilsson-Payant, Wen-Chun Liu, Rasmus Møller, Maryline Panis, David Sachs, Randy A. Albrecht, Benjamin R. tenOever
Cold Spring Harbor Laboratory (2020-03-24) https://doi.org/ggq65q
DOI: 10.1101/2020.03.24.004655
-1149. A New Predictor of Disease Severity in Patients with COVID-19 in Wuhan, China
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1150. A New Predictor of Disease Severity in Patients with COVID-19 in Wuhan, China
Ying Zhou, Zhen Yang, Yanan Guo, Shuang Geng, Shan Gao, Shenglan Ye, Yi Hu, Yafei Wang
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65r
DOI: 10.1101/2020.03.24.20042119
-1150. Metabolic disturbances and inflammatory dysfunction predict severity of coronavirus disease 2019 (COVID-19): a retrospective study
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1151. Metabolic disturbances and inflammatory dysfunction predict severity of coronavirus disease 2019 (COVID-19): a retrospective study
Shuke Nie, Xueqing Zhao, Kang Zhao, Zhaohui Zhang, Zhentao Zhang, Zhan Zhang
Cold Spring Harbor Laboratory (2020-03-26) https://doi.org/ggq65s
DOI: 10.1101/2020.03.24.20042283
-1151. Viral Kinetics and Antibody Responses in Patients with COVID-19
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1152. Viral Kinetics and Antibody Responses in Patients with COVID-19
Wenting Tan, Yanqiu Lu, Juan Zhang, Jing Wang, Yunjie Dan, Zhaoxia Tan, Xiaoqing He, Chunfang Qian, Qiangzhong Sun, Qingli Hu, … Guohong Deng
Cold Spring Harbor Laboratory (2020-03-26) https://doi.org/ggq65t
DOI: 10.1101/2020.03.24.20042382
-1152. Global profiling of SARS-CoV-2 specific IgG/ IgM responses of convalescents using a proteome microarray
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1153. Global profiling of SARS-CoV-2 specific IgG/ IgM responses of convalescents using a proteome microarray
He-wei Jiang, Yang Li, Hai-nan Zhang, Wei Wang, Dong Men, Xiao Yang, Huan Qi, Jie Zhou, Sheng-ce Tao
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65g
DOI: 10.1101/2020.03.20.20039495
-1153. COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome
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1154. COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome
Dan Zhang, Rui Guo, Lei Lei, Hongjuan Liu, Yawen Wang, Yili Wang, Hongbo Qian, Tongxin Dai, Tianxiao Zhang, Yanjun Lai, … Jinsong Hu
Cold Spring Harbor Laboratory (2020-03-26) https://doi.org/ggq65v
DOI: 10.1101/2020.03.24.20042655
-1154. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study
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1155. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study
Aaron Miller, Mac Josh Reandelar, Kimberly Fasciglione, Violeta Roumenova, Yan Li, Gonzalo H. Otazu
Cold Spring Harbor Laboratory (2020-03-28) https://doi.org/ggq65w
DOI: 10.1101/2020.03.24.20042937
-1155. Non-specific effects of BCG vaccine on viral infections
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1156. Non-specific effects of BCG vaccine on viral infections
S. J. C. F. M. Moorlag, R. J. W. Arts, R. van Crevel, M. G. Netea
Clinical Microbiology and Infection (2019-12) https://doi.org/ggq62z
DOI: 10.1016/j.cmi.2019.04.020 · PMID: 31055165
-1156. BCG vaccination to reduce the impact of COVID-19 in healthcare workers (The BRACE Trial)
+
1157. BCG vaccination to reduce the impact of COVID-19 in healthcare workers (The BRACE Trial)
Murdoch Children’s Research Institute
https://www.mcri.edu.au/BRACE
-1157. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia
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1158. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia
David H. Brann, Tatsuya Tsukahara, Caleb Weinreb, Marcela Lipovsek, Koen Van den Berge, Boying Gong, Rebecca Chance, Iain C. Macaulay, Hsin-jung Chou, Russell Fletcher, … Sandeep Robert Datta
Cold Spring Harbor Laboratory (2020-05-18) https://doi.org/ggqr4m
DOI: 10.1101/2020.03.25.009084
-1158. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract
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1159. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract
Joan C. Smith, Erin L. Sausville, Vishruth Girish, Monet Lou Yuan, Kristen M. John, Jason M. Sheltzer
Cold Spring Harbor Laboratory (2020-04-26) https://doi.org/ggq65x
DOI: 10.1101/2020.03.28.013672
-1159. The comparative superiority of IgM-IgG antibody test to real-time reverse transcriptase PCR detection for SARS-CoV-2 infection diagnosis
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1160. The comparative superiority of IgM-IgG antibody test to real-time reverse transcriptase PCR detection for SARS-CoV-2 infection diagnosis
Rui Liu, Xinghui Liu, Huan Han, Muhammad Adnan Shereen, Zhili Niu, Dong Li, Fang Liu, Kailang Wu, Zhen Luo, Chengliang Zhu
Cold Spring Harbor Laboratory (2020-03-30) https://doi.org/ggqtp5
DOI: 10.1101/2020.03.28.20045765
@@ -10360,7 +10366,7 @@
5.4.2.2.4 Summary of HCQ/CQ Research Findings
Early in vitro evidence indicated that HCQ could be an effective therapeutic against SARS-CoV-2 and COVID-19, leading to significant media attention and public interest in its potential as both a therapeutic and prophylactic. -Initially it was hypothesized that CQ/HCQ might be effective against SARS-CoV-2 in part because CQ and HCQ have both been found to inhibit the expression of CD154 in T-cells and to reduce TLR signaling that leads to the production of pro-inflammatory cytokines [486]. +Initially it was hypothesized that CQ/HCQ might be effective against SARS-CoV-2 in part because CQ and HCQ have both been found to inhibit the expression of CD154 in T-cells and to reduce TLR signaling that leads to the production of pro-inflammatory cytokines [487]. Clinical trials for COVID-19 have more often used HCQ rather than CQ because it offers the advantages of being cheaper and having fewer side effects than CQ. However, research has not found support for a positive effect of HCQ on COVID-19 patients. Multiple clinical studies have already been carried out to assess HCQ as a therapeutic agent for COVID-19, and many more are in progress. To date, none of these studies have used randomized, double-blind, placebo-controlled designs with a large sample size, which would be the gold standard. Despite the design limitations (which would be more likely to produce false positives than false negatives), initial optimism about HCQ has largely dissipated. -The most methodologically rigorous analysis of HCQ as a prophylactic [484] found no significant differences between the treatment and control groups, and the WHO’s global Solidarity trial similarly reported no effect of HCQ on mortality [390]. +The most methodologically rigorous analysis of HCQ as a prophylactic [485] found no significant differences between the treatment and control groups, and the WHO’s global Solidarity trial similarly reported no effect of HCQ on mortality [391]. Thus, HCQ/CQ are not likely to be effective therapeutic or prophylactic agents against COVID-19. -Additionally, one study identified an increased risk of mortality in older men receiving HCQ, and administration of HCQ and HCQ+AZ did not decrease the use of mechanical ventilation in these patients [481]. +Additionally, one study identified an increased risk of mortality in older men receiving HCQ, and administration of HCQ and HCQ + AZ did not decrease the use of mechanical ventilation in these patients [482]. HCQ use for COVID-19 could also lead to shortages for anti-malarial or anti-rheumatic use, where it has documented efficacy. Despite significant early attention, these drugs appear to be ineffective against COVID-19. Several countries have now removed CQ/HCQ from their SOC for COVID-19 due to the lack of evidence of efficacy and the frequency of adverse effects.
5.4.2.3 Dexamethasone
-Dexamethasone (9α-fluoro-16α-methylprednisolone) is a synthetic corticosteroid that binds to glucocorticoid receptors [487,488]. -It was first synthesized in the late 1950s as an anti-inflammatory and has been used to treat RA and other inflammatory conditions [489,490]. -Steroids such as dexamethasone are widely available and affordable, and they are often used to treat community-acquired pneumonia [491]. -A clinical trial that began in 2012 recently reported that dexamethasone may improve outcomes for patients with ARDS [492]. -However, a meta-analysis of a small amount of available data about dexamethasone as a treatment for SARS suggested that it may, in fact, be associated with patient harm [493]; however, these findings may have been biased by the fact that all of the studies examined were observational and a large number of inconclusive studies were not included [494]. -Dexamethasone works as an anti-inflammatory agent by binding to glucocorticoid receptors with higher affinity than endogenous cortisol [495]. +
Dexamethasone (9α-fluoro-16α-methylprednisolone) is a synthetic corticosteroid that binds to glucocorticoid receptors [488,489]. +It was first synthesized in the late 1950s as an anti-inflammatory and has been used to treat RA and other inflammatory conditions [490,491]. +Steroids such as dexamethasone are widely available and affordable, and they are often used to treat community-acquired pneumonia [492]. +A clinical trial that began in 2012 recently reported that dexamethasone may improve outcomes for patients with ARDS [493]. +However, a meta-analysis of a small amount of available data about dexamethasone as a treatment for SARS suggested that it may, in fact, be associated with patient harm [494]; however, these findings may have been biased by the fact that all of the studies examined were observational and a large number of inconclusive studies were not included [495].
+Dexamethasone works as an anti-inflammatory agent by binding to glucocorticoid receptors with higher affinity than endogenous cortisol [496]. In order to understand how dexamethasone reduces inflammation, it is necessary to consider the stress response broadly. -In response to stress, corticotropin‐releasing hormone stimulates the release of neurotransmitters known as catecholamines, such as epinephrine, and steroid hormones known as glucocorticoids, such as cortisol [496,497]. -While catecholamines are often associated with the fight-or-flight response, the specific role that glucocorticoids play is less clear, although they are thought to be important to restoring homeostasis [498]. +In response to stress, corticotropin‐releasing hormone stimulates the release of neurotransmitters known as catecholamines, such as epinephrine, and steroid hormones known as glucocorticoids, such as cortisol [497,498]. +While catecholamines are often associated with the fight-or-flight response, the specific role that glucocorticoids play is less clear, although they are thought to be important to restoring homeostasis [499]. Immune challenge is a stressor that is known to interact closely with the stress response. -The immune system can therefore interact with the central nervous system; for example, macrophages can both respond to and produce catecholamines [496]. -Additionally, the production of both catecholamines and glucocorticoids is associated with inhibition of proinflammatory cytokines such as IL-6, IL-12, and tumor necrosis factor-α (TNF‐α) and the stimulation of anti-inflammatory cytokines such as IL-10, meaning that the stress response can regulate inflammatory immune activity [497]. -Administration of dexamethasone has been found to correspond to dose-dependent inhibition of IL-12 production, but not to affect IL-10 [499]; the fact that this relationship could be disrupted by administration of a glucocorticoid-receptor antagonist suggests that it is regulated by the receptor itself [499]. +The immune system can therefore interact with the central nervous system; for example, macrophages can both respond to and produce catecholamines [497]. +Additionally, the production of both catecholamines and glucocorticoids is associated with inhibition of proinflammatory cytokines such as IL-6, IL-12, and tumor necrosis factor-α (TNF‐α) and the stimulation of anti-inflammatory cytokines such as IL-10, meaning that the stress response can regulate inflammatory immune activity [498]. +Administration of dexamethasone has been found to correspond to dose-dependent inhibition of IL-12 production, but not to affect IL-10 [500]; the fact that this relationship could be disrupted by administration of a glucocorticoid-receptor antagonist suggests that it is regulated by the receptor itself [500]. Thus, the administration of dexamethasone for COVID-19 is likely to simulate the release of glucocorticoids endogenously during stress, resulting in binding of the synthetic steroid to the glucocorticoid receptor and the associated inhibition of the production of proinflammatory cytokines. -In this model, dexamethasone reduces inflammation by stimulating the biological mechanism that reduces inflammation following a threat such as immune challenge. -Immunosuppressive drugs such as steroids are typically contraindicated in the setting of infection [500], but because COVID-19 results in hyperinflammation that appears to contribute to mortality via lung damage, immunosuppression may be a helpful approach to treatment [127]. -The decision of whether and/or when to counter hyperinflammation with immunosuppression in the setting of COVID-19 was an area of intense debate, as the risks of inhibiting antiviral immunity needed to be weighed against the beneficial anti-inflammatory effects [501]. -As a result, guidelines early in the pandemic typically recommended avoiding treating COVID-19 patients with corticosteroids such as dexamethasone [493].
-The application of dexamethasone for the treatment of COVID-19 was evaluated as part of the multi-site RECOVERY trial in the United Kingdom [502]. +In this model, dexamethasone reduces inflammation by stimulating the biological mechanism that reduces inflammation following a threat such as immune challenge.
+Immunosuppressive drugs such as steroids are typically contraindicated in the setting of infection [501], but because COVID-19 results in hyperinflammation that appears to contribute to mortality via lung damage, immunosuppression may be a helpful approach to treatment [129]. +The decision of whether and/or when to counter hyperinflammation with immunosuppression in the setting of COVID-19 was an area of intense debate, as the risks of inhibiting antiviral immunity needed to be weighed against the beneficial anti-inflammatory effects [502]. +As a result, guidelines early in the pandemic typically recommended avoiding treating COVID-19 patients with corticosteroids such as dexamethasone [494].
+The application of dexamethasone for the treatment of COVID-19 was evaluated as part of the multi-site RECOVERY trial in the United Kingdom [503]. Over 6,000 hospitalized COVID-19 patients were assigned into the SOC or treatment (dexamethasone) arms of the trial with a 2:1 ratio. At the time of randomization, some patients were ventilated (16%), others were on non-invasive oxygen (60%), and others were breathing independently (24%). Patients in the treatment arm were administered dexamethasone either orally or intravenously at 6 mg per day for up to 10 days. The primary end-point was the patient’s status at 28-days post-randomization (mortality, discharge, or continued hospitalization), and secondary outcomes analyzed included the progression to invasive mechanical ventilation over the same period. The 28-day mortality rate was found to be lower in the treatment group than in the SOC group (21.6% vs 24.6%, p < 0.001). However, this finding was driven by differences in mortality among patients who were receiving mechanical ventilation or supplementary oxygen at the start of the study. -The report indicated that dexamethasone reduced 28-day mortality relative to SOC in patients who were ventilated (29.3% vs. 41.4%) and among those who were receiving oxygen supplementation (23.3% vs. 26.2%) at randomization, but not in patients who were breathing independently (17.8% vs. 14.0%). +The report indicated that dexamethasone reduced 28-day mortality relative to SOC in patients who were ventilated (29.3% versus 41.4%) and among those who were receiving oxygen supplementation (23.3% versus 26.2%) at randomization, but not in patients who were breathing independently (17.8% versus 14.0%). One possible confounder is that patients receiving mechanical ventilation tended to be younger than patients who were not receiving respiratory support (by 10 years on average) and to have had symptoms for a longer period. However, adjusting for age did not change the conclusions, although the duration of symptoms was found to be significantly associated with the effect of dexamethasone administration. These findings also suggested that dexamethasone may have reduced progression to mechanical ventilation, especially among patients who were receiving oxygen support at randomization. Thus, this large, randomized, and multi-site, albeit not placebo-controlled, study suggests that administration of dexamethasone to patients who are unable to breathe independently may significantly improve survival outcomes. Additionally, dexamethasone is a widely available and affordable medication, raising the hope that it could be made available to COVID-19 patients globally.
-The results of the RECOVERY trial’s analysis of dexamethasone suggest that this therapeutic is effective primarily in patients who had been experiencing symptoms for at least seven days and patients who were not breathing independently [503]. -A meta-analysis that evaluated the results of the RECOVERY trial alongside trials of other corticosteroids, such as hydrocortisone, similarly concluded that corticosteroids may be beneficial to patients with severe COVID-19 who are receiving oxygen supplementation [504]. -Thus, it seems likely that dexamethasone is useful for treating inflammation associated with immunopathy or cytokine release syndrome. -In fact, corticosteroids such as dexamethasone are sometimes used to treat cytokine release syndrome (CRS) [505]. +
The results of the RECOVERY trial’s analysis of dexamethasone suggest that this therapeutic is effective primarily in patients who had been experiencing symptoms for at least seven days and patients who were not breathing independently [504]. +A meta-analysis that evaluated the results of the RECOVERY trial alongside trials of other corticosteroids, such as hydrocortisone, similarly concluded that corticosteroids may be beneficial to patients with severe COVID-19 who are receiving oxygen supplementation [505]. +Thus, it seems likely that dexamethasone is useful for treating inflammation associated with immunopathy or cytokine release syndrome (CRS). +In fact, corticosteroids such as dexamethasone are sometimes used to treat CRS [506]. It is not surprising that administration of an immunosuppressant would be most beneficial when the immune system was dysregulated towards inflammation. However, it is also unsurprising that care must be taken in administering an immunosuppressant to patients fighting a viral infection. -In particular, the concern has been raised that treatment with dexamethasone might increase patient susceptibility to concurrent (e.g., nosocomial) infections [506]. -Additionally, the drug could potentially slow viral clearance and inhibit patients’ ability to develop antibodies to SARS-CoV-2 [493,506], and the lack of data about viral clearance has been put forward as a major limitation of the RECOVERY trial [507]. -Furthermore, dexamethasone has been associated with side effects that include psychosis, glucocorticoid-induced diabetes, and avascular necrosis [493], and the RECOVERY trial did not report outcomes with enough detail to be able to determine whether they observed similar complications. -The effects of dexamethasone have also been found to differ among populations, especially in high-income versus middle- or low-income countries [508]. -However, since the RECOVERY trial’s results were released, strategies have been proposed for administering dexamethasone alongside more targeted treatments to minimize the likelihood of negative side effects [506]. +In particular, the concern has been raised that treatment with dexamethasone might increase patient susceptibility to concurrent (e.g., nosocomial) infections [507]. +Additionally, the drug could potentially slow viral clearance and inhibit patients’ ability to develop antibodies to SARS-CoV-2 [494,507], and the lack of data about viral clearance has been put forward as a major limitation of the RECOVERY trial [508]. +Furthermore, dexamethasone has been associated with side effects that include psychosis, glucocorticoid-induced diabetes, and avascular necrosis [494], and the RECOVERY trial did not report outcomes with enough detail to be able to determine whether they observed similar complications. +The effects of dexamethasone have also been found to differ among populations, especially in high-income versus middle- or low-income countries [509]. +However, since the RECOVERY trial’s results were released, strategies have been proposed for administering dexamethasone alongside more targeted treatments to minimize the likelihood of negative side effects [507]. Given the available evidence, dexamethasone is currently the most promising treatment for severe COVID-19.
5.5 Biologics
Biologics are produced from components of living organisms or viruses. -They include treatments such as humanized monoclonal antibodies (mAb) tocilizumab (TCZ), and neutralizing antibodies (nAbs), and can also include prophylactics such as vaccines. -Historically produced from animal tissue, biologics have become increasingly feasible to produce as recombinant DNA technologies have advanced [509]. -Often, they are glycoproteins or peptides [510], but whole viruses can also be used therapeutically or prophylactically, not only for vaccines but also as vectors for gene therapy or therapeutic proteins or for oncolytic virotherapy [511]. -They are typically catabolized by the body to their amino acid components [510]. +They include treatments such as humanized monoclonal antibodies (mAb), tocilizumab (TCZ), and neutralizing antibodies (nAbs), and can also include prophylactics such as vaccines. +Historically produced from animal tissue, biologics have become increasingly feasible to produce as recombinant DNA technologies have advanced [510]. +Often, they are glycoproteins or peptides [511], but whole viruses can also be used therapeutically or prophylactically, not only for vaccines but also as vectors for gene therapy or therapeutic proteins or for oncolytic virotherapy [512]. +They are typically catabolized by the body to their amino acid components [511]. There are many differences on the development side between biologics and synthesized pharmaceuticals, such as small molecule drugs. -Biologics are typically orders of magnitude larger than small molecule drugs, and their physiochemical properties are often much less understood [510]. -They are often heat sensitive, and their toxicity can vary, as it is not directly associated with the primary effects of the drug [510]. +Biologics are typically orders of magnitude larger than small molecule drugs, and their physiochemical properties are often much less understood [511]. +They are often heat sensitive, and their toxicity can vary, as it is not directly associated with the primary effects of the drug [511]. However, this class includes some extremely significant medical breakthroughs, including insulin for the management of diabetes and the smallpox vaccine. As a result, biologics are another possible avenue through which the pharmacological management of SARS-CoV-2 infection can be approached.
5.5.1 Tocilizumab
-TCZ is a receptor antibody that was developed to manage chronic inflammation caused by the continuous synthesis of the cytokine IL-6 [512]. +
TCZ is a receptor antibody that was developed to manage chronic inflammation caused by the continuous synthesis of the cytokine IL-6 [513]. IL-6 is a pro-inflammatory cytokine belonging to the interleukin family, which is comprised by immune system regulators that are primarily responsible for immune cell differentiation. -Often used to treat conditions such as RA [512], TCZ has become a pharmaceutical of interest for the treatment of COVID-19 because of the role IL-6 plays in this disease. -While secretion of IL-6 can be associated with chronic conditions, it is a key player in the innate immune response and is secreted by macrophages in response to the detection of pathogen-associated molecular patterns and damage-associated molecular patterns [512]. +Often used to treat conditions such as RA [513], TCZ has become a pharmaceutical of interest for the treatment of COVID-19 because of the role IL-6 plays in this disease. +While secretion of IL-6 can be associated with chronic conditions, it is a key player in the innate immune response and is secreted by macrophages in response to the detection of pathogen-associated molecular patterns and damage-associated molecular patterns [513]. An analysis of 191 in-patients at two Wuhan hospitals revealed that blood concentrations of IL-6 differed between patients who did and did not recover from COVID-19. -Patients who ultimately deceased had higher IL-6 levels at admission than those who recovered [35]. -Additionally, IL-6 levels remained higher throughout the course of hospitalization in the patients who ultimately deceased [35]. -This finding provided some early evidence that COVID-19 deaths may be induced by the hyperactive immune response, often referred to as CRS or cytokine storm syndrome (CSS), as IL-6 plays a key role in this response [114]. +Patients who ultimately deceased had higher IL-6 levels at admission than those who recovered [37]. +Additionally, IL-6 levels remained higher throughout the course of hospitalization in the patients who ultimately deceased [37]. +This finding provided some early evidence that COVID-19 deaths may be induced by the hyperactive immune response, often referred to as CRS or cytokine storm syndrome (CSS), as IL-6 plays a key role in this response [116]. In this context, the observation of elevated IL-6 in patients who died may reflect an over-production of proinflammatory interleukins, suggesting that TCZ could potentially palliate some of the most severe symptoms of COVID-19 associated with increased cytokine production.
Human IL-6 is a 26-kDa glycoprotein that consists of 184 amino acids and contains two potential N-glycosylation sites and four cysteine residues. -It binds to a type I cytokine receptor (IL-6Rα or glycoprotein 80) that exists in both membrane-bound (IL-6Rα) and soluble (sIL-6Rα) forms [513]. -It is not the binding of IL-6 to the receptor that initiates pro- and/or anti-inflammatory signaling, but rather the binding of the complex to another subunit, known as IL-6Rβ or glycoprotein 130 (gp13) [513,514]. -Unlike membrane-bound IL-6Rα, which is only found on hepatocytes and some types of leukocytes, gp130 is found on most cells [515]. -When IL-6 binds to sIL-6Rα, the complex can then bind to a gp130 protein on any cell [515]. -The binding of IL-6 to IL-6Rα is termed classical signaling, while its binding to sIL-6Rα is termed trans-signaling [515,516,517]. +It binds to a type I cytokine receptor (IL-6Rα or glycoprotein 80) that exists in both membrane-bound (IL-6Rα) and soluble (sIL-6Rα) forms [514]. +It is not the binding of IL-6 to the receptor that initiates pro- and/or anti-inflammatory signaling, but rather the binding of the complex to another subunit, known as IL-6Rβ or glycoprotein 130 (gp13) [514,515]. +Unlike membrane-bound IL-6Rα, which is only found on hepatocytes and some types of leukocytes, gp130 is found on most cells [516]. +When IL-6 binds to sIL-6Rα, the complex can then bind to a gp130 protein on any cell [516]. +The binding of IL-6 to IL-6Rα is termed classical signaling, while its binding to sIL-6Rα is termed trans-signaling [516,517,518]. These two signaling processes are thought to play different roles in health and illness. -For example, trans-signaling may play a role in the proliferation of mucosal T-helper TH2 cells associated with asthma, while an earlier step in this proliferation process may be regulated by classical signaling [515]. -Similarly, IL-6 is known to play a role in Crohn’s Disease via trans-, but not classical, signaling [515]. -Both classical and trans-signaling can occur through three independent pathways: the Janus-activated kinase-STAT3 pathway, the Ras/Mitogen-Activated Protein Kinases (MAPK) pathway and the Phosphoinositol-3 Kinase/Akt pathway [513]. -These signaling pathways are involved in a variety of different functions, including cell type differentiation, immunoglobulin synthesis, and cellular survival signaling pathways, respectively [513]. -The ultimate result of the IL-6 cascade is to direct transcriptional activity of various promoters of pro-inflammatory cytokines, such as IL-1, TFN, and even IL-6 itself, through the activity of NF-κB [513]. -IL-6 synthesis is tightly regulated both transcriptionally and post-transcriptionally, and it has been shown that viral proteins can enhance transcription of the IL-6 gene by strengthening the DNA-binding activity between several transcription factors and IL-6 gene-cis-regulatory elements [518]. +For example, trans-signaling may play a role in the proliferation of mucosal T-helper TH2 cells associated with asthma, while an earlier step in this proliferation process may be regulated by classical signaling [516]. +Similarly, IL-6 is known to play a role in Crohn’s Disease via trans-, but not classical, signaling [516]. +Both classical and trans-signaling can occur through three independent pathways: the Janus-activated kinase-STAT3 pathway, the Ras/Mitogen-Activated Protein Kinases (MAPK) pathway and the Phosphoinositol-3 Kinase/Akt pathway [514]. +These signaling pathways are involved in a variety of different functions, including cell type differentiation, immunoglobulin synthesis, and cellular survival signaling pathways, respectively [514]. +The ultimate result of the IL-6 cascade is to direct transcriptional activity of various promoters of pro-inflammatory cytokines, such as IL-1, TFN, and even IL-6 itself, through the activity of NF-κB [514]. +IL-6 synthesis is tightly regulated both transcriptionally and post-transcriptionally, and it has been shown that viral proteins can enhance transcription of the IL-6 gene by strengthening the DNA-binding activity between several transcription factors and IL-6 gene-cis-regulatory elements [519]. Therefore, drugs inhibiting the binding of IL-6 to IL-6Rα or sIL-6Rα are of interest for combating the hyperactive inflammatory response characteristic of CRS and CSS. TCZ is a humanized monoclonal antibody that binds both to the insoluble and soluble receptor of IL-6, providing de facto inhibition of the IL-6 immune cascade.
Tocilizumab is being administered either as an intervention or as concomitant medication in 84 COVID-19 clinical trials (Figure 3). No randomized, placebo-controlled studies of TCZ have currently released results. Therefore, no conclusions can be drawn about its efficacy for the treatment of COVID-19. -However, early interest in TCZ as a possible treatment for COVID-19 emerged from a very small retrospective study in China that examined 20 patients with severe symptoms in early February 2020 and reported rapid improvement in symptoms following treatment with TCZ [519]. +However, early interest in TCZ as a possible treatment for COVID-19 emerged from a very small retrospective study in China that examined 20 patients with severe symptoms in early February 2020 and reported rapid improvement in symptoms following treatment with TCZ [520]. Subsequently, a number of retrospective studies have been conducted in several countries. Many studies use a retrospective, observational design, where they compare outcomes for COVID-19 patients who received TCZ to those who did not over a set period of time. -For example, one of the largest retrospective, observational analysis released to date [520] compared the rates at which patients who received TCZ deceased or progressed to invasive medical ventilation over a 14-day period compared to patients receiving only SOC. +For example, one of the largest retrospective, observational analysis released to date [521] compared the rates at which patients who received TCZ deceased or progressed to invasive medical ventilation over a 14-day period compared to patients receiving only SOC. Under this definition, SOC could include other drugs such as HCQ, azithromycin, lopinavir-ritonavir or darunavir-cobicistat, or heparin. While this study was not randomized, a subset of patients who were eligible to receive TCZ were unable to obtain it due to shortages; however, these groups were not directly compared in the analysis. After adjusting for variables such as age, sex, and SOFA (sequential organ failure assessment) score, they found that patients treated with TCZ were less likely to progress to invasive medical ventilation and/or death (adjusted HR = 0.61, CI 0.40-0.92, p = 0.020), although analysis of death and ventilation separately suggests that this effect may have been driven by differences in the death rate (20% of control versus 7% of TCZ-treated patients). They reported particular benefits for patients whose PaO2/FiO2 ratio, also known as the Horowitz Index for Lung Function, fell below a 150 mm Hg threshold. They found no differences between groups administered subcutaneous versus intravenous TCZ.
-Another retrospective observational analysis of interest examined the charts of patients at a hospital in Connecticut, USA where 64% of all 239 COVID-19 patients in the study period were administered TCZ based on assignment by a standardized algorithm [521]. +
Another retrospective observational analysis of interest examined the charts of patients at a hospital in Connecticut, USA where 64% of all 239 COVID-19 patients in the study period were administered TCZ based on assignment by a standardized algorithm [522]. They found that TCZ administration was associated with more similar rates of survivorship in patients with severe versus nonsevere COVID-19 at intake, defined based on the amount of supplemental oxygen needed. They therefore proposed that their algorithm was able to identify patients presenting with or likely to develop CRS as good candidates for TCZ. This study also reported higher survivorship in Black and Hispanic patients compared to white patients when adjusted for age. The major limitation with interpretation for these studies is that there may be clinical characteristics that influenced medical practitioners decisions to administer TCZ to some patients and not others. -One interesting example therefore comes from an analysis of patients at a single hospital in Brescia, Italy, where TCZ was not available for a period of time [522]. +One interesting example therefore comes from an analysis of patients at a single hospital in Brescia, Italy, where TCZ was not available for a period of time [523]. This study compared COVID-19 patients admitted to the hospital before and after March 13, 2020, when the hospital received TCZ. Therefore, patients who would have been eligible for TCZ prior to this arbitrary date did not receive it as treatment, making this retrospective analysis something of a natural experiment. Despite this design, demographic factors did not appear to be consistent between the two groups, and the average age of the control group was older than the TCZ group. @@ -2111,113 +2110,114 @@
5.5
However, this study also holds a significant limitation: the time delay between the two groups means that knowledge about how to treat the disease likely improved over this timeframe as well.
All the same, the results of these observational retrospective studies provide support for TCZ as a pharmaceutical of interest for follow-up in clinical trials.
In addition to the retrospective observational studies, other analysis have utilized a retrospective case-control design to match pairs of patients with similar baseline characteristics, only one of whom received TCZ for COVID-19.
-In one such study, TCZ was significantly associated with a reduced risk of progression to ICU admission or death [523].
+In one such study, TCZ was significantly associated with a reduced risk of progression to ICU admission or death [524].
This study examined only 20 patients treated with TCZ (all but one of the patients treated with TCZ in the hospital during the study period) and compared them to 25 patients receiving SOC.
For the combined primary endpoint of death and/or ICU admission, only 25% of patients receiving TCZ progressed to an endpoint compared to 72% in the SOC group (p = 0.002, presumably based on a chi-square test based on the information provided in the text).
When the two endpoints were examined separately, progression to invasive medical ventilation remained significant (32% SOC compared to 0% TCZ, p = 0.006) but not for mortality (48% SOC compared to 25% TCZ, p = 0.066).
-In contrast, a study that compared 96 patients treated with TCZ to 97 patients treated with SOC only in New York City found that differences in mortality did not differ between the two groups, but that this difference did become significant when intubated patients were excluded from the analysis [524].
+In contrast, a study that compared 96 patients treated with TCZ to 97 patients treated with SOC only in New York City found that differences in mortality did not differ between the two groups, but that this difference did become significant when intubated patients were excluded from the analysis [525].
Taken together, these findings suggest that future clinical trials of TCZ may want to include intubation as an endpoint.
However, these studies should be approached with caution, not only because of the small number of patients enrolled and the retrospective design, but also because they performed a large number of statistical tests and did not account for multiple hypothesis testing.
These last findings highlight the need to search for a balance between impairing a harmful immune response, such as the one generated during CRS and CSS, and preventing the worsening of the clinical picture of the patients by potential new viral infections.
Though data about TCZ for COVID-19 is still only just emerging, some meta-analyses and systematic reviews have investigated the available data.
-One meta-analysis [525] evaluated 19 studies published or released as preprints prior to July 1, 2020 and found that the overall trends were supportive of the frequent conclusion that TCZ does improve survivorship, with a significant HR of 0.41 (p < 0.001).
+One meta-analysis [526] evaluated 19 studies published or released as preprints prior to July 1, 2020 and found that the overall trends were supportive of the frequent conclusion that TCZ does improve survivorship, with a significant HR of 0.41 (p < 0.001).
This trend improved when they excluded studies that administered a steroid alongside TCZ, with a significant HR of 0.04 (p < 0.001).
They also found some evidence for reduced invasive ventilation or ICU admission, but only when excluding all studies except a small number whose estimates were adjusted for the possible bias introduced by the challenges of stringency during the enrollment process.
-A systematic analysis of sixteen case-control studies of TCZ estimated an odds ratio of 0.453 (95% CI 0.376–0.547, p < 0.001), suggesting possible benefits associated with TCZ treatment [526].
+A systematic analysis of sixteen case-control studies of TCZ estimated an odds ratio of 0.453 (95% CI 0.376–0.547, p < 0.001), suggesting possible benefits associated with TCZ treatment [527].
Although these estimates are similar, it is important to note that they are drawing from the same literature and are therefore likely to be affected by the same biases in publication.
-A second systematic review of studies investigating TCZ treatment for COVID-19 analyzed 31 studies that had been published or released as pre-prints and reported that none carried a low risk of bias (RoB) [527].
+A second systematic review of studies investigating TCZ treatment for COVID-19 analyzed 31 studies that had been published or released as pre-prints and reported that none carried a low risk of bias [528].
Therefore, the present evidence is not likely to be sufficient for conclusions about the efficacy of TCZ.
Additionally, there are possible risks associated with the administration of TCZ for COVID-19.
-TCZ has been used for over a decade to treat RA [528], and a recent study found the drug to be safe for pregnant and breastfeeding women [529].
-However, TCZ may increase the risk of developing infections [528], and RA patients with chronic hepatitis B infections had a high risk of hepatitis B virus reactivation when TCZ was administered in combination with other RA drugs [530].
-As a result, TCZ is contraindicated in patients with active infections such as tuberculosis [531].
-Previous studies have investigated, with varying results, a possible increased risk of infection in RA patients administered TCZ [532,533], although another study reported that the incidence rate of infections was higher in clinical practice RA patients treated with TCZ than in the rates reported by clinical trials [534].
-In the investigation of 544 Italian COVID-19 patients, the group treated with TCZ was found to be more likely to develop secondary infections, with 24% compared to 4% in the control group [520].
+TCZ has been used for over a decade to treat RA [529], and a recent study found the drug to be safe for pregnant and breastfeeding women [530].
+However, TCZ may increase the risk of developing infections [529], and RA patients with chronic hepatitis B infections had a high risk of hepatitis B virus reactivation when TCZ was administered in combination with other RA drugs [531].
+As a result, TCZ is contraindicated in patients with active infections such as tuberculosis [532].
+Previous studies have investigated, with varying results, a possible increased risk of infection in RA patients administered TCZ [533,534], although another study reported that the incidence rate of infections was higher in clinical practice RA patients treated with TCZ than in the rates reported by clinical trials [535].
+In the investigation of 544 Italian COVID-19 patients, the group treated with TCZ was found to be more likely to develop secondary infections, with 24% compared to 4% in the control group [521].
Reactivation of hepatitis B and herpes simplex virus 1 was also reported in a small number of patients in this study, all of whom were receiving TCZ.
-A July 2020 case report described negative outcomes of two COVID-19 patients after receiving TCZ, including one death; however, both patients were intubated and had entered septic shock prior to receiving TCZ [535], likely indicating a severe level of cytokine production.
-Additionally, D-dimer and sIL2R levels were reported by one study to increase in patients treated with TCZ, which raised concerns because of the potential association between elevated D-dimer levels and thrombosis and between sIL2R and diseases where T-cell regulation is compromised [521].
-An increased risk of bacterial infection was also identified in a systematic review of the literature, based on the unadjusted estimates reported [525].
-In summary, TCZ administration to COVID-19 patients is not without risks, may introduce additional risk of developing secondary infections, and should be approached especially cautiously for patients who have latent viral infections.
-In summary, approximately 25% of coronavirus patients develop ARDS, which is caused by an excessive early response of the immune system which can be a component of cytokine release syndrome [521] and cytokine storm syndrome [531].
+A July 2020 case report described negative outcomes of two COVID-19 patients after receiving TCZ, including one death; however, both patients were intubated and had entered septic shock prior to receiving TCZ [536], likely indicating a severe level of cytokine production.
+Additionally, D-dimer and sIL2R levels were reported by one study to increase in patients treated with TCZ, which raised concerns because of the potential association between elevated D-dimer levels and thrombosis and between sIL2R and diseases where T-cell regulation is compromised [522].
+An increased risk of bacterial infection was also identified in a systematic review of the literature, based on the unadjusted estimates reported [526].
+TCZ administration to COVID-19 patients is not without risks, may introduce additional risk of developing secondary infections, and should be approached especially cautiously for patients who have latent viral infections.
+In summary, approximately 25% of coronavirus patients develop ARDS, which is caused by an excessive early response of the immune system which can be a component of CRS [522] and CSS [532].
This overwhelming inflammation is triggered by IL-6.
TCZ is an inhibitor of IL-6 and therefore may neutralize the inflammatory pathway that leads to the cytokine storm.
While the mechanism suggests TCZ could be beneficial for the treatment of COVID-19 patients experiencing excessive immune activity, no randomized controlled trials are available assessing its effect.
However, small initial studies have found preliminary indications that TCZ may reduce progression to invasive medical ventilation and/or death.
It should be noted that SOC varied widely across retrospective studies, with one study administering HCQ, lopinavir-ritonavir, antibiotics, and/or heparin as part of SOC.
-Interest in TCZ as a treatment for COVID-19 was supported by two meta-analyses [525,536], but a third meta-analysis found that all of the available literature carries a risk of bias, with even the largest available TCZ studies to date carrying a moderate risk of bias under the ROBINS-I criteria [527].
-Additionally, different studies used different dosages, number of doses, and methods of administration; ongoing research may be needed to optimize administration of TCZ [537], although similar results were reported by one study for intravenous and subcutaneous administration [520].
+Interest in TCZ as a treatment for COVID-19 was supported by two meta-analyses [526,537], but a third meta-analysis found that all of the available literature carries a risk of bias, with even the largest available TCZ studies to date carrying a moderate risk of bias under the ROBINS-I criteria [528].
+Additionally, different studies used different dosages, number of doses, and methods of administration.
+Ongoing research may be needed to optimize administration of TCZ [538], although similar results were reported by one study for intravenous and subcutaneous administration [521].
Clinical trials that are in progress are likely to provide additional insight into the effectiveness of this drug for the treatment of COVID-19 along with how it should be administered.
5.5.2 Neutralizing Antibodies
Monoclonal antibodies have revolutionized the way we treat human diseases.
-They have become some of the best-selling drugs in the pharmaceutical market in recent years [538].
-There are currently 79 FDA approved mAbs on the market, including antibodies for viral infections (e.g. Ibalizumab for HIV and Palivizumab for RSV) [538,539].
-Virus-specific neutralizing antibodies commonly target viral surface glycoproteins or host structures, thereby inhibiting viral entry through receptor binding interference [540,541].
-This section discusses current efforts in developing neutralizing antibodies against SARS-CoV-2 and how expertise gained from previous approaches for MERS-CoV and SARS-CoV-1 may benefit antibody development.
+They have become some of the best-selling drugs in the pharmaceutical market in recent years [539].
+There are currently 79 FDA approved mAbs on the market, including antibodies for viral infections (e.g. Ibalizumab for HIV and Palivizumab for RSV) [539,540].
+Virus-specific nAbs commonly target viral surface glycoproteins or host structures, thereby inhibiting viral entry through receptor binding interference [541,542].
+This section discusses current efforts in developing nAbs against SARS-CoV-2 and how expertise gained from previous approaches for MERS-CoV and SARS-CoV-1 may benefit antibody development.
5.5.2.1 Spike (S) Neutralizing Antibody
-During the first SARS epidemic in 2002, nAbs were found in SARS-CoV-1-infected patients [542,543].
-Several studies following up on these findings identified various S-glycoprotein epitopes as the major targets of neutralizing antibodies against SARS-CoV-1 [544].
-The passive transfer of immune serum containing nAbs from SARS-CoV-1-infected mice resulted in protection of naïve mice from viral lower respiratory tract infection upon intranasal challenge [545].
-Similarly, a meta-analysis suggested that administration of plasma from recovered SARS-CoV-1 patients reduced mortality upon SARS-CoV-1 infection [546].
+
During the first SARS epidemic in 2002, nAbs were found in SARS-CoV-1-infected patients [543,544].
+Several studies following up on these findings identified various S-glycoprotein epitopes as the major targets of nAbs against SARS-CoV-1 [545].
+The passive transfer of immune serum containing nAbs from SARS-CoV-1-infected mice resulted in protection of naïve mice from viral lower respiratory tract infection upon intranasal challenge [546].
+Similarly, a meta-analysis suggested that administration of plasma from recovered SARS-CoV-1 patients reduced mortality upon SARS-CoV-1 infection [547].
Similar results were observed in MERS-CoV infection during the second coronavirus-related epidemic of the 21st century.
-In these cases, neutralizing antibodies were identified against various epitopes of the receptor binding domain (RBD) of the S glycoprotein [547,548].
-Coronaviruses use trimeric spike (S) glycoproteins on their surface to bind to the host cell, allowing for cell entry [64,67].
+In these cases, nAbs were identified against various epitopes of the receptor binding domain (RBD) of the S glycoprotein [548,549].
+Coronaviruses use trimeric spike (S) glycoproteins on their surface to bind to the host cell, allowing for cell entry [66,69].
Each S glycoprotein protomer is comprised of an S1 domain, also called the RBD, and an S2 domain.
-The S1 domain binds to the host cell while the S2 domain facilitates the fusion between the viral envelope and host cell membranes [544].
-Although targeting of the host cell enzyme ACE2 shows efficacy in inhibiting SARS-CoV-2 infection [75], given the physiological relevance of ACE2 [549], it would be favorable to target virus-specific structures rather than host receptors.
-This concern underlies the rationale for developing neutralizing antibodies against the S glycoprotein, disrupting its interaction with ACE2 and other potential entry points and thereby inhibiting viral entry.
-The first human neutralizing antibody against SARS-CoV-2 targeting the S glycoproteins was developed using hybridoma technology [550], where antibody-producing B-cells developed by mice can be inserted into myeloma cells to produce a hybrid cell line (the hybridoma) that is grown in culture.
+The S1 domain binds to the host cell while the S2 domain facilitates the fusion between the viral envelope and host cell membranes [545].
+Although targeting of the host cell enzyme ACE2 shows efficacy in inhibiting SARS-CoV-2 infection [77], given the physiological relevance of ACE2 [550], it would be favorable to target virus-specific structures rather than host receptors.
+This concern underlies the rationale for developing nAbs against the S glycoprotein, disrupting its interaction with ACE2 and other potential entry points and thereby inhibiting viral entry.
+The first human nAb against SARS-CoV-2 targeting the S glycoproteins was developed using hybridoma technology [551], where antibody-producing B-cells developed by mice can be inserted into myeloma cells to produce a hybrid cell line (the hybridoma) that is grown in culture.
The 47D11 clone was able to cross-neutralize SARS-CoV-1 and SARS-CoV-2 by a mechanism that is different from receptor binding interference.
-The exact mechanism of how this clone neutralizes SARS-CoV-2 and inhibits infection in vitro remains unknown, but a potential mechanism might be antibody-induced destabilization of the membrane prefusion structure [550,551].
-The ability of this antibody to prevent infection at a feasible dose needs to be validated in vivo, especially since in vitro neutralization effects have been shown to not be reflective of in vivo efficacy [552].
-Only a week later, a different group successfully isolated multiple nAbs targeting the RBD of the S glycoprotein from blood samples taken from COVID-19 patients in China [154].
+The exact mechanism of how this clone neutralizes SARS-CoV-2 and inhibits infection in vitro remains unknown, but a potential mechanism might be antibody-induced destabilization of the membrane prefusion structure [551,552].
+The ability of this antibody to prevent infection at a feasible dose needs to be validated in vivo, especially since in vitro neutralization effects have been shown to not be reflective of in vivo efficacy [553].
+Only a week later, a different group successfully isolated multiple nAbs targeting the RBD of the S glycoprotein from blood samples taken from COVID-19 patients in China [156].
Interestingly, the patient-isolated antibodies did not cross-react with RBDs from SARS-CoV-1 and MERS-CoV, although cross-reactivity to the trimeric spike proteins of SARS-CoV-1 and MERS-CoV was observed.
This finding suggests that the RBDs between the three coronavirus species are immunologically distinct and that the isolated nAbs targeting the RBD of SARS-CoV-2 are species specific.
While this specificity is desirable, it also raises the question of whether these antibodies are more susceptible to viral escape mechanisms.
-Viral escape is a common resistance mechanism to nAb therapy due to selective pressure from neutralizing antibodies [553,554].
-For HIV, broadly neutralizing antibodies (bnAbs) targeting the CD4 binding site (CD4bs) show greater neutralization breadth than monoclonal antibodies, which target only specific HIV strains [555].
-For MERS-CoV, a combination of multiple neutralizing antibodies targeting different antigenic sites prevented neutralization escape [556].
-It was found that the different antibody isolates did not target the same epitopes, suggesting that using them in combination might produce a synergistic effect that prevents viral escape [154].
+Viral escape is a common resistance mechanism to nAb therapy due to selective pressure from nAbs [554,555].
+For HIV, broadly neutralizing antibodies (bnAbs) targeting the CD4 binding site (CD4bs) show greater neutralization breadth than monoclonal antibodies, which target only specific HIV strains [556].
+For MERS-CoV, a combination of multiple nAbs targeting different antigenic sites prevented neutralization escape [557].
+It was found that the different antibody isolates did not target the same epitopes, suggesting that using them in combination might produce a synergistic effect that prevents viral escape [156].
It was also demonstrated that binding affinity of the antibodies does not reflect their capability to compete with ACE2 binding.
-Furthermore, no conclusions about correlations between the severity of disease and the ability to produce neutralizing antibodies can be drawn at this point.
-Rather, higher neutralizing antibody titers were more frequently found in patients with severe disease.
-Correspondingly, higher levels of anti-spike IgG were observed in patients that deceased from infection compared to patient that recovered [557].
-Results from the SARS and MERS epidemics thus provide valuable lessons for the design of neutralizing antibodies for the current outbreak.
+Furthermore, no conclusions about correlations between the severity of disease and the ability to produce nAbs can be drawn at this point.
+Rather, higher nAb titers were more frequently found in patients with severe disease.
+Correspondingly, higher levels of anti-spike IgG were observed in patients that deceased from infection compared to patient that recovered [558].
+Results from the SARS and MERS epidemics thus provide valuable lessons for the design of nAbs for the current outbreak.
The findings for SARS-CoV-1 and MERS-CoV can aid in identifying which structures constitute suitable targets for nAbs, despite the fact that the RBD appears to be distinct between the three coronavirus species.
-These studies also suggest that a combination of nAbs targeting distinct antigens might be necessary to provide protection [556].
+These studies also suggest that a combination of nAbs targeting distinct antigens might be necessary to provide protection [557].
The biggest challenge remains identifying antibodies that not only bind to their target, but also prove to be beneficial for disease management.
-On that note, a recently published study indicates that anti-spike antibodies could make the disease worse rather than eliminating the virus [557].
+On that note, a recently published study indicates that anti-spike antibodies could make the disease worse rather than eliminating the virus [558].
These findings underscores our current lack of understanding the full immune response to SARS-CoV-2.
5.5.3 Interferons
IFNs are a family of cytokines critical to activating the innate immune response against viral infections.
-Interferons are classified into three categories based on their receptor specificity: types I, II and III [114].
-Specifically, IFNs I (IFN-𝛼 and 𝛽) and II (IFN-𝛾) induce the expression of antiviral proteins [558].
-Among these IFNs, IFN-𝛽 has already been found to strongly inhibit the replication of other coronaviruses, such as SARS-CoV-1, in cell culture, while IFN-𝛼 and 𝛾 were shown to be less effective in this context [558].
+Interferons are classified into three categories based on their receptor specificity: types I, II and III [116].
+Specifically, IFNs I (IFN-𝛼 and 𝛽) and II (IFN-𝛾) induce the expression of antiviral proteins [559].
+Among these IFNs, IFN-𝛽 has already been found to strongly inhibit the replication of other coronaviruses, such as SARS-CoV-1, in cell culture, while IFN-𝛼 and 𝛾 were shown to be less effective in this context [559].
There is evidence that patients with higher susceptibility to ARDS indeed show deficiency in IFN-𝛽.
-For instance, infection with other coronaviruses impairs IFN-𝛽 expression and synthesis, allowing the virus to escape the innate immune response [559].
-On March 18 2020, Synairgen plc received approval to start a phase II trial for SNG001, an IFN-𝛽-1a formulation to be delivered to the lungs via inhalation [560].
-SNG001, which contains recombinant interferon beta-1a, was previously shown to be effective in reducing viral load in an in vivo model of swine flu and in vitro models of other coronavirus infections [561].
-In July, a press release from Synairgen stated that SNG001 reduced progression to ventilation in a double-blind, placebo-controlled, multi-center study of 101 patients with an average age in the late 50s [562].
-These results were subsequently published in November 2020 [563].
+For instance, infection with other coronaviruses impairs IFN-𝛽 expression and synthesis, allowing the virus to escape the innate immune response [560].
+On March 18 2020, Synairgen plc received approval to start a phase II trial for SNG001, an IFN-𝛽-1a formulation to be delivered to the lungs via inhalation [561].
+SNG001, which contains recombinant interferon beta-1a, was previously shown to be effective in reducing viral load in an in vivo model of swine flu and in vitro models of other coronavirus infections [562].
+In July, a press release from Synairgen stated that SNG001 reduced progression to ventilation in a double-blind, placebo-controlled, multi-center study of 101 patients with an average age in the late 50s [563].
+These results were subsequently published in November 2020 [564].
The study reports that the participants were assigned at a ratio of 1:1 to receive either SNG001 or a placebo that lacked the active compound, by inhalation for up to 14 days.
The primary outcome they assessed was the change in patients’ score on the WHO Ordinal Scale for Clinical Improvement (OSCI) at trial day 15 or 16.
SNG001 was associated with an odds ratio (OR) of 2.32 (95% CI 1.07 – 5.04, p = 0.033) in the intention-to-treat analysis and 2.80 (95% CI 1.21 – 6.52, p = 0.017) in the per-protocol analysis, corresponding to significant improvement in the SNG001 group on the OSCI at day 15/16.
Some of the secondary endpoints analyzed also showed differences: at day 28, the OR for clinical improvement on the OSCI was 3.15 (95% CI 1.39 – 7.14, p = 0.006), and the odds of recovery at day 15/16 and at day 28 were also significant between the two groups.
Thus, this study suggested that IFN-𝛽1 administered via SNG001 may improve clinical outcomes.
-In contrast, the WHO Solidarity trial reported no significant effect of IFN-𝛽1a on patient survival during hospitalization [390].
-Here, the primary outcome analyzed was in-hospital mortality, and the rate ratio for the two groups was 1.16 (95% CI, 0.96 to 1.39; p = 0.11) administering IFN-𝛽-1a to 2050 patients and comparing their response to 2050 controls..
+
In contrast, the WHO Solidarity trial reported no significant effect of IFN-𝛽1a on patient survival during hospitalization [391].
+Here, the primary outcome analyzed was in-hospital mortality, and the rate ratio for the two groups was 1.16 (95% CI, 0.96 to 1.39; p = 0.11) administering IFN-𝛽-1a to 2050 patients and comparing their response to 2,050 controls.
However, there are a few reasons that the different findings of the two trials might not speak to the underlying efficacy of this treatment strategy.
One important consideration is the stage of COVID-19 infection analyzed in each study.
-The Synairgen trial enrolled only patients who were not receiving invasive ventilation, corresponding to a less severe stage of disease than many patients enrolled in the SOLIDARITY trial, as well as a lower overall rate of mortality [564].
-Additionally, the methods of administration differed between the two trials, with the SOLIDARITY trial administering IFN-𝛽-1a subcutaneously [564].
+The Synairgen trial enrolled only patients who were not receiving invasive ventilation, corresponding to a less severe stage of disease than many patients enrolled in the SOLIDARITY trial, as well as a lower overall rate of mortality [565].
+Additionally, the methods of administration differed between the two trials, with the SOLIDARITY trial administering IFN-𝛽-1a subcutaneously [565].
The differences in findings between the studies suggests that the method of administration might be relevant to outcomes, with nebulized IFN-𝛽-1a more directly targeting receptors in the lungs.
-A trial that analyzed the effect of subcutaneously administered IFN-β-1a on patients with ARDS between 2015 and 2017 had also reported no effect on 28-day mortality [565], while a smaller study analyzing the effect of subcutaneous IFN administration did find a significant improvement in 28-day mortality for COVID-19 [566].
-At present, several ongoing clinical trials are investigating the potential effects of IFN-𝛽-1a, including in combination with therapeutics such as remdesivir [567] and administered via inhalation [560].
+A trial that analyzed the effect of subcutaneously administered IFN-β-1a on patients with ARDS between 2015 and 2017 had also reported no effect on 28-day mortality [566], while a smaller study analyzing the effect of subcutaneous IFN administration did find a significant improvement in 28-day mortality for COVID-19 [567].
+At present, several ongoing clinical trials are investigating the potential effects of IFN-𝛽-1a, including in combination with therapeutics such as remdesivir [568] and administered via inhalation [561].
Thus, as additional information becomes available, a more detailed understanding of whether and under which circumstances IFN-𝛽-1a is beneficial to COVID-19 patients should develop.
5.6 Discussion
-With the emergence of the COVID-19 pandemic caused by the coronavirus SARS-CoV-2, the development and/or identification of therapeutic and prophylactic interventions became an issue of international urgency.
+
With the emergence of the COVID-19 pandemic caused by the coronavirus SARS-CoV-2, the development and identification of therapeutic and prophylactic interventions became issues of international urgency.
In previous outbreaks of HCoV, namely SARS and MERS, the development of these interventions was very limited.
-As research has progressed, several potential approaches to treatment have emerged (Figure 4)..
+As research has progressed, several potential approaches to treatment have emerged (Figure 4).
Most notably, remdesivir has been approved by the FDA for the treatment of COVID-19, and dexamethasone, which was approved by the FDA in 1958, has been found to improve outcomes for patients with severe COVID-19.
Other potential therapies are being still being explored and require additional data (Figure 3).
As more evidence becomes available, the potential for existing and novel therapies to improve outcomes for COVID-19 patients will become better understood.
@@ -2228,12 +2228,12 @@ 5.6
-Insights into the pathogenesis of and immune response to SARS-CoV-2 (see [367]) have also guided the identification of potential prophylactics and therapeutics.
+
Insights into the pathogenesis of and immune response to SARS-CoV-2 (see [1]) have also guided the identification of potential prophylactics and therapeutics.
As cases have become better characterized, it has become evident that many patients experience an initial immune response to the virus that is typically characterized by fever, cough, dyspnea, and related symptoms.
-However, the most serious concern is cytokine release syndrome, when the body’s immune response becomes dysregulated, resulting in an extreme inflammatory response.
-The RECOVERY trial, a large-scale, multi-arm trial enrolling about 15% of all COVID-19 patients in the United Kingdom, was the first to identify that the widely available steroid dexamethasone seems to be beneficial for patients suffering from this immune dysregulation [502].
+However, the most serious concern is CRS, when the body’s immune response becomes dysregulated, resulting in an extreme inflammatory response.
+The RECOVERY trial, a large-scale, multi-arm trial enrolling about 15% of all COVID-19 patients in the United Kingdom, was the first to identify that the widely available steroid dexamethasone seems to be beneficial for patients suffering from this immune dysregulation [503].
The results of efforts to identify therapeutic treatments to treat patients early in the course of infection have been more ambiguous.
-Early interest in the drugs hydroxychloroquine and chloroquine yielded no promising results from studies with robust experimental designs.
+Early interest in the drugs HCQ and CQ yielded no promising results from studies with robust experimental designs.
On the other hand, the experimental drug remdesivir, which was developed as a candidate therapeutic for EVD, has received enough support from early analyses to receive FDA approval, although results have been mixed.
The potential for other drugs, such as tocilizumab, to reduce recovery time remains unclear, but some early results were promising.
One additional concern is that the presentation of COVID-19 appears to be heterogeneous across the lifespan.
@@ -2245,33 +2245,33 @@
[568]
.
-Several other anti-inflammatory agents used for the treatment of autoimmune diseases may also be able to counter the effects of the cytokine storm induced by the virus, and some of these, such as cyclosporine, are likely to be more cost-effective and readily available than biologics [569].
+At the doses used for RA patients, the cost for tocilizumab ranges from $179.20 to $896 per dose for the IV form and $355 for the pre-filled syringe [569].
+Several other anti-inflammatory agents used for the treatment of autoimmune diseases may also be able to counter the effects of the cytokine storm induced by the virus, and some of these, such as cyclosporine, are likely to be more cost-effective and readily available than biologics [570].
While tocilizumab targets IL-6, several other inflammatory markers could be potential targets, including TNF-α.
-Inhibition of TNF-α by a compound such as Etanercept was previously suggested for treatment of SARS-CoV-1 [570] and may be relevant for SARS-CoV-2 as well.
-Another anti-IL-6 antibody, sarilumab, is also being investigated [571,572].
-Baricitinib and other small molecule inhibitors of the Janus-activated kinase pathway also curtail the inflammatory response and have been suggested as potential options for SARS-CoV-2 infections [573].
-Baricitinib, in particular, may be able to reduce the ability of SARS-CoV-2 to infect lung cells [574].
-Clinical trials studying baricitinib in COVID-19 have already begun in the US and in Italy [575,576].
+Inhibition of TNF-α by a compound such as Etanercept was previously suggested for treatment of SARS-CoV-1 [571] and may be relevant for SARS-CoV-2 as well.
+Another anti-IL-6 antibody, sarilumab, is also being investigated [572,573].
+Baricitinib and other small molecule inhibitors of the Janus-activated kinase pathway also curtail the inflammatory response and have been suggested as potential options for SARS-CoV-2 infections [574].
+Baricitinib, in particular, may be able to reduce the ability of SARS-CoV-2 to infect lung cells [575].
+Clinical trials studying baricitinib in COVID-19 have already begun in the US and in Italy [576,577].
Identification and targeting of further inflammatory markers that are relevant in SARS-CoV-2 infection may be of value for curtailing the inflammatory response and lung damage.
In addition to immunosuppressive treatments, which are most beneficial late in disease progression, much research is focused on identifying therapeutics for early-stage patients.
-For example, although studies of hydroxychloroquine have not supported the early theory-driven interest in this antiviral treatment, alternative compounds with related mechanisms may still have potential.
-Hydroxyferroquine derivatives of HCQ have been described as a class of bioorganometallic compounds that exert antiviral effects with some selectivity for SARS-CoV-1 in vitro [577].
+For example, although studies of HCQ have not supported the early theory-driven interest in this antiviral treatment, alternative compounds with related mechanisms may still have potential.
+Hydroxyferroquine derivatives of HCQ have been described as a class of bioorganometallic compounds that exert antiviral effects with some selectivity for SARS-CoV-1 in vitro [578].
Future work could explore whether such compounds exert antiviral effects against SARS-CoV-2 and whether they would be safer for use in COVID-19.
Another potential approach is the development of antivirals, which could be broad-spectrum, specific to coronaviruses, or targeted to SARS-CoV-2.
Development of new antivirals is complicated by the fact that none have yet been approved for human coronaviruses.
Intriguing new options are emerging, however.
-Beta-D-N4-hydroxycytidine (NHC) is an orally bioavailable ribonucleotide analog showing broad-spectrum activity against RNA viruses, which may inhibit SARS-CoV-2 replication in vitro and in vivo in mouse models of HCoVs [578].
+Beta-D-N4-hydroxycytidine (NHC) is an orally bioavailable ribonucleotide analog showing broad-spectrum activity against RNA viruses, which may inhibit SARS-CoV-2 replication in vitro and in vivo in mouse models of HCoVs [579].
A range of other antivirals are also in development.
Development of antivirals will be further facilitated as research reveals more information about the interaction of SARS-CoV-2 with the host cell and host cell genome, mechanisms of viral replication, mechanisms of viral assembly, and mechanisms of viral release to other cells; this can allow researchers to target specific stages and structures of the viral life cycle.
Finally, antibodies against viruses, also known as antiviral monoclonal antibodies, could be an alternative as well and are described in detail in an above section.
-The goal of antiviral antibodies is to neutralize viruses through either cell-killing activity or blocking of viral replication [579].
+The goal of antiviral antibodies is to neutralize viruses through either cell-killing activity or blocking of viral replication [580].
They may also engage the host immune response, encouraging the immune system to hone in on the virus.
-Given the cytokine storm that results from immune system activation in response to the virus, which has been implicated in worsening of the disease, a neutralizing antibody (nAb) may be preferable.
+Given the cytokine storm that results from immune system activation in response to the virus, which has been implicated in worsening of the disease, an nAb may be preferable.
Upcoming work may explore the specificity of nAbs for their target, mechanisms by which the nAbs impede the virus, and improvements to antibody structure that may enhance the ability of the antibody to block viral activity.
Some research is also investigating potential therapeutics and prophylactics that would interact with components of the innate immune response.
-For example, TLRs are PRRs that recognize pathogen- and damage-associated molecular patterns and contribute to innate immune recognition and, more generally, promotion of both the innate and adaptive immune responses [110].
-In mouse models, poly(I:C) and CpG, which are agonists of Toll-like receptors TLR3 and TLR9, respectively, showed protective effects when administered prior to SARS-CoV-1 infection [580].
+For example, TLRs are pattern recognition receptors that recognize pathogen- and damage-associated molecular patterns and contribute to innate immune recognition and, more generally, promotion of both the innate and adaptive immune responses [112].
+In mouse models, poly(I:C) and CpG, which are agonists of Toll-like receptors TLR3 and TLR9, respectively, showed protective effects when administered prior to SARS-CoV-1 infection [581].
Therefore, TLR agonists hold some potential for broad-spectrum prophylaxis.
Given that a large number of clinical trials are currently in progress, more information about the potential of these and other therapeutics should become available over time.
This information, combined with advances in understanding the molecular structure and viral pathogenesis of SARS-CoV-2, may lead to a more complete understanding of how the virus affects the human host and what strategies can improve outcomes.
@@ -2280,11 +2280,12 @@
[424,581]
, and efforts are already in place to perform screens for small molecule inhibitors of the main protease, which have yielded potential hits [424].
+Currently, crystal structures of the SARS-CoV-2 main protease have recently been resolved [425,582], and efforts are already in place to perform screens for small molecule inhibitors of the main protease, which have yielded potential hits [425].
Much work remains to be done to determine further crystal structures of other viral components, understand the relative utility of targeting different viral components, perform additional small molecule inhibitor screens, and determine the safety and efficacy of the potential inhibitors.
While still nascent, work in this area is promising.
-Over the longer term, this approach and others may lead to the development of novel therapeutics specifically for COVID-19 and SARS-CoV-2.
-5.6.2 Conclusions of the Present Analysis
+Over the longer term, this approach and others may lead to the development of novel therapeutics specifically for COVID-19 and SARS-CoV-2.
+
+5.6.2 Conclusions
Insights into the pathogenesis of and immune response to SARS-CoV-2 (see [367]) have also guided the identification of potential prophylactics and therapeutics. +
Insights into the pathogenesis of and immune response to SARS-CoV-2 (see [1]) have also guided the identification of potential prophylactics and therapeutics. As cases have become better characterized, it has become evident that many patients experience an initial immune response to the virus that is typically characterized by fever, cough, dyspnea, and related symptoms. -However, the most serious concern is cytokine release syndrome, when the body’s immune response becomes dysregulated, resulting in an extreme inflammatory response. -The RECOVERY trial, a large-scale, multi-arm trial enrolling about 15% of all COVID-19 patients in the United Kingdom, was the first to identify that the widely available steroid dexamethasone seems to be beneficial for patients suffering from this immune dysregulation [502]. +However, the most serious concern is CRS, when the body’s immune response becomes dysregulated, resulting in an extreme inflammatory response. +The RECOVERY trial, a large-scale, multi-arm trial enrolling about 15% of all COVID-19 patients in the United Kingdom, was the first to identify that the widely available steroid dexamethasone seems to be beneficial for patients suffering from this immune dysregulation [503]. The results of efforts to identify therapeutic treatments to treat patients early in the course of infection have been more ambiguous. -Early interest in the drugs hydroxychloroquine and chloroquine yielded no promising results from studies with robust experimental designs. +Early interest in the drugs HCQ and CQ yielded no promising results from studies with robust experimental designs. On the other hand, the experimental drug remdesivir, which was developed as a candidate therapeutic for EVD, has received enough support from early analyses to receive FDA approval, although results have been mixed. The potential for other drugs, such as tocilizumab, to reduce recovery time remains unclear, but some early results were promising.
One additional concern is that the presentation of COVID-19 appears to be heterogeneous across the lifespan. @@ -2245,33 +2245,33 @@
[568]
. -Several other anti-inflammatory agents used for the treatment of autoimmune diseases may also be able to counter the effects of the cytokine storm induced by the virus, and some of these, such as cyclosporine, are likely to be more cost-effective and readily available than biologics [569]. +At the doses used for RA patients, the cost for tocilizumab ranges from $179.20 to $896 per dose for the IV form and $355 for the pre-filled syringe [569]. +Several other anti-inflammatory agents used for the treatment of autoimmune diseases may also be able to counter the effects of the cytokine storm induced by the virus, and some of these, such as cyclosporine, are likely to be more cost-effective and readily available than biologics [570]. While tocilizumab targets IL-6, several other inflammatory markers could be potential targets, including TNF-α. -Inhibition of TNF-α by a compound such as Etanercept was previously suggested for treatment of SARS-CoV-1 [570] and may be relevant for SARS-CoV-2 as well. -Another anti-IL-6 antibody, sarilumab, is also being investigated [571,572]. -Baricitinib and other small molecule inhibitors of the Janus-activated kinase pathway also curtail the inflammatory response and have been suggested as potential options for SARS-CoV-2 infections [573]. -Baricitinib, in particular, may be able to reduce the ability of SARS-CoV-2 to infect lung cells [574]. -Clinical trials studying baricitinib in COVID-19 have already begun in the US and in Italy [575,576]. +Inhibition of TNF-α by a compound such as Etanercept was previously suggested for treatment of SARS-CoV-1 [571] and may be relevant for SARS-CoV-2 as well. +Another anti-IL-6 antibody, sarilumab, is also being investigated [572,573]. +Baricitinib and other small molecule inhibitors of the Janus-activated kinase pathway also curtail the inflammatory response and have been suggested as potential options for SARS-CoV-2 infections [574]. +Baricitinib, in particular, may be able to reduce the ability of SARS-CoV-2 to infect lung cells [575]. +Clinical trials studying baricitinib in COVID-19 have already begun in the US and in Italy [576,577]. Identification and targeting of further inflammatory markers that are relevant in SARS-CoV-2 infection may be of value for curtailing the inflammatory response and lung damage.Due to the large number of clinical trials currently under examination (Figure 3), not all candidates are examined here. Instead, this review seeks to provide an overview of the range of mechanisms that have been explored and to examine some prominent candidates in the context of the pathogenesis of and immune response to SARS-CoV-2. As more research becomes available, this review will be updated to include additional therapeutics that emerge and to include new findings that are released about those discussed here. @@ -2315,140 +2316,140 @@
6.
This rapid effort led to the identification of some promising pharmaceutical therapies for hospitalized patients, such as remdesivir and dexamethasone.
Furthermore, most societies have adopted non-pharmacological preventative measures such as utilizing public health strategies that reduce the transmission of SARS-CoV-2.
However, during this time, many individuals sought additional protections via the consumption of various dietary supplements and nutraceuticals that they believed to confer beneficial effects.
-While a patient’s nutritional status does seem to play a role in COVID-19 susceptibility and outcomes [582,583,584,585,586], the beginning of the pandemic saw sales of vitamins and other supplements to soar despite a lack of any evidence supporting their use against COVID-19.
-In the United States, for example, dietary supplement and nutraceutical sales have shown modest annual growth in recent years (approximately 5%, or a $345 million increase in 2019), but during the six-week period preceding April 5, 2020, they increased by 44% ($435 million) relative to the same period in 2019 [587].
-While growth subsequently leveled off, sales continued to boom, with a further 16% ($151 million) increase during the six weeks preceding May 17, 2020 relative to 2019 [587].
-In France, New Zealand, India, and China, similar trends in sales were reported [588,589,590,591].
-The increase in sales was driven by a consumer perception that dietary supplements and nutraceuticals would protect consumers from infection and/or mitigate the impact of infection due to the various “immune-boosting” claims of these products [592,593].
+While a patient’s nutritional status does seem to play a role in COVID-19 susceptibility and outcomes [583,584,585,586,587], the beginning of the pandemic saw sales of vitamins and other supplements to soar despite a lack of any evidence supporting their use against COVID-19.
+In the United States, for example, dietary supplement and nutraceutical sales have shown modest annual growth in recent years (approximately 5%, or a $345 million increase in 2019), but during the six-week period preceding April 5, 2020, they increased by 44% ($435 million) relative to the same period in 2019 [588].
+While growth subsequently leveled off, sales continued to boom, with a further 16% ($151 million) increase during the six weeks preceding May 17, 2020 relative to 2019 [588].
+In France, New Zealand, India, and China, similar trends in sales were reported [589,590,591,592].
+The increase in sales was driven by a consumer perception that dietary supplements and nutraceuticals would protect consumers from infection and/or mitigate the impact of infection due to the various “immune-boosting” claims of these products [593,594].
Due to the significant interest from the general public in dietary additives, whether and to what extent nutraceuticals or dietary supplements can provide any prophylactic or therapeutic benefit remains a topic of interest for the scientific community.
Nutraceuticals and dietary supplements are related but distinct non-pharmaceutical products.
-Nutraceuticals are classified as supplements with health benefits beyond their basic nutritional value [594,595].
-The key difference between a dietary supplement and a nutraceutical is that nutraceuticals should not only supplement the diet, but also aid in the prophylaxis and/or treatment of a disorder or disease [596].
+Nutraceuticals are classified as supplements with health benefits beyond their basic nutritional value [595,596].
+The key difference between a dietary supplement and a nutraceutical is that nutraceuticals should not only supplement the diet, but also aid in the prophylaxis and/or treatment of a disorder or disease [597].
However, dietary supplements and nutraceuticals, unlike pharmaceuticals, are not subject to the same regulatory protocols that protect consumers of medicines.
-Indeed, nutraceuticals do not entirely fall under the responsibility of the Food and Drug Administration (FDA), but they are monitored as dietary supplements according to the Dietary Supplement, Health and Education Act 1994 (DSHEA) [597] and the Food and Drug Administration Modernization Act 1997 (FDAMA) [598].
+Indeed, nutraceuticals do not entirely fall under the responsibility of the Food and Drug Administration (FDA), but they are monitored as dietary supplements according to the Dietary Supplement, Health and Education Act 1994 (DSHEA) [598] and the Food and Drug Administration Modernization Act 1997 (FDAMA) [599].
Due to increases in sales of dietary supplements and nutraceuticals, in 1996 the FDA established the Office of Dietary Supplement Programs (ODSP) to increase surveillance.
Novel products or nutraceuticals must now submit a new dietary ingredient notification to the ODSP for review.
-There are significant concerns that these legislations do not adequately protect the consumer as they ascribe responsibility to the manufacturers to ensure the safety of the product before manufacturing or marketing [599].
+There are significant concerns that these legislations do not adequately protect the consumer as they ascribe responsibility to the manufacturers to ensure the safety of the product before manufacturing or marketing [600].
Manufacturers are not required to register or even seek approval from the FDA to produce or sell food supplements or nutraceuticals.
-Health or nutrient content claims for labeling purposes are approved based on an authoritative statement from the Academy of Sciences or relevant federal authorities once the FDA has been notified and on the basis that the information is known to be true and not deceptive [599].
+Health or nutrient content claims for labeling purposes are approved based on an authoritative statement from the Academy of Sciences or relevant federal authorities once the FDA has been notified and on the basis that the information is known to be true and not deceptive [600].
Therefore, there is often a gap between perceptions by the American public about a nutraceutical or dietary supplement and the actual clinical evidence surrounding its effects.
Despite differences in regulations, similar challenges exist outside of the United States.
-In Europe, where the safety of supplements are monitored by the European Union (EU) under Directive 2002/46/EC [600].
+In Europe, where the safety of supplements are monitored by the European Union (EU) under Directive 2002/46/EC [601].
However, nutraceuticals are not directly mentioned.
-Consequently, nutraceuticals can be generally described as either a medicinal product under Directive 2004/27/EC [601] or as a ‘foodstuff’ under Directive 2002/46/EC of the European council.
+Consequently, nutraceuticals can be generally described as either a medicinal product under Directive 2004/27/EC [602] or as a ‘foodstuff’ under Directive 2002/46/EC of the European council.
In order to synchronize the various existing legislations, Regulation EC 1924/2006 on nutrition and health claims was put into effect to assure customers of safety and efficacy of products and to deliver understandable information to consumers.
However, specific legislation for nutraceuticals is still elusive.
-Health claims are permitted on a product label only following compliance and authorization according to the European Food Safety Authority (EFSA) guidelines on nutrition and health claims [602].
-EFSA does not currently distinguish between food supplements and nutraceuticals for health claim applications of new products, as claim authorization is dependent on the availability of clinical data in order to substantiate efficacy [603].
-These guidelines seem to provide more protection to consumers than the FDA regulations but potentially at the cost of innovation in the sector [604].
-The situation becomes even more complicated when comparing regulations at a global level, as countries such as China and India have existing regulatory frameworks for traditional medicines and phytomedicines not commonly consumed in Western society [605].
-Currently, there is debate among scientists and regulatory authorities surrounding the development of a widespread regulatory framework to deal with the challenges of safety and health claim substantiation for nutraceuticals [599,603], as these products do not necessarily follow the same rigorous clinical trial frameworks used to approve the use of pharmaceuticals.
+Health claims are permitted on a product label only following compliance and authorization according to the European Food Safety Authority (EFSA) guidelines on nutrition and health claims [603].
+EFSA does not currently distinguish between food supplements and nutraceuticals for health claim applications of new products, as claim authorization is dependent on the availability of clinical data in order to substantiate efficacy [604].
+These guidelines seem to provide more protection to consumers than the FDA regulations but potentially at the cost of innovation in the sector [605].
+The situation becomes even more complicated when comparing regulations at a global level, as countries such as China and India have existing regulatory frameworks for traditional medicines and phytomedicines not commonly consumed in Western society [606].
+Currently, there is debate among scientists and regulatory authorities surrounding the development of a widespread regulatory framework to deal with the challenges of safety and health claim substantiation for nutraceuticals [600,604], as these products do not necessarily follow the same rigorous clinical trial frameworks used to approve the use of pharmaceuticals.
Such regulatory disparities have been highlighted by the pandemic, as many individuals and companies have attempted to profit from the vulnerabilities of others by overstating claims in relation to the treatment of COVID-19 using supplements and nutraceuticals.
-The FDA has written several letters to prevent companies marketing or selling products based on false hyperbolic promises about preventing SARS-CoV-2 infection or treating COVID-19 [606,607,608].
-These letters came in response to efforts to market nutraceutical prophylactics against COVID-19, some of which charged the consumer as much as $23,000 [609].
-There have even been some incidents highlighted in the media because of their potentially life threatening consequences; for example, the use of oleandrin was touted as a potential “cure” by individuals close to the former President of the United States despite its high toxicity [610].
+The FDA has written several letters to prevent companies marketing or selling products based on false hyperbolic promises about preventing SARS-CoV-2 infection or treating COVID-19 [607,608,609].
+These letters came in response to efforts to market nutraceutical prophylactics against COVID-19, some of which charged the consumer as much as $23,000 [610].
+There have even been some incidents highlighted in the media because of their potentially life threatening consequences; for example, the use of oleandrin was touted as a potential “cure” by individuals close to the former President of the United States despite its high toxicity [611].
Thus, heterogeneous and at times relaxed regulatory standards have permitted high-profile cases of the sale of nutraceuticals and dietary supplements that are purported to provide protection against COVID-19, despite a lack of research into these compounds.
Notwithstanding the issues of poor safety, efficacy, and regulatory oversight, some dietary supplements and nutraceuticals have exhibited therapeutic and prophylactic potential.
-Some have been linked with reduced immunopathology, antiviral and anti-inflammatory activities, or even the prevention of acute respiratory distress syndrome (ARDS) [592,611,612].
+Some have been linked with reduced immunopathology, antiviral and anti-inflammatory activities, or even the prevention of acute respiratory distress syndrome (ARDS) [593,612,613].
A host of potential candidates have been highlighted in the literature that target various aspects of the COVID-19 viral pathology, while others are thought to prime the host immune system.
-These candidates include vitamins and minerals along with extracts and omega-3 polyunsaturated fatty acids (n-3 PUFA) [613].
-In vitro and in vivo studies suggest that nutraceuticals containing phycocyanobilin, N-acetylcysteine, glucosamine, selenium or phase 2 inductive nutraceuticals (e.g. ferulic acid, lipoic acid, or sulforaphane) can prevent or modulate RNA virus infections via amplification of the signaling activity of mitochondrial antiviral-signaling protein (MAVS) and activation of Toll-like receptor 7 [614].
+These candidates include vitamins and minerals along with extracts and omega-3 polyunsaturated fatty acids (n-3 PUFA) [614].
+In vitro and in vivo studies suggest that nutraceuticals containing phycocyanobilin, N-acetylcysteine, glucosamine, selenium or phase 2 inductive nutraceuticals (e.g. ferulic acid, lipoic acid, or sulforaphane) can prevent or modulate RNA virus infections via amplification of the signaling activity of mitochondrial antiviral-signaling protein (MAVS) and activation of Toll-like receptor 7 [615].
While promising, further animal and human studies are required to assess the therapeutic potential of these various nutrients and nutraceuticals against COVID-19.
For the purpose of this review, we have highlighted some of the main dietary supplements and nutraceuticals that are currently under investigation for their potential prophylactic and therapeutic applications.
These include n-3 PUFA, zinc, vitamins C and D, and probiotics.
6.4 n-3 PUFA
-One category of supplements that has been explored for beneficial effects against various viral infections are the n-3 PUFAs [613], commonly referred to as omega-3 fatty acids, which include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
-EPA and DHA intake can come from a diet high in fish or through dietary supplementation with fish oils or purified oils [615].
-Other, more sustainable sources of EPA and DHA include algae [616,617], which can also be exploited for their rich abundance of other bioactive compounds such as angiotensin converting enzyme inhibitor peptides and antiviral agents including phycobiliproteins, sulfated polysaccharides, and calcium-spirulan [618].
-n-3 PUFAs have been investigated for many years for their therapeutic potential [619].
-Supplementation with fish oils is generally well tolerated [619], and intake of n-3 PUFAs through dietary sources or supplementation is specifically encouraged for vulnerable groups such as pregnant and lactating women [620,621].
+
One category of supplements that has been explored for beneficial effects against various viral infections are the n-3 PUFAs [614], commonly referred to as omega-3 fatty acids, which include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
+EPA and DHA intake can come from a diet high in fish or through dietary supplementation with fish oils or purified oils [616].
+Other, more sustainable sources of EPA and DHA include algae [617,618], which can also be exploited for their rich abundance of other bioactive compounds such as angiotensin converting enzyme inhibitor peptides and antiviral agents including phycobiliproteins, sulfated polysaccharides, and calcium-spirulan [619].
+n-3 PUFAs have been investigated for many years for their therapeutic potential [620].
+Supplementation with fish oils is generally well tolerated [620], and intake of n-3 PUFAs through dietary sources or supplementation is specifically encouraged for vulnerable groups such as pregnant and lactating women [621,622].
As a result, these well-established compounds have drawn significant interest for their potential immune effects and therapeutic potential.
Particular interest has arisen in n-3 PUFAs as potential therapeutics against diseases associated with inflammation.
-n-3 PUFAs have been found to mediate inflammation by influencing processes such as leukocyte chemotaxis, adhesion molecule expression, and the production of eicosanoids [622,623].
-This and other evidence indicates that n-3 PUFAs may have the capacity to modulate the adaptive immune response [595,615,622]; for example, they have been found to influence antigen presentation and the production of CD4(+) Th1 cells, among other relevant effects [624].
-Certainly, preliminary evidence from banked blood samples from 100 COVID-19 patients suggests that patients with a higher omega-3 index, a measure of n-3 and n-6 fatty acids in red blood cells, had a lower risk of death due to COVID-19 [625].
-Interest has also arisen as to whether nutritional status related to n-3 PUFAs can also affect inflammation associated with severe disease, such as ARDS or sepsis [626,627].
-ARDS and sepsis hold particular concern in the treatment of severe COVID-19; an analysis of 82 deceased COVID-19 patients in Wuhan during January to February 2020 reported that respiratory failure (associated with ARDS) was the cause of death in 69.5% of cases, and sepsis or multi-organ failure accounted for 28.0% of deaths [628].
+n-3 PUFAs have been found to mediate inflammation by influencing processes such as leukocyte chemotaxis, adhesion molecule expression, and the production of eicosanoids [623,624].
+This and other evidence indicates that n-3 PUFAs may have the capacity to modulate the adaptive immune response [596,616,623]; for example, they have been found to influence antigen presentation and the production of CD4(+) Th1 cells, among other relevant effects [625].
+Certainly, preliminary evidence from banked blood samples from 100 COVID-19 patients suggests that patients with a higher omega-3 index, a measure of n-3 and n-6 fatty acids in red blood cells, had a lower risk of death due to COVID-19 [626].
+Interest has also arisen as to whether nutritional status related to n-3 PUFAs can also affect inflammation associated with severe disease, such as ARDS or sepsis [627,628].
+ARDS and sepsis hold particular concern in the treatment of severe COVID-19; an analysis of 82 deceased COVID-19 patients in Wuhan during January to February 2020 reported that respiratory failure (associated with ARDS) was the cause of death in 69.5% of cases, and sepsis or multi-organ failure accounted for 28.0% of deaths [629].
Research in ARDS prior to current pandemic suggests that n-3 PUFAs may hold some therapeutic potential.
-One study randomized 16 consecutive ARDS patients to receive either a fish oil-enriched lipid emulsion or a control lipid emulsion (comprised of 100% long-chain triglycerides) under a double-blinded design [629].
+One study randomized 16 consecutive ARDS patients to receive either a fish oil-enriched lipid emulsion or a control lipid emulsion (comprised of 100% long-chain triglycerides) under a double-blinded design [630].
They reported a statistically significant reduction in leukotriene B4 levels in the group receiving the fish oil-enriched emulsion, suggesting that the fish oil supplementation may have reduced inflammation.
However, they also reported that most of their tests were not statistically significant, and therefore it seems that additional research using larger sample sizes is required.
-A recent meta-analysis of 10 randomized controlled trials (RCTs) examining the effects of n-3 PUFAs on ARDS patients did not find evidence of any effect on mortality, although the effect on secondary outcomes could not be determined due to a low quality of evidence [630].
-However, another meta-analysis that examined 24 RCTs studying the effects of n-3 fatty acids on sepsis, including ARDS-induced sepsis, did find support for an effect on mortality when n-3 fatty acids were administered via enteral nutrition, although a paucity of high-quality evidence again limited conclusions [631].
+A recent meta-analysis of 10 randomized controlled trials (RCTs) examining the effects of n-3 PUFAs on ARDS patients did not find evidence of any effect on mortality, although the effect on secondary outcomes could not be determined due to a low quality of evidence [631].
+However, another meta-analysis that examined 24 RCTs studying the effects of n-3 fatty acids on sepsis, including ARDS-induced sepsis, did find support for an effect on mortality when n-3 fatty acids were administered via enteral nutrition, although a paucity of high-quality evidence again limited conclusions [632].
Therefore, despite theoretical support for an immunomodulatory effect of n-3 PUFAs in COVID-19, evidence from existing RCTs is insufficient to determine whether supplementation offers an advantage in a clinical setting that would be relevant to COVID-19.
-Another potential mechanism that has led to interest in n-3 PUFAs as protective against viral infections including COVID-19 is its potential as a precursor molecule for the biosynthesis of endogenous specialized proresolving mediators (SPM), such as protectins and resolvins, that actively resolve inflammation and infection [632].
-SPM have exhibited beneficial effects against a variety of lung infections, including some caused by RNA viruses [633,634].
-Indeed, protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [635].
-Several mechanisms for SPM have been proposed, including preventing the release of pro-inflammatory cytokines and chemokines or increasing phagocytosis of cellular debris by macrophages [636].
-In influenza, SPM promote antiviral B lymphocytic activities [637], and protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [635].
-It has thus been hypothesized that SPM could aid in the resolution of the cytokine storm and pulmonary inflammation associated with COVID-19 [638,639].
-Another theory is that some comorbidities, such as obesity, could lead to deficiencies of SPM, which could in turn be related to the occurrence of adverse outcomes for COVID-19 [640].
-However, not all studies are in agreement that n-3 PUFAs or their resulting SPM are effective against infections [641].
-At a minimum, the effectiveness of n-3 PUFAs against infections would be dependent on the dosage, timing, and the specific pathogens responsible [642].
-On another level, there is still the question of whether fish oils can raise the levels of SPM levels upon ingestion and in response to acute inflammation in humans [643].
-Currently, Karolinska University Hospital is running a trial that will measure the levels of SPM as a secondary outcome following intravenous supplementation of n-3 PUFAs in hospitalized COVID-19 patients to determine whether n-3 PUFAs provides therapeutic value [644,645].
+
Another potential mechanism that has led to interest in n-3 PUFAs as protective against viral infections including COVID-19 is its potential as a precursor molecule for the biosynthesis of endogenous specialized proresolving mediators (SPM), such as protectins and resolvins, that actively resolve inflammation and infection [633].
+SPM have exhibited beneficial effects against a variety of lung infections, including some caused by RNA viruses [634,635].
+Indeed, protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [636].
+Several mechanisms for SPM have been proposed, including preventing the release of pro-inflammatory cytokines and chemokines or increasing phagocytosis of cellular debris by macrophages [637].
+In influenza, SPM promote antiviral B lymphocytic activities [638], and protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [636].
+It has thus been hypothesized that SPM could aid in the resolution of the cytokine storm and pulmonary inflammation associated with COVID-19 [639,640].
+Another theory is that some comorbidities, such as obesity, could lead to deficiencies of SPM, which could in turn be related to the occurrence of adverse outcomes for COVID-19 [641].
+However, not all studies are in agreement that n-3 PUFAs or their resulting SPM are effective against infections [642].
+At a minimum, the effectiveness of n-3 PUFAs against infections would be dependent on the dosage, timing, and the specific pathogens responsible [643].
+On another level, there is still the question of whether fish oils can raise the levels of SPM levels upon ingestion and in response to acute inflammation in humans [644].
+Currently, Karolinska University Hospital is running a trial that will measure the levels of SPM as a secondary outcome following intravenous supplementation of n-3 PUFAs in hospitalized COVID-19 patients to determine whether n-3 PUFAs provides therapeutic value [645,646].
Therefore, while this mechanism provides theoretical support for a role for n-3 PUFAs against COVID-19, experimental support is still needed.
-A third possible mechanism by which n-3 PUFAs could benefit COVID-19 patients arises from the fact that some COVID-19 patients, particularly those with comorbidities, are at a significant risk of thrombotic complications including arterial and venous thrombosis [107,646].
-Therefore, the use of prophylactic and therapeutic anticoagulants and antithrombotic agents is under consideration [647,648].
-Considering that there is significant evidence that n-3 fatty acids and other fish oil-derived lipids possess antithrombotic properties and anti-inflammatory properties [615,649,650], they may have therapeutic value against the prothrombotic complications of COVID-19.
-In particular, concerns have been raised within the medical community about using investigational therapeutics on COVID-19 patients who are already on antiplatelet therapies due to pre-existing comorbidities because the introduction of such therapeutics could lead to issues with dosing and drug choice and/or negative drug-drug interactions [647].
+
A third possible mechanism by which n-3 PUFAs could benefit COVID-19 patients arises from the fact that some COVID-19 patients, particularly those with comorbidities, are at a significant risk of thrombotic complications including arterial and venous thrombosis [109,647].
+Therefore, the use of prophylactic and therapeutic anticoagulants and antithrombotic agents is under consideration [648,649].
+Considering that there is significant evidence that n-3 fatty acids and other fish oil-derived lipids possess antithrombotic properties and anti-inflammatory properties [616,650,651], they may have therapeutic value against the prothrombotic complications of COVID-19.
+In particular, concerns have been raised within the medical community about using investigational therapeutics on COVID-19 patients who are already on antiplatelet therapies due to pre-existing comorbidities because the introduction of such therapeutics could lead to issues with dosing and drug choice and/or negative drug-drug interactions [648].
In such cases, dietary sources of n-3 fatty acids or other nutraceuticals with antiplatelet activities could hold particular value for reducing the risk of thrombotic complications in patients already receiving pharmaceutical antiplatelet therapies.
-A new clinical trial [651] is currently recruiting COVID-19 positive patients to investigate the anti-inflammatory activity of a recently developed, highly purified nutraceutical derivative of EPA known as icosapent ethyl (VascepaTM) [652].
-Other randomized controlled trials that are in the preparatory stages intend to investigate the administration of EPA and other bioactive compounds to COVID-19 positive patients in order to observe whether anti-inflammatory effects or disease state improvements occur [653,654].
-Finally, while there have been studies investigating the therapeutic value of n-3 fatty acids against ARDS in humans, there is still limited evidence of their effectiveness [655].
+A new clinical trial [652] is currently recruiting COVID-19 positive patients to investigate the anti-inflammatory activity of a recently developed, highly purified nutraceutical derivative of EPA known as icosapent ethyl (VascepaTM) [653].
+Other randomized controlled trials that are in the preparatory stages intend to investigate the administration of EPA and other bioactive compounds to COVID-19 positive patients in order to observe whether anti-inflammatory effects or disease state improvements occur [654,655].
+Finally, while there have been studies investigating the therapeutic value of n-3 fatty acids against ARDS in humans, there is still limited evidence of their effectiveness [656].
It should be noted that the overall lack of human studies in this area means there is limited evidence as to whether these supplements could affect COVID-19 infection.
Consequently, the clinical trials that are underway and those that have been proposed will provide valuable insight into whether the anti-inflammatory potential of n-3 PUFAs and their derivatives can be beneficial to the treatment of COVID-19.
All the same, while the evidence is not present to draw conclusions about whether n-3 PUFAs will be useful in treating COVID-19, there is likely little harm associated with a diet rich in fish oils, and interest in n-3 PUFA supplementation by the general public is unlikely to have negative effects.
6.5 Zinc
Zinc is nutrient supplement that may exhibit some benefits against RNA viral infections.
-Zinc is a trace metal obtained from dietary sources or supplementation and is important for the maintenance of immune cells involved in adaptive and innate immunity [656].
+Zinc is a trace metal obtained from dietary sources or supplementation and is important for the maintenance of immune cells involved in adaptive and innate immunity [657].
Supplements can be administered orally as a tablet or as a lozenge and are available in many forms, such as zinc picolinate, zinc acetate, and zinc citrate.
Zinc is also available from dietary sources including meat, seafood, nuts, seeds, legumes, and dairy.
-The role of zinc in immune function has been extensively reviewed [656].
+The role of zinc in immune function has been extensively reviewed [657].
Zinc is an important signaling molecule, and zinc levels can alter host defense systems.
-In inflammatory situations such as an infection, zinc can regulate leukocyte immune responses and activate the nuclear factor kappa-light-chain-enhancer of activated B cells, thus altering cytokine production [657,658].
-In particular, zinc supplementation can increase natural killer cell levels, which are important cells for host defense against viral infections [656,659].
+In inflammatory situations such as an infection, zinc can regulate leukocyte immune responses and activate the nuclear factor kappa-light-chain-enhancer of activated B cells, thus altering cytokine production [658,659].
+In particular, zinc supplementation can increase natural killer cell levels, which are important cells for host defense against viral infections [657,660].
As a result of these immune-related functions, zinc is also under consideration for possible benefits against COVID-19.
-Adequate zinc intake has been associated with reduced incidence of infection [660] and antiviral immunity [661].
-A randomized, double-blind, placebo-controlled trial that administered zinc supplementation to elderly subjects over the course of a year found zinc deficiency to be associated with increased susceptibility to infection and that zinc deficiency could be prevented through supplementation [660].
-Clinical trial data supports the utility of zinc to diminish the duration and severity of symptoms associated with common colds when it is provided within 24 hours of the onset of symptoms [662,663].
-An observational study showed that COVID-19 patients had significantly lower zinc levels in comparison to healthy controls and that zinc-deficient COVID-19 patients (those with levels less than 80 μg/dl) tended to have more complications (70.4% vs 30.0%, p = 0.009) and potentially prolonged hospital stays (7.9 vs 5.7 days, p = 0.048) relative to patients who were not zinc deficient [664].
-In coronaviruses specifically, in vitro evidence has demonstrated that the combination of zinc (Zn2+) and zinc ionophores (pyrithione) can interrupt the replication mechanisms of SARS-CoV-GFP (a fluorescently tagged SARS-CoV-1) and a variety of other RNA viruses [665,666].
+
Adequate zinc intake has been associated with reduced incidence of infection [661] and antiviral immunity [662].
+A randomized, double-blind, placebo-controlled trial that administered zinc supplementation to elderly subjects over the course of a year found zinc deficiency to be associated with increased susceptibility to infection and that zinc deficiency could be prevented through supplementation [661].
+Clinical trial data supports the utility of zinc to diminish the duration and severity of symptoms associated with common colds when it is provided within 24 hours of the onset of symptoms [663,664].
+An observational study showed that COVID-19 patients had significantly lower zinc levels in comparison to healthy controls and that zinc-deficient COVID-19 patients (those with levels less than 80 μg/dl) tended to have more complications (70.4% vs 30.0%, p = 0.009) and potentially prolonged hospital stays (7.9 vs 5.7 days, p = 0.048) relative to patients who were not zinc deficient [665].
+In coronaviruses specifically, in vitro evidence has demonstrated that the combination of zinc (Zn2+) and zinc ionophores (pyrithione) can interrupt the replication mechanisms of SARS-CoV-GFP (a fluorescently tagged SARS-CoV-1) and a variety of other RNA viruses [666,667].
Currently, there are over twenty clinical trials registered with the intention to use zinc in a preventative or therapeutic manner for COVID-19.
-However, many of these trials proposed the use of zinc in conjunction with hydroxychloroquine and azithromycin [667,668,669,670], and it is not known how the lack of evidence supporting the use of hydroxychloroquine will affect investigation of zinc.
+However, many of these trials proposed the use of zinc in conjunction with hydroxychloroquine and azithromycin [668,669,670,671], and it is not known how the lack of evidence supporting the use of hydroxychloroquine will affect investigation of zinc.
One retrospective observational study of New York University Langone hospitals in New York compared outcomes among hospitalized COVID-19 patients administered hydroxychloroquine and azithromycin with zinc sulfate (n = 411) versus hydroxychloroquine and azithromycin alone (n = 521).
-Notably, zinc is the only treatment that was used in this trial that is still under consideration as a therapeutic agent due to the lack of efficacy and potential adverse events associated with hydroxychloroquine and azithromycin against COVID-19 [671,672,673].
-While the addition of zinc sulfate did not affect the duration of hospitalization, the length of ICU stays or patient ventilation duration, univariate analyses indicated that zinc did increase the frequency of patients discharged and decreased the requirement for ventilation, referrals to the ICU, mortality [674].
-However, a smaller retrospective study at Hoboken University Medical Center New Jersey failed to find an association between zinc supplementation and survival of hospitalized patients [675].
+Notably, zinc is the only treatment that was used in this trial that is still under consideration as a therapeutic agent due to the lack of efficacy and potential adverse events associated with hydroxychloroquine and azithromycin against COVID-19 [672,673,674].
+While the addition of zinc sulfate did not affect the duration of hospitalization, the length of ICU stays or patient ventilation duration, univariate analyses indicated that zinc did increase the frequency of patients discharged and decreased the requirement for ventilation, referrals to the ICU, mortality [675].
+However, a smaller retrospective study at Hoboken University Medical Center New Jersey failed to find an association between zinc supplementation and survival of hospitalized patients [676].
Therefore, whether zinc contributes to COVID-19 recovery remains unclear.
-Other trials are now investigating zinc in conjunction with other supplements such as vitamin C or n-3 PUFA [654,676].
+Other trials are now investigating zinc in conjunction with other supplements such as vitamin C or n-3 PUFA [655,677].
Though there is, overall, encouraging data for zinc supplementation against the common cold and viral infections, there is currently limited evidence to suggest zinc supplementation has any beneficial effects against the current novel COVID-19; thus, the clinical trials that are currently underway will provide vital information on the efficacious use of zinc in COVID-19 prevention and/or treatment.
However, given the limited risk and the potential association between zinc deficiency and illness, maintaining a healthy diet to ensure an adequate zinc status may be advisable for individuals seeking to reduce their likelihood of infection.
6.6 Vitamin C
-Vitamins B, C, D, and E have also been suggested as potential nutrient supplement interventions for COVID-19 [613,677].
-In particular vitamin C has been proposed as a potential therapeutic agent against COVID-19 due to its long history of use against the common cold and other respiratory infections [678,679].
+
Vitamins B, C, D, and E have also been suggested as potential nutrient supplement interventions for COVID-19 [614,678].
+In particular vitamin C has been proposed as a potential therapeutic agent against COVID-19 due to its long history of use against the common cold and other respiratory infections [679,680].
Vitamin C can be obtained via dietary sources such as fruits and vegetables or via supplementation.
Vitamin C plays a significant role in promoting immune function due to its effects on various immune cells.
-It affects inflammation by modulating cytokine production, decreasing histamine levels, enhancing the differentiation and proliferation of T- and B-lymphocytes, increasing antibody levels, and protecting against the negative effects of reactive oxygen species, among other effects related to COVID-19 pathology [680,681,682].
+It affects inflammation by modulating cytokine production, decreasing histamine levels, enhancing the differentiation and proliferation of T- and B-lymphocytes, increasing antibody levels, and protecting against the negative effects of reactive oxygen species, among other effects related to COVID-19 pathology [681,682,683].
Vitamin C is utilized by the body during viral infections, as evinced by lower concentrations in leukocytes and lower concentrations of urinary vitamin C.
-Post-infection, these levels return to baseline ranges [683,684,685,686,687].
-It has been shown that as little as 0.1 g/d of vitamin C can maintain normal plasma levels of vitamin C in healthy individuals, but higher doses of at least 1-3 g/d are required for critically ill patients in ICUs [688].
-Indeed, vitamin C deficiency appears to be common among COVID-19 patients [689,690].
-COVID-19 is also associated with the formation of microthrombi and coagulopathy [109] that contribute to its characteristic lung pathology [691], but these symptoms can be ameliorated by early infusions of vitamin C to inhibit endothelial surface P-selectin expression and platelet-endothelial adhesion [692].
-Intravenous vitamin C also reduced D-dimer levels, which are notably elevated in COVID-19 patients [105,106], in a case study of 17 COVID-19 patients [693].
+Post-infection, these levels return to baseline ranges [684,685,686,687,688].
+It has been shown that as little as 0.1 g/d of vitamin C can maintain normal plasma levels of vitamin C in healthy individuals, but higher doses of at least 1-3 g/d are required for critically ill patients in ICUs [689].
+Indeed, vitamin C deficiency appears to be common among COVID-19 patients [690,691].
+COVID-19 is also associated with the formation of microthrombi and coagulopathy [111] that contribute to its characteristic lung pathology [692], but these symptoms can be ameliorated by early infusions of vitamin C to inhibit endothelial surface P-selectin expression and platelet-endothelial adhesion [693].
+Intravenous vitamin C also reduced D-dimer levels, which are notably elevated in COVID-19 patients [107,108], in a case study of 17 COVID-19 patients [694].
There is therefore preliminary evidence suggesting that vitamin C status and vitamin C administration may be relevant to COVID-19 outcomes.
Larger-scale studies of vitamin C, however, have provided mixed results.
-A recent meta-analysis found consistent support for regular vitamin C supplementation reducing the duration of the common cold, but that supplementation with vitamin C (> 200 mg) failed to reduce the incidence of colds [694].
-Individual studies have found Vitamin C to reduce the susceptibility of patients to lower respiratory tract infections, such as pneumonia [695].
+A recent meta-analysis found consistent support for regular vitamin C supplementation reducing the duration of the common cold, but that supplementation with vitamin C (> 200 mg) failed to reduce the incidence of colds [695].
+Individual studies have found Vitamin C to reduce the susceptibility of patients to lower respiratory tract infections, such as pneumonia [696].
Another meta-analysis demonstrated that in twelve trials, vitamin C supplementation reduced the length of stay of patients in intensive care units (ICUs) by 7.8% (95% CI: 4.2% to 11.2%; p = 0.00003).
Furthermore, high doses (1-3 g/day) significantly reduced the length of an ICU stay by 8.6% in six trials (p = 0.003).
-Vitamin C also shortened the duration of mechanical ventilation by 18.2% in three trials in which patients required intervention for over 24 hours (95% CI 7.7% to 27%; p = 0.001) [688].
-Despite these findings, an RCT of 167 patients known as CITRUS ALI failed to show a benefit of a 96-hour infusion of vitamin C to treat ARDS [696].
-Clinical trials specifically investigating vitamin C in the context of COVID-19 have now begun, as highlighted by Carr et al. [679].
+Vitamin C also shortened the duration of mechanical ventilation by 18.2% in three trials in which patients required intervention for over 24 hours (95% CI 7.7% to 27%; p = 0.001) [689].
+Despite these findings, an RCT of 167 patients known as CITRUS ALI failed to show a benefit of a 96-hour infusion of vitamin C to treat ARDS [697].
+Clinical trials specifically investigating vitamin C in the context of COVID-19 have now begun, as highlighted by Carr et al. [680].
These trials intend to investigate the use of intravenous vitamin C in hospitalized COVID-19 patients.
-The first trial to report initial results took place in Wuhan, China [697].
-These initial results indicated that the administration of 12 g/12 hr of intravenous vitamin C for 7 days in 56 critically ill COVID-19 patients resulted in a promising reduction of 28-day mortality (p = 0.06) in univariate survival analysis [698].
-Indeed, the same study reported a significant decrease in IL-6 levels by day 7 of vitamin C infusion (p = 0.04) [699].
+The first trial to report initial results took place in Wuhan, China [698].
+These initial results indicated that the administration of 12 g/12 hr of intravenous vitamin C for 7 days in 56 critically ill COVID-19 patients resulted in a promising reduction of 28-day mortality (p = 0.06) in univariate survival analysis [699].
+Indeed, the same study reported a significant decrease in IL-6 levels by day 7 of vitamin C infusion (p = 0.04) [700].
Additional studies that are being conducted in Canada, China, Iran, and the USA will provide additional insight into whether vitamin C supplementation affects COVID-19 outcomes on a larger scale.
Even though evidence supporting the use of vitamin C is beginning to emerge, we will not know how effective vitamin C is as a therapeutic for quite some time.
Currently (as of January 2021) over fifteen trials are registered with clinicaltrials.gov that are either recruiting, active or are currently in preparation.
@@ -2456,166 +2457,166 @@
6.6[582].
-The recommended dietary allowance according to the FDA is 75-90 mg/d, whereas EFSA recommends 110 mg/d [700].
+To maintain vitamin C status, it would be prudent for individuals to ensure that they consume the recommended dietary allowance of vitamin C to maintain a healthy immune system [583].
+The recommended dietary allowance according to the FDA is 75-90 mg/d, whereas EFSA recommends 110 mg/d [701].
6.7 Vitamin D
Of all of the supplements currently under investigation, vitamin D has become a leading prophylactic and therapeutic candidate against SARS-CoV-2.
-Vitamin D can modulate both the adaptive and innate immune system and is associated with various aspects of immune health and antiviral defense [701,702,703,704,705].
+Vitamin D can modulate both the adaptive and innate immune system and is associated with various aspects of immune health and antiviral defense [702,703,704,705,706].
Vitamin D can be sourced through diet or supplementation, but it is mainly biosynthesized by the body on exposure to ultraviolet light (UVB) from sunlight.
-Vitamin D deficiency is associated with an increased susceptibility to infection [706].
-In particular, vitamin D deficient patients are at risk of developing acute respiratory infections [707] and ARDS [707].
+Vitamin D deficiency is associated with an increased susceptibility to infection [707].
+In particular, vitamin D deficient patients are at risk of developing acute respiratory infections [708] and ARDS [708].
1,25-dihydroxyvitamin D3 is the active form of vitamin D that is involved in adaptive and innate responses; however, due to its low concentration and a short half life of a few hours, vitamin D levels are typically measured by the longer lasting and more abundant precursor 25-hydroxyvitamin D.
-The vitamin D receptor is expressed in various immune cells, and vitamin D is an immunomodulator of antigen presenting cells, dendritic cells, macrophages, monocytes, and T- and B-lymphocytes [706,708].
+The vitamin D receptor is expressed in various immune cells, and vitamin D is an immunomodulator of antigen presenting cells, dendritic cells, macrophages, monocytes, and T- and B-lymphocytes [707,709].
Due to its potential immunomodulating properties, vitamin D supplementation may be advantageous to maintain a healthy immune system.
-Early in the pandemic it was postulated that an individual’s vitamin D status could significantly affect their risk of developing COVID-19 [709].
+
Early in the pandemic it was postulated that an individual’s vitamin D status could significantly affect their risk of developing COVID-19 [710].
This hypothesis was derived from the fact that the current pandemic emerged in Wuhan China during winter, when 25-hydroxyvitamin D concentrations are at their lowest due to a lack of sunlight, whereas in the Southern Hemisphere, where it was nearing the end of the summer and higher 25-hydroxyvitamin D concentrations would be higher, the number of cases was low.
-This led researchers to question whether there was a seasonal component to the SARS-CoV-2 pandemic and whether vitamin D levels might play a role [709,710,711,712].
+This led researchers to question whether there was a seasonal component to the SARS-CoV-2 pandemic and whether vitamin D levels might play a role [710,711,712,713].
Though it is assumed that COVID-19 is seasonal, multiple other factors that can affect vitamin D levels should also be considered.
These factors include an individual’s nutritional status, their age, their occupation, skin pigmentation, potential comorbidities, and the variation of exposure to sunlight due to latitude amongst others.
-Indeed, it has been estimated that each degree of latitude north of 28 degrees corresponded to a 4.4% increase of COVID-19 mortality, indirectly linking a persons vitamin D levels via exposure to UVB light to COVID-19 mortality [710].
-As the pandemic has evolved, additional research of varying quality has investigated some of the potential links identified early in the pandemic [709] between vitamin D and COVID-19.
+Indeed, it has been estimated that each degree of latitude north of 28 degrees corresponded to a 4.4% increase of COVID-19 mortality, indirectly linking a persons vitamin D levels via exposure to UVB light to COVID-19 mortality [711].
+As the pandemic has evolved, additional research of varying quality has investigated some of the potential links identified early in the pandemic [710] between vitamin D and COVID-19.
Indeed, studies are beginning to investigate whether there is any prophylactic and/or therapeutic relationship between vitamin D and COVID-19.
-A study in Switzerland demonstrated that 27 SARS-CoV-2 positive patients exhibited 25-hydroxyvitamin D plasma concentrations that were significantly lower (11.1 ng/ml) than those of SARS-CoV-2 negative patients (24.6 ng/ml; p = 0.004), an association that held when stratifying patients greater than 70 years old [713].
-These findings seem to be supported by a Belgian observational study of 186 SARS-CoV-2 positive patients exhibiting symptoms of pneumonia, where 25-hydroxyvitamin D plasma concentrations were measured and CT scans of the lungs were obtained upon hospitalization [714].
+A study in Switzerland demonstrated that 27 SARS-CoV-2 positive patients exhibited 25-hydroxyvitamin D plasma concentrations that were significantly lower (11.1 ng/ml) than those of SARS-CoV-2 negative patients (24.6 ng/ml; p = 0.004), an association that held when stratifying patients greater than 70 years old [714].
+These findings seem to be supported by a Belgian observational study of 186 SARS-CoV-2 positive patients exhibiting symptoms of pneumonia, where 25-hydroxyvitamin D plasma concentrations were measured and CT scans of the lungs were obtained upon hospitalization [715].
A significant difference in 25-hydroxyvitamin D levels was observed between the SARS-CoV-2 patients and 2,717 season-matched diseased controls.
Both female and male patients possessed lower median 25-hydroxyvitamin D concentrations than the control group as a whole (18.6 ng/ml versus 21.5 ng/ml; p = 0.0016) and a higher rate of vitamin D deficiency (58.6% versus 42.5%).
However, when comparisons were stratified by sex, evidence of sexual dimorphism became apparent, as female patients had equivalent levels of 25-hydroxyvitamin D to females in the control group, whereas male patients were deficient in 25-hydroxyvitamin D relative to male controls (67% versus 49%; p = 0.0006).
Notably, vitamin D deficiency was progressively lower in males with advancing radiological disease stages (p = 0.001).
-These studies are supported by several others that indicate that vitamin D status may be an independent risk factor for the severity of COVID-19 [715,716,717,718] and in COVID-19 patients relative to population-based controls [719].
-Indeed, serum concentrations of 25-hydroxyvitamin D above 30 ng/ml, which indicate vitamin D sufficiency, seems to be associated with a reduction in serum C-reactive protein, an inflammatory marker, along with increased lymphocyte levels, which suggests that vitamin D levels may modulate the immune response by reducing risk for cytokine storm in response to SARS-CoV-2 infection [719].
-A study in India determined that COVID-19 fatality was higher in patients with severe COVID-19 and low serum 25-hydroxyvitamin D (mean level 6.2 ng/ml; 97% vitamin D deficient) levels versus asymptomatic non-severe patients with higher levels of vitamin D (mean level 27.9 ng/ml; 33% vitamin D deficient) [720].
+These studies are supported by several others that indicate that vitamin D status may be an independent risk factor for the severity of COVID-19 [716,717,718,719] and in COVID-19 patients relative to population-based controls [720].
+Indeed, serum concentrations of 25-hydroxyvitamin D above 30 ng/ml, which indicate vitamin D sufficiency, seems to be associated with a reduction in serum C-reactive protein, an inflammatory marker, along with increased lymphocyte levels, which suggests that vitamin D levels may modulate the immune response by reducing risk for cytokine storm in response to SARS-CoV-2 infection [720].
+A study in India determined that COVID-19 fatality was higher in patients with severe COVID-19 and low serum 25-hydroxyvitamin D (mean level 6.2 ng/ml; 97% vitamin D deficient) levels versus asymptomatic non-severe patients with higher levels of vitamin D (mean level 27.9 ng/ml; 33% vitamin D deficient) [721].
In the same study, vitamin D deficiency was associated with higher levels of inflammatory markers including IL-6, ferritin, and tumor necrosis factor α.
-Collectively, these studies add to a multitude of observational studies reporting potential associations between low levels of 25-hydroxyvitamin D and COVID-19 incidence and severity [713,718,719,721,722,723,724,725,726,727].
-Despite the large number of studies establishing a link between vitamin D status and COVID-19 severity, an examination of data from the UK Biobank did not support this thesis [728,729].
+Collectively, these studies add to a multitude of observational studies reporting potential associations between low levels of 25-hydroxyvitamin D and COVID-19 incidence and severity [714,719,720,722,723,724,725,726,727,728].
+Despite the large number of studies establishing a link between vitamin D status and COVID-19 severity, an examination of data from the UK Biobank did not support this thesis [729,730].
These analyses examined 25-hydroxyvitamin D concentrations alongside SARS-CoV-2 positivity and COVID-19 mortality in over 340,000 UK Biobank participants.
-However, these studies have caused considerable debate that will likely be settled following further studies [730,731].
-Overall, while the evidence suggests that there is likely an association between low serum 25-hydroxyvitamin D and COVID-19 incidence, these studies must be interpreted with caution, as there is the potential for reverse causality, bias, and other confounding factors including that vitamin D deficiency is also associated with numerous pre-existing conditions and risk factors that can increase the risk for severe COVID-19 [582,710,732,733].
+However, these studies have caused considerable debate that will likely be settled following further studies [731,732].
+Overall, while the evidence suggests that there is likely an association between low serum 25-hydroxyvitamin D and COVID-19 incidence, these studies must be interpreted with caution, as there is the potential for reverse causality, bias, and other confounding factors including that vitamin D deficiency is also associated with numerous pre-existing conditions and risk factors that can increase the risk for severe COVID-19 [583,711,733,734].
While these studies inform us of the potential importance of vitamin D sufficiency and the risk of SARS-CoV-2 infection and severe COVID-19, they fail to conclusively determine whether vitamin D supplementation can therapeutically affect the clinical course of COVID-19.
In one study, 40 vitamin D deficient asymptomatic or mildly symptomatic participants patients were either randomized to receive 60,000 IU of cholecalciferol daily for at least 7 days (n = 16) or a placebo (n = 24) with a target serum 25-hydroxyvitamin D level >50 ng/ml.
At day 7, 10 patients achieved >50 ng/ml, followed by another 2 by day 14.
-By the end of the study, the treatment group had a greater proportion of vitamin D-deficient participants that tested negative for SARS-CoV-2 RNA, and they had a significantly lower fibrinogen levels, potentially indicating a beneficial effect [734].
-A pilot study in Spain determined that early administration of high dose calcifediol (~21,000 IU days 1-2 and ~11,000 IU days 3-7 of hospital admission) with hydroxychloroquine and azithromycin to 50 hospitalized COVID-19 patients significantly reduced ICU admissions and may have reduced disease severity versus hydroxychloroquine and azithromycin alone [735].
-Although this study received significant criticism from the National Institute for Health and Care Excellence (NICE) in the UK [736], an independent follow-up statistical analysis supported the findings of the study with respect to the results of cholecalciferol treatment [737].
-Another trial of 986 patients hospitalized for COVID-19 in three UK hospitals administered cholecalciferol supplementation (≥ 280,000 IU in a time period of 7 weeks) to 151 patients and found an association with a reduced risk of COVID-19 mortality, regardless of baseline 25-hydroxyvitamin D levels [738].
+By the end of the study, the treatment group had a greater proportion of vitamin D-deficient participants that tested negative for SARS-CoV-2 RNA, and they had a significantly lower fibrinogen levels, potentially indicating a beneficial effect [735].
+A pilot study in Spain determined that early administration of high dose calcifediol (~21,000 IU days 1-2 and ~11,000 IU days 3-7 of hospital admission) with hydroxychloroquine and azithromycin to 50 hospitalized COVID-19 patients significantly reduced ICU admissions and may have reduced disease severity versus hydroxychloroquine and azithromycin alone [736].
+Although this study received significant criticism from the National Institute for Health and Care Excellence (NICE) in the UK [737], an independent follow-up statistical analysis supported the findings of the study with respect to the results of cholecalciferol treatment [738].
+Another trial of 986 patients hospitalized for COVID-19 in three UK hospitals administered cholecalciferol supplementation (≥ 280,000 IU in a time period of 7 weeks) to 151 patients and found an association with a reduced risk of COVID-19 mortality, regardless of baseline 25-hydroxyvitamin D levels [739].
However, a double-blind, randomized, placebo-controlled trial of 240 hospitalized COVID-19 patients in São Paulo, Brazil administered a single 200,000 IU oral dose of vitamin D.
-While levels of 25-hydroxyvitamin D did increase from 21% to ~27% (p = 0.001) and the supplementation was well tolerated, there was no reduction in the length of hospital stay or mortality and no change to any other relevant secondary outcomes [739].
+While levels of 25-hydroxyvitamin D did increase from 21% to ~27% (p = 0.001) and the supplementation was well tolerated, there was no reduction in the length of hospital stay or mortality and no change to any other relevant secondary outcomes [740].
These early findings are thus still inconclusive with regards to the therapeutic value of vitamin D supplementation.
-However, other trials are underway, including one trial that is investigating the utility of vitamin D as an immune-modulating agent by monitoring whether administration of vitamin D precipitates an improvement of health status in non-severe symptomatic COVID-19 patients and whether vitamin D prevents patient deterioration [740].
-Other trials are examining various factors including mortality, symptom recovery, severity of disease, rates of ventilation, inflammatory markers such as C-reactive protein and IL-6, blood cell counts, and the prophylactic capacity of vitamin D administration [740,741,742,743].
-Concomitant administration of vitamin D with pharmaceuticals such as aspirin [744] and bioactive molecules such as resveratrol [745] are also under investigation.
+However, other trials are underway, including one trial that is investigating the utility of vitamin D as an immune-modulating agent by monitoring whether administration of vitamin D precipitates an improvement of health status in non-severe symptomatic COVID-19 patients and whether vitamin D prevents patient deterioration [741].
+Other trials are examining various factors including mortality, symptom recovery, severity of disease, rates of ventilation, inflammatory markers such as C-reactive protein and IL-6, blood cell counts, and the prophylactic capacity of vitamin D administration [741,742,743,744].
+Concomitant administration of vitamin D with pharmaceuticals such as aspirin [745] and bioactive molecules such as resveratrol [746] are also under investigation.
The effectiveness of vitamin D supplementation against COVID-19 remains open for debate.
-All the same, there is no doubt that vitamin D deficiency is a widespread issue and should be addressed not only because of its potential link to SARS-CoV-2 incidence [746], but also due to its importance for overall health.
+All the same, there is no doubt that vitamin D deficiency is a widespread issue and should be addressed not only because of its potential link to SARS-CoV-2 incidence [747], but also due to its importance for overall health.
There is a possibility that safe exposure to sunlight could improve endogenous synthesis of vitamin D, potentially strengthening the immune system.
However, sun exposure is not sufficient on its own, particularly in the winter months.
Indeed, while the possible link between vitamin D status and COVID-19 is further investigated, preemptive supplementation of vitamin D and encouraging people to maintain a healthy diet for optimum vitamin D status is likely to raise serum levels of 25-hydroxyvitamin D while being unlikely to carry major health risks.
These principles seem to be the basis of a number of guidelines issued by some countries and scientific organizations that have advised supplementation of vitamin D during the pandemic.
The Académie Nationale de Médecine in France recommends rapid testing of 25-hydroxyvitamin D for people over 60 years old to identify those most at risk of vitamin D deficiency and advises them to obtain a bolus dose of 50,000 to 100,000 IU vitamin D to limit respiratory complications.
-It has also recommended that those under 60 years old should take 800 to 1,000 IU daily if they receive a SARS-CoV-2 positive test [747].
-In Slovenia, doctors have been advised to provide nursing home patients with vitamin D [748].
-Both Public Health England and Public Health Scotland have advised members of the Black, Asian, and minority ethnic communities to supplement for vitamin D in light of evidence that they may be at higher risk for vitamin D deficiency along with other COVID-19 risk factors, a trend that has also been observed in the United States [749,750].
+It has also recommended that those under 60 years old should take 800 to 1,000 IU daily if they receive a SARS-CoV-2 positive test [748].
+In Slovenia, doctors have been advised to provide nursing home patients with vitamin D [749].
+Both Public Health England and Public Health Scotland have advised members of the Black, Asian, and minority ethnic communities to supplement for vitamin D in light of evidence that they may be at higher risk for vitamin D deficiency along with other COVID-19 risk factors, a trend that has also been observed in the United States [750,751].
However, other UK scientific bodies including the NICE recommend that individuals supplement for vitamin D as per usual UK government advice but warn that people should not supplement for vitamin D solely to prevent COVID-19.
-All the same, the NICE has provided guidelines for research to investigate the supplementation of vitamin D in the context of COVID-19 [751].
-Despite vitamin D deficiency being a widespread issue in the United States [752], the National Institutes of Health have stated that there is “insufficient data to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19” [753].
+All the same, the NICE has provided guidelines for research to investigate the supplementation of vitamin D in the context of COVID-19 [752].
+Despite vitamin D deficiency being a widespread issue in the United States [753], the National Institutes of Health have stated that there is “insufficient data to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19” [754].
These are just some examples of how public health guidance has responded to the emerging evidence regarding vitamin D and COVID-19.
-Outside of official recommendations, there is also evidence that individuals may be paying increased attention to their vitamin D levels, as a survey of Polish consumers showed that 56% of respondents used vitamin D during the pandemic [754].
-However, some companies have used the emerging evidence surrounding vitamin D to sell products that claim to prevent and treat COVID-19, which in one incident required a federal court to intervene and issue an injunction barring the sale of vitamin-D-related products due to the lack of clinical data supporting these claims [755].
+Outside of official recommendations, there is also evidence that individuals may be paying increased attention to their vitamin D levels, as a survey of Polish consumers showed that 56% of respondents used vitamin D during the pandemic [755].
+However, some companies have used the emerging evidence surrounding vitamin D to sell products that claim to prevent and treat COVID-19, which in one incident required a federal court to intervene and issue an injunction barring the sale of vitamin-D-related products due to the lack of clinical data supporting these claims [756].
It is clear that further studies and clinical trials are required to conclusively determine the prophylactic and therapeutic potential of vitamin D supplementation against COVID-19.
Until such time that sufficient evidence emerges, individuals should follow their national guidelines surrounding vitamin D intake to achieve vitamin D sufficiency.
6.8 Probiotics
-Probiotics are “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” [756].
-Some studies suggest that probiotics are beneficial against common viral infections, and there is modest evidence to suggest that they can modulate the immune response [757,758].
-As a result, it has been hypothesized that probiotics may have therapeutic value worthy of investigation against SARS-CoV-2 [759].
-Probiotics and next-generation probiotics, which are more akin to pharmacological-grade supplements, have been associated with multiple potential beneficial effects for allergies, digestive tract disorders, and even metabolic diseases through their anti-inflammatory and immunomodulatory effects [760,761].
-However, the mechanisms by which probiotics affect these various conditions would likely differ among strains, with the ultimate effect of the probiotic depending on the heterogeneous set of bacteria present [761].
-Some of the beneficial effects of probiotics include reducing inflammation by promoting the expression of anti-inflammatory mediators, inhibiting Toll-like receptors 2 and 4, competing directly with pathogens, synthesizing antimicrobial substances or other metabolites, improving intestinal barrier function, and/or favorably altering the gut microbiota and the brain-gut axis [761,762,763].
-It is also thought that lactobacilli such as Lactobacillus paracasei, Lactobacillus plantarum and Lactobacillus rhamnosus have the capacity to bind to and inactivate some viruses via adsorptive and/or trapping mechanisms [764].
-Other probiotic lactobacilli and even non-viable bacterium-like particles have been shown to reduce both viral attachment to host cells and viral titers, along with reducing cytokine synthesis, enhancing the antiviral IFN-α response, and inducing various other antiviral mechanisms [764,765,766,767,768,769,770,771,772].
-These antiviral and immunobiotic mechanisms and others have been reviewed in detail elsewhere [612,759,773].
-However, there is also a bi-directional relationship between the lungs and gut microbiota known as the gut-lung axis [774], whereby gut microbial metabolites and endotoxins may affect the lungs via the circulatory system and the lung microbiota in return may affect the gut [775].
-Therefore, the gut-lung axis may play role in our future understanding of COVID-19 pathogenesis and become a target for probiotic treatments [776].
-Moreover, as microbial dysbiosis of the respiratory tract and gut may play a role in some viral infections, it has been suggested that SARS-CoV-2 may interact with our commensal microbiota [612; 777; 10.3389/fmicb.2020.01840] and that the lung microbiome could play a role in developing immunity to viral infections [778].
+
Probiotics are “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” [757].
+Some studies suggest that probiotics are beneficial against common viral infections, and there is modest evidence to suggest that they can modulate the immune response [758,759].
+As a result, it has been hypothesized that probiotics may have therapeutic value worthy of investigation against SARS-CoV-2 [760].
+Probiotics and next-generation probiotics, which are more akin to pharmacological-grade supplements, have been associated with multiple potential beneficial effects for allergies, digestive tract disorders, and even metabolic diseases through their anti-inflammatory and immunomodulatory effects [761,762].
+However, the mechanisms by which probiotics affect these various conditions would likely differ among strains, with the ultimate effect of the probiotic depending on the heterogeneous set of bacteria present [762].
+Some of the beneficial effects of probiotics include reducing inflammation by promoting the expression of anti-inflammatory mediators, inhibiting Toll-like receptors 2 and 4, competing directly with pathogens, synthesizing antimicrobial substances or other metabolites, improving intestinal barrier function, and/or favorably altering the gut microbiota and the brain-gut axis [762,763,764].
+It is also thought that lactobacilli such as Lactobacillus paracasei, Lactobacillus plantarum and Lactobacillus rhamnosus have the capacity to bind to and inactivate some viruses via adsorptive and/or trapping mechanisms [765].
+Other probiotic lactobacilli and even non-viable bacterium-like particles have been shown to reduce both viral attachment to host cells and viral titers, along with reducing cytokine synthesis, enhancing the antiviral IFN-α response, and inducing various other antiviral mechanisms [765,766,767,768,769,770,771,772,773].
+These antiviral and immunobiotic mechanisms and others have been reviewed in detail elsewhere [613,760,774].
+However, there is also a bi-directional relationship between the lungs and gut microbiota known as the gut-lung axis [775], whereby gut microbial metabolites and endotoxins may affect the lungs via the circulatory system and the lung microbiota in return may affect the gut [776].
+Therefore, the gut-lung axis may play role in our future understanding of COVID-19 pathogenesis and become a target for probiotic treatments [777].
+Moreover, as microbial dysbiosis of the respiratory tract and gut may play a role in some viral infections, it has been suggested that SARS-CoV-2 may interact with our commensal microbiota [613; 778; 10.3389/fmicb.2020.01840] and that the lung microbiome could play a role in developing immunity to viral infections [779].
These postulations, if correct, could lead to the development of novel probiotic and prebiotic treatments.
However, significant research is required to confirm these associations and their relevance to patient care, if any.
Probiotic therapies and prophylactics may also confer some advantages for managing symptoms of COVID-19 or risks associated with its treatment.
-Probiotics have tentatively been associated with the reduction of risk and duration of viral upper respiratory tract infections [779,780,781].
-Some meta-analyses that have assessed the efficacy of probiotics in viral respiratory infections have reported moderate reductions in the incidence and duration of infection [780,782].
-Indeed, randomized controlled trials have shown that administering Bacillus subtilis and Enterococcus faecalis [783], Lactobacillus rhamnosus GG [784], or Lactobacillus casei and Bifidobacterium breve with galactooligosaccharides [785] via the nasogastric tube to ventilated patients reduced the occurrence of ventilator-associated pneumonia in comparison to the respective control groups in studies of viral infections and sepsis.
-These findings were also supported by a recent meta-analysis [786].
-Additionally, COVID-19 patients carry a significant risk of ventilator-associated bacterial pneumonia [787], but it can be challenging for clinicians to diagnose this infection due to the fact that severe COVID-19 infection presents with the symptoms of pneumonia [788].
+Probiotics have tentatively been associated with the reduction of risk and duration of viral upper respiratory tract infections [780,781,782].
+Some meta-analyses that have assessed the efficacy of probiotics in viral respiratory infections have reported moderate reductions in the incidence and duration of infection [781,783].
+Indeed, randomized controlled trials have shown that administering Bacillus subtilis and Enterococcus faecalis [784], Lactobacillus rhamnosus GG [785], or Lactobacillus casei and Bifidobacterium breve with galactooligosaccharides [786] via the nasogastric tube to ventilated patients reduced the occurrence of ventilator-associated pneumonia in comparison to the respective control groups in studies of viral infections and sepsis.
+These findings were also supported by a recent meta-analysis [787].
+Additionally, COVID-19 patients carry a significant risk of ventilator-associated bacterial pneumonia [788], but it can be challenging for clinicians to diagnose this infection due to the fact that severe COVID-19 infection presents with the symptoms of pneumonia [789].
Therefore, an effective prophylactic therapy for ventilator-associated pneumonia in severe COVID-19 patients would carry significant therapeutic value.
-Additionally, in recent years, probiotics have become almost synonymous with the treatment of gastrointestinal issues due to their supposed anti-inflammatory and immunomodulatory effects [789].
-Notably, gastrointestinal symptoms commonly occur in COVID-19 patients [790], and angiotensin-converting enzyme 2, the portal by which SARS-CoV-2 enters human cells, is highly expressed in enterocytes of the ileum and colon, suggesting that these organs may be a potential route of infection [791,792].
-Indeed, SARS-CoV-2 viral RNA has been detected in human feces [89,793], and fecal-oral transmission of the virus has not yet been ruled out [794].
-Rectal swabs of some SARS-CoV-2 positive pediatric patients persistently tested positive for several days despite negative nasopharyngeal tests, indicating the potential for fecal viral shedding [795].
-However, there is conflicting evidence for the therapeutic value of various probiotics against the incidence or severity of gastrointestinal symptoms in viral or bacterial infections such as gastroenteritis [796,797].
-Nevertheless, it has been proposed that the administration of probiotics to COVID-19 patients and healthcare workers may prevent or ameliorate the gastrointestinal symptoms of COVID-19, a hypothesis that several clinical trials are now preparing to investigate [798,799].
-Other studies are investigating whether probiotics may affect patient outcomes following SARS-CoV-2 infection [800].
+Additionally, in recent years, probiotics have become almost synonymous with the treatment of gastrointestinal issues due to their supposed anti-inflammatory and immunomodulatory effects [790].
+Notably, gastrointestinal symptoms commonly occur in COVID-19 patients [791], and angiotensin-converting enzyme 2, the portal by which SARS-CoV-2 enters human cells, is highly expressed in enterocytes of the ileum and colon, suggesting that these organs may be a potential route of infection [792,793].
+Indeed, SARS-CoV-2 viral RNA has been detected in human feces [91,794], and fecal-oral transmission of the virus has not yet been ruled out [795].
+Rectal swabs of some SARS-CoV-2 positive pediatric patients persistently tested positive for several days despite negative nasopharyngeal tests, indicating the potential for fecal viral shedding [796].
+However, there is conflicting evidence for the therapeutic value of various probiotics against the incidence or severity of gastrointestinal symptoms in viral or bacterial infections such as gastroenteritis [797,798].
+Nevertheless, it has been proposed that the administration of probiotics to COVID-19 patients and healthcare workers may prevent or ameliorate the gastrointestinal symptoms of COVID-19, a hypothesis that several clinical trials are now preparing to investigate [799,800].
+Other studies are investigating whether probiotics may affect patient outcomes following SARS-CoV-2 infection [801].
Generally, the efficacy of probiotic use is a controversial topic among scientists.
-In Europe, EFSA has banned the term probiotics on products labels, which has elicited either criticism for EFSA or support for probiotics from researchers in the field [756,801,802].
+In Europe, EFSA has banned the term probiotics on products labels, which has elicited either criticism for EFSA or support for probiotics from researchers in the field [757,802,803].
This regulation is due to the hyperbolic claims placed on the labels of various probiotic products, which lack rigorous scientific data to support their efficacy.
-Overall, the data supporting probiotics in the treatment or prevention of many different disorders and diseases is not conclusive, as the quality of the evidence is generally considered low [779].
+Overall, the data supporting probiotics in the treatment or prevention of many different disorders and diseases is not conclusive, as the quality of the evidence is generally considered low [780].
However, in the case of probiotics and respiratory infections, the evidence seems to be supportive of their potential therapeutic value.
Consequently, several investigations are underway to investigate the prophylactic and therapeutic potential of probiotics for COVID-19.
-The blind use of conventional probiotics for COVID-19 is currently cautioned against until the pathogenesis of SARS-CoV-2 can be further established [803].
+The blind use of conventional probiotics for COVID-19 is currently cautioned against until the pathogenesis of SARS-CoV-2 can be further established [804].
Until clinical trials investigating the prophylactic and therapeutic potential of probiotics for COVID-19 are complete, it is not possible to provide an evidence-based recommendation for their use.
-Despite these concerns, complementary use of probiotics as an adjuvant therapeutic has been proposed by the Chinese National Health Commission and National Administration of Traditional Chinese Medicine [90].
-While supply issues prevented the probiotics market from showing the same rapid response to the COVID-19 as some other supplements, many suppliers are reporting growth during the pandemic [804].
+Despite these concerns, complementary use of probiotics as an adjuvant therapeutic has been proposed by the Chinese National Health Commission and National Administration of Traditional Chinese Medicine [92].
+While supply issues prevented the probiotics market from showing the same rapid response to the COVID-19 as some other supplements, many suppliers are reporting growth during the pandemic [805].
Therefore, the public response once again seems to have adopted supplements promoted as bolstering the immune response despite a lack of evidence suggesting they are beneficial for preventing or mitigating COVID-19.
6.9 Discussion
In this review, we report the findings to date of analyses of several dietary supplements and nutraceuticals.
While existing evidence suggests potential benefits of n-3 PUFA and probiotic supplementation for COVID-19 treatment and prophylaxis, clinical data is still lacking, although trials are underway.
Both zinc and vitamin C supplementation in hospitalized patients seem to be associated with positive outcomes; however, further clinical trials are required.
In any case, both vitamin C and zinc intake are part of a healthy diet and both likely presents minimal risk when supplemented for, though their potential prophylactic or therapeutic effects against COVID-19 are yet to be determined.
-On the other hand, mounting evidence from observational studies indicates that there is an association between vitamin D deficiency and COVID-19 incidence has also been supported by meta-analysis [805].
+On the other hand, mounting evidence from observational studies indicates that there is an association between vitamin D deficiency and COVID-19 incidence has also been supported by meta-analysis [806].
Indeed, scientists are working to confirm these findings and to determine whether a patient’s serum 25-hydroxyvitamin D levels are also associated with COVID-19 severity.
Clinical trials are required to determine whether preemptive vitamin D supplementation may mitigate against severe COVID-19.
-In terms of the therapeutic potential of vitamin D, initial evidence from clinical trials are conflicting, but seem to indicate that vitamin D supplementation may reduce COVID-19 severity [735].
+In terms of the therapeutic potential of vitamin D, initial evidence from clinical trials are conflicting, but seem to indicate that vitamin D supplementation may reduce COVID-19 severity [736].
The various clinical trials currently underway will be imperative to provide information on the efficacious use of vitamin D supplementation for COVID-19 prevention and/or treatment.
The purported prophylactic and therapeutic benefits of dietary supplements and nutraceuticals for multiple disorders, diseases, and infections has been the subject of significant research and debate for the last few decades.
Inevitably, scientists are also investigating the potential for these various products to treat or prevent COVID-19.
This interest also extends to consumers, which led to a remarkable increase of sales of dietary supplements and nutraceuticals throughout the pandemic due to a desire to obtain additional protections from infection and disease.
The nutraceuticals discussed in this review, namely vitamin C, vitamin D, n-3 PUFA, zinc, and probiotics, were selected because of potential biological mechanisms that could beneficially affect viral and respiratory infections and because they are currently under clinical investigation.
Specifically, these compounds have all been found to influence cellular processes related to inflammation.
-Inflammation is particularly relevant to COVID-19 because of the negative outcomes (often death) observed in a large number of patients whose immune response becomes hyperactive in response to SARS-CoV-2, leading to severe outcomes such as ARDS and sepsis [806].
-Additionally, there is a well-established link between diet and inflammation [807], potentially mediated in part by the microbiome [808].
+Inflammation is particularly relevant to COVID-19 because of the negative outcomes (often death) observed in a large number of patients whose immune response becomes hyperactive in response to SARS-CoV-2, leading to severe outcomes such as ARDS and sepsis [807].
+Additionally, there is a well-established link between diet and inflammation [808], potentially mediated in part by the microbiome [809].
Thus, the idea that dietary modifications or supplementation could be used to modify the inflammatory response is tied to a broader view of how diet and the immune system are interconnected.
-The supplements and nutraceuticals discussed here therefore lie in sharp contrast to other alleged nutraceutical or dietary supplements that have attracted during the pandemic, such as colloidal silver [809], which have no known nutritional function and can be harmful.
+The supplements and nutraceuticals discussed here therefore lie in sharp contrast to other alleged nutraceutical or dietary supplements that have attracted during the pandemic, such as colloidal silver [810], which have no known nutritional function and can be harmful.
Importantly, while little clinical evidence is available about the effects of any supplements against COVID-19, the risks associated with those discussed above are likely to be low, and in some cases, they can be obtained from dietary sources alone.
There are various other products and molecules that have garnered scientific interest and could merit further investigation.
-These include polyphenols, lipid extracts, and tomato-based nutraceuticals, all of which have been suggested for the potential prevention of cardiovascular complications of COVID-19 such as thrombosis [612,648].
-Melatonin is another supplement that has been identified as a potential antiviral agent against SARS-CoV-2 using computational methods [810], and it has also been highlighted as a potential therapeutic agent for COVID-19 due to its documented antioxidant, anti-apoptotic, immunomodulatory, and anti-inflammatory effects [648,811,812].
-Notably, melatonin, vitamin D and zinc have attracted public attention because they were included in the treatment plan of the former President of the United States upon his hospitalization due to COVID-19 [813].
+These include polyphenols, lipid extracts, and tomato-based nutraceuticals, all of which have been suggested for the potential prevention of cardiovascular complications of COVID-19 such as thrombosis [613,649].
+Melatonin is another supplement that has been identified as a potential antiviral agent against SARS-CoV-2 using computational methods [811], and it has also been highlighted as a potential therapeutic agent for COVID-19 due to its documented antioxidant, anti-apoptotic, immunomodulatory, and anti-inflammatory effects [649,812,813].
+Notably, melatonin, vitamin D and zinc have attracted public attention because they were included in the treatment plan of the former President of the United States upon his hospitalization due to COVID-19 [814].
These are just some of the many substances and supplements that are currently under investigation but as of yet lack evidence to support their use for the prevention or treatment of COVID-19.
-While there is plenty of skepticism put forward by physicians and scientists surrounding the use of supplements, these statements have not stopped consumers from purchasing these products, with one study reporting that online searches for dietary supplements in Poland began trending with the start of the pandemic [754].
+While there is plenty of skepticism put forward by physicians and scientists surrounding the use of supplements, these statements have not stopped consumers from purchasing these products, with one study reporting that online searches for dietary supplements in Poland began trending with the start of the pandemic [755].
Additionally, supplement usage increased between the first and second wave of the pandemic.
Participants reported various reasons for their use of supplements, including to improve immunity (60%), to improve overall health (57%), and to fill nutrient gaps in their diet (53%).
Other efforts to collect large datasets regarding such behavior have also sought to explore a possible association between vitamin or supplement consumption and COVID-19.
-An observational analysis of survey responses from 327,720 users of the COVID Symptom Study App found that the consumption of n-3 PUFA supplements, probiotics, multivitamins, and vitamin D was associated with a lower risk of SARS-CoV-2 infection in women but not men after adjusting for potential confounders [814].
-According to the authors, the sexual dimorphism observed may in part be because supplements may better support females due to known differences between the male and female immune systems, or it could be due to behavioral and health consciousness differences between the sexes [814].
+An observational analysis of survey responses from 327,720 users of the COVID Symptom Study App found that the consumption of n-3 PUFA supplements, probiotics, multivitamins, and vitamin D was associated with a lower risk of SARS-CoV-2 infection in women but not men after adjusting for potential confounders [815].
+According to the authors, the sexual dimorphism observed may in part be because supplements may better support females due to known differences between the male and female immune systems, or it could be due to behavioral and health consciousness differences between the sexes [815].
Certainly, randomized controlled trials are required to investigate these findings further.
-Finally, it is known that a patient’s nutritional status affects health outcomes in various infectious diseases [586], and COVID-19 is no different [584,815,816].
-Some of the main risk factors for severe COVID-19, which also happen to be linked to poor nutritional status, include obesity, hypertension, cardiovascular diseases, type II diabetes mellitus, and indeed age-related malnutrition [582,584,817].
+
Finally, it is known that a patient’s nutritional status affects health outcomes in various infectious diseases [587], and COVID-19 is no different [585,816,817].
+Some of the main risk factors for severe COVID-19, which also happen to be linked to poor nutritional status, include obesity, hypertension, cardiovascular diseases, type II diabetes mellitus, and indeed age-related malnutrition [583,585,818].
Although not the main focus of this review, it is important to consider the nutritional challenges associated with severe COVID-19 patients.
-Hospitalized COVID-19 patients tend to report an unusually high loss of appetite preceding admission, some suffer diarrhea and gastrointestinal symptoms that result in significantly lower food intake, and patients with poorer nutritional status were more likely to have worse outcomes and require nutrition therapy [818].
-Dysphagia also seems to be a significant problem in pediatric patients that suffered multisystem inflammatory syndrome [819] and rehabilitating COVID-19 patients, potentially contributing to poor nutritional status [820].
-Almost two-thirds of discharged COVID-19 ICU patients exhibit significant weight loss, of which 26% had weight loss greater than 10% [816].
-As investigated in this review, hospitalized patients also tend to exhibit vitamin D deficiency or insufficiency, which may be associated with greater disease severity [805].
+Hospitalized COVID-19 patients tend to report an unusually high loss of appetite preceding admission, some suffer diarrhea and gastrointestinal symptoms that result in significantly lower food intake, and patients with poorer nutritional status were more likely to have worse outcomes and require nutrition therapy [819].
+Dysphagia also seems to be a significant problem in pediatric patients that suffered multisystem inflammatory syndrome [820] and rehabilitating COVID-19 patients, potentially contributing to poor nutritional status [821].
+Almost two-thirds of discharged COVID-19 ICU patients exhibit significant weight loss, of which 26% had weight loss greater than 10% [817].
+As investigated in this review, hospitalized patients also tend to exhibit vitamin D deficiency or insufficiency, which may be associated with greater disease severity [806].
Therefore, further research is required to determine how dietary supplements and nutraceuticals may contribute to the treatment of severely ill and rehabilitating patients, who often rely on enteral nutrition.
-6.10 Conclusions
+6.10 Conclusions
Despite all the potential benefits of nutraceutical and dietary supplement interventions presented, currently there is a paucity of clinical evidence to support their use for the prevention or mitigation of COVID-19 infection.
-Nevertheless, optimal nutritional status can prime an individual’s immune system to protect against the effects of acute respiratory viral infections by supporting normal maintenance of the immune system [582,586].
-Nutritional strategies can also play a role in the treatment of hospitalized patients, as malnutrition is a risk to COVID-19 patients [820].
+Nevertheless, optimal nutritional status can prime an individual’s immune system to protect against the effects of acute respiratory viral infections by supporting normal maintenance of the immune system [583,587].
+Nutritional strategies can also play a role in the treatment of hospitalized patients, as malnutrition is a risk to COVID-19 patients [821].
Overall, supplementation of vitamin C, vitamin D, and zinc may be an effective method of ensuring their adequate intake to maintain optimal immune function, which may also convey beneficial effects against viral infections due to their immunomodulatory effects.
Individuals should pay attention to their nutritional status, particularly their intake of vitamin D, considering that vitamin D deficiency is widespread.
-The prevailing evidence seems to indicate an association between vitamin D deficiency with COVID-19 incidence and, potentially, severity [710].
+The prevailing evidence seems to indicate an association between vitamin D deficiency with COVID-19 incidence and, potentially, severity [711].
As a result, some international authorities have advised the general public, particularly those at high risk of infection, to consider vitamin D supplementation.
However, further well-controlled clinical trials are required to confirm these observations.
-Many supplements and nutraceuticals designed for various ailments that are available in the United States and beyond are not strictly regulated [821].
+
Many supplements and nutraceuticals designed for various ailments that are available in the United States and beyond are not strictly regulated [822].
Consequently, there can be safety and efficacy concerns associated with many of these products.
Often, the vulnerable members of society can be exploited in this regard and, unfortunately, the COVID-19 pandemic has proven no different.
-As mentioned above, the FDA has issued warnings to several companies for advertising falsified claims in relation to the preventative and therapeutic capabilities of their products against COVID-19 [822].
+As mentioned above, the FDA has issued warnings to several companies for advertising falsified claims in relation to the preventative and therapeutic capabilities of their products against COVID-19 [823].
Further intensive investigation is required to establish the effects of these nutraceuticals, if any, against COVID-19.
-Until more effective therapeutics are established, the most effective mitigation strategies consist of encouraging standard public health practices such as regular hand washing with soap, wearing a face mask, and covering a cough with your elbow [823], along with following social distancing measures, “stay at home” guidelines, expansive testing, and contact tracing [824,825].
+Until more effective therapeutics are established, the most effective mitigation strategies consist of encouraging standard public health practices such as regular hand washing with soap, wearing a face mask, and covering a cough with your elbow [824], along with following social distancing measures, “stay at home” guidelines, expansive testing, and contact tracing [825,826].
Indeed, in light of this review, it would also be pertinent to adopt a healthy diet and lifestyle following national guidelines in order to maintain optimal immune health.
Because of the broad public appeal of dietary supplements and nutraceuticals, it is important to evaluate the evidence regarding the use of such products.
We will continue to update this review as more findings become available.
@@ -2624,21 +2625,21 @@ 7.17.2 Importance
7.3 Introduction
For a highly infectious virus like SARS-CoV-2, a vaccine would hold particular value because it could bolster the immune response to the virus of the population broadly, thereby driving a lower rate of infection and likely significantly reducing fatalities.
-However, the vaccine development process has historically been slow, and vaccines fail to provide immediate prophylactic protection or treat ongoing infections [826].
+However, the vaccine development process has historically been slow, and vaccines fail to provide immediate prophylactic protection or treat ongoing infections [827].
Flu-like illnesses caused by viruses are a common target of vaccine development programs, and influenza vaccine technology in particular has made many strides.
During the H1N1 influenza outbreak, vaccine development was accelerated because of the existing infrastructure, along with the fact that regulatory agencies had already decided that vaccines produced using egg- and cell-based platforms could be licensed under the regulations used for a strain change.
Critiques of the production and distribution of the H1N1 vaccine have stressed the need for alternative development-and-manufacturing platforms that can be readily adapted to new pathogens.
-Although a monovalent H1N1 vaccine was not available before the pandemic peaked in the United States and Europe, it was available soon afterward as a stand-alone vaccine that was eventually incorporated into commercially available seasonal influenza vaccines [827].
+Although a monovalent H1N1 vaccine was not available before the pandemic peaked in the United States and Europe, it was available soon afterward as a stand-alone vaccine that was eventually incorporated into commercially available seasonal influenza vaccines [828].
If H1N1 vaccine development provides any indication, considering developing and manufacturing platforms for promising COVID-19 vaccine trials early could hasten the emergence of an effective prophylactic vaccine against SARS-CoV-2.
-The first critical step towards developing a vaccine against SARS-CoV-2 was characterizing the target, which fortunately happened early in the COVID-19 outbreak with the sequencing and dissemination of the viral genome [828].
+
The first critical step towards developing a vaccine against SARS-CoV-2 was characterizing the target, which fortunately happened early in the COVID-19 outbreak with the sequencing and dissemination of the viral genome [829].
The Coalition for Epidemic Preparedness Innovations (CEPI) is coordinating global health agencies and pharmaceutical companies to develop vaccines against SARS-CoV-2.
-As of September 2020, there were over 180 vaccine candidates against SARS-CoV-2 in development [829].
+As of September 2020, there were over 180 vaccine candidates against SARS-CoV-2 in development [830].
Unlike many global vaccine development programs previously, such as with H1N1, the vaccine development landscape for COVID-19 includes vaccines produced by a wide array of technologies.
-Experience in the field of oncology is encouraging COVID-19 vaccine developers to use next-generation approaches to vaccine development, which have led to the great diversity of vaccine development programs [830].
+Experience in the field of oncology is encouraging COVID-19 vaccine developers to use next-generation approaches to vaccine development, which have led to the great diversity of vaccine development programs [831].
These diverse technology platforms include DNA, RNA, virus-like particle, recombinant protein, both replicating and non-replicating viral vectors, live attenuated virus, and inactivated virus approaches (Figure 5).
Given the wide range of vaccines under development, it is possible that some vaccine products may eventually be shown to be more effective in certain subpopulations, such as children, pregnant women, immunocompromised patients, the elderly, etc.
-The requirements for a successful vaccine trial and deployment are complex and may require coordination between government, industry, academia, and philanthropic entities [831].
-While little is currently known about immunity to SARS-CoV-2, vaccine development typically tests for serum neutralizing activity, as this has been established as a biomarker for adaptive immunity in other respiratory illnesses [832].
+The requirements for a successful vaccine trial and deployment are complex and may require coordination between government, industry, academia, and philanthropic entities [832].
+While little is currently known about immunity to SARS-CoV-2, vaccine development typically tests for serum neutralizing activity, as this has been established as a biomarker for adaptive immunity in other respiratory illnesses [833].
Figure 5: Vaccine Development Strategies.
@@ -2647,13 +2648,13 @@ 7.
7.4 DNA Vaccines
-This vaccination method involves the direct introduction of a plasmid containing a DNA sequence encoding the antigen(s) against which an immune response is sought into appropriate tissues [833].
+
This vaccination method involves the direct introduction of a plasmid containing a DNA sequence encoding the antigen(s) against which an immune response is sought into appropriate tissues [834].
This approach may offer several advantages over traditional vaccination approaches, such as the stimulation of both B- as well as T-cell responses and the absence of any infectious agent.
-Currently, a Phase I safety and immunogenicity clinical trial of INO-4800, a prophylactic vaccine against SARS-CoV-2, is underway [834].
+Currently, a Phase I safety and immunogenicity clinical trial of INO-4800, a prophylactic vaccine against SARS-CoV-2, is underway [835].
The vaccine developer Inovio Pharmaceuticals Technology is overseeing administration of INO-4800 by intradermal injection followed by electroporation with the CELLECTRA® device to healthy volunteers.
Electroporation is the application of brief electric pulses to tissues in order to permeabilize cell membranes in a transient and reversible manner.
-It has been shown that electroporation can enhance vaccine efficacy by up to 100-fold, as measured by increases in antigen-specific antibody titers [835].
-The safety of the CELLECTRA® device has been studied for over seven years, and these studies support the further development of electroporation as a safe vaccine delivery method [836].
+It has been shown that electroporation can enhance vaccine efficacy by up to 100-fold, as measured by increases in antigen-specific antibody titers [836].
+The safety of the CELLECTRA® device has been studied for over seven years, and these studies support the further development of electroporation as a safe vaccine delivery method [837].
The temporary formation of pores through electroporation facilitates the successful transportation of macromolecules into cells, allowing cells to robustly take up INO-4800 for the production of an antibody response.
Approved by the U.S. FDA on April 6, 2020, the Phase I study is enrolling up to 40 healthy adult volunteers in Philadelphia, PA at the Perelman School of Medicine and at the Center for Pharmaceutical Research in Kansas City, MO.
The trial has two experimental arms corresponding to the two locations.
@@ -2664,98 +2665,98 @@
7.4<
Although exciting, the cost of vaccine manufacturing and electroporation may make scaling the use of this technology for prophylactic use for the general public difficult.
7.5 RNA Vaccines
RNA vaccines are nucleic-acid based modalities that code for viral antigens against which the human body elicits a humoral and cellular immune response.
-The mRNA technology is transcribed in vitro and delivered to cells via lipid nanoparticles (LNP) [837].
-They are recognized by ribosomes in vivo and then translated and modified into functional proteins [838].
-The resulting intracellular viral proteins are displayed on surface MHC proteins, provoking a strong CD8+ T cell response as well as a CD4+ T cell and B cell-associated antibody responses [838].
+The mRNA technology is transcribed in vitro and delivered to cells via lipid nanoparticles (LNP) [838].
+They are recognized by ribosomes in vivo and then translated and modified into functional proteins [839].
+The resulting intracellular viral proteins are displayed on surface MHC proteins, provoking a strong CD8+ T cell response as well as a CD4+ T cell and B cell-associated antibody responses [839].
Naturally, mRNA is not very stable and can degrade quickly in the extracellular environment or the cytoplasm.
-The LNP covering protects the mRNA from enzymatic degradation outside of the cell [839].
+The LNP covering protects the mRNA from enzymatic degradation outside of the cell [840].
Codon optimization to prevent secondary structure formation and modifications of the poly-A tail as well as the 5’ untranslated region to promote ribosomal complex binding can increase mRNA expression in cells.
-Furthermore, purifying out double-stranded RNA and immature RNA with FPLC (fast performance liquid chromatography) and HPLC (high performance liquid chromatography) technology will improve translation of the mRNA in the cell [838,840].
+Furthermore, purifying out double-stranded RNA and immature RNA with FPLC (fast performance liquid chromatography) and HPLC (high performance liquid chromatography) technology will improve translation of the mRNA in the cell [839,841].
Vaccines based on mRNA delivery confer many advantages over traditional viral vectored vaccines and DNA vaccines.
-In comparison to live attenuated viruses, mRNA vaccines are non-infectious and can be synthetically produced in an egg-free, cell-free environment, thereby reducing the risk of a detrimental immune response in the host [841].
-Unlike DNA vaccines, mRNA technologies are naturally degradable and non-integrating, and they do not need to cross the nuclear membrane in addition to the plasma membrane for their effects to be seen [838].
+In comparison to live attenuated viruses, mRNA vaccines are non-infectious and can be synthetically produced in an egg-free, cell-free environment, thereby reducing the risk of a detrimental immune response in the host [842].
+Unlike DNA vaccines, mRNA technologies are naturally degradable and non-integrating, and they do not need to cross the nuclear membrane in addition to the plasma membrane for their effects to be seen [839].
Furthermore, mRNA vaccines are easily, affordably, and rapidly scalable.
Although mRNA vaccines have been developed for therapeutic and prophylactic purposes, none have previously been licensed or commercialized.
-Nevertheless, they have shown promise in animal models and preliminary clinical trials for several indications, including rabies, coronavirus, influenza, and cytomegalovirus [842].
-Preclinical data previously identified effective antibody generation against full-length FPLC-purified influenza hemagglutinin stalk-encoding mRNA in mice, rabbits, and ferrets [843].
-Similar immunological responses for mRNA vaccines were observed in humans in Phase I and II clinical trials operated by the pharmaceutical-development companies Curevac and Moderna for rabies, flu, and zika [840].
-Positively charged bilayer LNPs carrying the mRNA attract negatively charged cell membranes, endocytose into the cytoplasm [839], and facilitate endosomal escape.
-LNPs can be coated with modalities recognized and engulfed by specific cell types, and LNPs that are 150 nm or less effectively enter into lymphatic vessels [839,844].
+Nevertheless, they have shown promise in animal models and preliminary clinical trials for several indications, including rabies, coronavirus, influenza, and cytomegalovirus [843].
+Preclinical data previously identified effective antibody generation against full-length FPLC-purified influenza hemagglutinin stalk-encoding mRNA in mice, rabbits, and ferrets [844].
+Similar immunological responses for mRNA vaccines were observed in humans in Phase I and II clinical trials operated by the pharmaceutical-development companies Curevac and Moderna for rabies, flu, and zika [841].
+Positively charged bilayer LNPs carrying the mRNA attract negatively charged cell membranes, endocytose into the cytoplasm [840], and facilitate endosomal escape.
+LNPs can be coated with modalities recognized and engulfed by specific cell types, and LNPs that are 150 nm or less effectively enter into lymphatic vessels [840,845].
Therefore, this technology holds great potential for targeted delivery of modified mRNA.
-There are three types of RNA vaccines: non-replicating, in vivo self-replicating, and in vitro dendritic cell non-replicating [845].
+
There are three types of RNA vaccines: non-replicating, in vivo self-replicating, and in vitro dendritic cell non-replicating [846].
Non-replicating mRNA vaccines consist of a simple open reading frame (ORF) for the viral antigen flanked by the 5’ UTR and 3’ poly-A tail.
-In vivo self-replicating vaccines encode a modified viral genome derived from single-stranded, positive sense RNA alphaviruses [838,840].
+In vivo self-replicating vaccines encode a modified viral genome derived from single-stranded, positive sense RNA alphaviruses [839,841].
The RNA genome encodes the viral antigen along with proteins of the genome replication machinery, including an RNA polymerase.
-Structural proteins required for viral assembly are not included in the engineered genome [838].
-Self-replicating vaccines produce more viral antigens over a longer period of time, thereby evoking a more robust immune response [845].
+Structural proteins required for viral assembly are not included in the engineered genome [839].
+Self-replicating vaccines produce more viral antigens over a longer period of time, thereby evoking a more robust immune response [846].
Finally, in vitro dendritic cell non-replicating RNA vaccines limit transfection to dendritic cells.
Dendritic cells are potent antigen-presenting immune cells that easily take up mRNA and present fragments of the translated peptide on their MHC proteins, which can then interact with T cell receptors.
-Ultimately, primed T follicular helper cells can stimulate germinal center B cells that also present the viral antigen to produce antibodies against the virus [846].
-These cells are isolated from the patient, grown and transfected ex vivo, and reintroduced to the patient [847].
+Ultimately, primed T follicular helper cells can stimulate germinal center B cells that also present the viral antigen to produce antibodies against the virus [847].
+These cells are isolated from the patient, grown and transfected ex vivo, and reintroduced to the patient [848].
Given the potential for this technology to be quickly adapted for a new pathogen, it has held significant interest for the treatment of COVID-19.
-In the vaccines developed under this approach, the spike protein, which is immunogenic [39], can be furnished to the immune system in order to train its response.
-The vaccine candidates developed against SARS-CoV-2 using mRNA vectors utilize similar principles and technologies, although there are slight differences in implementation among candidates such as the formulation of the platform and the specific components of the spike protein encapsulated (e.g., the full Spike protein vs. the RBD alone) [848].
+In the vaccines developed under this approach, the spike protein, which is immunogenic [41], can be furnished to the immune system in order to train its response.
+The vaccine candidates developed against SARS-CoV-2 using mRNA vectors utilize similar principles and technologies, although there are slight differences in implementation among candidates such as the formulation of the platform and the specific components of the spike protein encapsulated (e.g., the full Spike protein vs. the RBD alone) [849].
The results of the interim analyses of two mRNA vaccine candidates became available at the end of 2020 and provided strong support for this emerging approach to vaccination.
Below we describe the results available as of February 2021 for two such candidates, mRNA-1273 produced by ModernaTX and BNT162b2 produced by Pfizer, Inc. and BioNTech.
7.5.1 ModernaTX mRNA Vaccine
ModernaTX’s mRNA-1273 vaccine, which is an was the first COVID-19 vaccine to enter a phase I clinical trial in the United States.
-In this trial, Moderna spearheaded an investigation on the immunogenicity and reactogenicity of mRNA-1273, a conventional lipid nanoparticle encapsulated RNA encoding a full-length prefusion stabilized S protein for SARS-CoV-2 [849].
-An initial report described the results of enrolling forty-five participants who were administered intramuscular injections of mRNA-1273 in their deltoid muscle on day 1 and day 29, and then followed for the next twelve months [832].
+In this trial, Moderna spearheaded an investigation on the immunogenicity and reactogenicity of mRNA-1273, a conventional lipid nanoparticle encapsulated RNA encoding a full-length prefusion stabilized S protein for SARS-CoV-2 [850].
+An initial report described the results of enrolling forty-five participants who were administered intramuscular injections of mRNA-1273 in their deltoid muscle on day 1 and day 29, and then followed for the next twelve months [833].
Healthy males and non-pregnant females aged 18-55 years were recruited for this study and divided into three groups receiving 25, 100, or 250 micrograms (μg) of mRNA-1273.
-IgG ELISA assays on patient serology samples were used to examine the immunogenicity of the vaccine [849].
+IgG ELISA assays on patient serology samples were used to examine the immunogenicity of the vaccine [850].
Binding antibodies were observed at two weeks after the first dose at all concentrations.
At the time point one week after the second dose was administered on day 29, the pseudotyped lentivirus reporter single-round-of-infection neutralization assay (PsVNA), which was used to assess neutralizing activity, reached a median level similar to the median observed in convalescent plasma samples.
Participants reported mild and moderate systemic adverse events after the day 1 injection, and one severe local event was observed in each of the two highest dose levels.
The second injection led to severe systemic adverse events for three of the participants at the highest dose levels, with one participant in the group being evaluated at an urgent care center on the day after the second dose.
The reported localized adverse events from the second dose were similar to those from the first.
-Several months later, a press release from ModernaTX described the results of the first interim analysis of the vaccine [850].
-On November 16, 2020, a report was released describing the initial results from Phase III testing, corresponding to the first 95 cases of COVID-19 in the 30,000 enrolled participants [850], with additional data released to the FDA on December 17, 2020 [851].
-These results were subsequently published in a peer-reviewed journal (The New England Journal of Medicine) on December 30, 2020 [852].
-The first group of 30,420 study participants were randomized to receive the vaccine or a placebo at a ratio of 1:1 [852].
-Administration occurred at 99 sites within the United States in two sessions, spaced 28 days apart [852,853].
-Patients reporting COVID-19 symptoms upon follow-up were tested for SARS-CoV-2 using a nasopharyngeal swab that was evaluated with RT-PCR [853].
+
Several months later, a press release from ModernaTX described the results of the first interim analysis of the vaccine [851].
+On November 16, 2020, a report was released describing the initial results from Phase III testing, corresponding to the first 95 cases of COVID-19 in the 30,000 enrolled participants [851], with additional data released to the FDA on December 17, 2020 [852].
+These results were subsequently published in a peer-reviewed journal (The New England Journal of Medicine) on December 30, 2020 [853].
+The first group of 30,420 study participants were randomized to receive the vaccine or a placebo at a ratio of 1:1 [853].
+Administration occurred at 99 sites within the United States in two sessions, spaced 28 days apart [853,854].
+Patients reporting COVID-19 symptoms upon follow-up were tested for SARS-CoV-2 using a nasopharyngeal swab that was evaluated with RT-PCR [854].
The initial preliminary analysis reported the results of the cases observed up until a cut-off date of November 11, 2020.
-Of these first 95 cases reported, 90 occurred in participants receiving the placebo compared to 5 cases in the group receiving the vaccine [850].
+Of these first 95 cases reported, 90 occurred in participants receiving the placebo compared to 5 cases in the group receiving the vaccine [851].
These results suggested the vaccine is 94.5% effective in preventing COVID-19.
Additionally, eleven severe cases of COVID-19 were observed, and all eleven occurred in participants receiving the placebo.
-The publication reported the results through an extended cut-off date of November 21, 2020, corresponding to 196 cases [852].
+The publication reported the results through an extended cut-off date of November 21, 2020, corresponding to 196 cases [853].
Of these, 11 occurred in the vaccine group and 185 in the placebo group, corresponding to an efficacy of 94.1%.
Once again, all of the severe cases of COVID-19 observed (n=30) occurred in the placebo group, including one death.
Thus, as more cases are reported, the efficacy of the vaccine has remained above 90%, and no cases of severe COVID-19 have yet been reported in participants receiving the vaccine.
These findings suggest the possibility that the vaccine might bolster immune defenses even for subjects who do still develop a SARS-CoV-2 infection.
-The study was designed with an explicit goal of including individuals at high risk for COVID-19, including older adults, people with underlying health conditions, and people of color [854].
-The Phase III trial population was comprised by approximately 25.3% adults over age 65 in the initial report and 24.8% in the publication [853].
-Among the cases reported by both interim analyses, 16-17% occurred in older adults [850,852]..
-Additionally, approximately 10% of participants identified a Black or African-American background and 20% identified Hispanic or Latino ethnicity [852,853].
-Among the first 95 cases, 12.6% occurred in participants identifying a Hispanic or Latino background and 4% in participants reporting a Black or African-American background [850]; in the publication, they indicated only that 41 of the cases reported in the placebo group and 1 case in the treatment group occurred in “communities of color”, corresponding to 21.4% of all cases [852].
+The study was designed with an explicit goal of including individuals at high risk for COVID-19, including older adults, people with underlying health conditions, and people of color [855].
+The Phase III trial population was comprised by approximately 25.3% adults over age 65 in the initial report and 24.8% in the publication [854].
+Among the cases reported by both interim analyses, 16-17% occurred in older adults [851,853]..
+Additionally, approximately 10% of participants identified a Black or African-American background and 20% identified Hispanic or Latino ethnicity [853,854].
+Among the first 95 cases, 12.6% occurred in participants identifying a Hispanic or Latino background and 4% in participants reporting a Black or African-American background [851]; in the publication, they indicated only that 41 of the cases reported in the placebo group and 1 case in the treatment group occurred in “communities of color”, corresponding to 21.4% of all cases [853].
While the sample size in both analyses is small relative to the study population of over 30,000, these results suggest that the vaccine is likely to be effective in people from a variety of backgrounds.
By all indications, this vaccine is likely to be highly useful in mitigating the damage of SARS-CoV-2.
-In-depth safety data was released by ModernaTX as part of their application for an EUA from the FDA and summarized in the associated publication [852,853].
+
In-depth safety data was released by ModernaTX as part of their application for an EUA from the FDA and summarized in the associated publication [853,854].
Because the detail provided in the report is greater than that provided in the publication, here we emphasize the results observed at the time of the first analysis.
-Overall, a large percentage of participants reported adverse effects when solicited, and these reports were higher in the vaccine group than in the placebo group (94.5% versus 59.5%, respectively, at the time of the initial analysis) [853].
-Some of these events met the criteria for grade 3 (local or systemic) or grade 4 (systemic only) toxicity [853], but most were grade 1 or grade 2 and lasted 2-3 days [852].
-The most common local adverse reaction was pain at the injection site, reported by 83.7% of participants receiving the first dose of the vaccine and 88.4% upon receiving the second dose, compared to 19.8% and 19.8% and 17.0%, respectively, of patients in the placebo condition [853].
+Overall, a large percentage of participants reported adverse effects when solicited, and these reports were higher in the vaccine group than in the placebo group (94.5% versus 59.5%, respectively, at the time of the initial analysis) [854].
+Some of these events met the criteria for grade 3 (local or systemic) or grade 4 (systemic only) toxicity [854], but most were grade 1 or grade 2 and lasted 2-3 days [853].
+The most common local adverse reaction was pain at the injection site, reported by 83.7% of participants receiving the first dose of the vaccine and 88.4% upon receiving the second dose, compared to 19.8% and 19.8% and 17.0%, respectively, of patients in the placebo condition [854].
Fewer than 5% of vaccine recipients reported grade 3 pain at either administration.
-Other frequent local reactions included erythema, swelling, and lymphadenopathy [853].
-For systemic adverse reactions, fatigue was the most common [853].
-Among participants receiving either dose of the vaccine, 68.5% reported fatigue compared to 36.1% participants receiving the placebo [853].
-The level of fatigue experienced was usually fairly mild, with only 9.6% and 1.3% of participants in the vaccine and placebo conditions, respectively, reporting grade 3 fatigue [853], which corresponds to significant interference with daily activity [855].
-Based on the results of the report, an EUA was issued on December 18, 2020 to allow distribution of this vaccine in the United States [856], and it was shortly followed by an Interim Order authorizing distribution of the vaccine in Canada [857] and a conditional marketing authorization by the European Medicines Agency to facilitate distribution in the European Union [858].
+Other frequent local reactions included erythema, swelling, and lymphadenopathy [854].
+For systemic adverse reactions, fatigue was the most common [854].
+Among participants receiving either dose of the vaccine, 68.5% reported fatigue compared to 36.1% participants receiving the placebo [854].
+The level of fatigue experienced was usually fairly mild, with only 9.6% and 1.3% of participants in the vaccine and placebo conditions, respectively, reporting grade 3 fatigue [854], which corresponds to significant interference with daily activity [856].
+Based on the results of the report, an EUA was issued on December 18, 2020 to allow distribution of this vaccine in the United States [857], and it was shortly followed by an Interim Order authorizing distribution of the vaccine in Canada [858] and a conditional marketing authorization by the European Medicines Agency to facilitate distribution in the European Union [859].
7.5.2 Pfizer/BioNTech BNT162b2
ModernaTX was, in fact, the second company to release news of a successful interim analysis of an mRNA vaccine and receive an EUA.
-The first report came from Pfizer and BioNTech’s mRNA vaccine BNT162b2 on November 9, 2020 [859], and a preliminary report was published in the New England Journal of Medicine one month later [304].
-The vaccine candidate is contains the full prefusion stabilized, membrane-anchored SARS-CoV-2 spike protein in a vaccine formulation based on modified mRNA (modRNA) technology [860,861].
-This vaccine candidate should not be confused with a similar candidate from Pfizer/BioNTech, BNT162b1, that delivered only the RBD of the spike protein [862,863], which was not advanced to a stage III trial because of the improved reactogenicity/immunogenicity profile of BNT162b2 [305].
-During the Phase III trial of BNT162b2, 43,538 participants were enrolled 1:1 in the placebo and the vaccine candidate and received two 30-μg doses 21 days apart [304].
-Of these enrolled participants, 21,720 received BNT162b2 and 21,728 received a placebo [304].
+The first report came from Pfizer and BioNTech’s mRNA vaccine BNT162b2 on November 9, 2020 [860], and a preliminary report was published in the New England Journal of Medicine one month later [306].
+The vaccine candidate is contains the full prefusion stabilized, membrane-anchored SARS-CoV-2 spike protein in a vaccine formulation based on modified mRNA (modRNA) technology [861,862].
+This vaccine candidate should not be confused with a similar candidate from Pfizer/BioNTech, BNT162b1, that delivered only the RBD of the spike protein [863,864], which was not advanced to a stage III trial because of the improved reactogenicity/immunogenicity profile of BNT162b2 [307].
+During the Phase III trial of BNT162b2, 43,538 participants were enrolled 1:1 in the placebo and the vaccine candidate and received two 30-μg doses 21 days apart [306].
+Of these enrolled participants, 21,720 received BNT162b2 and 21,728 received a placebo [306].
Recruitment occurred at 135 sites across six countries: Argentina, Brazil, Germany, South Africa, Turkey, and the United States.
-An initial press release described the first 94 cases, which were consistent with 90% efficacy of the vaccine at 7 days following the second dose [859].
+An initial press release described the first 94 cases, which were consistent with 90% efficacy of the vaccine at 7 days following the second dose [860].
The release of the full trial information covered a longer period and analyzed the first 170 cases occurring at least 7 days after the second dose, 8 of which occurred in patients who had received BNT162b2.
-The press release characterized the study population as diverse, reporting that 42% of the participants worldwide came from non-white backgrounds, including 10% Black and 26% Hispanic or Latino [864].
-Within the United States, 10% and 13% of participants, respectively, identified themselves as having Black or Hispanic/Latino backgrounds [864].
-Additionally, 41% of participants worldwide were 56 years of age or older [864], and they reported that the efficacy of the vaccine in adults over 65 was 94% [865].
-The primary efficacy analysis of the Phase III study was concluded on November 18, 2020 [865], and the final results indicted 94.6% efficacy of the vaccine [304]v.
-The safety profile of the vaccine was also assessed [304].
+The press release characterized the study population as diverse, reporting that 42% of the participants worldwide came from non-white backgrounds, including 10% Black and 26% Hispanic or Latino [865].
+Within the United States, 10% and 13% of participants, respectively, identified themselves as having Black or Hispanic/Latino backgrounds [865].
+Additionally, 41% of participants worldwide were 56 years of age or older [865], and they reported that the efficacy of the vaccine in adults over 65 was 94% [866].
+The primary efficacy analysis of the Phase III study was concluded on November 18, 2020 [866], and the final results indicted 94.6% efficacy of the vaccine [306]v.
+The safety profile of the vaccine was also assessed [306].
A subset of patients were followed for reactogenicity using electronic diaries, with the data collected from these 8,183 participants comprising the solicited safety events analyzed.
Much like those who received the ModernaTX vaccine candidate, a large proportion of participants reported experiencing site injection pain within 7 days of vaccination.
While percentages are broken down by age group in the publication, these proportions correspond to approximately 78% and 73% of all participants after the first and second doses, respectively, overall.
@@ -2764,8 +2765,8 @@
[866,867].
-As of December 11, 2020, the United States FDA approved this vaccine under an emergency use authorization [868].
+Based on the efficacy and safety information released, the vaccine was approved in early December by the United Kingdom’s Medicines and Healthcare Products Regulatory Agency with administration outside of a clinical trial beginning on December 8, 2020 [867,868].
+As of December 11, 2020, the United States FDA approved this vaccine under an emergency use authorization [869].
7.6 Viral Vector Vaccines
7.6.1 COVID-19 Vaccine AstraZeneca
7.6.2 Sputnik-V
@@ -2784,121 +2785,121 @@ also included a brief summary of the potential of adjuvants for these vaccines, including a brief description of some already commonly used adjuvants.
+A review on the development of SARS-CoV-2 vaccines [870] also included a brief summary of the potential of adjuvants for these vaccines, including a brief description of some already commonly used adjuvants.
Different adjuvants can regulate different types of immune responses, so the type or combination of adjuvants used in a vaccine will depend on both the type of vaccine and concern related to efficacy and safety.
-A variety of possible mechanisms for adjuvants have been researched [870,871,872], including the following: induction of DAMPs that can be recognized by certain PRRs of the innate immune system; functioning as PAMP that can also be recognized by certain PRRs; and more generally enhancing the humoral or cellular immune responses.
+A variety of possible mechanisms for adjuvants have been researched [871,872,873], including the following: induction of DAMPs that can be recognized by certain PRRs of the innate immune system; functioning as PAMP that can also be recognized by certain PRRs; and more generally enhancing the humoral or cellular immune responses.
Selection of one or more adjuvants requires considering how to promote the advantageous effects of the components and/or immune response and, likewise, to inhibit possible deleterious effects.
There are also considerations related to the method of delivering (or co-delivering) the adjuvant and antigen components of a vaccine.
7.10.2 Trained Immunity
Another approach that is being investigated explores the potential for vaccines that are not made from the SARS-CoV-2 virus to confer what has been termed trained immunity.
-In a recent review [873], trained immunity was defined as forms of memory that are temporary (e.g., months or years) and reversible.
+In a recent review [874], trained immunity was defined as forms of memory that are temporary (e.g., months or years) and reversible.
It is induced by exposure to whole-microorganism vaccines or other microbial stimuli that generates heterologous protective effects.
Trained immunity can be displayed by innate immune cells or innate immune features of other cells, and it is characterized by alterations to immune responsiveness to future immune challenges due to epigenetic and metabolic mechanisms.
These alterations can take the form of either an increased or decreased response to immune challenge by a pathogen.
-Trained immunity elicited by non-SARS-CoV-2 whole-microorganism vaccines could potentially improve SARS-CoV-2 susceptibility or severity [874].
+Trained immunity elicited by non-SARS-CoV-2 whole-microorganism vaccines could potentially improve SARS-CoV-2 susceptibility or severity [875].
One type of stimulus which research indicates can induce trained immunity is bacillus Calmette-Guerin (BCG) vaccination.
BCG is an attenuated form of bacteria Mycobacterium bovis.
The vaccine is most commonly administered for the prevention of tuberculosis in humans.
Clinical trials in non-SARS-CoV-2-infected adults have been designed to assess whether BCG vaccination could have prophylactic effects against SARS-CoV-2 by reducing susceptibility, preventing infection, or reducing disease severity.
-A number of trials are now evaluating the effects of the BCG vaccine or the related vaccine VPM1002 [874,875,876,877,878,879,880,881,882,883,884,885,886,887,888].
+A number of trials are now evaluating the effects of the BCG vaccine or the related vaccine VPM1002 [875,876,877,878,879,880,881,882,883,884,885,886,887,888,889].
The ongoing trials are using a number of different approaches.
Some trials enroll healthcare workers, other trials hospitalized elderly adults without immunosuppression who get vaccinated with placebo or BCG at hospital discharge, and yet another set of trials older adults (>50 years) under chronic care for conditions like hypertension and diabetes.
One set of trials, for example, uses time until first infection as the primary study endpoint; more generally, outcomes measured in some of these trials are related to incidence of disease and disease severity or symptoms.
-Some analyses have suggested a possible correlation at the country level between the frequency of BCG vaccination (or BCG vaccination policies) and the severity of COVID-19 [874].
+Some analyses have suggested a possible correlation at the country level between the frequency of BCG vaccination (or BCG vaccination policies) and the severity of COVID-19 [875].
Currently it is unclear whether this correlation has any connection to trained immunity.
Many possible confounding factors are also likely to vary among countries, such as age distribution, detection efficiency, stochastic epidemic dynamic effects, differences in healthcare capacity over time in relation to epidemic dynamics, and these have not been adequately accounted for in current analyses.
It is unclear whether there is an effect of the timing of BCG vaccination, both during an individual’s life cycle and relative to the COVID-19 pandemic.
-Additionally, given that severe SARS-CoV-2 may be associated with a dysregulated immune response, it is unclear what alterations to the immune response would be most likely to be protective versus pathogenic (e.g., [112,874,889,890]).
-The article [874] proposes that trained immunity might lead to an earlier and stronger response, which could in turn reduce viremia and the risk of later, detrimental immunopathology.
+Additionally, given that severe SARS-CoV-2 may be associated with a dysregulated immune response, it is unclear what alterations to the immune response would be most likely to be protective versus pathogenic (e.g., [114,875,890,891]).
+The article [875] proposes that trained immunity might lead to an earlier and stronger response, which could in turn reduce viremia and the risk of later, detrimental immunopathology.
While trained immunity is an interesting possible avenue to complement vaccine development efforts through the use of an existing vaccine, additional research is required to assess whether the BCG vaccine is likely to confer trained immunity in the case of SARS-CoV-2.
7.11 Discussion
Additionally, major advances in vaccines using mRNA and adenoviruses that have led to three vaccines becoming available or close to becoming available in late 2020 (Figure 4).
Though some concerns remain about the duration of sustained immunity for convalescents, vaccine development efforts are ongoing and show initial promising results.
The Moderna trial, for example, reported that the neutralizing activity in participants who received two doses of the vaccine was similar to that observed in convalescent plasma.
-One of the two mRNA vaccines, Pfizer and BioNTech’s BNT162b2, has been issued an EUA for patients as young as 16 [891], while ModernaTX has begun a clinical trial to assess its mRNA vaccine in adolescents ages 12 to 18 [892].
+One of the two mRNA vaccines, Pfizer and BioNTech’s BNT162b2, has been issued an EUA for patients as young as 16 [892], while ModernaTX has begun a clinical trial to assess its mRNA vaccine in adolescents ages 12 to 18 [893].
8 Social Factors Influencing COVID-19 Exposure and Outcomes
8.1 Social Factors Influencing COVID-19 Outcomes
In addition to understanding the fundamental biology of the SARS-CoV-2 virus and COVID-19, it is critical to consider how the broader environment can influence both COVID-19 outcomes and efforts to develop and implement treatments for the disease.
The evidence clearly indicates that social environmental factors are critical determinants of individuals’ and communities’ risks related to COVID-19.
There are distinct components to COVID-19 susceptibility, and an individual’s risk can be elevated at one or all stages from exposure to recovery/mortality: an individual may be more likely to be exposed to the virus, more likely to get infected once exposed, more likely to have serious complications once infected, and be less likely to receive adequate care once they are seriously ill.
-The fact that differences in survival between Black and white patients were no longer significant after controlling for comorbidities and socioeconomic status (type of insurance, neighborhood deprivation score, and hospital where treatment was received) in addition to sex and age [893] underscores the relevance of social factors to understanding mortality differences between racial and ethnic groups.
-Moreover, the Black patients were younger and more likely to be female than white patients, yet still had a higher mortality rate without correction for the other variables [893].
+The fact that differences in survival between Black and white patients were no longer significant after controlling for comorbidities and socioeconomic status (type of insurance, neighborhood deprivation score, and hospital where treatment was received) in addition to sex and age [894] underscores the relevance of social factors to understanding mortality differences between racial and ethnic groups.
+Moreover, the Black patients were younger and more likely to be female than white patients, yet still had a higher mortality rate without correction for the other variables [894].
Here, we outline a few systemic reasons that may exacerbate the COVID-19 pandemic in communities of color.
8.2 Factors Observed to be Associated with Susceptibility
As COVID-19 has spread into communities around the globe, it has become clear that the risks associated with this disease are not equally shared by all individuals or all communities.
Significant disparities in outcomes have led to interest in the demographic, biomedical, and social factors that influence COVID-19 severity.
Untangling the factors influencing COVID-19 susceptibility is a complex undertaking.
-Among patients who are admitted to the hospital, outcomes have generally been poor, with rates of admission to the intensive care unit (ICU) upwards of 15% in both Wuhan, China and Italy [34,894,895].
-However, hospitalization rates vary by location [896].
+Among patients who are admitted to the hospital, outcomes have generally been poor, with rates of admission to the intensive care unit (ICU) upwards of 15% in both Wuhan, China and Italy [36,895,896].
+However, hospitalization rates vary by location [897].
This variation may be influenced by demographic (e.g., average age in the area), medical (e.g., the prevalence of comorbid conditions such as diabetes), and social (e.g., income or healthcare availability) factors that vary geographically.
Additionally, some of the same factors may influence an individual’s probability of exposure to SARS-CoV-2, their risk of developing a more serious case of COVID-19 that would require hospitalization, and their access to medical support.
As a result, quantifying or comparing susceptibility among individuals, communities, or other groups requires consideration of a number of complex phenomena that intersect across many disciplines of research.
In this section, the term “risk factor” is used to refer to variables that are statistically associated with more severe COVID-19 outcomes.
Some are intrinsic characteristics that have been observed to carry an association with variation in outcomes, whereas others may be more functionally linked to the pathophysiology of COVID-19.
8.2.1 Patient Traits Associated with Increased Risk
-Two traits that have been consistently associated with more severe COVID-19 outcomes are male sex and advanced age (typically defined as 60 or older, with the greatest risk among those 85 and older [897]).
-In the United States, males and older individuals diagnosed with COVID-19 were found to be more likely to require hospitalization [898,899].
-A retrospective study of hospitalized Chinese patients [35] found that a higher probability of mortality was associated with older age, and world-wide, population age structure has been found to be an important variable for explaining differences in outbreak severity [900].
-The CFR for adults over 80 has been estimated upwards of 14% or even 20% [901].
-Male sex has also been identified as a risk factor for severe COVID-19 outcomes, including death [902,903,904].
-Early reports from China and Europe indicated that even though the case rates were similar across males and females, males were at elevated risk for hospital admission, ICU admission, and death [903], although data from some US states indicates more cases among females, potentially due to gender representation in care-taking professions [905].
-In older age groups (e.g., age 60 and older), comparable absolute numbers of male and female cases actually suggests a higher rate of occurrence in males, due to increased skew in the sex ratio [903].
-Current estimates based on worldwide data suggest that, compared to females, males may be 30% more likely to be hospitalized, 80% more likely to be admitted to the ICU, and 40% more likely to die as a result of COVID-19 [904].
-There also may be a compounding effect of advanced age and male sex, with differences time to recovery worst for males over 60 years old relative to female members of their age cohort [906].
+Two traits that have been consistently associated with more severe COVID-19 outcomes are male sex and advanced age (typically defined as 60 or older, with the greatest risk among those 85 and older [898]).
+In the United States, males and older individuals diagnosed with COVID-19 were found to be more likely to require hospitalization [899,900].
+A retrospective study of hospitalized Chinese patients [37] found that a higher probability of mortality was associated with older age, and world-wide, population age structure has been found to be an important variable for explaining differences in outbreak severity [901].
+The CFR for adults over 80 has been estimated upwards of 14% or even 20% [902].
+Male sex has also been identified as a risk factor for severe COVID-19 outcomes, including death [903,904,905].
+Early reports from China and Europe indicated that even though the case rates were similar across males and females, males were at elevated risk for hospital admission, ICU admission, and death [904], although data from some US states indicates more cases among females, potentially due to gender representation in care-taking professions [906].
+In older age groups (e.g., age 60 and older), comparable absolute numbers of male and female cases actually suggests a higher rate of occurrence in males, due to increased skew in the sex ratio [904].
+Current estimates based on worldwide data suggest that, compared to females, males may be 30% more likely to be hospitalized, 80% more likely to be admitted to the ICU, and 40% more likely to die as a result of COVID-19 [905].
+There also may be a compounding effect of advanced age and male sex, with differences time to recovery worst for males over 60 years old relative to female members of their age cohort [907].
Both of these risk factors can be approached through the lens of biology.
-The biological basis for greater susceptibility with age is likely linked to the prevalence of extenuating health conditions such as heart failure or diabetes [901].
+The biological basis for greater susceptibility with age is likely linked to the prevalence of extenuating health conditions such as heart failure or diabetes [902].
Several hypotheses have been proposed to account for differences in severity between males and females.
-For example, some evidence suggests that female sex hormones may be protective [903,905].
-ACE2 expression in the kidneys of male mice was observed to be twice as high as that of females, and a regulatory effect of estradiol on ACE2 expression was demonstrated by removing the gonads and then supplementing with estradiol [905,907].
-Other work in mice has shown an inverse association between mortality due to SARS-CoV-1 and estradiol, suggesting a protective role for the sex hormone [905].
+For example, some evidence suggests that female sex hormones may be protective [904,906].
+ACE2 expression in the kidneys of male mice was observed to be twice as high as that of females, and a regulatory effect of estradiol on ACE2 expression was demonstrated by removing the gonads and then supplementing with estradiol [906,908].
+Other work in mice has shown an inverse association between mortality due to SARS-CoV-1 and estradiol, suggesting a protective role for the sex hormone [906].
Similarly, evidence suggests that similar patterns might be found in other tissues.
-A preliminary analysis identified higher levels of ACE2 expression in the myocardium of male patients with aortic valve stenosis showed than female patients, although this pattern was not found in controls [903].
-Additionally, research has indicated that females respond to lower doses than males of heart medications that act on the Renin angiotensin aldosterone system (RAAS) pathway, which is shared with ACE2 [903].
-Additionally, several components of the immune response, including the inflammatory response, may differ in intensity and timing between males and females [905,907].
-This hypothesis is supported by some preliminary evidence showing that female patients who recovered from severe COVID-19 had higher antibody titers than males [905].
-Sex steroids can also bind to immune cell receptors to influence cytokine production [903].
-Additionally, social factors may influence risks related to both age and sex: for example, older adults are more likely to live in care facilities, which have been a source for a large number of outbreaks [908], and gender roles may also influence exposure and/or susceptibility due to differences in care-taking and/or risky behaviors (e.g., caring for elder relatives and smoking, respectively) [903] among men and women (however, it should be noted that both transgender men and women are suspected to be at heightened risk [909].)
+A preliminary analysis identified higher levels of ACE2 expression in the myocardium of male patients with aortic valve stenosis showed than female patients, although this pattern was not found in controls [904].
+Additionally, research has indicated that females respond to lower doses than males of heart medications that act on the Renin angiotensin aldosterone system (RAAS) pathway, which is shared with ACE2 [904].
+Additionally, several components of the immune response, including the inflammatory response, may differ in intensity and timing between males and females [906,908].
+This hypothesis is supported by some preliminary evidence showing that female patients who recovered from severe COVID-19 had higher antibody titers than males [906].
+Sex steroids can also bind to immune cell receptors to influence cytokine production [904].
+Additionally, social factors may influence risks related to both age and sex: for example, older adults are more likely to live in care facilities, which have been a source for a large number of outbreaks [909], and gender roles may also influence exposure and/or susceptibility due to differences in care-taking and/or risky behaviors (e.g., caring for elder relatives and smoking, respectively) [904] among men and women (however, it should be noted that both transgender men and women are suspected to be at heightened risk [910].)
8.2.2 Comorbid Health Conditions
A number of pre-existing or comorbid conditions have repeatedly been identified as risk factors for more severe COVID-19 outcomes.
-Several underlying health conditions were identified at high prevalence among hospitalized patients, including obesity, diabetes, hypertension, lung disease, and cardiovascular disease [896].
-Higher Sequential Organ Failure Assessment (SOFA) scores have been associated with a higher probability of mortality [35], and comorbid conditions such as cardiovascular and lung disease as well as obesity were also associated with an increased risk of hospitalization and death, even when correcting for age and sex [902].
-Diabetes may increase the risk of lengthy hospitalization [910] or of death [910,911].
-[912] and [913] discuss possible ways in which COVID-19 and diabetes may interact.
-Obesity also appears to be associated with higher risk of severe outcomes from SARS-CoV-2 [914,915].
-Obesity is considered an underlying risk factor for other health problems, and the mechanism for its contributions to COVID-19 hospitalization or mortality is not yet clear [916].
-Dementia and cancer were also associated with the risk of death in an analysis of a large number (more than 20,000) COVID-19 patients in the United Kingdom [902].
-It should be noted that comorbid conditions are inextricably tied to age, as conditions tend to be accumulated over time, but that the prevalence of individual comorbidities or of population health overall can vary regionally [917].
-Several comorbidities that are highly prevalent in older adults, such as COPD, hypertension, cardiovascular disease, and diabetes, have been associated with CFRs upwards of 8% compared to an estimate of 1.4% in people without comorbidities [901,918].
-Therefore, both age and health are important considerations when predicting the impact of COVID-19 on a population [917].
-However, other associations may exist, such as patients with sepsis having higher SOFA scores – in fact, SOFA was developed for the assessment of organ failure in the context of sepsis, and the acronym originally stood for Sepsis-Related Organ Failure Assessment [919,920].
+Several underlying health conditions were identified at high prevalence among hospitalized patients, including obesity, diabetes, hypertension, lung disease, and cardiovascular disease [897].
+Higher Sequential Organ Failure Assessment (SOFA) scores have been associated with a higher probability of mortality [37], and comorbid conditions such as cardiovascular and lung disease as well as obesity were also associated with an increased risk of hospitalization and death, even when correcting for age and sex [903].
+Diabetes may increase the risk of lengthy hospitalization [911] or of death [911,912].
+[913] and [914] discuss possible ways in which COVID-19 and diabetes may interact.
+Obesity also appears to be associated with higher risk of severe outcomes from SARS-CoV-2 [915,916].
+Obesity is considered an underlying risk factor for other health problems, and the mechanism for its contributions to COVID-19 hospitalization or mortality is not yet clear [917].
+Dementia and cancer were also associated with the risk of death in an analysis of a large number (more than 20,000) COVID-19 patients in the United Kingdom [903].
+It should be noted that comorbid conditions are inextricably tied to age, as conditions tend to be accumulated over time, but that the prevalence of individual comorbidities or of population health overall can vary regionally [918].
+Several comorbidities that are highly prevalent in older adults, such as COPD, hypertension, cardiovascular disease, and diabetes, have been associated with CFRs upwards of 8% compared to an estimate of 1.4% in people without comorbidities [902,919].
+Therefore, both age and health are important considerations when predicting the impact of COVID-19 on a population [918].
+However, other associations may exist, such as patients with sepsis having higher SOFA scores – in fact, SOFA was developed for the assessment of organ failure in the context of sepsis, and the acronym originally stood for Sepsis-Related Organ Failure Assessment [920,921].
Additionally, certain conditions are likely to be more prevalent under or exacerbated by social conditions, especially poverty, as is discussed further below.
8.2.3 Ancestry
A number of studies have suggested associations between individuals’ racial and ethnic backgrounds and their COVID-19 risk.
-In particular, Black Americans are consistently identified as carrying a higher burden of COVID-19 than white Americans [898,899], with differences in the rates of kidney complications from COVID-19 particularly pronounced [94].
-Statistics from a number of cities indicate significant discrepancies between the proportion of COVID-19 cases and deaths in Black Americans relative to their representation in the general population [921].
-In addition to Black Americans, disproportionate harm and mortality from COVID-19 has also been noted in Latino/Hispanic Americans and in Native American and Alaskan Native communities, including the Navajo nation [922,923,924,925,926,927].
-In Brazil, indigenous communities likewise carry an increased burden of COVID-19 [928].
-In the United Kingdom, nonwhite ethnicity (principally Black or South Asian) was one of several factors found to be associated with a higher risk of death from COVID-19 [929].
+In particular, Black Americans are consistently identified as carrying a higher burden of COVID-19 than white Americans [899,900], with differences in the rates of kidney complications from COVID-19 particularly pronounced [96].
+Statistics from a number of cities indicate significant discrepancies between the proportion of COVID-19 cases and deaths in Black Americans relative to their representation in the general population [922].
+In addition to Black Americans, disproportionate harm and mortality from COVID-19 has also been noted in Latino/Hispanic Americans and in Native American and Alaskan Native communities, including the Navajo nation [923,924,925,926,927,928].
+In Brazil, indigenous communities likewise carry an increased burden of COVID-19 [929].
+In the United Kingdom, nonwhite ethnicity (principally Black or South Asian) was one of several factors found to be associated with a higher risk of death from COVID-19 [930].
From a genetic standpoint, it is highly unlikely that ancestry itself predisposes individuals to contracting COVID-19 or to experiencing severe COVID-19 outcomes.
-Examining human genetic diversity indicates variation over a geographic continuum, and that most human genetic variation is associated with the African continent [930].
-African-Americans are also a more genetically diverse group relative to European-Americans, with a large number of rare alleles and a much smaller fraction of common alleles identified in African-Americans [931].
-Therefore, the idea that African ancestry (at the continent level) might convey some sort of genetic risk for severe COVID-19 contrasts with what is known about worldwide human genetic diversity [932].
+Examining human genetic diversity indicates variation over a geographic continuum, and that most human genetic variation is associated with the African continent [931].
+African-Americans are also a more genetically diverse group relative to European-Americans, with a large number of rare alleles and a much smaller fraction of common alleles identified in African-Americans [932].
+Therefore, the idea that African ancestry (at the continent level) might convey some sort of genetic risk for severe COVID-19 contrasts with what is known about worldwide human genetic diversity [933].
The possibility for genetic variants that confer some risk or some protection remains possible, but has not been widely explored, especially at a global level.
-Research in Beijing of a small number (n=80) hospitalized COVID-19 patients revealed an association between severe COVID-19 outcomes and homozygosity for an allele in the interferon-induced transmembrane protein 3 (IFITM3) gene, which was selected as a candidate because it was previously found to be associated with influenza outcomes in Chinese patients [933].
-Genetic factors may also play a role in the risk of respiratory failure for COVID-19 [934,935,936].
+Research in Beijing of a small number (n=80) hospitalized COVID-19 patients revealed an association between severe COVID-19 outcomes and homozygosity for an allele in the interferon-induced transmembrane protein 3 (IFITM3) gene, which was selected as a candidate because it was previously found to be associated with influenza outcomes in Chinese patients [934].
+Genetic factors may also play a role in the risk of respiratory failure for COVID-19 [935,936,937].
However, genetic variants associated with outcomes within ancestral groups are far less surprising than genetic variants explaining outcomes between groups.
-Alleles in ACE2 and TMPRSS2 have been identified that vary in frequency among ancestral groups [937], but whether these variants are associated with COVID-19 susceptibility has not been explored.
+Alleles in ACE2 and TMPRSS2 have been identified that vary in frequency among ancestral groups [938], but whether these variants are associated with COVID-19 susceptibility has not been explored.
Instead, examining patterns of COVID-19 susceptibility on a global scale that suggest that social factors are of primary importance in predicting mortality.
Reports from several sub-Saharan African countries have indicated that the effects of the COVID-19 pandemic have been less severe than expected based on the outbreaks in China and Italy.
-In Kenya, for example, estimates of national prevalence based on testing blood donors for SARS-CoV-2 antibodies were consistent with 5% of Kenyan adults having recovered from COVID-19 [938].
-This high seroprevalence of antibodies lies in sharp contrast to the low number of COVID-19 fatalities in Kenya, which at the time was 71 out of 2093 known cases [938].
-Likewise, a serosurvey of health care workers in Blantyre City, Malawi reported an adjusted antibody prevalence of 12.3%, suggesting that the virus had been circulating more widely than thought and that the death rate was up eight times lower than models had predicted [939].
-While several possible hypotheses for the apparent reduced impact of COVID-19 on the African continent are being explored, such as young demographics in many places [940], these reports present a stark contrast to the severity of COVID-19 in Americans and Europeans of African descent.
-Additionally, ethnic minorities in the United Kingdom also tend to be younger than white British living in the same areas, yet the burden of COVID-19 is still more serious for minorities, especially people of Black Caribbean ancestry, both in absolute numbers and when controlling for age and location [941].
+In Kenya, for example, estimates of national prevalence based on testing blood donors for SARS-CoV-2 antibodies were consistent with 5% of Kenyan adults having recovered from COVID-19 [939].
+This high seroprevalence of antibodies lies in sharp contrast to the low number of COVID-19 fatalities in Kenya, which at the time was 71 out of 2093 known cases [939].
+Likewise, a serosurvey of health care workers in Blantyre City, Malawi reported an adjusted antibody prevalence of 12.3%, suggesting that the virus had been circulating more widely than thought and that the death rate was up eight times lower than models had predicted [940].
+While several possible hypotheses for the apparent reduced impact of COVID-19 on the African continent are being explored, such as young demographics in many places [941], these reports present a stark contrast to the severity of COVID-19 in Americans and Europeans of African descent.
+Additionally, ethnic minorities in the United Kingdom also tend to be younger than white British living in the same areas, yet the burden of COVID-19 is still more serious for minorities, especially people of Black Caribbean ancestry, both in absolute numbers and when controlling for age and location [942].
Furthermore, the groups in the United States and United Kingdom that have been identified as carrying elevated COVID-19 burden, namely Black American, indigenous American, and Black and South Asian British, are quite distinct in their position on the human ancestral tree.
What is shared across these groups is instead a history of disenfranchisement under colonialism and ongoing systematic racism.
-A large analysis of over 11,000 COVID-19 patients hospitalized in 92 hospitals across U.S. states revealed that Black patients were younger, more often female, more likely to be on Medicaid, more likely to have comorbidities, and came from neighborhoods identified as more economically deprived than white patients [893].
+A large analysis of over 11,000 COVID-19 patients hospitalized in 92 hospitals across U.S. states revealed that Black patients were younger, more often female, more likely to be on Medicaid, more likely to have comorbidities, and came from neighborhoods identified as more economically deprived than white patients [894].
This study reported that when these factors were accounted for, the differences in mortality between Black and white patients were no longer significant.
Thus, the current evidence suggests that the apparent correlations between ancestry and health outcomes must be examined in the appropriate social context.
8.3 Environmental Influences on Susceptibility
@@ -2906,83 +2907,83 @@ .
-A linear relationship was observed between counties’ reduction in mobility and their wealth and health, as measured by access to health care, food security, income, space, and other factors [942].
-Counties with greater reductions in mobility were also found to have much lower child poverty and household crowding and to be more racially segregated, and to have fewer youth and more elderly residents [942].
-Similar associations between wealth and decreased mobility were observed in cellphone GPS data from Colombia, Indonesia, and Mexico collected between January and May 2020 [943], as well as in a very large data set from several US cities [944].
+In U.S. counties with and without stay-at-home orders, smartphone tracking indicated a significant decrease in the general population’s mobility in April relative to February through March of 2020 (-52.3% and -60.8%, respectively) [943].
+A linear relationship was observed between counties’ reduction in mobility and their wealth and health, as measured by access to health care, food security, income, space, and other factors [943].
+Counties with greater reductions in mobility were also found to have much lower child poverty and household crowding and to be more racially segregated, and to have fewer youth and more elderly residents [943].
+Similar associations between wealth and decreased mobility were observed in cellphone GPS data from Colombia, Indonesia, and Mexico collected between January and May 2020 [944], as well as in a very large data set from several US cities [945].
These disparities in mobility are likely to be related to the role that essential workers have played during the pandemic.
-Essential workers are disproportionately likely to be female, people of color, immigrants, and to have an income below 200% of the poverty line [945].
-Black Americans in particular are over-represented among front-line workers and in professions where social distancing is infeasible [946].
-Health care work in particular presents an increased risk of exposure to SARS-CoV-2 [946,947,948,949,950].
-In the United Kingdom, (South) Asians are more likely than their white counterparts to be medical professionals [941], although BAME medical professionals are still disproportionately represented in the proportion of National Health Service staff deaths [951].
-Similar trends have been reported for nurses, especially nurses of color, in the United States [952].
-Furthermore, beyond the risks associated with work itself, use of public transportation may also impact COVID-19 risk [953].
+Essential workers are disproportionately likely to be female, people of color, immigrants, and to have an income below 200% of the poverty line [946].
+Black Americans in particular are over-represented among front-line workers and in professions where social distancing is infeasible [947].
+Health care work in particular presents an increased risk of exposure to SARS-CoV-2 [947,948,949,950,951].
+In the United Kingdom, (South) Asians are more likely than their white counterparts to be medical professionals [942], although BAME medical professionals are still disproportionately represented in the proportion of National Health Service staff deaths [952].
+Similar trends have been reported for nurses, especially nurses of color, in the United States [953].
+Furthermore, beyond the risks associated with work itself, use of public transportation may also impact COVID-19 risk [954].
The socioeconomic and racial/ethnic gaps in who is working on the front lines of the pandemic make it clear that socioeconomic privilege is likely to decrease the probability of exposure to SARS-CoV-2.
Increased risk of exposure can also arise outside the workplace.
-Nursing homes and skilled nursing facilities received attention early on as high-risk locations for COVID-19 outbreaks [954].
-Prisons and detention centers also confer a high risk of exposure or infection [955,956].
-Populations in care facilities are largely older adults, and in the United States, incarcerated people are more likely to be male and persons of color, especially Black [957].
-Additionally, multi-generational households are less common among non-Hispanic white Americans than people of other racial and ethnic backgrounds [958], increasing the risk of exposure for more susceptible family members.
-Analysis suggests that household crowding may also be associated with increased risk of COVID-19 exposure [942], and household crowding is associated with poverty [959].
-Forms of economic insecurity like housing insecurity, which is associated with poverty and more pronounced in communities subjected to racism [960,961], would be likely to increase household crowding and other possible sources of exposure.
+Nursing homes and skilled nursing facilities received attention early on as high-risk locations for COVID-19 outbreaks [955].
+Prisons and detention centers also confer a high risk of exposure or infection [956,957].
+Populations in care facilities are largely older adults, and in the United States, incarcerated people are more likely to be male and persons of color, especially Black [958].
+Additionally, multi-generational households are less common among non-Hispanic white Americans than people of other racial and ethnic backgrounds [959], increasing the risk of exposure for more susceptible family members.
+Analysis suggests that household crowding may also be associated with increased risk of COVID-19 exposure [943], and household crowding is associated with poverty [960].
+Forms of economic insecurity like housing insecurity, which is associated with poverty and more pronounced in communities subjected to racism [961,962], would be likely to increase household crowding and other possible sources of exposure.
As a result, facets of systemic inequality such as mass incarceration of Black Americans and poverty are likely to increase the risk of exposure outside of the workplace.
8.3.2 Severity of COVID-19 Following Exposure
Following exposure to SARS-CoV-2, the likelihood that an individual develops COVID-19 and the severity of the disease presentation can be influenced by a number of social factors.
As discussed above, a number of patient characteristics are associated with the likelihood of severe COVID-19 symptoms.
-In some cases, these trends run counter to those expected given rates of exposure: for example, although women are more likely to be exposed, men are more likely to be diagnosed with, hospitalized from, or die from COVID-19 [905].
+In some cases, these trends run counter to those expected given rates of exposure: for example, although women are more likely to be exposed, men are more likely to be diagnosed with, hospitalized from, or die from COVID-19 [906].
In the case of comorbid conditions and racial/ethnic demographics, however, social factors are highly likely to modulate or at least influence the apparent association between these traits and the increased risk from COVID-19.
In particular, the comorbidities and racial/ethnic correlates of severe COVID-19 outcomes suggest that poverty confers additional risk for COVID-19.
In order to explore the relationship between poverty and COVID-19 outcomes, it is necessary to consider how poverty impacts biology.
In particular, we focus on the United States and the United Kingdom.
-Comorbidities that increase risk for COVID-19, including obesity, type II diabetes, hypertension, and cardiovascular disease, are known to be intercorrelated [962].
-Metabolic conditions related to heightened inflammation, like obesity, type II diabetes, and hypertension, are more strongly associated with negative COVID-19 outcomes than other comorbid conditions, such as chronic heart disease [963].
+Comorbidities that increase risk for COVID-19, including obesity, type II diabetes, hypertension, and cardiovascular disease, are known to be intercorrelated [963].
+Metabolic conditions related to heightened inflammation, like obesity, type II diabetes, and hypertension, are more strongly associated with negative COVID-19 outcomes than other comorbid conditions, such as chronic heart disease [964].
As discussed above, dysregulated inflammation characteristic of cytokine release syndrome is one of the greatest concerns for COVID-19-related death.
-Therefore, it is possible that chronic inflammation characteristic of these metabolic conditions predisposes patients to COVID-19-related death [963].
-The association between these diseases and severe COVID-19 outcomes is a concern from a health equity perspective because poverty exposes people to “obesogenic” conditions [964] and is therefore unsurprisingly associated with higher incidence of obesity and associated disorders [965].
-Furthermore, cell phone GPS data suggests that lower socioeconomic status may also be associated with decreased access to healthy food choices during the COVID-19 pandemic [966,967], suggesting that health-related risk factors for COVID-19 may be exacerbated as the pandemic continues [968].
-Chronic inflammation is a known outcome of chronic stress (e.g., [969,970,971,972]).
-Therefore, the chronic stress of poverty is likely to influence health broadly (as summarized in [973]) and especially during the stress of the ongoing pandemic.
-A preprint [974] provided observational evidence that geographical areas in the United States that suffer from worse air pollution by fine particulate matter have also suffered more COVID-19 deaths per capita, after adjusting for demographic covariates.
-Although lack of individual-level exposure data and the impossibility of randomization make it difficult to elucidate the exact causal mechanism, this finding would be consistent with similar findings for all-cause mortality (e.g., [975]).
-Exposure to air pollution is associated with both poverty (e.g., [976]) and chronic inflammation [977].
-Other outcomes of environmental racism, such as the proximity of abandoned uranium mines to Navajo land, can also cause respiratory illnesses and other health issues [927].
-Similarly, preliminary findings indicate that nutritional status (e.g., vitamin D deficiency [719]) may be associated with COVID-19 outcomes, and reduced access to grocery stores and fresh food often co-occurs with environmental racism [927,978].
+Therefore, it is possible that chronic inflammation characteristic of these metabolic conditions predisposes patients to COVID-19-related death [964].
+The association between these diseases and severe COVID-19 outcomes is a concern from a health equity perspective because poverty exposes people to “obesogenic” conditions [965] and is therefore unsurprisingly associated with higher incidence of obesity and associated disorders [966].
+Furthermore, cell phone GPS data suggests that lower socioeconomic status may also be associated with decreased access to healthy food choices during the COVID-19 pandemic [967,968], suggesting that health-related risk factors for COVID-19 may be exacerbated as the pandemic continues [969].
+Chronic inflammation is a known outcome of chronic stress (e.g., [970,971,972,973]).
+Therefore, the chronic stress of poverty is likely to influence health broadly (as summarized in [974]) and especially during the stress of the ongoing pandemic.
+A preprint [975] provided observational evidence that geographical areas in the United States that suffer from worse air pollution by fine particulate matter have also suffered more COVID-19 deaths per capita, after adjusting for demographic covariates.
+Although lack of individual-level exposure data and the impossibility of randomization make it difficult to elucidate the exact causal mechanism, this finding would be consistent with similar findings for all-cause mortality (e.g., [976]).
+Exposure to air pollution is associated with both poverty (e.g., [977]) and chronic inflammation [978].
+Other outcomes of environmental racism, such as the proximity of abandoned uranium mines to Navajo land, can also cause respiratory illnesses and other health issues [928].
+Similarly, preliminary findings indicate that nutritional status (e.g., vitamin D deficiency [720]) may be associated with COVID-19 outcomes, and reduced access to grocery stores and fresh food often co-occurs with environmental racism [928,979].
Taken together, the evidence suggests that low-income workers who face greater exposure to SARS-CoV-2 due to their home or work conditions are also more likely to face environmental and social stressors associated with increased inflammation, and therefore with increased risk from COVID-19.
In particular, structural racism can play an important role on disease severity after SARS-CoV-2 exposure, due to consequences of racism which include an increased likelihood of poverty and its associated food and housing instability.
-COVID-19 can thus be considered a “syndemic”, or a synergistic interaction between several epidemics [979].
+COVID-19 can thus be considered a “syndemic”, or a synergistic interaction between several epidemics [980].
As a result, it is not surprising that people from minoritized backgrounds and/or with certain pre-existing conditions are more likely to suffer severe effects of COVID-19, but these “risk factors” are likely to be causally linked to poverty.
8.3.3 Access to Treatment
Finally, COVID-19 outcomes can be influenced by access to healthcare.
Receiving care for COVID-19 can, but does not always, include receiving a positive test for the SARS-CoV-2 virus.
-For example, it is common to see treatment guidelines for suspected cases regardless of whether the presence of SARS-CoV-2 has been confirmed (e.g., [980]).
+For example, it is common to see treatment guidelines for suspected cases regardless of whether the presence of SARS-CoV-2 has been confirmed (e.g., [981]).
Whether and where a patient is diagnosed can depend on their access to testing, which can vary both between and within countries.
-In the United States, it is not always clear whether an individual will have access to free testing [981,982].
-The concern has been raised that more economic privilege is likely to correspond to increased access to testing, at least within the United States [983].
-This is supported by the fact that African Americans seem to be more likely to be diagnosed in the hospital, while individuals from other groups were more likely to have been diagnosed in ambulatory settings in the community [898].
-Any delays in treatment are a cause for concern [983], which could potentially be increased by an inability to acquire testing because in the United States, insurance coverage for care received can depend on a positive test [984].
+In the United States, it is not always clear whether an individual will have access to free testing [982,983].
+The concern has been raised that more economic privilege is likely to correspond to increased access to testing, at least within the United States [984].
+This is supported by the fact that African Americans seem to be more likely to be diagnosed in the hospital, while individuals from other groups were more likely to have been diagnosed in ambulatory settings in the community [899].
+Any delays in treatment are a cause for concern [984], which could potentially be increased by an inability to acquire testing because in the United States, insurance coverage for care received can depend on a positive test [985].
Another important question is whether patients with moderate to severe cases are able to access hospital facilities and treatments, to the extent that they have been identified.
-Early findings from China as of February 2020 suggested the COVID-19 mortality rate to be much lower in the most developed regions of the country [985], although reported mortality is generally an estimate of CFR, which is dependent on rates of testing.
-Efforts to make treatment accessible for all confirmed and suspected cases of COVID-19 in China are credited with expanding care to people with fewer economic resources [986].
-In the United States, access to healthcare varies widely, with certain sectors of the workforce less likely to have health insurance; many essential workers in transportation, food service, and other frontline fields are among those likely to be uninsured or underinsured [983].
-As of 2018, Hispanic Americans of all races were much less likely to have health insurance than people from non-Hispanic backgrounds [987].
+Early findings from China as of February 2020 suggested the COVID-19 mortality rate to be much lower in the most developed regions of the country [986], although reported mortality is generally an estimate of CFR, which is dependent on rates of testing.
+Efforts to make treatment accessible for all confirmed and suspected cases of COVID-19 in China are credited with expanding care to people with fewer economic resources [987].
+In the United States, access to healthcare varies widely, with certain sectors of the workforce less likely to have health insurance; many essential workers in transportation, food service, and other frontline fields are among those likely to be uninsured or underinsured [984].
+As of 2018, Hispanic Americans of all races were much less likely to have health insurance than people from non-Hispanic backgrounds [988].
Therefore, access to diagnostics and care prior to the development of severe COVID-19 is likely to vary depending on socioeconomic and social factors, many of which overlap with the risks of exposure and of developing more severe COVID-19 symptoms.
This discrepancy ties into concerns about broad infrastructural challenges imposed by COVID-19.
-A major concern in many countries has been the saturation of healthcare systems due to the volume of COVID-19 hospitalizations (e.g., [240]).
-Similarly, there have been shortages of supplies such as ventilators that are critical to the survival of many COVID-19 patients, leading to extensive ethical discussions about how to allocate limited resources among patients [988,989,990,991].
-Although it is generally considered unethical to consider demographic factors such as age, sex, race, or ethnicity while making such decisions, and ideally this information would not be shared with triage teams tasked with allocating limited resources among patients [992], there are substantial concerns about implicit and explicit biases against older adults [993], premature infants [994], and people with disabilities or comorbidities [992,995,996].
-Because of the greater burden of chronic disease in populations subjected to systemic racism, algorithms intended to be blind to race and ethnicity could, in fact, reinforce systemic inequalities caused by structural racism [997,998,999].
-Because of this inequality, it has been argued that groups facing health disparities should be prioritized by these algorithms [1000].
-This approach would carry its own ethical concerns, including the fact that many resources that need to be distributed do not have well-established risks and benefits [1000].
-As the pandemic has progressed, it has become clear that ICU beds and ventilators are not the only limited resources that needs to be allocated, and, in fact, the survival rate for patients who receive mechanical ventilation is lower than these discussions would suggest [1001].
-Allocation of interventions that may reduce suffering, including palliative care, has become critically important [1001,1002].
-The ambiguities surrounding the risks and benefits associated with therapeutics that have been approved under emergency use authorizations also present ethical concerns related to the distribution of resources [1000].
-For example, remdesivir, discussed above, is currently available for the treatment of COVID-19 under compassionate use guidelines and through expanded access programs, and in many cases has been donated to hospitals by Gilead [1003,1004].
-Regulations guiding the distribution of drugs in situations like these typically do not address how to determine which patients receive them [1004].
-Prioritizing marginalized groups for treatment with a drug like remdesivir would also be unethical because it would entail disproportionately exposing these groups to a therapeutic that may or not be beneficial [1000].
+A major concern in many countries has been the saturation of healthcare systems due to the volume of COVID-19 hospitalizations (e.g., [242]).
+Similarly, there have been shortages of supplies such as ventilators that are critical to the survival of many COVID-19 patients, leading to extensive ethical discussions about how to allocate limited resources among patients [989,990,991,992].
+Although it is generally considered unethical to consider demographic factors such as age, sex, race, or ethnicity while making such decisions, and ideally this information would not be shared with triage teams tasked with allocating limited resources among patients [993], there are substantial concerns about implicit and explicit biases against older adults [994], premature infants [995], and people with disabilities or comorbidities [993,996,997].
+Because of the greater burden of chronic disease in populations subjected to systemic racism, algorithms intended to be blind to race and ethnicity could, in fact, reinforce systemic inequalities caused by structural racism [998,999,1000].
+Because of this inequality, it has been argued that groups facing health disparities should be prioritized by these algorithms [1001].
+This approach would carry its own ethical concerns, including the fact that many resources that need to be distributed do not have well-established risks and benefits [1001].
+As the pandemic has progressed, it has become clear that ICU beds and ventilators are not the only limited resources that needs to be allocated, and, in fact, the survival rate for patients who receive mechanical ventilation is lower than these discussions would suggest [1002].
+Allocation of interventions that may reduce suffering, including palliative care, has become critically important [1002,1003].
+The ambiguities surrounding the risks and benefits associated with therapeutics that have been approved under emergency use authorizations also present ethical concerns related to the distribution of resources [1001].
+For example, remdesivir, discussed above, is currently available for the treatment of COVID-19 under compassionate use guidelines and through expanded access programs, and in many cases has been donated to hospitals by Gilead [1004,1005].
+Regulations guiding the distribution of drugs in situations like these typically do not address how to determine which patients receive them [1005].
+Prioritizing marginalized groups for treatment with a drug like remdesivir would also be unethical because it would entail disproportionately exposing these groups to a therapeutic that may or not be beneficial [1001].
On the other hand, given that the drug is one of the most promising treatments available for many patients, using a framework that tacitly feeds into structural biases would also be unethical.
-At present, the report prepared for the Director of the CDC by Ethics Subcommittee of the CDC fails to address the complexity of this ethical question given the state of structural racism in the United States, instead stating that “prioritizing individuals according to their chances for short-term survival also avoids ethically irrelevant considerations, such as race or socioeconomic status” [1005].
-In many cases, experimental therapeutics are made available only through participation in clinical trials [1006].
-However, given the history of medical trials abusing minority communities, especially Black Americans, there is a history of unequal representation in clinical trial enrollment [1006].
+At present, the report prepared for the Director of the CDC by Ethics Subcommittee of the CDC fails to address the complexity of this ethical question given the state of structural racism in the United States, instead stating that “prioritizing individuals according to their chances for short-term survival also avoids ethically irrelevant considerations, such as race or socioeconomic status” [1006].
+In many cases, experimental therapeutics are made available only through participation in clinical trials [1007].
+However, given the history of medical trials abusing minority communities, especially Black Americans, there is a history of unequal representation in clinical trial enrollment [1007].
As a result, the standard practice of requiring enrollment in a clinical trial in order to receive experimental treatment may also reinforce patterns established by systemic racism.
8.3.4 Access to and Representation in Clinical Trials
@@ -2999,7 +3000,7 @@ [1007]
.
+The WHO Director‐General Tedros Adhanom Ghebreyesus stated his condemnation of utilizing low and middle income countries as test subjects for clinical trials, yet having highly developed countries as the majority of clinical trial representation is also not the answer [1008].
Figure 6 showcases two choropleths detailing COVID-19 clinical trial recruitment by country.
China, the United States, and France are among the countries with the most clinical trial recruiting for trials with single-country enrollment.
Many countries have little to no clinical trial recruiting, with the continents of Africa and South America much less represented than Asia, Europe, and North America.
@@ -3008,46 +3009,46 @@
Figure 6: Geographic distribution of COVID-19 clinical trials.
The density of clinical trials is reported at the country level.
-As of November 9, 2020, there are 6,417 trials in the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [371].
+As of November 9, 2020, there are 6,417 trials in the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [372].
The top figure demonstrates the density of trials recruiting only from a singular country, while the bottom shows the distribution of recruitment for trials that involve more than one country.
A few different concerns arise from this skewed geographic representation in clinical trial recruitment.
First, treatments such as remdesivir that are promising but primarily available to clinical trial participants are unlikely to be accessible by people in many countries.
Second, it raises the concern that the findings of clinical trials will be based on participants from many of the wealthiest countries, which may lead to ambiguity in whether the findings can be extrapolated to COVID-19 patients elsewhere.
-Especially with the global nature of COVID-19, equitable access to therapeutics and vaccines has been a concern at the forefront of many discussions about policy (e.g., [1008], yet data like that shown in Figure 6 demonstrates that accessibility is likely to be a significant issue.
-Another concern with the heterogeneous international distribution of clinical trials is that the governments of countries leading these clinical trials might prioritize their own populations once vaccines are developed, causing unequal health outcomes [1009].
-Additionally, even within a single state in the United States (Maryland), geography was found to influence the likelihood of being recruited into or enrolled in a clinical trial, with patients in under-served rural areas less likely to enroll [1010].
+Especially with the global nature of COVID-19, equitable access to therapeutics and vaccines has been a concern at the forefront of many discussions about policy (e.g., [1009], yet data like that shown in Figure 6 demonstrates that accessibility is likely to be a significant issue.
+Another concern with the heterogeneous international distribution of clinical trials is that the governments of countries leading these clinical trials might prioritize their own populations once vaccines are developed, causing unequal health outcomes [1010].
+Additionally, even within a single state in the United States (Maryland), geography was found to influence the likelihood of being recruited into or enrolled in a clinical trial, with patients in under-served rural areas less likely to enroll [1011].
Thus, geography both on the global and local levels may influence when treatments and vaccines are available and who is able to access them.
-Efforts such as the African Union’s efforts to coordinate and promote vaccine development [1011] are therefore critical to promoting equity in the COVID-19 response.
+Efforts such as the African Union’s efforts to coordinate and promote vaccine development [1012] are therefore critical to promoting equity in the COVID-19 response.
Even when patients are located within the geographic recruitment area of clinical trials, however, there can still be demographic inequalities in enrollment.
-When efforts are made to ensure equal opportunity to participate in clinical trials, there is no significant difference in participation among racial/ethnic groups [1012].
-However, within the United States, real clinical trial recruitment numbers have indicated for many years that racial minorities, especially African-Americans, tend to be under-represented (e.g., [1013,1014,1015,1016]).
+When efforts are made to ensure equal opportunity to participate in clinical trials, there is no significant difference in participation among racial/ethnic groups [1013].
+However, within the United States, real clinical trial recruitment numbers have indicated for many years that racial minorities, especially African-Americans, tend to be under-represented (e.g., [1014,1015,1016,1017]).
This trend is especially concerning given the disproportionate impact of COVID-19 on African-Americans.
-Early evidence suggests that the proportion of Black, Latinx, and Native American participants in clinical trials for drugs such as remdesivir is much lower than the representation of these groups among COVID-19 patients [1017].
+Early evidence suggests that the proportion of Black, Latinx, and Native American participants in clinical trials for drugs such as remdesivir is much lower than the representation of these groups among COVID-19 patients [1018].
One proposed explanation for differences among racial and ethnic groups in clinical trial enrollment refers to different experiences in healthcare settings.
-While some plausible reasons for the disparity in communication between physicians and patients could be a lack of awareness and education, mistrust in healthcare professionals, and a lack of health insurance [1012], a major concern is that patients from certain racial and ethnic groups are marginalized even while seeking healthcare.
-In the United States, many patients experience “othering” from physicians and other medical professionals due to their race or other external characteristics such as gender (e.g., [1018]).
+While some plausible reasons for the disparity in communication between physicians and patients could be a lack of awareness and education, mistrust in healthcare professionals, and a lack of health insurance [1013], a major concern is that patients from certain racial and ethnic groups are marginalized even while seeking healthcare.
+In the United States, many patients experience “othering” from physicians and other medical professionals due to their race or other external characteristics such as gender (e.g., [1019]).
Many studies have sought to characterize implicit biases in healthcare providers and whether they affect their perceptions or treatment of patients.
-A systematic review that examined 37 such studies reported that most (31) identified racial and/or ethnic biases in healthcare providers in many different roles, although the evidence about whether these biases translated to different attitudes towards patients was mixed [1019], with similar findings reported by a second systematic review [1020].
-However, data about real-world patient outcomes are very limited, with most studies relying on clinical vignette-based exercises [1019], and other analyses suggest that physician implicit bias could impact the patient’s perception of the negativity/positivity of the interaction regardless of the physician’s explicit behavior towards the patient [1021].
-Because racism is a common factor in both, negative patient experiences with medical professionals are likely to compound other issues of systemic inequality, such as a lack of access to adequate care, a lack of insurance, or increased exposure to SARS-CoV-2 [1022].
+A systematic review that examined 37 such studies reported that most (31) identified racial and/or ethnic biases in healthcare providers in many different roles, although the evidence about whether these biases translated to different attitudes towards patients was mixed [1020], with similar findings reported by a second systematic review [1021].
+However, data about real-world patient outcomes are very limited, with most studies relying on clinical vignette-based exercises [1020], and other analyses suggest that physician implicit bias could impact the patient’s perception of the negativity/positivity of the interaction regardless of the physician’s explicit behavior towards the patient [1022].
+Because racism is a common factor in both, negative patient experiences with medical professionals are likely to compound other issues of systemic inequality, such as a lack of access to adequate care, a lack of insurance, or increased exposure to SARS-CoV-2 [1023].
Furthermore, the experience of being othered is not only expected to impact patients’ trust in and comfort with their provider, but also may directly impact whether or not the patient is offered the opportunity to participate in a clinical trial at all.
Some studies suggest communication between physicians and patients impacts whether or not a physician offers a patient participation in a clinical trial.
-For example, researchers utilized a linguistic analysis to assess mean word count of phrases related to clinical trial enrollment, such as voluntary participation, clinical trial, etc. [1012].
+For example, researchers utilized a linguistic analysis to assess mean word count of phrases related to clinical trial enrollment, such as voluntary participation, clinical trial, etc. [1013].
The data indicated that the mean word count of the entire visit was 1.5 times more for white patients in comparison to Black patients.
-In addition, the greatest disparity between white and Black patients’ experience was the discussion of risks, with over 2 times as many risk-related words spoken with white patients than Black patients [1012].
+In addition, the greatest disparity between white and Black patients’ experience was the discussion of risks, with over 2 times as many risk-related words spoken with white patients than Black patients [1013].
The trends observed for other clinical trials raise the concern that COVID-19 clinical trial information may not be discussed as thoroughly or as often with Black patients compared to white patients.
These discrepancies are especially concerning given that many COVID-19 treatments are being or are considered being made available to patients prior to FDA approval through Emergency Use Authorizations.
-In the past, African-Americans have been over-represented relative to national demographics in use of the FDA’s Exception From Informed Consent (EFIC) pathway [1023].
+In the past, African-Americans have been over-represented relative to national demographics in use of the FDA’s Exception From Informed Consent (EFIC) pathway [1024].
Through this pathway, people who are incapacitated can receive an experimental treatment even if they are not able to consent and there is not sufficient time to seek approval from an authorized representative.
-This pathway presents concerns, however, when it is considered in the context of a long history of systematic abuses in medical experimentation where informed consent was not obtained from people of color, such as the Tuskegee syphilis experiments [1024].
+This pathway presents concerns, however, when it is considered in the context of a long history of systematic abuses in medical experimentation where informed consent was not obtained from people of color, such as the Tuskegee syphilis experiments [1025].
While the goal of EFIC approval is to provide treatment to patients who urgently need it, the combination of the ongoing legacy of racism in medicine renders this trend concerning.
-With COVID-19, efforts to prioritize people who suffer from systemic racism are often designed with the goal of righting some of these inequalities (e.g., [1025]), but particular attention to informed consent will be imperative in ensuring these trials are ethical given that the benefits and risks of emerging treatments are still poorly characterized.
+With COVID-19, efforts to prioritize people who suffer from systemic racism are often designed with the goal of righting some of these inequalities (e.g., [1026]), but particular attention to informed consent will be imperative in ensuring these trials are ethical given that the benefits and risks of emerging treatments are still poorly characterized.
Making a substantial effort to run inclusive clinical trials is also important because of the possibility that racism could impact how a patient responds to a treatment.
For example, as discussed above, dexamethasone has been identified as a promising treatment for patients experiencing cytokine release syndrome, but the mechanism of action is tied to the stress response.
-A study from 2005 reported that Black asthma patients showed reduced responsiveness to dexamethasone in comparison to white patients and suggested Black patients might therefore require higher doses of the drug [1026].
-In the context of chronic stress caused by systemic racism, this result is not surprising: chronic stress is associated with dysregulated production of glucocorticoids [1027] and glucocorticoid receptor resistance [1028].
+A study from 2005 reported that Black asthma patients showed reduced responsiveness to dexamethasone in comparison to white patients and suggested Black patients might therefore require higher doses of the drug [1027].
+In the context of chronic stress caused by systemic racism, this result is not surprising: chronic stress is associated with dysregulated production of glucocorticoids [1028] and glucocorticoid receptor resistance [1029].
However, it underscores the critical need for treatment guidelines to take into account differences in life experience, which would be facilitated by the recruitment of patients from a wide range of backgrounds.
Attention to the social aspects of clinical trial enrollment must therefore be an essential component of the medical research community’s response to COVID-19.
-Our primary goal is to sort and distill informative content out of the overwhelming flood of information [5] and help the broader scientific community become more conversant on this critical subject.
+Our primary goal is to sort and distill informative content out of the overwhelming flood of information [7] and help the broader scientific community become more conversant on this critical subject.
Thus, our approach has been to develop a real-time, collaborative effort that welcomes submissions from scientists worldwide into this ongoing effort.
This document represents the first snapshot, which aims to reflect the state of the field as of October, 2020.
We plan to refine and expand this document until technologies to mitigate the pandemic are widely available.
-In an effort to keep pace as new information about COVID-19 and SARS-CoV-2 becomes available, this project is an open, collaborative effort that invited contributions from the scientific community broadly, similar to previous efforts to develop collaborative reviews [1029,1030].
+
In an effort to keep pace as new information about COVID-19 and SARS-CoV-2 becomes available, this project is an open, collaborative effort that invited contributions from the scientific community broadly, similar to previous efforts to develop collaborative reviews [1030,1031].
Contributors were recruited by word of mouth and on Twitter.
-Existing efforts to train early-career scientists were also integrated: Appendix A contains summaries written by the students, post-docs, and faculty of the Immunology Institute at the Mount Sinai School of Medicine [1031,1032], and two of the authors were recruited through the American Physician Scientist Association’s Virtual Summer Research Program [1033].
-The project was managed through GitHub [1034] using Manubot [6] to continuously generate a version of the manuscript online [1035].
+Existing efforts to train early-career scientists were also integrated: Appendix A contains summaries written by the students, post-docs, and faculty of the Immunology Institute at the Mount Sinai School of Medicine [1032,1033], and two of the authors were recruited through the American Physician Scientist Association’s Virtual Summer Research Program [1034].
+The project was managed through GitHub [1035] using Manubot [8] to continuously generate a version of the manuscript online [1036].
Contributors developed text that was proposed through GitHub’s pull request system and then reviewed and approved by at least one other author.
While this document reflects the current version of record, the online version will continue to be developed as information about the pandemic emerges.
Below, we will describe the processes used to synthesize the literature.
10.3 Technical Infrastructure
10.3.1 Collaborative Writing and Manuscript Generation
-Manubot [6] is a collaborative framework developed to adapt open-source software development techniques and version control for manuscript writing.
+
Manubot [8] is a collaborative framework developed to adapt open-source software development techniques and version control for manuscript writing.
Here, Manubot was used to generate a manuscript from text maintained using GitHub, a popular, online version control interface.
The GitHub implementation allowed users to contribute either using git on the command line or using the GitHub user interface, and we developed documentation for users with less experience with this platform.
Manubot also provides a functionality to create a bibliography using digital object identifiers (DOIs), website URLs, or other identifiers such as PubMed identifiers and arXiv IDs.
Due to the needs of this project, project contributors also implemented new features in Manubot and Zotero, which Manubot uses to extract metadata for some types of citations.
-These features support directly citing clinical trial identifiers such as clinicaltrials:NCT04292899 [399] and generating the complete review manuscript along with the individual manuscripts reviewing specific topics.
+These features support directly citing clinical trial identifiers such as clinicaltrials:NCT04292899 [400] and generating the complete review manuscript along with the individual manuscripts reviewing specific topics.
Finally, Manubot and GitHub Actions continuous integration allowed for scripted updates to be run each time the manuscript was generated.
These scripts were used to check that the manuscript was built correctly, run spellchecking, and cross-reference the manuscripts cited in this review, summarized in Appendix A, and discussed in the project’s issues and pull requests.
10.3.2 Data Analysis and Visualization
The combination of Manubot and GitHub Actions also made it possible to dynamically update information such as statistics and visualizations in the manuscript.
-Data about worldwide cases and deaths from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [368] were read using a Python script.
-Similarly, the clinical trials statistics and figure were generated based on data from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [371].
-In both cases, frequency data were plotted using Matplotlib [1036] in Python.
+Data about worldwide cases and deaths from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [369] were read using a Python script.
+Similarly, the clinical trials statistics and figure were generated based on data from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [372].
+In both cases, frequency data were plotted using Matplotlib [1037] in Python.
The figure showing the geographic distribution of COVID-19 clinical trials was generated using the countries associated with the trials listed in the COVID-19 TrialsTracker, converting the country names to 3-letter ISO codes using pycountry or manual adjustment when necessary, and visualizing the geographic distribution of trial recruitment using geopandas.
GitHub Actions runs a nightly workflow to update these external data and regenerate the statistics and figures for the manuscript.
The workflow uses the GitHub API to detect and save the latest commit of the external data sources, which are both GitHub repositories.
@@ -3202,7 +3203,7 @@
10.4 Article Selection and Evaluation
Relevant articles were identified and submitted as issues on GitHub for review.
Articles were classified as diagnostic, therapeutic, or other, and a template was developed to guide the review of papers and preprints in each category.
-Following a framework often used for assessing medical literature, the review consisted of examining methods used in each relevant article, assignment (whether the study was observational or randomized), assessment, results, interpretation, and how well the study extrapolates [1037].
+Following a framework often used for assessing medical literature, the review consisted of examining methods used in each relevant article, assignment (whether the study was observational or randomized), assessment, results, interpretation, and how well the study extrapolates [1038].
For examples of each template, please see Appendices B-D.
10.4.1 Diagnostic Papers
10.4.1.1 Methods
@@ -3245,15 +3246,15 @@ 10.4.2.6 Extrapolation
Reviewers describe how the study may extrapolate to a different species or population.
-10.5 Conclusions
+10.5 Conclusions
Figure 7: Summary of the relationships among topics covered in this review.
Several review articles on aspects of COVID-19 have already been published.
-These have included reviews on the disease epidemiology [38], immunological response [39], diagnostics [40], and pharmacological treatments [39,41].
-Others [42,43] provide narrative reviews of progress on some important ongoing COVID-19 research questions.
+These have included reviews on the disease epidemiology [40], immunological response [41], diagnostics [42], and pharmacological treatments [41,43].
+Others [44,45] provide narrative reviews of progress on some important ongoing COVID-19 research questions.
With the worldwide scientific community uniting during 2020 to investigate SARS-CoV-2 and COVID-19 from a wide range of perspectives, findings from many disciplines are relevant on a rapid timescale to a broad scientific audience.
Additionally, many findings are published as preprints, which are available prior to going through the peer review process.
As a result, centralizing, summarizing, and critiquing new literature broadly relevant to COVID-19 can help to expedite the interdisciplinary scientific process that is currently happening at an advanced pace.
@@ -3724,6631 +3725,6636 @@
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886. A Randomized Clinical Trial for Enhanced Trained Immune Responses Through Bacillus Calmette-Guérin Vaccination to Prevent Infections by COVID-19: The ACTIVATE II Trial
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Martha I. Huizar, Ross Arena, Deepika R. Laddu
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978. Early life stress, air pollution, inflammation, and disease: An integrative review and immunologic model of social-environmental adversity and lifespan health
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980. Systemic racism, chronic health inequities, and ‐19: A syndemic in the making?
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984. COVID-19 and racial disparities
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986. Potential association between COVID-19 mortality and health-care resource availability
Yunpeng Ji, Zhongren Ma, Maikel P Peppelenbosch, Qiuwei Pan
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987. Combating COVID-19: health equity matters
Zhicheng Wang, Kun Tang
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Dumache Raluca, Ciocan Veronica, Muresan Camelia Oana, Enache Alexandra
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John Raffensperger, Marygail Brauner, R. Briggs
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Parag A. Pathak, Tayfun Sönmez, M. Utku Ünver, M. Bumin Yenmez
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Quyen Chu, Ricardo Correa, Tracey L. Henry, Kyle A. McGregor, Hanni Stoklosa, Loren Robinson, Sachin Jha, Alagappan Annamalai, Benson S. Hsu, Rohit Gupta, … SreyRam Kuy
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1001. Allocating Remdesivir Under Scarcity: Social Justice or More Systemic Racism
Eli Weber, Mark J. Bliton
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Titilola Falasinnu, Yashaar Chaichian, Michelle B. Bass, Julia F. Simard
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Joy L. Johnson, Joan L. Bottorff, Annette J. Browne, Sukhdev Grewal, B. Ann Hilton, Heather Clarke
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Ivy W. Maina, Tanisha D. Belton, Sara Ginzberg, Ajit Singh, Tiffani J. Johnson
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Louis A. Penner, John F. Dovidio, Tessa V. West, Samuel L. Gaertner, Terrance L. Albrecht, Rhonda K. Dailey, Tsveti Markova
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-1022. Intersection of Bias, Structural Racism, and Social Determinants With Health Care Inequities
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Tiffani J. Johnson
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-1023. A Systematic Review Of The Food And Drug Administration’s “Exception From Informed Consent” Pathway
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1024. A Systematic Review Of The Food And Drug Administration’s “Exception From Informed Consent” Pathway
William B. Feldman, Spencer Phillips Hey, Aaron S. Kesselheim
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-1025. CDC officials are considering a plan to distribute COVID-19 vaccines to the most vulnerable first — including people of color
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1026. CDC officials are considering a plan to distribute COVID-19 vaccines to the most vulnerable first — including people of color
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Monica J. Federico, Ronina A. Covar, Eleanor E. Brown, Donald Y. M. Leung, Joseph D. Spahn
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1028. ENDOCRINOLOGY OF THE STRESS RESPONSE
Evangelia Charmandari, Constantine Tsigos, George Chrousos
Annual Review of Physiology (2005-03-17) https://doi.org/brcm9n
DOI: 10.1146/annurev.physiol.67.040403.120816 · PMID: 15709959
-1028. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk
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1029. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk
S. Cohen, D. Janicki-Deverts, W. J. Doyle, G. E. Miller, E. Frank, B. S. Rabin, R. B. Turner
Proceedings of the National Academy of Sciences (2012-04-02) https://doi.org/f4n6r8
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-1029. Opportunities and obstacles for deep learning in biology and medicine
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1030. Opportunities and obstacles for deep learning in biology and medicine
Travers Ching, Daniel S. Himmelstein, Brett K. Beaulieu-Jones, Alexandr A. Kalinin, Brian T. Do, Gregory P. Way, Enrico Ferrero, Paul-Michael Agapow, Michael Zietz, Michael M. Hoffman, … Casey S. Greene
Journal of The Royal Society Interface (2018-04-04) https://doi.org/gddkhn
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-1030. Opportunities and obstacles for deep learning in biology and medicine [update in progress]
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1031. Opportunities and obstacles for deep learning in biology and medicine [update in progress]
Casey S. Greene, Daniel S. Himmelstein, Daniel C. Elton, Brock C. Christensen, Anthony Gitter, Alexander J. Titus, Joshua J. Levy
Manubot (2020-11-10) https://greenelab.github.io/deep-review/
-1031. ismms-himc/covid-19_sinai_reviews
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1032. ismms-himc/covid-19_sinai_reviews
Human Immune Monitoring Center at Mount Sinai
(2020-07-09) https://github.com/ismms-himc/covid-19_sinai_reviews
-1032. Advancing scientific knowledge in times of pandemics
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1033. Advancing scientific knowledge in times of pandemics
Nicolas Vabret, Robert Samstein, Nicolas Fernandez, Miriam Merad, The Sinai Immunology Review Project, Trainees, Faculty
Nature Reviews Immunology (2020-04-23) https://doi.org/ghjs79
DOI: 10.1038/s41577-020-0319-0 · PMID: 32327718 · PMCID: PMC7187143
-1033. Undergraduate Mentoring - American Physician Scientists Association https://www.physicianscientists.org/page/summer-research-pilot-program
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-1034. greenelab/covid19-review
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1035. greenelab/covid19-review
Greene Laboratory
(2021-02-08) https://github.com/greenelab/covid19-review
-1035. SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics
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1036. SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics
Halie M. Rando, Casey S. Greene, Michael P. Robson, Simina M. Boca, Nils Wellhausen, Ronan Lordan, Christian Brueffer, Sandipan Ray, Lucy D\’Agostino McGowan, Anthony Gitter, … Rishi Raj Goel
Manubot (2021-02-08) https://greenelab.github.io/covid19-review/
-1036. Matplotlib: A 2D Graphics Environment
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John D. Hunter
Computing in Science & Engineering (2007) https://doi.org/drbjhg
DOI: 10.1109/mcse.2007.55
-1037. Using the MAARIE Framework To Read the Research Literature
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1038. Using the MAARIE Framework To Read the Research Literature
M. Corcoran
American Journal of Occupational Therapy (2006-07-01) https://doi.org/bqh97x
DOI: 10.5014/ajot.60.4.367 · PMID: 16915865
-1038. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody
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1039. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody
Xiaolong Tian, Cheng Li, Ailing Huang, Shuai Xia, Sicong Lu, Zhengli Shi, Lu Lu, Shibo Jiang, Zhenlin Yang, Yanling Wu, Tianlei Ying
Cold Spring Harbor Laboratory (2020-01-28) https://doi.org/ggjqfd
DOI: 10.1101/2020.01.28.923011
-1039. Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of 2019-nCoV
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1040. Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of 2019-nCoV
Xiang He, Lei Zhang, Qin Ran, Junyi Wang, Anying Xiong, Dehong Wu, Feng Chen, Guoping Li
Cold Spring Harbor Laboratory (2020-02-05) https://doi.org/ggrbd8
DOI: 10.1101/2020.02.03.20020206
-1040. Diarrhea may be underestimated: a missing link in 2019 novel coronavirus
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1041. Diarrhea may be underestimated: a missing link in 2019 novel coronavirus
Weicheng Liang, Zhijie Feng, Shitao Rao, Cuicui Xiao, Ze-Xiao Lin, Qi Zhang, Qi Wei
Cold Spring Harbor Laboratory (2020-02-17) https://doi.org/ggrbdw
DOI: 10.1101/2020.02.03.20020289
-1041. Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection
+
1042. Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection
Xiaoqiang Chai, Longfei Hu, Yan Zhang, Weiyu Han, Zhou Lu, Aiwu Ke, Jian Zhou, Guoming Shi, Nan Fang, Jia Fan, … Fei Lan
Cold Spring Harbor Laboratory (2020-02-04) https://doi.org/ggq626
DOI: 10.1101/2020.02.03.931766
-1042. Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids
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1043. Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids
Bing Zhao, Chao Ni, Ran Gao, Yuyan Wang, Li Yang, Jinsong Wei, Ting Lv, Jianqing Liang, Qisheng Zhang, Wei Xu, … Xinhua Lin
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq648
DOI: 10.1101/2020.03.16.990317
-1043. ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism
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1044. ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism
Jun Wang, Shanmeizi Zhao, Ming Liu, Zhiyao Zhao, Yiping Xu, Ping Wang, Meng Lin, Yanhui Xu, Bing Huang, Xiaoyu Zuo, … Yuxia Zhang
Cold Spring Harbor Laboratory (2020-02-07) https://doi.org/ggrfbx
DOI: 10.1101/2020.02.05.20020545
-1044. The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice
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1045. The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice
Linlin Bao, Wei Deng, Baoying Huang, Hong Gao, Jiangning Liu, Lili Ren, Qiang Wei, Pin Yu, Yanfeng Xu, Feifei Qi, … Chuan Qin
Cold Spring Harbor Laboratory (2020-02-28) https://doi.org/dph2
DOI: 10.1101/2020.02.07.939389
-1045. Caution on Kidney Dysfunctions of COVID-19 Patients
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1046. Caution on Kidney Dysfunctions of COVID-19 Patients
Zhen Li, Ming Wu, Jiwei Yao, Jie Guo, Xiang Liao, Siji Song, Jiali Li, Guangjie Duan, Yuanxiu Zhou, Xiaojun Wu, … Junan Yan
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq627
DOI: 10.1101/2020.02.08.20021212
-1046. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome
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1047. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome
Kwok Hong Chu, Wai Kay Tsang, Colin S. Tang, Man Fai Lam, Fernand M. Lai, Ka Fai To, Ka Shun Fung, Hon Lok Tang, Wing Wa Yan, Hilda W. H. Chan, … Kar Neng Lai
Kidney International (2005-02) https://doi.org/b7tgtx
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-1047. Single-cell Analysis of ACE2 Expression in Human Kidneys and Bladders Reveals a Potential Route of 2019-nCoV Infection
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1048. Single-cell Analysis of ACE2 Expression in Human Kidneys and Bladders Reveals a Potential Route of 2019-nCoV Infection
Wei Lin, Longfei Hu, Yan Zhang, Joshua D. Ooi, Ting Meng, Peng Jin, Xiang Ding, Longkai Peng, Lei Song, Zhou Xiao, … Yong Zhong
Cold Spring Harbor Laboratory (2020-02-18) https://doi.org/ggq629
DOI: 10.1101/2020.02.08.939892
-1048. The immune vulnerability landscape of the 2019 Novel Coronavirus, SARS-CoV-2
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1049. The immune vulnerability landscape of the 2019 Novel Coronavirus, SARS-CoV-2
James Zhu, Jiwoong Kim, Xue Xiao, Yunguan Wang, Danni Luo, Shuang Jiang, Ran Chen, Lin Xu, He Zhang, Lenny Moise, … Yang Xie
Cold Spring Harbor Laboratory (2020-09-04) https://doi.org/ggq628
DOI: 10.1101/2020.02.08.939553 · PMID: 32908981
-1049. Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection
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1050. Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection
Yaseen M. Arabi, Ahmed A. Arifi, Hanan H. Balkhy, Hani Najm, Abdulaziz S. Aldawood, Alaa Ghabashi, Hassan Hawa, Adel Alothman, Abdulaziz Khaldi, Basel Al Raiy
Annals of Internal Medicine (2014-03-18) https://doi.org/ggptxw
DOI: 10.7326/m13-2486 · PMID: 24474051
-1050. Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage
+
1051. Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage
Jingyuan Liu, Yao Liu, Pan Xiang, Lin Pu, Haofeng Xiong, Chuansheng Li, Ming Zhang, Jianbo Tan, Yanli Xu, Rui Song, … Xianbo Wang
Cold Spring Harbor Laboratory (2020-02-12) https://doi.org/ggrbdx
DOI: 10.1101/2020.02.10.20021584
-1051. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China
+
1052. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China
Chuan Qin, Luoqi Zhou, Ziwei Hu, Shuoqi Zhang, Sheng Yang, Yu Tao, Cuihong Xie, Ke Ma, Ke Shang, Wei Wang, Dai-Shi Tian
Clinical Infectious Diseases (2020-08-01) https://doi.org/ggpxcf
DOI: 10.1093/cid/ciaa248 · PMID: 32161940 · PMCID: PMC7108125
-1052. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)
+
1053. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)
Suxin Wan, Qingjie Yi, Shibing Fan, Jinglong Lv, Xianxiang Zhang, Lian Guo, Chunhui Lang, Qing Xiao, Kaihu Xiao, Zhengjun Yi, … Yongping Chen
Cold Spring Harbor Laboratory (2020-02-12) https://doi.org/ggq63b
DOI: 10.1101/2020.02.10.20021832
-1053. Longitudinal Characteristics of Lymphocyte Responses and Cytokine Profiles in the Peripheral Blood of SARS-CoV-2 Infected Patients
+
1054. Longitudinal Characteristics of Lymphocyte Responses and Cytokine Profiles in the Peripheral Blood of SARS-CoV-2 Infected Patients
Jing Liu, Sumeng Li, Jia Liu, Boyun Liang, Xiaobei Wang, Wei Li, Hua Wang, Qiaoxia Tong, Jianhua Yi, Lei Zhao, … Xin Zheng
SSRN Electronic Journal (2020) https://doi.org/ggq655
DOI: 10.2139/ssrn.3539682
-1054. Epidemiological and Clinical Characteristics of 17 Hospitalized Patients with 2019 Novel Coronavirus Infections Outside Wuhan, China
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1055. Epidemiological and Clinical Characteristics of 17 Hospitalized Patients with 2019 Novel Coronavirus Infections Outside Wuhan, China
Jie Li, Shilin Li, Yurui Cai, Qin Liu, Xue Li, Zhaoping Zeng, Yanpeng Chu, Fangcheng Zhu, Fanxin Zeng
Cold Spring Harbor Laboratory (2020-02-12) https://doi.org/ggq63c
DOI: 10.1101/2020.02.11.20022053
-1055. ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection
+
1056. ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection
Caibin Fan, Kai Li, Yanhong Ding, Wei Lu, Jianqing Wang
Cold Spring Harbor Laboratory (2020-02-13) https://doi.org/ggq63d
DOI: 10.1101/2020.02.12.20022418
-1056. Aberrant pathogenic GM-CSF + T cells and inflammatory CD14 + CD16 + monocytes in severe pulmonary syndrome patients of a new coronavirus
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1057. Aberrant pathogenic GM-CSF + T cells and inflammatory CD14 + CD16 + monocytes in severe pulmonary syndrome patients of a new coronavirus
Yonggang Zhou, Binqing Fu, Xiaohu Zheng, Dongsheng Wang, Changcheng Zhao, Yingjie qi, Rui Sun, Zhigang Tian, Xiaoling Xu, Haiming Wei
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggq63f
DOI: 10.1101/2020.02.12.945576
-1057. Clinical Characteristics of 2019 Novel Infected Coronavirus Pneumonia: A Systemic Review and Meta-analysis
+
1058. Clinical Characteristics of 2019 Novel Infected Coronavirus Pneumonia: A Systemic Review and Meta-analysis
Kai Qian, Yi Deng, Yong-Hang Tai, Jun Peng, Hao Peng, Li-Hong Jiang
Cold Spring Harbor Laboratory (2020-02-17) https://doi.org/ggrgbq
DOI: 10.1101/2020.02.14.20021535
-1058. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients
+
1059. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients
Jing Liu, Sumeng Li, Jia Liu, Boyun Liang, Xiaobei Wang, Hua Wang, Wei Li, Qiaoxia Tong, Jianhua Yi, Lei Zhao, … Xin Zheng
Cold Spring Harbor Laboratory (2020-02-22) https://doi.org/ggq63g
DOI: 10.1101/2020.02.16.20023671
-1059. Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019
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1060. Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019
Guang Chen, Di Wu, Wei Guo, Yong Cao, Da Huang, Hongwu Wang, Tao Wang, Xiaoyun Zhang, Huilong Chen, Haijing Yu, … Qin Ning
Cold Spring Harbor Laboratory (2020-02-19) https://doi.org/ggq63h
DOI: 10.1101/2020.02.16.20023903
-1060. SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development
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1061. SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development
Chunyun Sun, Long Chen, Ji Yang, Chunxia Luo, Yanjing Zhang, Jing Li, Jiahui Yang, Jie Zhang, Liangzhi Xie
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggq63j
DOI: 10.1101/2020.02.16.951723
-1061. Protection of Rhesus Macaque from SARS-Coronavirus challenge by recombinant adenovirus vaccine
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1062. Protection of Rhesus Macaque from SARS-Coronavirus challenge by recombinant adenovirus vaccine
Yiyou Chen, Qiang Wei, Ruobing Li, Hong Gao, Hua Zhu, Wei Deng, Linlin Bao, Wei Tong, Zhe Cong, Hong Jiang, Chuan Qin
Cold Spring Harbor Laboratory (2020-02-21) https://doi.org/ggq63k
DOI: 10.1101/2020.02.17.951939
-1062. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)
+
1063. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)
Bo Diao, Chenhui Wang, Yingjun Tan, Xiewan Chen, Ying Liu, Lifen Ning, Li Chen, Min Li, Yueping Liu, Gang Wang, … Yongwen Chen
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggq63m
DOI: 10.1101/2020.02.18.20024364
-1063. Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China
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1064. Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China
Xun Li, Luwen Wang, Shaonan Yan, Fan Yang, Longkui Xiang, Jiling Zhu, Bo Shen, Zuojiong Gong
Cold Spring Harbor Laboratory (2020-02-25) https://doi.org/ggq63n
DOI: 10.1101/2020.02.19.20025239
-1064. SARS-CoV-2 infection does not significantly cause acute renal injury: an analysis of 116 hospitalized patients with COVID-19 in a single hospital, Wuhan, China
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1065. SARS-CoV-2 infection does not significantly cause acute renal injury: an analysis of 116 hospitalized patients with COVID-19 in a single hospital, Wuhan, China
Luwen Wang, Xun Li, Hui Chen, Shaonan Yan, Yan Li, Dong Li, Zuojiong Gong
Cold Spring Harbor Laboratory (2020-02-23) https://doi.org/ggq63p
DOI: 10.1101/2020.02.19.20025288
-1065. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China
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1066. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China
Dawei Wang, Bo Hu, Chang Hu, Fangfang Zhu, Xing Liu, Jing Zhang, Binbin Wang, Hui Xiang, Zhenshun Cheng, Yong Xiong, … Zhiyong Peng
JAMA (2020-03-17) https://doi.org/ggkh48
DOI: 10.1001/jama.2020.1585 · PMID: 32031570 · PMCID: PMC7042881
-1066. Clinical characteristics of 2019 novel coronavirus infection in China
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1067. Clinical characteristics of 2019 novel coronavirus infection in China
Wei-jie Guan, Zheng-yi Ni, Yu Hu, Wen-hua Liang, Chun-quan Ou, Jian-xing He, Lei Liu, Hong Shan, Chun-liang Lei, David S. C. Hui, … Nan-shan Zhong
Cold Spring Harbor Laboratory (2020-02-09) https://doi.org/ggkj9s
DOI: 10.1101/2020.02.06.20020974
-1067. Potential T-cell and B-cell Epitopes of 2019-nCoV
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1068. Potential T-cell and B-cell Epitopes of 2019-nCoV
Ethan Fast, Russ B. Altman, Binbin Chen
Cold Spring Harbor Laboratory (2020-03-18) https://doi.org/ggq63q
DOI: 10.1101/2020.02.19.955484
-1068. Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein
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1069. Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein
Alexandra C. Walls, Young-Jun Park, M. Alexandra Tortorici, Abigail Wall, Andrew T. McGuire, David Veesler
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggrgbr
DOI: 10.1101/2020.02.19.956581
-1069. Breadth of concomitant immune responses underpinning viral clearance and patient recovery in a non-severe case of COVID-19
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1070. Breadth of concomitant immune responses underpinning viral clearance and patient recovery in a non-severe case of COVID-19
Irani Thevarajan, Thi HO Nguyen, Marios Koutsakos, Julian Druce, Leon Caly, Carolien E van de Sandt, Xiaoxiao Jia, Suellen Nicholson, Mike Catton, Benjamin Cowie, … Katherine Kedzierska
Cold Spring Harbor Laboratory (2020-02-23) https://doi.org/ggq63r
DOI: 10.1101/2020.02.20.20025841
-1070. The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing
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1071. The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing
Minfeng Liao, Yang Liu, Jin Yuan, Yanling Wen, Gang Xu, Juanjuan Zhao, Lin Chen, Jinxiu Li, Xin Wang, Fuxiang Wang, … Zheng Zhang
Cold Spring Harbor Laboratory (2020-02-26) https://doi.org/ggq63s
DOI: 10.1101/2020.02.23.20026690
-1071. Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells
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1072. Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells
Marlena Scharenberg, Sindhu Vangeti, Eliisa Kekäläinen, Per Bergman, Mamdoh Al-Ameri, Niclas Johansson, Klara Sondén, Sara Falck-Jones, Anna Färnert, Hans-Gustaf Ljunggren, … Nicole Marquardt
Frontiers in Immunology (2019-05-17) https://doi.org/ggq656
DOI: 10.3389/fimmu.2019.01116 · PMID: 31156653 · PMCID: PMC6534051
-1072. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
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1073. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
Chaolin Huang, Yeming Wang, Xingwang Li, Lili Ren, Jianping Zhao, Yi Hu, Li Zhang, Guohui Fan, Jiuyang Xu, Xiaoying Gu, … Bin Cao
The Lancet (2020-02) https://doi.org/ggjfnn
DOI: 10.1016/s0140-6736(20)30183-5
-1073. Alveolar Macrophages in the Resolution of Inflammation, Tissue Repair, and Tolerance to Infection
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1074. Alveolar Macrophages in the Resolution of Inflammation, Tissue Repair, and Tolerance to Infection
Benoit Allard, Alice Panariti, James G. Martin
Frontiers in Immunology (2018-07-31) https://doi.org/gd3bnz
DOI: 10.3389/fimmu.2018.01777 · PMID: 30108592 · PMCID: PMC6079255
-1074. PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery following Respiratory Viral Infection
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1075. PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery following Respiratory Viral Infection
Su Huang, Bibo Zhu, In Su Cheon, Nick P. Goplen, Li Jiang, Ruixuan Zhang, R. Stokes Peebles, Matthias Mack, Mark H. Kaplan, Andrew H. Limper, Jie Sun
Journal of Virology (2019-04-17) https://doi.org/ggq652
DOI: 10.1128/jvi.00030-19 · PMID: 30787149 · PMCID: PMC6475778
-1075. Can routine laboratory tests discriminate 2019 novel coronavirus infected pneumonia from other community-acquired pneumonia?
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1076. Can routine laboratory tests discriminate 2019 novel coronavirus infected pneumonia from other community-acquired pneumonia?
Yunbao Pan, Guangming Ye, Xiantao Zeng, Guohong Liu, Xiaojiao Zeng, Xianghu Jiang, Jin Zhao, Liangjun Chen, Shuang Guo, Qiaoling Deng, … Xinghuan Wang
Cold Spring Harbor Laboratory (2020-02-25) https://doi.org/ggq63t
DOI: 10.1101/2020.02.25.20024711
-1076. Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia
+
1077. Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia
Jing Gong, Hui Dong, Qingsong Xia, Zhaoyi Huang, Dingkun Wang, Yan Zhao, Wenhua Liu, Shenghao Tu, Mingmin Zhang, Qi Wang, Fuer Lu
Cold Spring Harbor Laboratory (2020-02-26) https://doi.org/ggq63v
DOI: 10.1101/2020.02.25.20025643
-1077. An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors’ CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design
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1078. An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors’ CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design
CV Herst, S Burkholz, J Sidney, A Sette, PE Harris, S Massey, T Brasel, E Cunha-Neto, DS Rosa, WCH Chao, … R Rubsamen
Cold Spring Harbor Laboratory (2020-04-06) https://doi.org/ggq63x
DOI: 10.1101/2020.02.25.963546
-1078. Epitope-based peptide vaccine design and target site characterization against novel coronavirus disease caused by SARS-CoV-2
+
1079. Epitope-based peptide vaccine design and target site characterization against novel coronavirus disease caused by SARS-CoV-2
Lin Li, Ting Sun, Yufei He, Wendong Li, Yubo Fan, Jing Zhang
Cold Spring Harbor Laboratory (2020-02-27) https://doi.org/ggnqwt
DOI: 10.1101/2020.02.25.965434
-1079. The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and Retrospective Analysis
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1080. The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and Retrospective Analysis
Wang Wenjun, Liu Xiaoqing, Wu Sipei, Lie Puyi, Huang Liyan, Li Yimin, Cheng Linling, Chen Sibei, Nong Lingbo, Lin Yongping, He Jianxing
Cold Spring Harbor Laboratory (2020-02-27) https://doi.org/ggrgbs
DOI: 10.1101/2020.02.26.20026989
-1080. Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China
+
1081. Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China
Ying Huang, Rui Yang, Ying Xu, Ping Gong
Cold Spring Harbor Laboratory (2020-03-05) https://doi.org/ggq63z
DOI: 10.1101/2020.02.27.20029009
-1081. Risk factors related to hepatic injury in patients with corona virus disease 2019
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1082. Risk factors related to hepatic injury in patients with corona virus disease 2019
Lu Li, Shuang Li, Manman Xu, Pengfei Yu, Sujun Zheng, Zhongping Duan, Jing Liu, Yu Chen, Junfeng Li
Cold Spring Harbor Laboratory (2020-03-10) https://doi.org/ggq632
DOI: 10.1101/2020.02.28.20028514
-1082. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients
+
1083. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients
Xiaohua Chen, Binghong Zhao, Yueming Qu, Yurou Chen, Jie Xiong, Yong Feng, Dong Men, Qianchuan Huang, Ying Liu, Bo Yang, … Feng Li
Cold Spring Harbor Laboratory (2020-03-03) https://doi.org/ggq633
DOI: 10.1101/2020.02.29.20029520
-1083. Prognostic factors in the acute respiratory distress syndrome
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1084. Prognostic factors in the acute respiratory distress syndrome
Wei Chen, Lorraine B Ware
Clinical and Translational Medicine (2015-07-02) https://doi.org/ggq653
DOI: 10.1186/s40169-015-0065-2 · PMID: 26162279 · PMCID: PMC4534483
-1084. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study
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1085. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study
Li Tan, Qi Wang, Duanyang Zhang, Jinya Ding, Qianchuan Huang, Yi-Quan Tang, Qiongshu Wang, Hongming Miao
Cold Spring Harbor Laboratory (2020-03-03) https://doi.org/ggq634
DOI: 10.1101/2020.03.01.20029074
-1085. The potential role of IL-6 in monitoring severe case of coronavirus disease 2019
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1086. The potential role of IL-6 in monitoring severe case of coronavirus disease 2019
Tao Liu, Jieying Zhang, Yuhui Yang, Hong Ma, Zhengyu Li, Jiaoyu Zhang, Ji Cheng, Xiaoyun Zhang, Yanxia Zhao, Zihan Xia, … Jianhua Yi
Cold Spring Harbor Laboratory (2020-03-10) https://doi.org/ggq635
DOI: 10.1101/2020.03.01.20029769
-1086. Clinical and Laboratory Profiles of 75 Hospitalized Patients with Novel Coronavirus Disease 2019 in Hefei, China
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1087. Clinical and Laboratory Profiles of 75 Hospitalized Patients with Novel Coronavirus Disease 2019 in Hefei, China
Zonghao Zhao, Jiajia Xie, Ming Yin, Yun Yang, Hongliang He, Tengchuan Jin, Wenting Li, Xiaowu Zhu, Jing Xu, Changcheng Zhao, … Xiaoling Ma
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq636
DOI: 10.1101/2020.03.01.20029785
-1087. Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome
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1088. Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome
Yang Yang, Chenguang Shen, Jinxiu Li, Jing Yuan, Minghui Yang, Fuxiang Wang, Guobao Li, Yanjie Li, Li Xing, Ling Peng, … Yingxia Liu
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq637
DOI: 10.1101/2020.03.02.20029975
-1088. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019
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1089. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019
Juanjuan Zhao, Quan Yuan, Haiyan Wang, Wei Liu, Xuejiao Liao, Yingying Su, Xin Wang, Jing Yuan, Tingdong Li, Jinxiu Li, … Zheng Zhang
Cold Spring Harbor Laboratory (2020-03-02) https://doi.org/ggrbj6
DOI: 10.1101/2020.03.02.20030189
-1089. Restoration of leukomonocyte counts is associated with viral clearance in COVID-19 hospitalized patients
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1090. Restoration of leukomonocyte counts is associated with viral clearance in COVID-19 hospitalized patients
Xiaoping Chen, Jiaxin Ling, Pingzheng Mo, Yongxi Zhang, Qunqun Jiang, Zhiyong Ma, Qian Cao, Wenjia Hu, Shi Zou, Liangjun Chen, … Yong Xiong
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq639
DOI: 10.1101/2020.03.03.20030437
-1090. Effects of Systemically Administered Hydrocortisone on the Human Immunome
+
1091. Effects of Systemically Administered Hydrocortisone on the Human Immunome
Matthew J. Olnes, Yuri Kotliarov, Angélique Biancotto, Foo Cheung, Jinguo Chen, Rongye Shi, Huizhi Zhou, Ena Wang, John S. Tsang, Robert Nussenblatt, The CHI Consortium
Scientific Reports (2016-03-14) https://doi.org/f8dmvw
DOI: 10.1038/srep23002 · PMID: 26972611 · PMCID: PMC4789739
-1091. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis
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1092. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis
Giuseppe Lippi, Mario Plebani
Clinica Chimica Acta (2020-06) https://doi.org/ggpxp7
DOI: 10.1016/j.cca.2020.03.004 · PMID: 32145275 · PMCID: PMC7094472
-1092. Clinical findings in critically ill patients infected with SARS-CoV-2 in Guangdong Province, China: a multi-center, retrospective, observational study
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1093. Clinical findings in critically ill patients infected with SARS-CoV-2 in Guangdong Province, China: a multi-center, retrospective, observational study
Yonghao Xu, Zhiheng Xu, Xuesong Liu, Lihua Cai, Haichong Zheng, Yongbo Huang, Lixin Zhou, Linxi Huang, Yun Lin, Liehua Deng, … Yimin Li
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq64b
DOI: 10.1101/2020.03.03.20030668
-1093. Multi-epitope vaccine design using an immunoinformatics approach for 2019 novel coronavirus (SARS-CoV-2)
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1094. Multi-epitope vaccine design using an immunoinformatics approach for 2019 novel coronavirus (SARS-CoV-2)
Ye Feng, Min Qiu, Liang Liu, Shengmei Zou, Yun Li, Kai Luo, Qianpeng Guo, Ning Han, Yingqiang Sun, Kui Wang, … Fan Mo
Cold Spring Harbor Laboratory (2020-06-30) https://doi.org/ggq64c
DOI: 10.1101/2020.03.03.962332
-1094. Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19) in Shanghai, China
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1095. Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19) in Shanghai, China
Min Cao, Dandan Zhang, Youhua Wang, Yunfei Lu, Xiangdong Zhu, Ying Li, Honghao Xue, Yunxiao Lin, Min Zhang, Yiguo Sun, … Hongzhou Lu
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq64d
DOI: 10.1101/2020.03.04.20030395 · PMID: 32511465
-1095. Serological detection of 2019-nCoV respond to the epidemic: A useful complement to nucleic acid testing
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1096. Serological detection of 2019-nCoV respond to the epidemic: A useful complement to nucleic acid testing
Jin Zhang, Jianhua Liu, Na Li, Yong Liu, Rui Ye, Xiaosong Qin, Rui Zheng
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq64f
DOI: 10.1101/2020.03.04.20030916
-1096. Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection
+
1097. Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection
Bo Diao, Chenhui Wang, Rongshuai Wang, Zeqing Feng, Yingjun Tan, Huiming Wang, Changsong Wang, Liang Liu, Ying Liu, Yueping Liu, … Yongwen Chen
Cold Spring Harbor Laboratory (2020-04-10) https://doi.org/ggq64g
DOI: 10.1101/2020.03.04.20031120
-1097. COVID-19 early warning score: a multi-parameter screening tool to identify highly suspected patients
+
1098. COVID-19 early warning score: a multi-parameter screening tool to identify highly suspected patients
Cong-Ying Song, Jia Xu, Jian-Qin He, Yuan-Qiang Lu
Cold Spring Harbor Laboratory (2020-03-08) https://doi.org/ggq64h
DOI: 10.1101/2020.03.05.20031906
-1098. LY6E impairs coronavirus fusion and confers immune control of viral disease
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1099. LY6E impairs coronavirus fusion and confers immune control of viral disease
Stephanie Pfaender, Katrina B. Mar, Eleftherios Michailidis, Annika Kratzel, Dagny Hirt, Philip V’kovski, Wenchun Fan, Nadine Ebert, Hanspeter Stalder, Hannah Kleine-Weber, … Volker Thiel
Cold Spring Harbor Laboratory (2020-03-07) https://doi.org/dpvn
DOI: 10.1101/2020.03.05.979260 · PMID: 32511345
-1099. A preliminary study on serological assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 238 admitted hospital patients
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1100. A preliminary study on serological assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 238 admitted hospital patients
Lei Liu, Wanbing Liu, Yaqiong Zheng, Xiaojing Jiang, Guomei Kou, Jinya Ding, Qiongshu Wang, Qianchuan Huang, Yinjuan Ding, Wenxu Ni, … Shangen Zheng
Cold Spring Harbor Laboratory (2020-03-08) https://doi.org/ggq64j
DOI: 10.1101/2020.03.06.20031856
-1100. Monoclonal antibodies for the S2 subunit of spike of SARS-CoV cross-react with the newly-emerged SARS-CoV-2
+
1101. Monoclonal antibodies for the S2 subunit of spike of SARS-CoV cross-react with the newly-emerged SARS-CoV-2
Zhiqiang Zheng, Vanessa M. Monteil, Sebastian Maurer-Stroh, Chow Wenn Yew, Carol Leong, Nur Khairiah Mohd-Ismail, Suganya Cheyyatraivendran Arularasu, Vincent Tak Kwong Chow, Raymond Lin Tzer Pin, Ali Mirazimi, … Yee-Joo Tan
Cold Spring Harbor Laboratory (2020-03-07) https://doi.org/ggrbj7
DOI: 10.1101/2020.03.06.980037
-1101. Mortality of COVID-19 is Associated with Cellular Immune Function Compared to Immune Function in Chinese Han Population
+
1102. Mortality of COVID-19 is Associated with Cellular Immune Function Compared to Immune Function in Chinese Han Population
Qiang Zeng, Yong-zhe Li, Gang Huang, Wei Wu, Sheng-yong Dong, Yang Xu
Cold Spring Harbor Laboratory (2020-03-13) https://doi.org/ggq64k
DOI: 10.1101/2020.03.08.20031229
-1102. Retrospective Analysis of Clinical Features in 101 Death Cases with COVID-19
+
1103. Retrospective Analysis of Clinical Features in 101 Death Cases with COVID-19
Hua Fan, Lin Zhang, Bin Huang, Muxin Zhu, Yong Zhou, Huan Zhang, Xiaogen Tao, Shaohui Cheng, Wenhu Yu, Liping Zhu, Jian Chen
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq64n
DOI: 10.1101/2020.03.09.20033068
-1103. Relationship between the ABO Blood Group and the COVID-19 Susceptibility
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1104. Relationship between the ABO Blood Group and the COVID-19 Susceptibility
Jiao Zhao, Yan Yang, Hanping Huang, Dong Li, Dongfeng Gu, Xiangfeng Lu, Zheng Zhang, Lei Liu, Ting Liu, Yukun Liu, … Peng George Wang
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggpn3d
DOI: 10.1101/2020.03.11.20031096
-1104. The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15
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1105. The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15
Shutoku Matsuyama, Miyuki Kawase, Naganori Nao, Kazuya Shirato, Makoto Ujike, Wataru Kamitani, Masayuki Shimojima, Shuetsu Fukushi
Cold Spring Harbor Laboratory (2020-03-12) https://doi.org/ggq64p
DOI: 10.1101/2020.03.11.987016
-1105. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19
+
1106. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19
Bicheng Zhang, Xiaoyang Zhou, Chengliang Zhu, Fan Feng, Yanru Qiu, Jia Feng, Qingzhu Jia, Qibin Song, Bo Zhu, Jun Wang
Cold Spring Harbor Laboratory (2020-03-16) https://doi.org/ggq64q
DOI: 10.1101/2020.03.12.20035048
-1106. Lack of Reinfection in Rhesus Macaques Infected with SARS-CoV-2
+
1107. Lack of Reinfection in Rhesus Macaques Infected with SARS-CoV-2
Linlin Bao, Wei Deng, Hong Gao, Chong Xiao, Jiayi Liu, Jing Xue, Qi Lv, Jiangning Liu, Pin Yu, Yanfeng Xu, … Chuan Qin
Cold Spring Harbor Laboratory (2020-05-01) https://doi.org/ggn8r8
DOI: 10.1101/2020.03.13.990226
-1107. A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV
+
1108. A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV
Meng Yuan, Nicholas C. Wu, Xueyong Zhu, Chang-Chun D. Lee, Ray T. Y. So, Huibin Lv, Chris K. P. Mok, Ian A. Wilson
Cold Spring Harbor Laboratory (2020-03-14) https://doi.org/ggq64s
DOI: 10.1101/2020.03.13.991570
-1108. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein
+
1109. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein
Ke Wang, Wei Chen, Yu-Sen Zhou, Jian-Qi Lian, Zheng Zhang, Peng Du, Li Gong, Yang Zhang, Hong-Yong Cui, Jie-Jie Geng, … Zhi-Nan Chen
Cold Spring Harbor Laboratory (2020-03-14) https://doi.org/ggq64t
DOI: 10.1101/2020.03.14.988345
-1109. CD147 (EMMPRIN/Basigin) in kidney diseases: from an inflammation and immune system viewpoint
+
1110. CD147 (EMMPRIN/Basigin) in kidney diseases: from an inflammation and immune system viewpoint
Tomoki Kosugi, Kayaho Maeda, Waichi Sato, Shoichi Maruyama, Kenji Kadomatsu
Nephrology Dialysis Transplantation (2015-07) https://doi.org/ggq624
DOI: 10.1093/ndt/gfu302 · PMID: 25248362
-1110. The roles of CyPA and CD147 in cardiac remodelling
+
1111. The roles of CyPA and CD147 in cardiac remodelling
Hongyan Su, Yi Yang
Experimental and Molecular Pathology (2018-06) https://doi.org/ggq622
DOI: 10.1016/j.yexmp.2018.05.001 · PMID: 29772453
-1111. Cancer-related issues of CD147.
+
1112. Cancer-related issues of CD147.
Ulrich H Weidle, Werner Scheuer, Daniela Eggle, Stefan Klostermann, Hannes Stockinger
Cancer genomics & proteomics https://www.ncbi.nlm.nih.gov/pubmed/20551248
PMID: 20551248
-1112. Blood single cell immune profiling reveals the interferon-MAPK pathway mediated adaptive immune response for COVID-19
+
1113. Blood single cell immune profiling reveals the interferon-MAPK pathway mediated adaptive immune response for COVID-19
Lulin Huang, Yi Shi, Bo Gong, Li Jiang, Xiaoqi Liu, Jialiang Yang, Juan Tang, Chunfang You, Qi Jiang, Bo Long, … Zhenglin Yang
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq64v
DOI: 10.1101/2020.03.15.20033472
-1113. Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections
+
1114. Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections
Huibin Lv, Nicholas C. Wu, Owen Tak-Yin Tsang, Meng Yuan, Ranawaka A. P. M. Perera, Wai Shing Leung, Ray T. Y. So, Jacky Man Chun Chan, Garrick K. Yip, Thomas Shiu Hong Chik, … Chris K. P. Mok
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq64w
DOI: 10.1101/2020.03.15.993097 · PMID: 32511317
-1114. The feasibility of convalescent plasma therapy in severe COVID- 19 patients: a pilot study
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1115. The feasibility of convalescent plasma therapy in severe COVID- 19 patients: a pilot study
Kai Duan, Bende Liu, Cesheng Li, Huajun Zhang, Ting Yu, Jieming Qu, Min Zhou, Li Chen, Shengli Meng, Yong Hu, … Xiaoming Yang
Cold Spring Harbor Laboratory (2020-03-23) https://doi.org/dqrs
DOI: 10.1101/2020.03.16.20036145
-1115. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial
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1116. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial
Philippe Gautret, Jean-Christophe Lagier, Philippe Parola, Van Thuan Hoang, Line Meddeb, Morgane Mailhe, Barbara Doudier, Johan Courjon, Valérie Giordanengo, Vera Esteves Vieira, … Didier Raoult
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/dqbv
DOI: 10.1101/2020.03.16.20037135
-1116. Chloroquine: Modes of action of an undervalued drug
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1117. Chloroquine: Modes of action of an undervalued drug
Rodolfo Thomé, Stefanie Costa Pinto Lopes, Fabio Trindade Maranhão Costa, Liana Verinaud
Immunology Letters (2013-06) https://doi.org/f5b5cr
DOI: 10.1016/j.imlet.2013.07.004 · PMID: 23891850
-1117. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy
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1118. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy
B. Lo, K. Zhang, W. Lu, L. Zheng, Q. Zhang, C. Kanellopoulou, Y. Zhang, Z. Liu, J. M. Fritz, R. Marsh, … M. B. Jordan
Science (2015-07-23) https://doi.org/f7kc8d
DOI: 10.1126/science.aaa1663 · PMID: 26206937
-1118. The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2
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1119. The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2
Erik Procko
Cold Spring Harbor Laboratory (2020-05-11) https://doi.org/ggrbj8
DOI: 10.1101/2020.03.16.994236 · PMID: 32511321
-1119. Comparative Pathogenesis Of COVID-19, MERS And SARS In A Non-Human Primate Model
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1120. Comparative Pathogenesis Of COVID-19, MERS And SARS In A Non-Human Primate Model
Barry Rockx, Thijs Kuiken, Sander Herfst, Theo Bestebroer, Mart M. Lamers, Dennis de Meulder, Geert van Amerongen, Judith van den Brand, Nisreen M. A. Okba, Debby Schipper, … Bart L. Haagmans
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq649
DOI: 10.1101/2020.03.17.995639
-1120. Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus
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1121. Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus
Paul B. McCray, Lecia Pewe, Christine Wohlford-Lenane, Melissa Hickey, Lori Manzel, Lei Shi, Jason Netland, Hong Peng Jia, Carmen Halabi, Curt D. Sigmund, … Stanley Perlman
Journal of Virology (2007-01-15) https://doi.org/b2dr3s
DOI: 10.1128/jvi.02012-06 · PMID: 17079315 · PMCID: PMC1797474
-1121. Modeling the Impact of Asymptomatic Carriers on COVID-19 Transmission Dynamics During Lockdown
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1122. Modeling the Impact of Asymptomatic Carriers on COVID-19 Transmission Dynamics During Lockdown
Jacob B. Aguilar, Jeremy Samuel Faust, Lauren M. Westafer, Juan B. Gutierrez
Cold Spring Harbor Laboratory (2020-08-11) https://doi.org/ggqnvp
DOI: 10.1101/2020.03.18.20037994
-1122. Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice
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1123. Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice
Quan-xin Long, Hai-jun Deng, Juan Chen, Jie-li Hu, Bei-zhong Liu, Pu Liao, Yong Lin, Li-hua Yu, Zhan Mo, Yin-yin Xu, … Ai-long Huang
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggpvz3
DOI: 10.1101/2020.03.18.20038018
-1123. Heat inactivation of serum interferes with the immunoanalysis of antibodies to SARS-CoV-2
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1124. Heat inactivation of serum interferes with the immunoanalysis of antibodies to SARS-CoV-2
Xiumei Hu, Taixue An, Bo Situ, Yuhai Hu, Zihao Ou, Qiang Li, Xiaojing He, Ye Zhang, Peifu Tian, Dehua Sun, … Lei Zheng
Cold Spring Harbor Laboratory (2020-03-16) https://doi.org/ggq646
DOI: 10.1101/2020.03.12.20034231
-1124. SARS-CoV-2 specific antibody responses in COVID-19 patients
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1125. SARS-CoV-2 specific antibody responses in COVID-19 patients
Nisreen M. A. Okba, Marcel A. Müller, Wentao Li, Chunyan Wang, Corine H. GeurtsvanKessel, Victor M. Corman, Mart M. Lamers, Reina S. Sikkema, Erwin de Bruin, Felicity D. Chandler, … Bart L. Haagmans
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggpvz2
DOI: 10.1101/2020.03.18.20038059
-1125. A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19
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1126. A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19
Drifa Belhadi, Nathan Peiffer-Smadja, François-Xavier Lescure, Yazdan Yazdanpanah, France Mentré, Cédric Laouénan
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65b
DOI: 10.1101/2020.03.18.20038190
-1126. ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19
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1127. ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19
Janice M. Leung, Chen X. Yang, Anthony Tam, Tawimas Shaipanich, Tillie-Louise Hackett, Gurpreet K. Singhera, Delbert R. Dorscheid, Don D. Sin
Cold Spring Harbor Laboratory (2020-03-23) https://doi.org/dqx2
DOI: 10.1101/2020.03.18.20038455
-1127. Dynamic profile of severe or critical COVID-19 cases
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1128. Dynamic profile of severe or critical COVID-19 cases
Yang Xu
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggrbj9
DOI: 10.1101/2020.03.18.20038513
-1128. Association between Clinical, Laboratory and CT Characteristics and RT-PCR Results in the Follow-up of COVID-19 patients
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1129. Association between Clinical, Laboratory and CT Characteristics and RT-PCR Results in the Follow-up of COVID-19 patients
Hang Fu, Huayan Xu, Na Zhang, Hong Xu, Zhenlin Li, Huizhu Chen, Rong Xu, Ran Sun, Lingyi Wen, Linjun Xie, … Yingkun Guo
Cold Spring Harbor Laboratory (2020-03-23) https://doi.org/ggq65c
DOI: 10.1101/2020.03.19.20038315
-1129. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus
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1130. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus
Timothy P. Sheahan, Amy C. Sims, Shuntai Zhou, Rachel L. Graham, Collin S. Hill, Sarah R. Leist, Alexandra Schäfer, Kenneth H. Dinnon, Stephanie A. Montgomery, Maria L. Agostini, … Ralph S. Baric
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggrbkb
DOI: 10.1101/2020.03.19.997890
-1130. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs
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1131. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs
Sangeun Jeon, Meehyun Ko, Jihye Lee, Inhee Choi, Soo Young Byun, Soonju Park, David Shum, Seungtaek Kim
Cold Spring Harbor Laboratory (2020-03-28) https://doi.org/ggq65h
DOI: 10.1101/2020.03.20.999730
-1131. Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2
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1132. Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2
Vincent J. Munster, Friederike Feldmann, Brandi N. Williamson, Neeltje van Doremalen, Lizzette Pérez-Pérez, Jonathan Schulz, Kimberly Meade-White, Atsushi Okumura, Julie Callison, Beniah Brumbaugh, … Emmie de Wit
Cold Spring Harbor Laboratory (2020-03-21) https://doi.org/ggq65j
DOI: 10.1101/2020.03.21.001628 · PMID: 32511299
-1132. Ocular conjunctival inoculation of SARS-CoV-2 can cause mild COVID-19 in Rhesus macaques
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1133. Ocular conjunctival inoculation of SARS-CoV-2 can cause mild COVID-19 in Rhesus macaques
Wei Deng, Linlin Bao, Hong Gao, Zhiguang Xiang, Yajin Qu, Zhiqi Song, Shunran Gong, Jiayi Liu, Jiangning Liu, Pin Yu, … Chuan Qin
Cold Spring Harbor Laboratory (2020-03-30) https://doi.org/ggq64r
DOI: 10.1101/2020.03.13.990036
-1133. ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19
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1134. ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19
Bruna G. G. Pinto, Antonio E. R. Oliveira, Youvika Singh, Leandro Jimenez, Andre N A. Gonçalves, Rodrigo L. T. Ogava, Rachel Creighton, Jean Pierre Schatzmann Peron, Helder I. Nakaya
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65k
DOI: 10.1101/2020.03.21.20040261 · PMID: 32511627
-1134. Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial
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1135. Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial
Huijie Bian, Zhao-Hui Zheng, Ding Wei, Zheng Zhang, Wen-Zhen Kang, Chun-Qiu Hao, Ke Dong, Wen Kang, Jie-Lai Xia, Jin-Lin Miao, … Ping Zhu
Cold Spring Harbor Laboratory (2020-07-15) https://doi.org/ggq65m
DOI: 10.1101/2020.03.21.20040691
-1135. CD147 facilitates HIV-1 infection by interacting with virus-associated cyclophilin A
+
1136. CD147 facilitates HIV-1 infection by interacting with virus-associated cyclophilin A
T. Pushkarsky, G. Zybarth, L. Dubrovsky, V. Yurchenko, H. Tang, H. Guo, B. Toole, B. Sherry, M. Bukrinsky
Proceedings of the National Academy of Sciences (2001-05-15) https://doi.org/cc4c7p
DOI: 10.1073/pnas.111583198 · PMID: 11353871 · PMCID: PMC33473
-1136. CD147/EMMPRIN Acts as a Functional Entry Receptor for Measles Virus on Epithelial Cells
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1137. CD147/EMMPRIN Acts as a Functional Entry Receptor for Measles Virus on Epithelial Cells
Akira Watanabe, Misako Yoneda, Fusako Ikeda, Yuri Terao-Muto, Hiroki Sato, Chieko Kai
Journal of Virology (2010-05-01) https://doi.org/dpcsqg
DOI: 10.1128/jvi.02168-09 · PMID: 20147391 · PMCID: PMC2863760
-1137. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum
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1138. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum
Cécile Crosnier, Leyla Y. Bustamante, S. Josefin Bartholdson, Amy K. Bei, Michel Theron, Makoto Uchikawa, Souleymane Mboup, Omar Ndir, Dominic P. Kwiatkowski, Manoj T. Duraisingh, … Gavin J. Wright
Nature (2011-11-09) https://doi.org/dm59hf
DOI: 10.1038/nature10606 · PMID: 22080952 · PMCID: PMC3245779
-1138. Function of HAb18G/CD147 in Invasion of Host Cells by Severe Acute Respiratory Syndrome Coronavirus
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1139. Function of HAb18G/CD147 in Invasion of Host Cells by Severe Acute Respiratory Syndrome Coronavirus
Zhinan Chen, Li Mi, Jing Xu, Jiyun Yu, Xianhui Wang, Jianli Jiang, Jinliang Xing, Peng Shang, Airong Qian, Yu Li, … Ping Zhu
The Journal of Infectious Diseases (2005-03) https://doi.org/cd8snd
DOI: 10.1086/427811 · PMID: 15688292 · PMCID: PMC7110046
-1139. CD147 mediates intrahepatic leukocyte aggregation and determines the extent of liver injury
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1140. CD147 mediates intrahepatic leukocyte aggregation and determines the extent of liver injury
Christine Yee, Nathan M. Main, Alexandra Terry, Igor Stevanovski, Annette Maczurek, Alison J. Morgan, Sarah Calabro, Alison J. Potter, Tina L. Iemma, David G. Bowen, … Nicholas A. Shackel
PLOS ONE (2019-07-10) https://doi.org/ggq654
DOI: 10.1371/journal.pone.0215557 · PMID: 31291257 · PMCID: PMC6619953
-1140. Characterisation of the transcriptome and proteome of SARS-CoV-2 using direct RNA sequencing and tandem mass spectrometry reveals evidence for a cell passage induced in-frame deletion in the spike glycoprotein that removes the furin-like cleavage site
+
1141. Characterisation of the transcriptome and proteome of SARS-CoV-2 using direct RNA sequencing and tandem mass spectrometry reveals evidence for a cell passage induced in-frame deletion in the spike glycoprotein that removes the furin-like cleavage site
Andrew D. Davidson, Maia Kavanagh Williamson, Sebastian Lewis, Deborah Shoemark, Miles W. Carroll, Kate Heesom, Maria Zambon, Joanna Ellis, Phillip A. Lewis, Julian A. Hiscox, David A. Matthews
Cold Spring Harbor Laboratory (2020-03-24) https://doi.org/ggq65n
DOI: 10.1101/2020.03.22.002204
-1141. Modifications to the Hemagglutinin Cleavage Site Control the Virulence of a Neurotropic H1N1 Influenza Virus
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1142. Modifications to the Hemagglutinin Cleavage Site Control the Virulence of a Neurotropic H1N1 Influenza Virus
Xiangjie Sun, Longping V. Tse, A Damon Ferguson, Gary R. Whittaker
Journal of Virology (2010-09-01) https://doi.org/drs2zt
DOI: 10.1128/jvi.00797-10 · PMID: 20554779 · PMCID: PMC2919019
-1142. The architecture of SARS-CoV-2 transcriptome
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1143. The architecture of SARS-CoV-2 transcriptome
Dongwan Kim, Joo-Yeon Lee, Jeong-Sun Yang, Jun Won Kim, V. Narry Kim, Hyeshik Chang
Cold Spring Harbor Laboratory (2020-03-14) https://doi.org/ggpx9q
DOI: 10.1101/2020.03.12.988865
-1143. First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naïve and Experienced COVID-19 Patients
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1144. First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naïve and Experienced COVID-19 Patients
Hongyi Chen, Zhicheng Zhang, Li Wang, Zhihua Huang, Fanghua Gong, Xiaodong Li, Yahong Chen, Jinzi J. Wu
Cold Spring Harbor Laboratory (2020-03-24) https://doi.org/ggrgbt
DOI: 10.1101/2020.03.22.20034041
-1144. Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)
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1145. Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)
Scott D. Seiwert, Steven W. Andrews, Yutong Jiang, Vladimir Serebryany, Hua Tan, Karl Kossen, P. T. Ravi Rajagopalan, Shawn Misialek, Sarah K. Stevens, Antitsa Stoycheva, … Lawrence M. Blatt
Antimicrobial Agents and Chemotherapy (2008-12) https://doi.org/btpg52
DOI: 10.1128/aac.00699-08 · PMID: 18824605 · PMCID: PMC2592891
-1145. Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China
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1146. Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China
Xiaoyuan Xu, Bo Feng, Yujuan Guan, Sujun Zheng, Jifang Sheng, Xingxiang Yang, Yuanji Ma, Yan Huang, Yi Kang, Xiaofeng Wen, … Lai Wei
Journal of Clinical and Translational Hepatology (2019-09-30) https://doi.org/ggrbkd
DOI: 10.14218/jcth.2019.00033 · PMID: 31608212 · PMCID: PMC6783683
-1146. Potentially highly potent drugs for 2019-nCoV
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1147. Potentially highly potent drugs for 2019-nCoV
Duc Duy Nguyen, Kaifu Gao, Jiahui Chen, Rui Wang, Guo-Wei Wei
Cold Spring Harbor Laboratory (2020-02-13) https://doi.org/ggrbj5
DOI: 10.1101/2020.02.05.936013 · PMID: 32511344
-1147. Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset
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1148. Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset
Bin Lou, Ting-Dong Li, Shu-Fa Zheng, Ying-Ying Su, Zhi-Yong Li, Wei Liu, Fei Yu, Sheng-Xiang Ge, Qian-Da Zou, Quan Yuan, … Yu Chen
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggrbkc
DOI: 10.1101/2020.03.23.20041707
-1148. SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems
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1149. SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems
Daniel Blanco-Melo, Benjamin E. Nilsson-Payant, Wen-Chun Liu, Rasmus Møller, Maryline Panis, David Sachs, Randy A. Albrecht, Benjamin R. tenOever
Cold Spring Harbor Laboratory (2020-03-24) https://doi.org/ggq65q
DOI: 10.1101/2020.03.24.004655
-1149. A New Predictor of Disease Severity in Patients with COVID-19 in Wuhan, China
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1150. A New Predictor of Disease Severity in Patients with COVID-19 in Wuhan, China
Ying Zhou, Zhen Yang, Yanan Guo, Shuang Geng, Shan Gao, Shenglan Ye, Yi Hu, Yafei Wang
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65r
DOI: 10.1101/2020.03.24.20042119
-1150. Metabolic disturbances and inflammatory dysfunction predict severity of coronavirus disease 2019 (COVID-19): a retrospective study
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1151. Metabolic disturbances and inflammatory dysfunction predict severity of coronavirus disease 2019 (COVID-19): a retrospective study
Shuke Nie, Xueqing Zhao, Kang Zhao, Zhaohui Zhang, Zhentao Zhang, Zhan Zhang
Cold Spring Harbor Laboratory (2020-03-26) https://doi.org/ggq65s
DOI: 10.1101/2020.03.24.20042283
-1151. Viral Kinetics and Antibody Responses in Patients with COVID-19
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1152. Viral Kinetics and Antibody Responses in Patients with COVID-19
Wenting Tan, Yanqiu Lu, Juan Zhang, Jing Wang, Yunjie Dan, Zhaoxia Tan, Xiaoqing He, Chunfang Qian, Qiangzhong Sun, Qingli Hu, … Guohong Deng
Cold Spring Harbor Laboratory (2020-03-26) https://doi.org/ggq65t
DOI: 10.1101/2020.03.24.20042382
-1152. Global profiling of SARS-CoV-2 specific IgG/ IgM responses of convalescents using a proteome microarray
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1153. Global profiling of SARS-CoV-2 specific IgG/ IgM responses of convalescents using a proteome microarray
He-wei Jiang, Yang Li, Hai-nan Zhang, Wei Wang, Dong Men, Xiao Yang, Huan Qi, Jie Zhou, Sheng-ce Tao
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65g
DOI: 10.1101/2020.03.20.20039495
-1153. COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome
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1154. COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome
Dan Zhang, Rui Guo, Lei Lei, Hongjuan Liu, Yawen Wang, Yili Wang, Hongbo Qian, Tongxin Dai, Tianxiao Zhang, Yanjun Lai, … Jinsong Hu
Cold Spring Harbor Laboratory (2020-03-26) https://doi.org/ggq65v
DOI: 10.1101/2020.03.24.20042655
-1154. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study
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1155. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study
Aaron Miller, Mac Josh Reandelar, Kimberly Fasciglione, Violeta Roumenova, Yan Li, Gonzalo H. Otazu
Cold Spring Harbor Laboratory (2020-03-28) https://doi.org/ggq65w
DOI: 10.1101/2020.03.24.20042937
-1155. Non-specific effects of BCG vaccine on viral infections
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1156. Non-specific effects of BCG vaccine on viral infections
S. J. C. F. M. Moorlag, R. J. W. Arts, R. van Crevel, M. G. Netea
Clinical Microbiology and Infection (2019-12) https://doi.org/ggq62z
DOI: 10.1016/j.cmi.2019.04.020 · PMID: 31055165
-1156. BCG vaccination to reduce the impact of COVID-19 in healthcare workers (The BRACE Trial)
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1157. BCG vaccination to reduce the impact of COVID-19 in healthcare workers (The BRACE Trial)
Murdoch Children’s Research Institute
https://www.mcri.edu.au/BRACE
-1157. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia
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1158. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia
David H. Brann, Tatsuya Tsukahara, Caleb Weinreb, Marcela Lipovsek, Koen Van den Berge, Boying Gong, Rebecca Chance, Iain C. Macaulay, Hsin-jung Chou, Russell Fletcher, … Sandeep Robert Datta
Cold Spring Harbor Laboratory (2020-05-18) https://doi.org/ggqr4m
DOI: 10.1101/2020.03.25.009084
-1158. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract
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1159. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract
Joan C. Smith, Erin L. Sausville, Vishruth Girish, Monet Lou Yuan, Kristen M. John, Jason M. Sheltzer
Cold Spring Harbor Laboratory (2020-04-26) https://doi.org/ggq65x
DOI: 10.1101/2020.03.28.013672
-1159. The comparative superiority of IgM-IgG antibody test to real-time reverse transcriptase PCR detection for SARS-CoV-2 infection diagnosis
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1160. The comparative superiority of IgM-IgG antibody test to real-time reverse transcriptase PCR detection for SARS-CoV-2 infection diagnosis
Rui Liu, Xinghui Liu, Huan Han, Muhammad Adnan Shereen, Zhili Niu, Dong Li, Fang Liu, Kailang Wu, Zhen Luo, Chengliang Zhu
Cold Spring Harbor Laboratory (2020-03-30) https://doi.org/ggqtp5
DOI: 10.1101/2020.03.28.20045765
@@ -10360,7 +10366,7 @@
6.7 Vitamin D
7.
7.5 RNA Vaccines
RNA vaccines are nucleic-acid based modalities that code for viral antigens against which the human body elicits a humoral and cellular immune response. -The mRNA technology is transcribed in vitro and delivered to cells via lipid nanoparticles (LNP) [837]. -They are recognized by ribosomes in vivo and then translated and modified into functional proteins [838]. -The resulting intracellular viral proteins are displayed on surface MHC proteins, provoking a strong CD8+ T cell response as well as a CD4+ T cell and B cell-associated antibody responses [838]. +The mRNA technology is transcribed in vitro and delivered to cells via lipid nanoparticles (LNP) [838]. +They are recognized by ribosomes in vivo and then translated and modified into functional proteins [839]. +The resulting intracellular viral proteins are displayed on surface MHC proteins, provoking a strong CD8+ T cell response as well as a CD4+ T cell and B cell-associated antibody responses [839]. Naturally, mRNA is not very stable and can degrade quickly in the extracellular environment or the cytoplasm. -The LNP covering protects the mRNA from enzymatic degradation outside of the cell [839]. +The LNP covering protects the mRNA from enzymatic degradation outside of the cell [840]. Codon optimization to prevent secondary structure formation and modifications of the poly-A tail as well as the 5’ untranslated region to promote ribosomal complex binding can increase mRNA expression in cells. -Furthermore, purifying out double-stranded RNA and immature RNA with FPLC (fast performance liquid chromatography) and HPLC (high performance liquid chromatography) technology will improve translation of the mRNA in the cell [838,840]. +Furthermore, purifying out double-stranded RNA and immature RNA with FPLC (fast performance liquid chromatography) and HPLC (high performance liquid chromatography) technology will improve translation of the mRNA in the cell [839,841]. Vaccines based on mRNA delivery confer many advantages over traditional viral vectored vaccines and DNA vaccines. -In comparison to live attenuated viruses, mRNA vaccines are non-infectious and can be synthetically produced in an egg-free, cell-free environment, thereby reducing the risk of a detrimental immune response in the host [841]. -Unlike DNA vaccines, mRNA technologies are naturally degradable and non-integrating, and they do not need to cross the nuclear membrane in addition to the plasma membrane for their effects to be seen [838]. +In comparison to live attenuated viruses, mRNA vaccines are non-infectious and can be synthetically produced in an egg-free, cell-free environment, thereby reducing the risk of a detrimental immune response in the host [842]. +Unlike DNA vaccines, mRNA technologies are naturally degradable and non-integrating, and they do not need to cross the nuclear membrane in addition to the plasma membrane for their effects to be seen [839]. Furthermore, mRNA vaccines are easily, affordably, and rapidly scalable.
Although mRNA vaccines have been developed for therapeutic and prophylactic purposes, none have previously been licensed or commercialized. -Nevertheless, they have shown promise in animal models and preliminary clinical trials for several indications, including rabies, coronavirus, influenza, and cytomegalovirus [842]. -Preclinical data previously identified effective antibody generation against full-length FPLC-purified influenza hemagglutinin stalk-encoding mRNA in mice, rabbits, and ferrets [843]. -Similar immunological responses for mRNA vaccines were observed in humans in Phase I and II clinical trials operated by the pharmaceutical-development companies Curevac and Moderna for rabies, flu, and zika [840]. -Positively charged bilayer LNPs carrying the mRNA attract negatively charged cell membranes, endocytose into the cytoplasm [839], and facilitate endosomal escape. -LNPs can be coated with modalities recognized and engulfed by specific cell types, and LNPs that are 150 nm or less effectively enter into lymphatic vessels [839,844]. +Nevertheless, they have shown promise in animal models and preliminary clinical trials for several indications, including rabies, coronavirus, influenza, and cytomegalovirus [843]. +Preclinical data previously identified effective antibody generation against full-length FPLC-purified influenza hemagglutinin stalk-encoding mRNA in mice, rabbits, and ferrets [844]. +Similar immunological responses for mRNA vaccines were observed in humans in Phase I and II clinical trials operated by the pharmaceutical-development companies Curevac and Moderna for rabies, flu, and zika [841]. +Positively charged bilayer LNPs carrying the mRNA attract negatively charged cell membranes, endocytose into the cytoplasm [840], and facilitate endosomal escape. +LNPs can be coated with modalities recognized and engulfed by specific cell types, and LNPs that are 150 nm or less effectively enter into lymphatic vessels [840,845]. Therefore, this technology holds great potential for targeted delivery of modified mRNA.
-There are three types of RNA vaccines: non-replicating, in vivo self-replicating, and in vitro dendritic cell non-replicating [845]. +
There are three types of RNA vaccines: non-replicating, in vivo self-replicating, and in vitro dendritic cell non-replicating [846]. Non-replicating mRNA vaccines consist of a simple open reading frame (ORF) for the viral antigen flanked by the 5’ UTR and 3’ poly-A tail. -In vivo self-replicating vaccines encode a modified viral genome derived from single-stranded, positive sense RNA alphaviruses [838,840]. +In vivo self-replicating vaccines encode a modified viral genome derived from single-stranded, positive sense RNA alphaviruses [839,841]. The RNA genome encodes the viral antigen along with proteins of the genome replication machinery, including an RNA polymerase. -Structural proteins required for viral assembly are not included in the engineered genome [838]. -Self-replicating vaccines produce more viral antigens over a longer period of time, thereby evoking a more robust immune response [845]. +Structural proteins required for viral assembly are not included in the engineered genome [839]. +Self-replicating vaccines produce more viral antigens over a longer period of time, thereby evoking a more robust immune response [846]. Finally, in vitro dendritic cell non-replicating RNA vaccines limit transfection to dendritic cells. Dendritic cells are potent antigen-presenting immune cells that easily take up mRNA and present fragments of the translated peptide on their MHC proteins, which can then interact with T cell receptors. -Ultimately, primed T follicular helper cells can stimulate germinal center B cells that also present the viral antigen to produce antibodies against the virus [846]. -These cells are isolated from the patient, grown and transfected ex vivo, and reintroduced to the patient [847].
+Ultimately, primed T follicular helper cells can stimulate germinal center B cells that also present the viral antigen to produce antibodies against the virus [847]. +These cells are isolated from the patient, grown and transfected ex vivo, and reintroduced to the patient [848].Given the potential for this technology to be quickly adapted for a new pathogen, it has held significant interest for the treatment of COVID-19. -In the vaccines developed under this approach, the spike protein, which is immunogenic [39], can be furnished to the immune system in order to train its response. -The vaccine candidates developed against SARS-CoV-2 using mRNA vectors utilize similar principles and technologies, although there are slight differences in implementation among candidates such as the formulation of the platform and the specific components of the spike protein encapsulated (e.g., the full Spike protein vs. the RBD alone) [848]. +In the vaccines developed under this approach, the spike protein, which is immunogenic [41], can be furnished to the immune system in order to train its response. +The vaccine candidates developed against SARS-CoV-2 using mRNA vectors utilize similar principles and technologies, although there are slight differences in implementation among candidates such as the formulation of the platform and the specific components of the spike protein encapsulated (e.g., the full Spike protein vs. the RBD alone) [849]. The results of the interim analyses of two mRNA vaccine candidates became available at the end of 2020 and provided strong support for this emerging approach to vaccination. Below we describe the results available as of February 2021 for two such candidates, mRNA-1273 produced by ModernaTX and BNT162b2 produced by Pfizer, Inc. and BioNTech.
7.5.1 ModernaTX mRNA Vaccine
ModernaTX’s mRNA-1273 vaccine, which is an was the first COVID-19 vaccine to enter a phase I clinical trial in the United States. -In this trial, Moderna spearheaded an investigation on the immunogenicity and reactogenicity of mRNA-1273, a conventional lipid nanoparticle encapsulated RNA encoding a full-length prefusion stabilized S protein for SARS-CoV-2 [849]. -An initial report described the results of enrolling forty-five participants who were administered intramuscular injections of mRNA-1273 in their deltoid muscle on day 1 and day 29, and then followed for the next twelve months [832]. +In this trial, Moderna spearheaded an investigation on the immunogenicity and reactogenicity of mRNA-1273, a conventional lipid nanoparticle encapsulated RNA encoding a full-length prefusion stabilized S protein for SARS-CoV-2 [850]. +An initial report described the results of enrolling forty-five participants who were administered intramuscular injections of mRNA-1273 in their deltoid muscle on day 1 and day 29, and then followed for the next twelve months [833]. Healthy males and non-pregnant females aged 18-55 years were recruited for this study and divided into three groups receiving 25, 100, or 250 micrograms (μg) of mRNA-1273. -IgG ELISA assays on patient serology samples were used to examine the immunogenicity of the vaccine [849]. +IgG ELISA assays on patient serology samples were used to examine the immunogenicity of the vaccine [850]. Binding antibodies were observed at two weeks after the first dose at all concentrations. At the time point one week after the second dose was administered on day 29, the pseudotyped lentivirus reporter single-round-of-infection neutralization assay (PsVNA), which was used to assess neutralizing activity, reached a median level similar to the median observed in convalescent plasma samples. Participants reported mild and moderate systemic adverse events after the day 1 injection, and one severe local event was observed in each of the two highest dose levels. The second injection led to severe systemic adverse events for three of the participants at the highest dose levels, with one participant in the group being evaluated at an urgent care center on the day after the second dose. The reported localized adverse events from the second dose were similar to those from the first.
-Several months later, a press release from ModernaTX described the results of the first interim analysis of the vaccine [850]. -On November 16, 2020, a report was released describing the initial results from Phase III testing, corresponding to the first 95 cases of COVID-19 in the 30,000 enrolled participants [850], with additional data released to the FDA on December 17, 2020 [851]. -These results were subsequently published in a peer-reviewed journal (The New England Journal of Medicine) on December 30, 2020 [852]. -The first group of 30,420 study participants were randomized to receive the vaccine or a placebo at a ratio of 1:1 [852]. -Administration occurred at 99 sites within the United States in two sessions, spaced 28 days apart [852,853]. -Patients reporting COVID-19 symptoms upon follow-up were tested for SARS-CoV-2 using a nasopharyngeal swab that was evaluated with RT-PCR [853]. +
Several months later, a press release from ModernaTX described the results of the first interim analysis of the vaccine [851]. +On November 16, 2020, a report was released describing the initial results from Phase III testing, corresponding to the first 95 cases of COVID-19 in the 30,000 enrolled participants [851], with additional data released to the FDA on December 17, 2020 [852]. +These results were subsequently published in a peer-reviewed journal (The New England Journal of Medicine) on December 30, 2020 [853]. +The first group of 30,420 study participants were randomized to receive the vaccine or a placebo at a ratio of 1:1 [853]. +Administration occurred at 99 sites within the United States in two sessions, spaced 28 days apart [853,854]. +Patients reporting COVID-19 symptoms upon follow-up were tested for SARS-CoV-2 using a nasopharyngeal swab that was evaluated with RT-PCR [854]. The initial preliminary analysis reported the results of the cases observed up until a cut-off date of November 11, 2020. -Of these first 95 cases reported, 90 occurred in participants receiving the placebo compared to 5 cases in the group receiving the vaccine [850]. +Of these first 95 cases reported, 90 occurred in participants receiving the placebo compared to 5 cases in the group receiving the vaccine [851]. These results suggested the vaccine is 94.5% effective in preventing COVID-19. Additionally, eleven severe cases of COVID-19 were observed, and all eleven occurred in participants receiving the placebo. -The publication reported the results through an extended cut-off date of November 21, 2020, corresponding to 196 cases [852]. +The publication reported the results through an extended cut-off date of November 21, 2020, corresponding to 196 cases [853]. Of these, 11 occurred in the vaccine group and 185 in the placebo group, corresponding to an efficacy of 94.1%. Once again, all of the severe cases of COVID-19 observed (n=30) occurred in the placebo group, including one death. Thus, as more cases are reported, the efficacy of the vaccine has remained above 90%, and no cases of severe COVID-19 have yet been reported in participants receiving the vaccine.
These findings suggest the possibility that the vaccine might bolster immune defenses even for subjects who do still develop a SARS-CoV-2 infection. -The study was designed with an explicit goal of including individuals at high risk for COVID-19, including older adults, people with underlying health conditions, and people of color [854]. -The Phase III trial population was comprised by approximately 25.3% adults over age 65 in the initial report and 24.8% in the publication [853]. -Among the cases reported by both interim analyses, 16-17% occurred in older adults [850,852].. -Additionally, approximately 10% of participants identified a Black or African-American background and 20% identified Hispanic or Latino ethnicity [852,853]. -Among the first 95 cases, 12.6% occurred in participants identifying a Hispanic or Latino background and 4% in participants reporting a Black or African-American background [850]; in the publication, they indicated only that 41 of the cases reported in the placebo group and 1 case in the treatment group occurred in “communities of color”, corresponding to 21.4% of all cases [852]. +The study was designed with an explicit goal of including individuals at high risk for COVID-19, including older adults, people with underlying health conditions, and people of color [855]. +The Phase III trial population was comprised by approximately 25.3% adults over age 65 in the initial report and 24.8% in the publication [854]. +Among the cases reported by both interim analyses, 16-17% occurred in older adults [851,853].. +Additionally, approximately 10% of participants identified a Black or African-American background and 20% identified Hispanic or Latino ethnicity [853,854]. +Among the first 95 cases, 12.6% occurred in participants identifying a Hispanic or Latino background and 4% in participants reporting a Black or African-American background [851]; in the publication, they indicated only that 41 of the cases reported in the placebo group and 1 case in the treatment group occurred in “communities of color”, corresponding to 21.4% of all cases [853]. While the sample size in both analyses is small relative to the study population of over 30,000, these results suggest that the vaccine is likely to be effective in people from a variety of backgrounds. By all indications, this vaccine is likely to be highly useful in mitigating the damage of SARS-CoV-2.
-In-depth safety data was released by ModernaTX as part of their application for an EUA from the FDA and summarized in the associated publication [852,853]. +
In-depth safety data was released by ModernaTX as part of their application for an EUA from the FDA and summarized in the associated publication [853,854]. Because the detail provided in the report is greater than that provided in the publication, here we emphasize the results observed at the time of the first analysis. -Overall, a large percentage of participants reported adverse effects when solicited, and these reports were higher in the vaccine group than in the placebo group (94.5% versus 59.5%, respectively, at the time of the initial analysis) [853]. -Some of these events met the criteria for grade 3 (local or systemic) or grade 4 (systemic only) toxicity [853], but most were grade 1 or grade 2 and lasted 2-3 days [852]. -The most common local adverse reaction was pain at the injection site, reported by 83.7% of participants receiving the first dose of the vaccine and 88.4% upon receiving the second dose, compared to 19.8% and 19.8% and 17.0%, respectively, of patients in the placebo condition [853]. +Overall, a large percentage of participants reported adverse effects when solicited, and these reports were higher in the vaccine group than in the placebo group (94.5% versus 59.5%, respectively, at the time of the initial analysis) [854]. +Some of these events met the criteria for grade 3 (local or systemic) or grade 4 (systemic only) toxicity [854], but most were grade 1 or grade 2 and lasted 2-3 days [853]. +The most common local adverse reaction was pain at the injection site, reported by 83.7% of participants receiving the first dose of the vaccine and 88.4% upon receiving the second dose, compared to 19.8% and 19.8% and 17.0%, respectively, of patients in the placebo condition [854]. Fewer than 5% of vaccine recipients reported grade 3 pain at either administration. -Other frequent local reactions included erythema, swelling, and lymphadenopathy [853]. -For systemic adverse reactions, fatigue was the most common [853]. -Among participants receiving either dose of the vaccine, 68.5% reported fatigue compared to 36.1% participants receiving the placebo [853]. -The level of fatigue experienced was usually fairly mild, with only 9.6% and 1.3% of participants in the vaccine and placebo conditions, respectively, reporting grade 3 fatigue [853], which corresponds to significant interference with daily activity [855]. -Based on the results of the report, an EUA was issued on December 18, 2020 to allow distribution of this vaccine in the United States [856], and it was shortly followed by an Interim Order authorizing distribution of the vaccine in Canada [857] and a conditional marketing authorization by the European Medicines Agency to facilitate distribution in the European Union [858].
+Other frequent local reactions included erythema, swelling, and lymphadenopathy [854]. +For systemic adverse reactions, fatigue was the most common [854]. +Among participants receiving either dose of the vaccine, 68.5% reported fatigue compared to 36.1% participants receiving the placebo [854]. +The level of fatigue experienced was usually fairly mild, with only 9.6% and 1.3% of participants in the vaccine and placebo conditions, respectively, reporting grade 3 fatigue [854], which corresponds to significant interference with daily activity [856]. +Based on the results of the report, an EUA was issued on December 18, 2020 to allow distribution of this vaccine in the United States [857], and it was shortly followed by an Interim Order authorizing distribution of the vaccine in Canada [858] and a conditional marketing authorization by the European Medicines Agency to facilitate distribution in the European Union [859].7.5.2 Pfizer/BioNTech BNT162b2
ModernaTX was, in fact, the second company to release news of a successful interim analysis of an mRNA vaccine and receive an EUA. -The first report came from Pfizer and BioNTech’s mRNA vaccine BNT162b2 on November 9, 2020 [859], and a preliminary report was published in the New England Journal of Medicine one month later [304]. -The vaccine candidate is contains the full prefusion stabilized, membrane-anchored SARS-CoV-2 spike protein in a vaccine formulation based on modified mRNA (modRNA) technology [860,861]. -This vaccine candidate should not be confused with a similar candidate from Pfizer/BioNTech, BNT162b1, that delivered only the RBD of the spike protein [862,863], which was not advanced to a stage III trial because of the improved reactogenicity/immunogenicity profile of BNT162b2 [305].
-During the Phase III trial of BNT162b2, 43,538 participants were enrolled 1:1 in the placebo and the vaccine candidate and received two 30-μg doses 21 days apart [304]. -Of these enrolled participants, 21,720 received BNT162b2 and 21,728 received a placebo [304]. +The first report came from Pfizer and BioNTech’s mRNA vaccine BNT162b2 on November 9, 2020 [860], and a preliminary report was published in the New England Journal of Medicine one month later [306]. +The vaccine candidate is contains the full prefusion stabilized, membrane-anchored SARS-CoV-2 spike protein in a vaccine formulation based on modified mRNA (modRNA) technology [861,862]. +This vaccine candidate should not be confused with a similar candidate from Pfizer/BioNTech, BNT162b1, that delivered only the RBD of the spike protein [863,864], which was not advanced to a stage III trial because of the improved reactogenicity/immunogenicity profile of BNT162b2 [307].
+During the Phase III trial of BNT162b2, 43,538 participants were enrolled 1:1 in the placebo and the vaccine candidate and received two 30-μg doses 21 days apart [306]. +Of these enrolled participants, 21,720 received BNT162b2 and 21,728 received a placebo [306]. Recruitment occurred at 135 sites across six countries: Argentina, Brazil, Germany, South Africa, Turkey, and the United States. -An initial press release described the first 94 cases, which were consistent with 90% efficacy of the vaccine at 7 days following the second dose [859]. +An initial press release described the first 94 cases, which were consistent with 90% efficacy of the vaccine at 7 days following the second dose [860]. The release of the full trial information covered a longer period and analyzed the first 170 cases occurring at least 7 days after the second dose, 8 of which occurred in patients who had received BNT162b2. -The press release characterized the study population as diverse, reporting that 42% of the participants worldwide came from non-white backgrounds, including 10% Black and 26% Hispanic or Latino [864]. -Within the United States, 10% and 13% of participants, respectively, identified themselves as having Black or Hispanic/Latino backgrounds [864]. -Additionally, 41% of participants worldwide were 56 years of age or older [864], and they reported that the efficacy of the vaccine in adults over 65 was 94% [865]. -The primary efficacy analysis of the Phase III study was concluded on November 18, 2020 [865], and the final results indicted 94.6% efficacy of the vaccine [304]v.
-The safety profile of the vaccine was also assessed [304]. +The press release characterized the study population as diverse, reporting that 42% of the participants worldwide came from non-white backgrounds, including 10% Black and 26% Hispanic or Latino [865]. +Within the United States, 10% and 13% of participants, respectively, identified themselves as having Black or Hispanic/Latino backgrounds [865]. +Additionally, 41% of participants worldwide were 56 years of age or older [865], and they reported that the efficacy of the vaccine in adults over 65 was 94% [866]. +The primary efficacy analysis of the Phase III study was concluded on November 18, 2020 [866], and the final results indicted 94.6% efficacy of the vaccine [306]v.
+The safety profile of the vaccine was also assessed [306]. A subset of patients were followed for reactogenicity using electronic diaries, with the data collected from these 8,183 participants comprising the solicited safety events analyzed. Much like those who received the ModernaTX vaccine candidate, a large proportion of participants reported experiencing site injection pain within 7 days of vaccination. While percentages are broken down by age group in the publication, these proportions correspond to approximately 78% and 73% of all participants after the first and second doses, respectively, overall. @@ -2764,8 +2765,8 @@
[866,867].
-As of December 11, 2020, the United States FDA approved this vaccine under an emergency use authorization [868].
+Based on the efficacy and safety information released, the vaccine was approved in early December by the United Kingdom’s Medicines and Healthcare Products Regulatory Agency with administration outside of a clinical trial beginning on December 8, 2020 [867,868].
+As of December 11, 2020, the United States FDA approved this vaccine under an emergency use authorization [869].
7.6 Viral Vector Vaccines
7.6.1 COVID-19 Vaccine AstraZeneca
7.6.2 Sputnik-V
@@ -2784,121 +2785,121 @@ also included a brief summary of the potential of adjuvants for these vaccines, including a brief description of some already commonly used adjuvants.
+A review on the development of SARS-CoV-2 vaccines [870] also included a brief summary of the potential of adjuvants for these vaccines, including a brief description of some already commonly used adjuvants.
Different adjuvants can regulate different types of immune responses, so the type or combination of adjuvants used in a vaccine will depend on both the type of vaccine and concern related to efficacy and safety.
-A variety of possible mechanisms for adjuvants have been researched [870,871,872], including the following: induction of DAMPs that can be recognized by certain PRRs of the innate immune system; functioning as PAMP that can also be recognized by certain PRRs; and more generally enhancing the humoral or cellular immune responses.
+A variety of possible mechanisms for adjuvants have been researched [871,872,873], including the following: induction of DAMPs that can be recognized by certain PRRs of the innate immune system; functioning as PAMP that can also be recognized by certain PRRs; and more generally enhancing the humoral or cellular immune responses.
Selection of one or more adjuvants requires considering how to promote the advantageous effects of the components and/or immune response and, likewise, to inhibit possible deleterious effects.
There are also considerations related to the method of delivering (or co-delivering) the adjuvant and antigen components of a vaccine.
7.10.2 Trained Immunity
7.10.2 Trained Immunity
Another approach that is being investigated explores the potential for vaccines that are not made from the SARS-CoV-2 virus to confer what has been termed trained immunity. -In a recent review [873], trained immunity was defined as forms of memory that are temporary (e.g., months or years) and reversible. +In a recent review [874], trained immunity was defined as forms of memory that are temporary (e.g., months or years) and reversible. It is induced by exposure to whole-microorganism vaccines or other microbial stimuli that generates heterologous protective effects. Trained immunity can be displayed by innate immune cells or innate immune features of other cells, and it is characterized by alterations to immune responsiveness to future immune challenges due to epigenetic and metabolic mechanisms. These alterations can take the form of either an increased or decreased response to immune challenge by a pathogen. -Trained immunity elicited by non-SARS-CoV-2 whole-microorganism vaccines could potentially improve SARS-CoV-2 susceptibility or severity [874].
+Trained immunity elicited by non-SARS-CoV-2 whole-microorganism vaccines could potentially improve SARS-CoV-2 susceptibility or severity [875].One type of stimulus which research indicates can induce trained immunity is bacillus Calmette-Guerin (BCG) vaccination. BCG is an attenuated form of bacteria Mycobacterium bovis. The vaccine is most commonly administered for the prevention of tuberculosis in humans. Clinical trials in non-SARS-CoV-2-infected adults have been designed to assess whether BCG vaccination could have prophylactic effects against SARS-CoV-2 by reducing susceptibility, preventing infection, or reducing disease severity. -A number of trials are now evaluating the effects of the BCG vaccine or the related vaccine VPM1002 [874,875,876,877,878,879,880,881,882,883,884,885,886,887,888].
+A number of trials are now evaluating the effects of the BCG vaccine or the related vaccine VPM1002 [875,876,877,878,879,880,881,882,883,884,885,886,887,888,889].The ongoing trials are using a number of different approaches. Some trials enroll healthcare workers, other trials hospitalized elderly adults without immunosuppression who get vaccinated with placebo or BCG at hospital discharge, and yet another set of trials older adults (>50 years) under chronic care for conditions like hypertension and diabetes. One set of trials, for example, uses time until first infection as the primary study endpoint; more generally, outcomes measured in some of these trials are related to incidence of disease and disease severity or symptoms. -Some analyses have suggested a possible correlation at the country level between the frequency of BCG vaccination (or BCG vaccination policies) and the severity of COVID-19 [874]. +Some analyses have suggested a possible correlation at the country level between the frequency of BCG vaccination (or BCG vaccination policies) and the severity of COVID-19 [875]. Currently it is unclear whether this correlation has any connection to trained immunity. Many possible confounding factors are also likely to vary among countries, such as age distribution, detection efficiency, stochastic epidemic dynamic effects, differences in healthcare capacity over time in relation to epidemic dynamics, and these have not been adequately accounted for in current analyses. It is unclear whether there is an effect of the timing of BCG vaccination, both during an individual’s life cycle and relative to the COVID-19 pandemic. -Additionally, given that severe SARS-CoV-2 may be associated with a dysregulated immune response, it is unclear what alterations to the immune response would be most likely to be protective versus pathogenic (e.g., [112,874,889,890]). -The article [874] proposes that trained immunity might lead to an earlier and stronger response, which could in turn reduce viremia and the risk of later, detrimental immunopathology. +Additionally, given that severe SARS-CoV-2 may be associated with a dysregulated immune response, it is unclear what alterations to the immune response would be most likely to be protective versus pathogenic (e.g., [114,875,890,891]). +The article [875] proposes that trained immunity might lead to an earlier and stronger response, which could in turn reduce viremia and the risk of later, detrimental immunopathology. While trained immunity is an interesting possible avenue to complement vaccine development efforts through the use of an existing vaccine, additional research is required to assess whether the BCG vaccine is likely to confer trained immunity in the case of SARS-CoV-2.
7.11 Discussion
Additionally, major advances in vaccines using mRNA and adenoviruses that have led to three vaccines becoming available or close to becoming available in late 2020 (Figure 4).
Though some concerns remain about the duration of sustained immunity for convalescents, vaccine development efforts are ongoing and show initial promising results. The Moderna trial, for example, reported that the neutralizing activity in participants who received two doses of the vaccine was similar to that observed in convalescent plasma.
-One of the two mRNA vaccines, Pfizer and BioNTech’s BNT162b2, has been issued an EUA for patients as young as 16 [891], while ModernaTX has begun a clinical trial to assess its mRNA vaccine in adolescents ages 12 to 18 [892].
+One of the two mRNA vaccines, Pfizer and BioNTech’s BNT162b2, has been issued an EUA for patients as young as 16 [892], while ModernaTX has begun a clinical trial to assess its mRNA vaccine in adolescents ages 12 to 18 [893].
8 Social Factors Influencing COVID-19 Exposure and Outcomes
8.1 Social Factors Influencing COVID-19 Outcomes
In addition to understanding the fundamental biology of the SARS-CoV-2 virus and COVID-19, it is critical to consider how the broader environment can influence both COVID-19 outcomes and efforts to develop and implement treatments for the disease. The evidence clearly indicates that social environmental factors are critical determinants of individuals’ and communities’ risks related to COVID-19. There are distinct components to COVID-19 susceptibility, and an individual’s risk can be elevated at one or all stages from exposure to recovery/mortality: an individual may be more likely to be exposed to the virus, more likely to get infected once exposed, more likely to have serious complications once infected, and be less likely to receive adequate care once they are seriously ill. -The fact that differences in survival between Black and white patients were no longer significant after controlling for comorbidities and socioeconomic status (type of insurance, neighborhood deprivation score, and hospital where treatment was received) in addition to sex and age [893] underscores the relevance of social factors to understanding mortality differences between racial and ethnic groups. -Moreover, the Black patients were younger and more likely to be female than white patients, yet still had a higher mortality rate without correction for the other variables [893]. +The fact that differences in survival between Black and white patients were no longer significant after controlling for comorbidities and socioeconomic status (type of insurance, neighborhood deprivation score, and hospital where treatment was received) in addition to sex and age [894] underscores the relevance of social factors to understanding mortality differences between racial and ethnic groups. +Moreover, the Black patients were younger and more likely to be female than white patients, yet still had a higher mortality rate without correction for the other variables [894]. Here, we outline a few systemic reasons that may exacerbate the COVID-19 pandemic in communities of color.
8.2 Factors Observed to be Associated with Susceptibility
As COVID-19 has spread into communities around the globe, it has become clear that the risks associated with this disease are not equally shared by all individuals or all communities. Significant disparities in outcomes have led to interest in the demographic, biomedical, and social factors that influence COVID-19 severity. Untangling the factors influencing COVID-19 susceptibility is a complex undertaking. -Among patients who are admitted to the hospital, outcomes have generally been poor, with rates of admission to the intensive care unit (ICU) upwards of 15% in both Wuhan, China and Italy [34,894,895]. -However, hospitalization rates vary by location [896]. +Among patients who are admitted to the hospital, outcomes have generally been poor, with rates of admission to the intensive care unit (ICU) upwards of 15% in both Wuhan, China and Italy [36,895,896]. +However, hospitalization rates vary by location [897]. This variation may be influenced by demographic (e.g., average age in the area), medical (e.g., the prevalence of comorbid conditions such as diabetes), and social (e.g., income or healthcare availability) factors that vary geographically. Additionally, some of the same factors may influence an individual’s probability of exposure to SARS-CoV-2, their risk of developing a more serious case of COVID-19 that would require hospitalization, and their access to medical support. As a result, quantifying or comparing susceptibility among individuals, communities, or other groups requires consideration of a number of complex phenomena that intersect across many disciplines of research. In this section, the term “risk factor” is used to refer to variables that are statistically associated with more severe COVID-19 outcomes. Some are intrinsic characteristics that have been observed to carry an association with variation in outcomes, whereas others may be more functionally linked to the pathophysiology of COVID-19.
8.2.1 Patient Traits Associated with Increased Risk
-Two traits that have been consistently associated with more severe COVID-19 outcomes are male sex and advanced age (typically defined as 60 or older, with the greatest risk among those 85 and older [897]). -In the United States, males and older individuals diagnosed with COVID-19 were found to be more likely to require hospitalization [898,899]. -A retrospective study of hospitalized Chinese patients [35] found that a higher probability of mortality was associated with older age, and world-wide, population age structure has been found to be an important variable for explaining differences in outbreak severity [900]. -The CFR for adults over 80 has been estimated upwards of 14% or even 20% [901]. -Male sex has also been identified as a risk factor for severe COVID-19 outcomes, including death [902,903,904]. -Early reports from China and Europe indicated that even though the case rates were similar across males and females, males were at elevated risk for hospital admission, ICU admission, and death [903], although data from some US states indicates more cases among females, potentially due to gender representation in care-taking professions [905]. -In older age groups (e.g., age 60 and older), comparable absolute numbers of male and female cases actually suggests a higher rate of occurrence in males, due to increased skew in the sex ratio [903]. -Current estimates based on worldwide data suggest that, compared to females, males may be 30% more likely to be hospitalized, 80% more likely to be admitted to the ICU, and 40% more likely to die as a result of COVID-19 [904]. -There also may be a compounding effect of advanced age and male sex, with differences time to recovery worst for males over 60 years old relative to female members of their age cohort [906].
+Two traits that have been consistently associated with more severe COVID-19 outcomes are male sex and advanced age (typically defined as 60 or older, with the greatest risk among those 85 and older [898]). +In the United States, males and older individuals diagnosed with COVID-19 were found to be more likely to require hospitalization [899,900]. +A retrospective study of hospitalized Chinese patients [37] found that a higher probability of mortality was associated with older age, and world-wide, population age structure has been found to be an important variable for explaining differences in outbreak severity [901]. +The CFR for adults over 80 has been estimated upwards of 14% or even 20% [902]. +Male sex has also been identified as a risk factor for severe COVID-19 outcomes, including death [903,904,905]. +Early reports from China and Europe indicated that even though the case rates were similar across males and females, males were at elevated risk for hospital admission, ICU admission, and death [904], although data from some US states indicates more cases among females, potentially due to gender representation in care-taking professions [906]. +In older age groups (e.g., age 60 and older), comparable absolute numbers of male and female cases actually suggests a higher rate of occurrence in males, due to increased skew in the sex ratio [904]. +Current estimates based on worldwide data suggest that, compared to females, males may be 30% more likely to be hospitalized, 80% more likely to be admitted to the ICU, and 40% more likely to die as a result of COVID-19 [905]. +There also may be a compounding effect of advanced age and male sex, with differences time to recovery worst for males over 60 years old relative to female members of their age cohort [907].
Both of these risk factors can be approached through the lens of biology. -The biological basis for greater susceptibility with age is likely linked to the prevalence of extenuating health conditions such as heart failure or diabetes [901]. +The biological basis for greater susceptibility with age is likely linked to the prevalence of extenuating health conditions such as heart failure or diabetes [902]. Several hypotheses have been proposed to account for differences in severity between males and females. -For example, some evidence suggests that female sex hormones may be protective [903,905]. -ACE2 expression in the kidneys of male mice was observed to be twice as high as that of females, and a regulatory effect of estradiol on ACE2 expression was demonstrated by removing the gonads and then supplementing with estradiol [905,907]. -Other work in mice has shown an inverse association between mortality due to SARS-CoV-1 and estradiol, suggesting a protective role for the sex hormone [905]. +For example, some evidence suggests that female sex hormones may be protective [904,906]. +ACE2 expression in the kidneys of male mice was observed to be twice as high as that of females, and a regulatory effect of estradiol on ACE2 expression was demonstrated by removing the gonads and then supplementing with estradiol [906,908]. +Other work in mice has shown an inverse association between mortality due to SARS-CoV-1 and estradiol, suggesting a protective role for the sex hormone [906]. Similarly, evidence suggests that similar patterns might be found in other tissues. -A preliminary analysis identified higher levels of ACE2 expression in the myocardium of male patients with aortic valve stenosis showed than female patients, although this pattern was not found in controls [903]. -Additionally, research has indicated that females respond to lower doses than males of heart medications that act on the Renin angiotensin aldosterone system (RAAS) pathway, which is shared with ACE2 [903]. -Additionally, several components of the immune response, including the inflammatory response, may differ in intensity and timing between males and females [905,907]. -This hypothesis is supported by some preliminary evidence showing that female patients who recovered from severe COVID-19 had higher antibody titers than males [905]. -Sex steroids can also bind to immune cell receptors to influence cytokine production [903]. -Additionally, social factors may influence risks related to both age and sex: for example, older adults are more likely to live in care facilities, which have been a source for a large number of outbreaks [908], and gender roles may also influence exposure and/or susceptibility due to differences in care-taking and/or risky behaviors (e.g., caring for elder relatives and smoking, respectively) [903] among men and women (however, it should be noted that both transgender men and women are suspected to be at heightened risk [909].)
+A preliminary analysis identified higher levels of ACE2 expression in the myocardium of male patients with aortic valve stenosis showed than female patients, although this pattern was not found in controls [904]. +Additionally, research has indicated that females respond to lower doses than males of heart medications that act on the Renin angiotensin aldosterone system (RAAS) pathway, which is shared with ACE2 [904]. +Additionally, several components of the immune response, including the inflammatory response, may differ in intensity and timing between males and females [906,908]. +This hypothesis is supported by some preliminary evidence showing that female patients who recovered from severe COVID-19 had higher antibody titers than males [906]. +Sex steroids can also bind to immune cell receptors to influence cytokine production [904]. +Additionally, social factors may influence risks related to both age and sex: for example, older adults are more likely to live in care facilities, which have been a source for a large number of outbreaks [909], and gender roles may also influence exposure and/or susceptibility due to differences in care-taking and/or risky behaviors (e.g., caring for elder relatives and smoking, respectively) [904] among men and women (however, it should be noted that both transgender men and women are suspected to be at heightened risk [910].)8.2.2 Comorbid Health Conditions
A number of pre-existing or comorbid conditions have repeatedly been identified as risk factors for more severe COVID-19 outcomes. -Several underlying health conditions were identified at high prevalence among hospitalized patients, including obesity, diabetes, hypertension, lung disease, and cardiovascular disease [896]. -Higher Sequential Organ Failure Assessment (SOFA) scores have been associated with a higher probability of mortality [35], and comorbid conditions such as cardiovascular and lung disease as well as obesity were also associated with an increased risk of hospitalization and death, even when correcting for age and sex [902]. -Diabetes may increase the risk of lengthy hospitalization [910] or of death [910,911]. -[912] and [913] discuss possible ways in which COVID-19 and diabetes may interact. -Obesity also appears to be associated with higher risk of severe outcomes from SARS-CoV-2 [914,915]. -Obesity is considered an underlying risk factor for other health problems, and the mechanism for its contributions to COVID-19 hospitalization or mortality is not yet clear [916]. -Dementia and cancer were also associated with the risk of death in an analysis of a large number (more than 20,000) COVID-19 patients in the United Kingdom [902]. -It should be noted that comorbid conditions are inextricably tied to age, as conditions tend to be accumulated over time, but that the prevalence of individual comorbidities or of population health overall can vary regionally [917]. -Several comorbidities that are highly prevalent in older adults, such as COPD, hypertension, cardiovascular disease, and diabetes, have been associated with CFRs upwards of 8% compared to an estimate of 1.4% in people without comorbidities [901,918]. -Therefore, both age and health are important considerations when predicting the impact of COVID-19 on a population [917]. -However, other associations may exist, such as patients with sepsis having higher SOFA scores – in fact, SOFA was developed for the assessment of organ failure in the context of sepsis, and the acronym originally stood for Sepsis-Related Organ Failure Assessment [919,920]. +Several underlying health conditions were identified at high prevalence among hospitalized patients, including obesity, diabetes, hypertension, lung disease, and cardiovascular disease [897]. +Higher Sequential Organ Failure Assessment (SOFA) scores have been associated with a higher probability of mortality [37], and comorbid conditions such as cardiovascular and lung disease as well as obesity were also associated with an increased risk of hospitalization and death, even when correcting for age and sex [903]. +Diabetes may increase the risk of lengthy hospitalization [911] or of death [911,912]. +[913] and [914] discuss possible ways in which COVID-19 and diabetes may interact. +Obesity also appears to be associated with higher risk of severe outcomes from SARS-CoV-2 [915,916]. +Obesity is considered an underlying risk factor for other health problems, and the mechanism for its contributions to COVID-19 hospitalization or mortality is not yet clear [917]. +Dementia and cancer were also associated with the risk of death in an analysis of a large number (more than 20,000) COVID-19 patients in the United Kingdom [903]. +It should be noted that comorbid conditions are inextricably tied to age, as conditions tend to be accumulated over time, but that the prevalence of individual comorbidities or of population health overall can vary regionally [918]. +Several comorbidities that are highly prevalent in older adults, such as COPD, hypertension, cardiovascular disease, and diabetes, have been associated with CFRs upwards of 8% compared to an estimate of 1.4% in people without comorbidities [902,919]. +Therefore, both age and health are important considerations when predicting the impact of COVID-19 on a population [918]. +However, other associations may exist, such as patients with sepsis having higher SOFA scores – in fact, SOFA was developed for the assessment of organ failure in the context of sepsis, and the acronym originally stood for Sepsis-Related Organ Failure Assessment [920,921]. Additionally, certain conditions are likely to be more prevalent under or exacerbated by social conditions, especially poverty, as is discussed further below.
8.2.3 Ancestry
A number of studies have suggested associations between individuals’ racial and ethnic backgrounds and their COVID-19 risk. -In particular, Black Americans are consistently identified as carrying a higher burden of COVID-19 than white Americans [898,899], with differences in the rates of kidney complications from COVID-19 particularly pronounced [94]. -Statistics from a number of cities indicate significant discrepancies between the proportion of COVID-19 cases and deaths in Black Americans relative to their representation in the general population [921]. -In addition to Black Americans, disproportionate harm and mortality from COVID-19 has also been noted in Latino/Hispanic Americans and in Native American and Alaskan Native communities, including the Navajo nation [922,923,924,925,926,927]. -In Brazil, indigenous communities likewise carry an increased burden of COVID-19 [928]. -In the United Kingdom, nonwhite ethnicity (principally Black or South Asian) was one of several factors found to be associated with a higher risk of death from COVID-19 [929].
+In particular, Black Americans are consistently identified as carrying a higher burden of COVID-19 than white Americans [899,900], with differences in the rates of kidney complications from COVID-19 particularly pronounced [96]. +Statistics from a number of cities indicate significant discrepancies between the proportion of COVID-19 cases and deaths in Black Americans relative to their representation in the general population [922]. +In addition to Black Americans, disproportionate harm and mortality from COVID-19 has also been noted in Latino/Hispanic Americans and in Native American and Alaskan Native communities, including the Navajo nation [923,924,925,926,927,928]. +In Brazil, indigenous communities likewise carry an increased burden of COVID-19 [929]. +In the United Kingdom, nonwhite ethnicity (principally Black or South Asian) was one of several factors found to be associated with a higher risk of death from COVID-19 [930].From a genetic standpoint, it is highly unlikely that ancestry itself predisposes individuals to contracting COVID-19 or to experiencing severe COVID-19 outcomes. -Examining human genetic diversity indicates variation over a geographic continuum, and that most human genetic variation is associated with the African continent [930]. -African-Americans are also a more genetically diverse group relative to European-Americans, with a large number of rare alleles and a much smaller fraction of common alleles identified in African-Americans [931]. -Therefore, the idea that African ancestry (at the continent level) might convey some sort of genetic risk for severe COVID-19 contrasts with what is known about worldwide human genetic diversity [932]. +Examining human genetic diversity indicates variation over a geographic continuum, and that most human genetic variation is associated with the African continent [931]. +African-Americans are also a more genetically diverse group relative to European-Americans, with a large number of rare alleles and a much smaller fraction of common alleles identified in African-Americans [932]. +Therefore, the idea that African ancestry (at the continent level) might convey some sort of genetic risk for severe COVID-19 contrasts with what is known about worldwide human genetic diversity [933]. The possibility for genetic variants that confer some risk or some protection remains possible, but has not been widely explored, especially at a global level. -Research in Beijing of a small number (n=80) hospitalized COVID-19 patients revealed an association between severe COVID-19 outcomes and homozygosity for an allele in the interferon-induced transmembrane protein 3 (IFITM3) gene, which was selected as a candidate because it was previously found to be associated with influenza outcomes in Chinese patients [933]. -Genetic factors may also play a role in the risk of respiratory failure for COVID-19 [934,935,936]. +Research in Beijing of a small number (n=80) hospitalized COVID-19 patients revealed an association between severe COVID-19 outcomes and homozygosity for an allele in the interferon-induced transmembrane protein 3 (IFITM3) gene, which was selected as a candidate because it was previously found to be associated with influenza outcomes in Chinese patients [934]. +Genetic factors may also play a role in the risk of respiratory failure for COVID-19 [935,936,937]. However, genetic variants associated with outcomes within ancestral groups are far less surprising than genetic variants explaining outcomes between groups. -Alleles in ACE2 and TMPRSS2 have been identified that vary in frequency among ancestral groups [937], but whether these variants are associated with COVID-19 susceptibility has not been explored.
+Alleles in ACE2 and TMPRSS2 have been identified that vary in frequency among ancestral groups [938], but whether these variants are associated with COVID-19 susceptibility has not been explored.Instead, examining patterns of COVID-19 susceptibility on a global scale that suggest that social factors are of primary importance in predicting mortality. Reports from several sub-Saharan African countries have indicated that the effects of the COVID-19 pandemic have been less severe than expected based on the outbreaks in China and Italy. -In Kenya, for example, estimates of national prevalence based on testing blood donors for SARS-CoV-2 antibodies were consistent with 5% of Kenyan adults having recovered from COVID-19 [938]. -This high seroprevalence of antibodies lies in sharp contrast to the low number of COVID-19 fatalities in Kenya, which at the time was 71 out of 2093 known cases [938]. -Likewise, a serosurvey of health care workers in Blantyre City, Malawi reported an adjusted antibody prevalence of 12.3%, suggesting that the virus had been circulating more widely than thought and that the death rate was up eight times lower than models had predicted [939]. -While several possible hypotheses for the apparent reduced impact of COVID-19 on the African continent are being explored, such as young demographics in many places [940], these reports present a stark contrast to the severity of COVID-19 in Americans and Europeans of African descent. -Additionally, ethnic minorities in the United Kingdom also tend to be younger than white British living in the same areas, yet the burden of COVID-19 is still more serious for minorities, especially people of Black Caribbean ancestry, both in absolute numbers and when controlling for age and location [941]. +In Kenya, for example, estimates of national prevalence based on testing blood donors for SARS-CoV-2 antibodies were consistent with 5% of Kenyan adults having recovered from COVID-19 [939]. +This high seroprevalence of antibodies lies in sharp contrast to the low number of COVID-19 fatalities in Kenya, which at the time was 71 out of 2093 known cases [939]. +Likewise, a serosurvey of health care workers in Blantyre City, Malawi reported an adjusted antibody prevalence of 12.3%, suggesting that the virus had been circulating more widely than thought and that the death rate was up eight times lower than models had predicted [940]. +While several possible hypotheses for the apparent reduced impact of COVID-19 on the African continent are being explored, such as young demographics in many places [941], these reports present a stark contrast to the severity of COVID-19 in Americans and Europeans of African descent. +Additionally, ethnic minorities in the United Kingdom also tend to be younger than white British living in the same areas, yet the burden of COVID-19 is still more serious for minorities, especially people of Black Caribbean ancestry, both in absolute numbers and when controlling for age and location [942]. Furthermore, the groups in the United States and United Kingdom that have been identified as carrying elevated COVID-19 burden, namely Black American, indigenous American, and Black and South Asian British, are quite distinct in their position on the human ancestral tree. What is shared across these groups is instead a history of disenfranchisement under colonialism and ongoing systematic racism. -A large analysis of over 11,000 COVID-19 patients hospitalized in 92 hospitals across U.S. states revealed that Black patients were younger, more often female, more likely to be on Medicaid, more likely to have comorbidities, and came from neighborhoods identified as more economically deprived than white patients [893]. +A large analysis of over 11,000 COVID-19 patients hospitalized in 92 hospitals across U.S. states revealed that Black patients were younger, more often female, more likely to be on Medicaid, more likely to have comorbidities, and came from neighborhoods identified as more economically deprived than white patients [894]. This study reported that when these factors were accounted for, the differences in mortality between Black and white patients were no longer significant. Thus, the current evidence suggests that the apparent correlations between ancestry and health outcomes must be examined in the appropriate social context.
8.3 Environmental Influences on Susceptibility
@@ -2906,83 +2907,83 @@. -A linear relationship was observed between counties’ reduction in mobility and their wealth and health, as measured by access to health care, food security, income, space, and other factors [942]. -Counties with greater reductions in mobility were also found to have much lower child poverty and household crowding and to be more racially segregated, and to have fewer youth and more elderly residents [942]. -Similar associations between wealth and decreased mobility were observed in cellphone GPS data from Colombia, Indonesia, and Mexico collected between January and May 2020 [943], as well as in a very large data set from several US cities [944]. +In U.S. counties with and without stay-at-home orders, smartphone tracking indicated a significant decrease in the general population’s mobility in April relative to February through March of 2020 (-52.3% and -60.8%, respectively) [943]. +A linear relationship was observed between counties’ reduction in mobility and their wealth and health, as measured by access to health care, food security, income, space, and other factors [943]. +Counties with greater reductions in mobility were also found to have much lower child poverty and household crowding and to be more racially segregated, and to have fewer youth and more elderly residents [943]. +Similar associations between wealth and decreased mobility were observed in cellphone GPS data from Colombia, Indonesia, and Mexico collected between January and May 2020 [944], as well as in a very large data set from several US cities [945]. These disparities in mobility are likely to be related to the role that essential workers have played during the pandemic. -Essential workers are disproportionately likely to be female, people of color, immigrants, and to have an income below 200% of the poverty line [945]. -Black Americans in particular are over-represented among front-line workers and in professions where social distancing is infeasible [946]. -Health care work in particular presents an increased risk of exposure to SARS-CoV-2 [946,947,948,949,950]. -In the United Kingdom, (South) Asians are more likely than their white counterparts to be medical professionals [941], although BAME medical professionals are still disproportionately represented in the proportion of National Health Service staff deaths [951]. -Similar trends have been reported for nurses, especially nurses of color, in the United States [952]. -Furthermore, beyond the risks associated with work itself, use of public transportation may also impact COVID-19 risk [953]. +Essential workers are disproportionately likely to be female, people of color, immigrants, and to have an income below 200% of the poverty line [946]. +Black Americans in particular are over-represented among front-line workers and in professions where social distancing is infeasible [947]. +Health care work in particular presents an increased risk of exposure to SARS-CoV-2 [947,948,949,950,951]. +In the United Kingdom, (South) Asians are more likely than their white counterparts to be medical professionals [942], although BAME medical professionals are still disproportionately represented in the proportion of National Health Service staff deaths [952]. +Similar trends have been reported for nurses, especially nurses of color, in the United States [953]. +Furthermore, beyond the risks associated with work itself, use of public transportation may also impact COVID-19 risk [954]. The socioeconomic and racial/ethnic gaps in who is working on the front lines of the pandemic make it clear that socioeconomic privilege is likely to decrease the probability of exposure to SARS-CoV-2.
Increased risk of exposure can also arise outside the workplace. -Nursing homes and skilled nursing facilities received attention early on as high-risk locations for COVID-19 outbreaks [954]. -Prisons and detention centers also confer a high risk of exposure or infection [955,956]. -Populations in care facilities are largely older adults, and in the United States, incarcerated people are more likely to be male and persons of color, especially Black [957]. -Additionally, multi-generational households are less common among non-Hispanic white Americans than people of other racial and ethnic backgrounds [958], increasing the risk of exposure for more susceptible family members. -Analysis suggests that household crowding may also be associated with increased risk of COVID-19 exposure [942], and household crowding is associated with poverty [959]. -Forms of economic insecurity like housing insecurity, which is associated with poverty and more pronounced in communities subjected to racism [960,961], would be likely to increase household crowding and other possible sources of exposure. +Nursing homes and skilled nursing facilities received attention early on as high-risk locations for COVID-19 outbreaks [955]. +Prisons and detention centers also confer a high risk of exposure or infection [956,957]. +Populations in care facilities are largely older adults, and in the United States, incarcerated people are more likely to be male and persons of color, especially Black [958]. +Additionally, multi-generational households are less common among non-Hispanic white Americans than people of other racial and ethnic backgrounds [959], increasing the risk of exposure for more susceptible family members. +Analysis suggests that household crowding may also be associated with increased risk of COVID-19 exposure [943], and household crowding is associated with poverty [960]. +Forms of economic insecurity like housing insecurity, which is associated with poverty and more pronounced in communities subjected to racism [961,962], would be likely to increase household crowding and other possible sources of exposure. As a result, facets of systemic inequality such as mass incarceration of Black Americans and poverty are likely to increase the risk of exposure outside of the workplace.
8.3.2 Severity of COVID-19 Following Exposure
Following exposure to SARS-CoV-2, the likelihood that an individual develops COVID-19 and the severity of the disease presentation can be influenced by a number of social factors. As discussed above, a number of patient characteristics are associated with the likelihood of severe COVID-19 symptoms. -In some cases, these trends run counter to those expected given rates of exposure: for example, although women are more likely to be exposed, men are more likely to be diagnosed with, hospitalized from, or die from COVID-19 [905]. +In some cases, these trends run counter to those expected given rates of exposure: for example, although women are more likely to be exposed, men are more likely to be diagnosed with, hospitalized from, or die from COVID-19 [906]. In the case of comorbid conditions and racial/ethnic demographics, however, social factors are highly likely to modulate or at least influence the apparent association between these traits and the increased risk from COVID-19. In particular, the comorbidities and racial/ethnic correlates of severe COVID-19 outcomes suggest that poverty confers additional risk for COVID-19.
In order to explore the relationship between poverty and COVID-19 outcomes, it is necessary to consider how poverty impacts biology. In particular, we focus on the United States and the United Kingdom. -Comorbidities that increase risk for COVID-19, including obesity, type II diabetes, hypertension, and cardiovascular disease, are known to be intercorrelated [962]. -Metabolic conditions related to heightened inflammation, like obesity, type II diabetes, and hypertension, are more strongly associated with negative COVID-19 outcomes than other comorbid conditions, such as chronic heart disease [963]. +Comorbidities that increase risk for COVID-19, including obesity, type II diabetes, hypertension, and cardiovascular disease, are known to be intercorrelated [963]. +Metabolic conditions related to heightened inflammation, like obesity, type II diabetes, and hypertension, are more strongly associated with negative COVID-19 outcomes than other comorbid conditions, such as chronic heart disease [964]. As discussed above, dysregulated inflammation characteristic of cytokine release syndrome is one of the greatest concerns for COVID-19-related death. -Therefore, it is possible that chronic inflammation characteristic of these metabolic conditions predisposes patients to COVID-19-related death [963]. -The association between these diseases and severe COVID-19 outcomes is a concern from a health equity perspective because poverty exposes people to “obesogenic” conditions [964] and is therefore unsurprisingly associated with higher incidence of obesity and associated disorders [965]. -Furthermore, cell phone GPS data suggests that lower socioeconomic status may also be associated with decreased access to healthy food choices during the COVID-19 pandemic [966,967], suggesting that health-related risk factors for COVID-19 may be exacerbated as the pandemic continues [968]. -Chronic inflammation is a known outcome of chronic stress (e.g., [969,970,971,972]). -Therefore, the chronic stress of poverty is likely to influence health broadly (as summarized in [973]) and especially during the stress of the ongoing pandemic.
-A preprint [974] provided observational evidence that geographical areas in the United States that suffer from worse air pollution by fine particulate matter have also suffered more COVID-19 deaths per capita, after adjusting for demographic covariates. -Although lack of individual-level exposure data and the impossibility of randomization make it difficult to elucidate the exact causal mechanism, this finding would be consistent with similar findings for all-cause mortality (e.g., [975]). -Exposure to air pollution is associated with both poverty (e.g., [976]) and chronic inflammation [977]. -Other outcomes of environmental racism, such as the proximity of abandoned uranium mines to Navajo land, can also cause respiratory illnesses and other health issues [927]. -Similarly, preliminary findings indicate that nutritional status (e.g., vitamin D deficiency [719]) may be associated with COVID-19 outcomes, and reduced access to grocery stores and fresh food often co-occurs with environmental racism [927,978]. +Therefore, it is possible that chronic inflammation characteristic of these metabolic conditions predisposes patients to COVID-19-related death [964]. +The association between these diseases and severe COVID-19 outcomes is a concern from a health equity perspective because poverty exposes people to “obesogenic” conditions [965] and is therefore unsurprisingly associated with higher incidence of obesity and associated disorders [966]. +Furthermore, cell phone GPS data suggests that lower socioeconomic status may also be associated with decreased access to healthy food choices during the COVID-19 pandemic [967,968], suggesting that health-related risk factors for COVID-19 may be exacerbated as the pandemic continues [969]. +Chronic inflammation is a known outcome of chronic stress (e.g., [970,971,972,973]). +Therefore, the chronic stress of poverty is likely to influence health broadly (as summarized in [974]) and especially during the stress of the ongoing pandemic.
+A preprint [975] provided observational evidence that geographical areas in the United States that suffer from worse air pollution by fine particulate matter have also suffered more COVID-19 deaths per capita, after adjusting for demographic covariates. +Although lack of individual-level exposure data and the impossibility of randomization make it difficult to elucidate the exact causal mechanism, this finding would be consistent with similar findings for all-cause mortality (e.g., [976]). +Exposure to air pollution is associated with both poverty (e.g., [977]) and chronic inflammation [978]. +Other outcomes of environmental racism, such as the proximity of abandoned uranium mines to Navajo land, can also cause respiratory illnesses and other health issues [928]. +Similarly, preliminary findings indicate that nutritional status (e.g., vitamin D deficiency [720]) may be associated with COVID-19 outcomes, and reduced access to grocery stores and fresh food often co-occurs with environmental racism [928,979]. Taken together, the evidence suggests that low-income workers who face greater exposure to SARS-CoV-2 due to their home or work conditions are also more likely to face environmental and social stressors associated with increased inflammation, and therefore with increased risk from COVID-19. In particular, structural racism can play an important role on disease severity after SARS-CoV-2 exposure, due to consequences of racism which include an increased likelihood of poverty and its associated food and housing instability. -COVID-19 can thus be considered a “syndemic”, or a synergistic interaction between several epidemics [979]. +COVID-19 can thus be considered a “syndemic”, or a synergistic interaction between several epidemics [980]. As a result, it is not surprising that people from minoritized backgrounds and/or with certain pre-existing conditions are more likely to suffer severe effects of COVID-19, but these “risk factors” are likely to be causally linked to poverty.
8.3.3 Access to Treatment
Finally, COVID-19 outcomes can be influenced by access to healthcare. Receiving care for COVID-19 can, but does not always, include receiving a positive test for the SARS-CoV-2 virus. -For example, it is common to see treatment guidelines for suspected cases regardless of whether the presence of SARS-CoV-2 has been confirmed (e.g., [980]). +For example, it is common to see treatment guidelines for suspected cases regardless of whether the presence of SARS-CoV-2 has been confirmed (e.g., [981]). Whether and where a patient is diagnosed can depend on their access to testing, which can vary both between and within countries. -In the United States, it is not always clear whether an individual will have access to free testing [981,982]. -The concern has been raised that more economic privilege is likely to correspond to increased access to testing, at least within the United States [983]. -This is supported by the fact that African Americans seem to be more likely to be diagnosed in the hospital, while individuals from other groups were more likely to have been diagnosed in ambulatory settings in the community [898]. -Any delays in treatment are a cause for concern [983], which could potentially be increased by an inability to acquire testing because in the United States, insurance coverage for care received can depend on a positive test [984].
+In the United States, it is not always clear whether an individual will have access to free testing [982,983]. +The concern has been raised that more economic privilege is likely to correspond to increased access to testing, at least within the United States [984]. +This is supported by the fact that African Americans seem to be more likely to be diagnosed in the hospital, while individuals from other groups were more likely to have been diagnosed in ambulatory settings in the community [899]. +Any delays in treatment are a cause for concern [984], which could potentially be increased by an inability to acquire testing because in the United States, insurance coverage for care received can depend on a positive test [985].Another important question is whether patients with moderate to severe cases are able to access hospital facilities and treatments, to the extent that they have been identified. -Early findings from China as of February 2020 suggested the COVID-19 mortality rate to be much lower in the most developed regions of the country [985], although reported mortality is generally an estimate of CFR, which is dependent on rates of testing. -Efforts to make treatment accessible for all confirmed and suspected cases of COVID-19 in China are credited with expanding care to people with fewer economic resources [986]. -In the United States, access to healthcare varies widely, with certain sectors of the workforce less likely to have health insurance; many essential workers in transportation, food service, and other frontline fields are among those likely to be uninsured or underinsured [983]. -As of 2018, Hispanic Americans of all races were much less likely to have health insurance than people from non-Hispanic backgrounds [987]. +Early findings from China as of February 2020 suggested the COVID-19 mortality rate to be much lower in the most developed regions of the country [986], although reported mortality is generally an estimate of CFR, which is dependent on rates of testing. +Efforts to make treatment accessible for all confirmed and suspected cases of COVID-19 in China are credited with expanding care to people with fewer economic resources [987]. +In the United States, access to healthcare varies widely, with certain sectors of the workforce less likely to have health insurance; many essential workers in transportation, food service, and other frontline fields are among those likely to be uninsured or underinsured [984]. +As of 2018, Hispanic Americans of all races were much less likely to have health insurance than people from non-Hispanic backgrounds [988]. Therefore, access to diagnostics and care prior to the development of severe COVID-19 is likely to vary depending on socioeconomic and social factors, many of which overlap with the risks of exposure and of developing more severe COVID-19 symptoms. This discrepancy ties into concerns about broad infrastructural challenges imposed by COVID-19. -A major concern in many countries has been the saturation of healthcare systems due to the volume of COVID-19 hospitalizations (e.g., [240]). -Similarly, there have been shortages of supplies such as ventilators that are critical to the survival of many COVID-19 patients, leading to extensive ethical discussions about how to allocate limited resources among patients [988,989,990,991]. -Although it is generally considered unethical to consider demographic factors such as age, sex, race, or ethnicity while making such decisions, and ideally this information would not be shared with triage teams tasked with allocating limited resources among patients [992], there are substantial concerns about implicit and explicit biases against older adults [993], premature infants [994], and people with disabilities or comorbidities [992,995,996]. -Because of the greater burden of chronic disease in populations subjected to systemic racism, algorithms intended to be blind to race and ethnicity could, in fact, reinforce systemic inequalities caused by structural racism [997,998,999]. -Because of this inequality, it has been argued that groups facing health disparities should be prioritized by these algorithms [1000]. -This approach would carry its own ethical concerns, including the fact that many resources that need to be distributed do not have well-established risks and benefits [1000].
-As the pandemic has progressed, it has become clear that ICU beds and ventilators are not the only limited resources that needs to be allocated, and, in fact, the survival rate for patients who receive mechanical ventilation is lower than these discussions would suggest [1001]. -Allocation of interventions that may reduce suffering, including palliative care, has become critically important [1001,1002]. -The ambiguities surrounding the risks and benefits associated with therapeutics that have been approved under emergency use authorizations also present ethical concerns related to the distribution of resources [1000]. -For example, remdesivir, discussed above, is currently available for the treatment of COVID-19 under compassionate use guidelines and through expanded access programs, and in many cases has been donated to hospitals by Gilead [1003,1004]. -Regulations guiding the distribution of drugs in situations like these typically do not address how to determine which patients receive them [1004]. -Prioritizing marginalized groups for treatment with a drug like remdesivir would also be unethical because it would entail disproportionately exposing these groups to a therapeutic that may or not be beneficial [1000]. +A major concern in many countries has been the saturation of healthcare systems due to the volume of COVID-19 hospitalizations (e.g., [242]). +Similarly, there have been shortages of supplies such as ventilators that are critical to the survival of many COVID-19 patients, leading to extensive ethical discussions about how to allocate limited resources among patients [989,990,991,992]. +Although it is generally considered unethical to consider demographic factors such as age, sex, race, or ethnicity while making such decisions, and ideally this information would not be shared with triage teams tasked with allocating limited resources among patients [993], there are substantial concerns about implicit and explicit biases against older adults [994], premature infants [995], and people with disabilities or comorbidities [993,996,997]. +Because of the greater burden of chronic disease in populations subjected to systemic racism, algorithms intended to be blind to race and ethnicity could, in fact, reinforce systemic inequalities caused by structural racism [998,999,1000]. +Because of this inequality, it has been argued that groups facing health disparities should be prioritized by these algorithms [1001]. +This approach would carry its own ethical concerns, including the fact that many resources that need to be distributed do not have well-established risks and benefits [1001].
+As the pandemic has progressed, it has become clear that ICU beds and ventilators are not the only limited resources that needs to be allocated, and, in fact, the survival rate for patients who receive mechanical ventilation is lower than these discussions would suggest [1002]. +Allocation of interventions that may reduce suffering, including palliative care, has become critically important [1002,1003]. +The ambiguities surrounding the risks and benefits associated with therapeutics that have been approved under emergency use authorizations also present ethical concerns related to the distribution of resources [1001]. +For example, remdesivir, discussed above, is currently available for the treatment of COVID-19 under compassionate use guidelines and through expanded access programs, and in many cases has been donated to hospitals by Gilead [1004,1005]. +Regulations guiding the distribution of drugs in situations like these typically do not address how to determine which patients receive them [1005]. +Prioritizing marginalized groups for treatment with a drug like remdesivir would also be unethical because it would entail disproportionately exposing these groups to a therapeutic that may or not be beneficial [1001]. On the other hand, given that the drug is one of the most promising treatments available for many patients, using a framework that tacitly feeds into structural biases would also be unethical. -At present, the report prepared for the Director of the CDC by Ethics Subcommittee of the CDC fails to address the complexity of this ethical question given the state of structural racism in the United States, instead stating that “prioritizing individuals according to their chances for short-term survival also avoids ethically irrelevant considerations, such as race or socioeconomic status” [1005]. -In many cases, experimental therapeutics are made available only through participation in clinical trials [1006]. -However, given the history of medical trials abusing minority communities, especially Black Americans, there is a history of unequal representation in clinical trial enrollment [1006]. +At present, the report prepared for the Director of the CDC by Ethics Subcommittee of the CDC fails to address the complexity of this ethical question given the state of structural racism in the United States, instead stating that “prioritizing individuals according to their chances for short-term survival also avoids ethically irrelevant considerations, such as race or socioeconomic status” [1006]. +In many cases, experimental therapeutics are made available only through participation in clinical trials [1007]. +However, given the history of medical trials abusing minority communities, especially Black Americans, there is a history of unequal representation in clinical trial enrollment [1007]. As a result, the standard practice of requiring enrollment in a clinical trial in order to receive experimental treatment may also reinforce patterns established by systemic racism.
8.3.4 Access to and Representation in Clinical Trials
@@ -2999,7 +3000,7 @@[1007]
.
+The WHO Director‐General Tedros Adhanom Ghebreyesus stated his condemnation of utilizing low and middle income countries as test subjects for clinical trials, yet having highly developed countries as the majority of clinical trial representation is also not the answer [1008].
Figure 6 showcases two choropleths detailing COVID-19 clinical trial recruitment by country.
China, the United States, and France are among the countries with the most clinical trial recruiting for trials with single-country enrollment.
Many countries have little to no clinical trial recruiting, with the continents of Africa and South America much less represented than Asia, Europe, and North America.
@@ -3008,46 +3009,46 @@
Figure 6: Geographic distribution of COVID-19 clinical trials.
The density of clinical trials is reported at the country level.
-As of November 9, 2020, there are 6,417 trials in the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [371].
+As of November 9, 2020, there are 6,417 trials in the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [372].
The top figure demonstrates the density of trials recruiting only from a singular country, while the bottom shows the distribution of recruitment for trials that involve more than one country.
A few different concerns arise from this skewed geographic representation in clinical trial recruitment.
First, treatments such as remdesivir that are promising but primarily available to clinical trial participants are unlikely to be accessible by people in many countries.
Second, it raises the concern that the findings of clinical trials will be based on participants from many of the wealthiest countries, which may lead to ambiguity in whether the findings can be extrapolated to COVID-19 patients elsewhere.
-Especially with the global nature of COVID-19, equitable access to therapeutics and vaccines has been a concern at the forefront of many discussions about policy (e.g., [1008], yet data like that shown in Figure 6 demonstrates that accessibility is likely to be a significant issue.
-Another concern with the heterogeneous international distribution of clinical trials is that the governments of countries leading these clinical trials might prioritize their own populations once vaccines are developed, causing unequal health outcomes [1009].
-Additionally, even within a single state in the United States (Maryland), geography was found to influence the likelihood of being recruited into or enrolled in a clinical trial, with patients in under-served rural areas less likely to enroll [1010].
+Especially with the global nature of COVID-19, equitable access to therapeutics and vaccines has been a concern at the forefront of many discussions about policy (e.g., [1009], yet data like that shown in Figure 6 demonstrates that accessibility is likely to be a significant issue.
+Another concern with the heterogeneous international distribution of clinical trials is that the governments of countries leading these clinical trials might prioritize their own populations once vaccines are developed, causing unequal health outcomes [1010].
+Additionally, even within a single state in the United States (Maryland), geography was found to influence the likelihood of being recruited into or enrolled in a clinical trial, with patients in under-served rural areas less likely to enroll [1011].
Thus, geography both on the global and local levels may influence when treatments and vaccines are available and who is able to access them.
-Efforts such as the African Union’s efforts to coordinate and promote vaccine development [1011] are therefore critical to promoting equity in the COVID-19 response.
+Efforts such as the African Union’s efforts to coordinate and promote vaccine development [1012] are therefore critical to promoting equity in the COVID-19 response.
Even when patients are located within the geographic recruitment area of clinical trials, however, there can still be demographic inequalities in enrollment.
-When efforts are made to ensure equal opportunity to participate in clinical trials, there is no significant difference in participation among racial/ethnic groups [1012].
-However, within the United States, real clinical trial recruitment numbers have indicated for many years that racial minorities, especially African-Americans, tend to be under-represented (e.g., [1013,1014,1015,1016]).
+When efforts are made to ensure equal opportunity to participate in clinical trials, there is no significant difference in participation among racial/ethnic groups [1013].
+However, within the United States, real clinical trial recruitment numbers have indicated for many years that racial minorities, especially African-Americans, tend to be under-represented (e.g., [1014,1015,1016,1017]).
This trend is especially concerning given the disproportionate impact of COVID-19 on African-Americans.
-Early evidence suggests that the proportion of Black, Latinx, and Native American participants in clinical trials for drugs such as remdesivir is much lower than the representation of these groups among COVID-19 patients [1017].
+Early evidence suggests that the proportion of Black, Latinx, and Native American participants in clinical trials for drugs such as remdesivir is much lower than the representation of these groups among COVID-19 patients [1018].
One proposed explanation for differences among racial and ethnic groups in clinical trial enrollment refers to different experiences in healthcare settings.
-While some plausible reasons for the disparity in communication between physicians and patients could be a lack of awareness and education, mistrust in healthcare professionals, and a lack of health insurance [1012], a major concern is that patients from certain racial and ethnic groups are marginalized even while seeking healthcare.
-In the United States, many patients experience “othering” from physicians and other medical professionals due to their race or other external characteristics such as gender (e.g., [1018]).
+While some plausible reasons for the disparity in communication between physicians and patients could be a lack of awareness and education, mistrust in healthcare professionals, and a lack of health insurance [1013], a major concern is that patients from certain racial and ethnic groups are marginalized even while seeking healthcare.
+In the United States, many patients experience “othering” from physicians and other medical professionals due to their race or other external characteristics such as gender (e.g., [1019]).
Many studies have sought to characterize implicit biases in healthcare providers and whether they affect their perceptions or treatment of patients.
-A systematic review that examined 37 such studies reported that most (31) identified racial and/or ethnic biases in healthcare providers in many different roles, although the evidence about whether these biases translated to different attitudes towards patients was mixed [1019], with similar findings reported by a second systematic review [1020].
-However, data about real-world patient outcomes are very limited, with most studies relying on clinical vignette-based exercises [1019], and other analyses suggest that physician implicit bias could impact the patient’s perception of the negativity/positivity of the interaction regardless of the physician’s explicit behavior towards the patient [1021].
-Because racism is a common factor in both, negative patient experiences with medical professionals are likely to compound other issues of systemic inequality, such as a lack of access to adequate care, a lack of insurance, or increased exposure to SARS-CoV-2 [1022].
+A systematic review that examined 37 such studies reported that most (31) identified racial and/or ethnic biases in healthcare providers in many different roles, although the evidence about whether these biases translated to different attitudes towards patients was mixed [1020], with similar findings reported by a second systematic review [1021].
+However, data about real-world patient outcomes are very limited, with most studies relying on clinical vignette-based exercises [1020], and other analyses suggest that physician implicit bias could impact the patient’s perception of the negativity/positivity of the interaction regardless of the physician’s explicit behavior towards the patient [1022].
+Because racism is a common factor in both, negative patient experiences with medical professionals are likely to compound other issues of systemic inequality, such as a lack of access to adequate care, a lack of insurance, or increased exposure to SARS-CoV-2 [1023].
Furthermore, the experience of being othered is not only expected to impact patients’ trust in and comfort with their provider, but also may directly impact whether or not the patient is offered the opportunity to participate in a clinical trial at all.
Some studies suggest communication between physicians and patients impacts whether or not a physician offers a patient participation in a clinical trial.
-For example, researchers utilized a linguistic analysis to assess mean word count of phrases related to clinical trial enrollment, such as voluntary participation, clinical trial, etc. [1012].
+For example, researchers utilized a linguistic analysis to assess mean word count of phrases related to clinical trial enrollment, such as voluntary participation, clinical trial, etc. [1013].
The data indicated that the mean word count of the entire visit was 1.5 times more for white patients in comparison to Black patients.
-In addition, the greatest disparity between white and Black patients’ experience was the discussion of risks, with over 2 times as many risk-related words spoken with white patients than Black patients [1012].
+In addition, the greatest disparity between white and Black patients’ experience was the discussion of risks, with over 2 times as many risk-related words spoken with white patients than Black patients [1013].
The trends observed for other clinical trials raise the concern that COVID-19 clinical trial information may not be discussed as thoroughly or as often with Black patients compared to white patients.
These discrepancies are especially concerning given that many COVID-19 treatments are being or are considered being made available to patients prior to FDA approval through Emergency Use Authorizations.
-In the past, African-Americans have been over-represented relative to national demographics in use of the FDA’s Exception From Informed Consent (EFIC) pathway [1023].
+In the past, African-Americans have been over-represented relative to national demographics in use of the FDA’s Exception From Informed Consent (EFIC) pathway [1024].
Through this pathway, people who are incapacitated can receive an experimental treatment even if they are not able to consent and there is not sufficient time to seek approval from an authorized representative.
-This pathway presents concerns, however, when it is considered in the context of a long history of systematic abuses in medical experimentation where informed consent was not obtained from people of color, such as the Tuskegee syphilis experiments [1024].
+This pathway presents concerns, however, when it is considered in the context of a long history of systematic abuses in medical experimentation where informed consent was not obtained from people of color, such as the Tuskegee syphilis experiments [1025].
While the goal of EFIC approval is to provide treatment to patients who urgently need it, the combination of the ongoing legacy of racism in medicine renders this trend concerning.
-With COVID-19, efforts to prioritize people who suffer from systemic racism are often designed with the goal of righting some of these inequalities (e.g., [1025]), but particular attention to informed consent will be imperative in ensuring these trials are ethical given that the benefits and risks of emerging treatments are still poorly characterized.
+With COVID-19, efforts to prioritize people who suffer from systemic racism are often designed with the goal of righting some of these inequalities (e.g., [1026]), but particular attention to informed consent will be imperative in ensuring these trials are ethical given that the benefits and risks of emerging treatments are still poorly characterized.
Making a substantial effort to run inclusive clinical trials is also important because of the possibility that racism could impact how a patient responds to a treatment.
For example, as discussed above, dexamethasone has been identified as a promising treatment for patients experiencing cytokine release syndrome, but the mechanism of action is tied to the stress response.
-A study from 2005 reported that Black asthma patients showed reduced responsiveness to dexamethasone in comparison to white patients and suggested Black patients might therefore require higher doses of the drug [1026].
-In the context of chronic stress caused by systemic racism, this result is not surprising: chronic stress is associated with dysregulated production of glucocorticoids [1027] and glucocorticoid receptor resistance [1028].
+A study from 2005 reported that Black asthma patients showed reduced responsiveness to dexamethasone in comparison to white patients and suggested Black patients might therefore require higher doses of the drug [1027].
+In the context of chronic stress caused by systemic racism, this result is not surprising: chronic stress is associated with dysregulated production of glucocorticoids [1028] and glucocorticoid receptor resistance [1029].
However, it underscores the critical need for treatment guidelines to take into account differences in life experience, which would be facilitated by the recruitment of patients from a wide range of backgrounds.
Attention to the social aspects of clinical trial enrollment must therefore be an essential component of the medical research community’s response to COVID-19.
-Our primary goal is to sort and distill informative content out of the overwhelming flood of information [5] and help the broader scientific community become more conversant on this critical subject.
+Our primary goal is to sort and distill informative content out of the overwhelming flood of information [7] and help the broader scientific community become more conversant on this critical subject.
Thus, our approach has been to develop a real-time, collaborative effort that welcomes submissions from scientists worldwide into this ongoing effort.
This document represents the first snapshot, which aims to reflect the state of the field as of October, 2020.
We plan to refine and expand this document until technologies to mitigate the pandemic are widely available.
-In an effort to keep pace as new information about COVID-19 and SARS-CoV-2 becomes available, this project is an open, collaborative effort that invited contributions from the scientific community broadly, similar to previous efforts to develop collaborative reviews [1029,1030].
+
In an effort to keep pace as new information about COVID-19 and SARS-CoV-2 becomes available, this project is an open, collaborative effort that invited contributions from the scientific community broadly, similar to previous efforts to develop collaborative reviews [1030,1031].
Contributors were recruited by word of mouth and on Twitter.
-Existing efforts to train early-career scientists were also integrated: Appendix A contains summaries written by the students, post-docs, and faculty of the Immunology Institute at the Mount Sinai School of Medicine [1031,1032], and two of the authors were recruited through the American Physician Scientist Association’s Virtual Summer Research Program [1033].
-The project was managed through GitHub [1034] using Manubot [6] to continuously generate a version of the manuscript online [1035].
+Existing efforts to train early-career scientists were also integrated: Appendix A contains summaries written by the students, post-docs, and faculty of the Immunology Institute at the Mount Sinai School of Medicine [1032,1033], and two of the authors were recruited through the American Physician Scientist Association’s Virtual Summer Research Program [1034].
+The project was managed through GitHub [1035] using Manubot [8] to continuously generate a version of the manuscript online [1036].
Contributors developed text that was proposed through GitHub’s pull request system and then reviewed and approved by at least one other author.
While this document reflects the current version of record, the online version will continue to be developed as information about the pandemic emerges.
Below, we will describe the processes used to synthesize the literature.
10.3 Technical Infrastructure
10.3.1 Collaborative Writing and Manuscript Generation
-Manubot [6] is a collaborative framework developed to adapt open-source software development techniques and version control for manuscript writing.
+
Manubot [8] is a collaborative framework developed to adapt open-source software development techniques and version control for manuscript writing.
Here, Manubot was used to generate a manuscript from text maintained using GitHub, a popular, online version control interface.
The GitHub implementation allowed users to contribute either using git on the command line or using the GitHub user interface, and we developed documentation for users with less experience with this platform.
Manubot also provides a functionality to create a bibliography using digital object identifiers (DOIs), website URLs, or other identifiers such as PubMed identifiers and arXiv IDs.
Due to the needs of this project, project contributors also implemented new features in Manubot and Zotero, which Manubot uses to extract metadata for some types of citations.
-These features support directly citing clinical trial identifiers such as clinicaltrials:NCT04292899 [399] and generating the complete review manuscript along with the individual manuscripts reviewing specific topics.
+These features support directly citing clinical trial identifiers such as clinicaltrials:NCT04292899 [400] and generating the complete review manuscript along with the individual manuscripts reviewing specific topics.
Finally, Manubot and GitHub Actions continuous integration allowed for scripted updates to be run each time the manuscript was generated.
These scripts were used to check that the manuscript was built correctly, run spellchecking, and cross-reference the manuscripts cited in this review, summarized in Appendix A, and discussed in the project’s issues and pull requests.
10.3.2 Data Analysis and Visualization
The combination of Manubot and GitHub Actions also made it possible to dynamically update information such as statistics and visualizations in the manuscript.
-Data about worldwide cases and deaths from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [368] were read using a Python script.
-Similarly, the clinical trials statistics and figure were generated based on data from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [371].
-In both cases, frequency data were plotted using Matplotlib [1036] in Python.
+Data about worldwide cases and deaths from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [369] were read using a Python script.
+Similarly, the clinical trials statistics and figure were generated based on data from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [372].
+In both cases, frequency data were plotted using Matplotlib [1037] in Python.
The figure showing the geographic distribution of COVID-19 clinical trials was generated using the countries associated with the trials listed in the COVID-19 TrialsTracker, converting the country names to 3-letter ISO codes using pycountry or manual adjustment when necessary, and visualizing the geographic distribution of trial recruitment using geopandas.
GitHub Actions runs a nightly workflow to update these external data and regenerate the statistics and figures for the manuscript.
The workflow uses the GitHub API to detect and save the latest commit of the external data sources, which are both GitHub repositories.
@@ -3202,7 +3203,7 @@
10.4 Article Selection and Evaluation
A few different concerns arise from this skewed geographic representation in clinical trial recruitment. First, treatments such as remdesivir that are promising but primarily available to clinical trial participants are unlikely to be accessible by people in many countries. Second, it raises the concern that the findings of clinical trials will be based on participants from many of the wealthiest countries, which may lead to ambiguity in whether the findings can be extrapolated to COVID-19 patients elsewhere. -Especially with the global nature of COVID-19, equitable access to therapeutics and vaccines has been a concern at the forefront of many discussions about policy (e.g., [1008], yet data like that shown in Figure 6 demonstrates that accessibility is likely to be a significant issue. -Another concern with the heterogeneous international distribution of clinical trials is that the governments of countries leading these clinical trials might prioritize their own populations once vaccines are developed, causing unequal health outcomes [1009]. -Additionally, even within a single state in the United States (Maryland), geography was found to influence the likelihood of being recruited into or enrolled in a clinical trial, with patients in under-served rural areas less likely to enroll [1010]. +Especially with the global nature of COVID-19, equitable access to therapeutics and vaccines has been a concern at the forefront of many discussions about policy (e.g., [1009], yet data like that shown in Figure 6 demonstrates that accessibility is likely to be a significant issue. +Another concern with the heterogeneous international distribution of clinical trials is that the governments of countries leading these clinical trials might prioritize their own populations once vaccines are developed, causing unequal health outcomes [1010]. +Additionally, even within a single state in the United States (Maryland), geography was found to influence the likelihood of being recruited into or enrolled in a clinical trial, with patients in under-served rural areas less likely to enroll [1011]. Thus, geography both on the global and local levels may influence when treatments and vaccines are available and who is able to access them. -Efforts such as the African Union’s efforts to coordinate and promote vaccine development [1011] are therefore critical to promoting equity in the COVID-19 response.
+Efforts such as the African Union’s efforts to coordinate and promote vaccine development [1012] are therefore critical to promoting equity in the COVID-19 response.Even when patients are located within the geographic recruitment area of clinical trials, however, there can still be demographic inequalities in enrollment. -When efforts are made to ensure equal opportunity to participate in clinical trials, there is no significant difference in participation among racial/ethnic groups [1012]. -However, within the United States, real clinical trial recruitment numbers have indicated for many years that racial minorities, especially African-Americans, tend to be under-represented (e.g., [1013,1014,1015,1016]). +When efforts are made to ensure equal opportunity to participate in clinical trials, there is no significant difference in participation among racial/ethnic groups [1013]. +However, within the United States, real clinical trial recruitment numbers have indicated for many years that racial minorities, especially African-Americans, tend to be under-represented (e.g., [1014,1015,1016,1017]). This trend is especially concerning given the disproportionate impact of COVID-19 on African-Americans. -Early evidence suggests that the proportion of Black, Latinx, and Native American participants in clinical trials for drugs such as remdesivir is much lower than the representation of these groups among COVID-19 patients [1017].
+Early evidence suggests that the proportion of Black, Latinx, and Native American participants in clinical trials for drugs such as remdesivir is much lower than the representation of these groups among COVID-19 patients [1018].One proposed explanation for differences among racial and ethnic groups in clinical trial enrollment refers to different experiences in healthcare settings. -While some plausible reasons for the disparity in communication between physicians and patients could be a lack of awareness and education, mistrust in healthcare professionals, and a lack of health insurance [1012], a major concern is that patients from certain racial and ethnic groups are marginalized even while seeking healthcare. -In the United States, many patients experience “othering” from physicians and other medical professionals due to their race or other external characteristics such as gender (e.g., [1018]). +While some plausible reasons for the disparity in communication between physicians and patients could be a lack of awareness and education, mistrust in healthcare professionals, and a lack of health insurance [1013], a major concern is that patients from certain racial and ethnic groups are marginalized even while seeking healthcare. +In the United States, many patients experience “othering” from physicians and other medical professionals due to their race or other external characteristics such as gender (e.g., [1019]). Many studies have sought to characterize implicit biases in healthcare providers and whether they affect their perceptions or treatment of patients. -A systematic review that examined 37 such studies reported that most (31) identified racial and/or ethnic biases in healthcare providers in many different roles, although the evidence about whether these biases translated to different attitudes towards patients was mixed [1019], with similar findings reported by a second systematic review [1020]. -However, data about real-world patient outcomes are very limited, with most studies relying on clinical vignette-based exercises [1019], and other analyses suggest that physician implicit bias could impact the patient’s perception of the negativity/positivity of the interaction regardless of the physician’s explicit behavior towards the patient [1021]. -Because racism is a common factor in both, negative patient experiences with medical professionals are likely to compound other issues of systemic inequality, such as a lack of access to adequate care, a lack of insurance, or increased exposure to SARS-CoV-2 [1022]. +A systematic review that examined 37 such studies reported that most (31) identified racial and/or ethnic biases in healthcare providers in many different roles, although the evidence about whether these biases translated to different attitudes towards patients was mixed [1020], with similar findings reported by a second systematic review [1021]. +However, data about real-world patient outcomes are very limited, with most studies relying on clinical vignette-based exercises [1020], and other analyses suggest that physician implicit bias could impact the patient’s perception of the negativity/positivity of the interaction regardless of the physician’s explicit behavior towards the patient [1022]. +Because racism is a common factor in both, negative patient experiences with medical professionals are likely to compound other issues of systemic inequality, such as a lack of access to adequate care, a lack of insurance, or increased exposure to SARS-CoV-2 [1023]. Furthermore, the experience of being othered is not only expected to impact patients’ trust in and comfort with their provider, but also may directly impact whether or not the patient is offered the opportunity to participate in a clinical trial at all. Some studies suggest communication between physicians and patients impacts whether or not a physician offers a patient participation in a clinical trial. -For example, researchers utilized a linguistic analysis to assess mean word count of phrases related to clinical trial enrollment, such as voluntary participation, clinical trial, etc. [1012]. +For example, researchers utilized a linguistic analysis to assess mean word count of phrases related to clinical trial enrollment, such as voluntary participation, clinical trial, etc. [1013]. The data indicated that the mean word count of the entire visit was 1.5 times more for white patients in comparison to Black patients. -In addition, the greatest disparity between white and Black patients’ experience was the discussion of risks, with over 2 times as many risk-related words spoken with white patients than Black patients [1012]. +In addition, the greatest disparity between white and Black patients’ experience was the discussion of risks, with over 2 times as many risk-related words spoken with white patients than Black patients [1013]. The trends observed for other clinical trials raise the concern that COVID-19 clinical trial information may not be discussed as thoroughly or as often with Black patients compared to white patients.
These discrepancies are especially concerning given that many COVID-19 treatments are being or are considered being made available to patients prior to FDA approval through Emergency Use Authorizations. -In the past, African-Americans have been over-represented relative to national demographics in use of the FDA’s Exception From Informed Consent (EFIC) pathway [1023]. +In the past, African-Americans have been over-represented relative to national demographics in use of the FDA’s Exception From Informed Consent (EFIC) pathway [1024]. Through this pathway, people who are incapacitated can receive an experimental treatment even if they are not able to consent and there is not sufficient time to seek approval from an authorized representative. -This pathway presents concerns, however, when it is considered in the context of a long history of systematic abuses in medical experimentation where informed consent was not obtained from people of color, such as the Tuskegee syphilis experiments [1024]. +This pathway presents concerns, however, when it is considered in the context of a long history of systematic abuses in medical experimentation where informed consent was not obtained from people of color, such as the Tuskegee syphilis experiments [1025]. While the goal of EFIC approval is to provide treatment to patients who urgently need it, the combination of the ongoing legacy of racism in medicine renders this trend concerning. -With COVID-19, efforts to prioritize people who suffer from systemic racism are often designed with the goal of righting some of these inequalities (e.g., [1025]), but particular attention to informed consent will be imperative in ensuring these trials are ethical given that the benefits and risks of emerging treatments are still poorly characterized. +With COVID-19, efforts to prioritize people who suffer from systemic racism are often designed with the goal of righting some of these inequalities (e.g., [1026]), but particular attention to informed consent will be imperative in ensuring these trials are ethical given that the benefits and risks of emerging treatments are still poorly characterized. Making a substantial effort to run inclusive clinical trials is also important because of the possibility that racism could impact how a patient responds to a treatment. For example, as discussed above, dexamethasone has been identified as a promising treatment for patients experiencing cytokine release syndrome, but the mechanism of action is tied to the stress response. -A study from 2005 reported that Black asthma patients showed reduced responsiveness to dexamethasone in comparison to white patients and suggested Black patients might therefore require higher doses of the drug [1026]. -In the context of chronic stress caused by systemic racism, this result is not surprising: chronic stress is associated with dysregulated production of glucocorticoids [1027] and glucocorticoid receptor resistance [1028]. +A study from 2005 reported that Black asthma patients showed reduced responsiveness to dexamethasone in comparison to white patients and suggested Black patients might therefore require higher doses of the drug [1027]. +In the context of chronic stress caused by systemic racism, this result is not surprising: chronic stress is associated with dysregulated production of glucocorticoids [1028] and glucocorticoid receptor resistance [1029]. However, it underscores the critical need for treatment guidelines to take into account differences in life experience, which would be facilitated by the recruitment of patients from a wide range of backgrounds. Attention to the social aspects of clinical trial enrollment must therefore be an essential component of the medical research community’s response to COVID-19.
-Our primary goal is to sort and distill informative content out of the overwhelming flood of information [5] and help the broader scientific community become more conversant on this critical subject. +Our primary goal is to sort and distill informative content out of the overwhelming flood of information [7] and help the broader scientific community become more conversant on this critical subject. Thus, our approach has been to develop a real-time, collaborative effort that welcomes submissions from scientists worldwide into this ongoing effort. This document represents the first snapshot, which aims to reflect the state of the field as of October, 2020. We plan to refine and expand this document until technologies to mitigate the pandemic are widely available. -In an effort to keep pace as new information about COVID-19 and SARS-CoV-2 becomes available, this project is an open, collaborative effort that invited contributions from the scientific community broadly, similar to previous efforts to develop collaborative reviews [1029,1030]. +
In an effort to keep pace as new information about COVID-19 and SARS-CoV-2 becomes available, this project is an open, collaborative effort that invited contributions from the scientific community broadly, similar to previous efforts to develop collaborative reviews [1030,1031]. Contributors were recruited by word of mouth and on Twitter. -Existing efforts to train early-career scientists were also integrated: Appendix A contains summaries written by the students, post-docs, and faculty of the Immunology Institute at the Mount Sinai School of Medicine [1031,1032], and two of the authors were recruited through the American Physician Scientist Association’s Virtual Summer Research Program [1033]. -The project was managed through GitHub [1034] using Manubot [6] to continuously generate a version of the manuscript online [1035]. +Existing efforts to train early-career scientists were also integrated: Appendix A contains summaries written by the students, post-docs, and faculty of the Immunology Institute at the Mount Sinai School of Medicine [1032,1033], and two of the authors were recruited through the American Physician Scientist Association’s Virtual Summer Research Program [1034]. +The project was managed through GitHub [1035] using Manubot [8] to continuously generate a version of the manuscript online [1036]. Contributors developed text that was proposed through GitHub’s pull request system and then reviewed and approved by at least one other author. While this document reflects the current version of record, the online version will continue to be developed as information about the pandemic emerges. Below, we will describe the processes used to synthesize the literature.
10.3 Technical Infrastructure
10.3.1 Collaborative Writing and Manuscript Generation
-Manubot [6] is a collaborative framework developed to adapt open-source software development techniques and version control for manuscript writing. +
Manubot [8] is a collaborative framework developed to adapt open-source software development techniques and version control for manuscript writing.
Here, Manubot was used to generate a manuscript from text maintained using GitHub, a popular, online version control interface.
The GitHub implementation allowed users to contribute either using git on the command line or using the GitHub user interface, and we developed documentation for users with less experience with this platform.
Manubot also provides a functionality to create a bibliography using digital object identifiers (DOIs), website URLs, or other identifiers such as PubMed identifiers and arXiv IDs.
Due to the needs of this project, project contributors also implemented new features in Manubot and Zotero, which Manubot uses to extract metadata for some types of citations.
-These features support directly citing clinical trial identifiers such as clinicaltrials:NCT04292899 [399] and generating the complete review manuscript along with the individual manuscripts reviewing specific topics.
+These features support directly citing clinical trial identifiers such as clinicaltrials:NCT04292899 [400] and generating the complete review manuscript along with the individual manuscripts reviewing specific topics.
Finally, Manubot and GitHub Actions continuous integration allowed for scripted updates to be run each time the manuscript was generated.
These scripts were used to check that the manuscript was built correctly, run spellchecking, and cross-reference the manuscripts cited in this review, summarized in Appendix A, and discussed in the project’s issues and pull requests.
10.3.2 Data Analysis and Visualization
The combination of Manubot and GitHub Actions also made it possible to dynamically update information such as statistics and visualizations in the manuscript. -Data about worldwide cases and deaths from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [368] were read using a Python script. -Similarly, the clinical trials statistics and figure were generated based on data from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [371]. -In both cases, frequency data were plotted using Matplotlib [1036] in Python. +Data about worldwide cases and deaths from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [369] were read using a Python script. +Similarly, the clinical trials statistics and figure were generated based on data from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [372]. +In both cases, frequency data were plotted using Matplotlib [1037] in Python. The figure showing the geographic distribution of COVID-19 clinical trials was generated using the countries associated with the trials listed in the COVID-19 TrialsTracker, converting the country names to 3-letter ISO codes using pycountry or manual adjustment when necessary, and visualizing the geographic distribution of trial recruitment using geopandas.
GitHub Actions runs a nightly workflow to update these external data and regenerate the statistics and figures for the manuscript. The workflow uses the GitHub API to detect and save the latest commit of the external data sources, which are both GitHub repositories. @@ -3202,7 +3203,7 @@
10.4 Article Selection and Evaluation
1. Pathogenesis, Symptomatology, and Transmission of SARS-CoV-2 through analysis of Viral Genomics and Structure
+Halie M. Rando, Adam L. MacLean, Alexandra J. Lee, Sandipan Ray, Vikas Bansal, Ashwin N. Skelly, Elizabeth Sell, John J. Dziak, Lamonica Shinholster, Lucy D’Agostino McGowan, … Casey S. Greene
+arXiv (2021-02-03) https://arxiv.org/abs/2102.01521
2. Dietary Supplements and Nutraceuticals Under Investigation for COVID-19 Prevention and Treatment
+Ronan Lordan, Halie M. Rando, COVID-19 Review Consortium, Casey S. Greene
+arXiv (2021-02-05) https://arxiv.org/abs/2102.02250
1. Novel Coronavirus (2019-nCoV) SITUATION REPORT - 1
+
3. Novel Coronavirus (2019-nCoV) SITUATION REPORT - 1
World Health Organization
(2020-01-21) https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200121-sitrep-1-2019-ncov.pdf
2. Novel Coronavirus (2019-nCoV) Situation Report - 8
+
4. Novel Coronavirus (2019-nCoV) Situation Report - 8
World Health Organization
(2020-01-28) https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200128-sitrep-8-ncov-cleared.pdf
3. Novel Coronavirus (2019-nCoV) Situation Report - 51
+
5. Novel Coronavirus (2019-nCoV) Situation Report - 51
World Health Organization
(2020-03-11) https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200311-sitrep-51-covid-19.pdf
4. Novel Coronavirus (2019-nCoV) Situation Report - 75
+
6. Novel Coronavirus (2019-nCoV) Situation Report - 75
World Health Organization
(2020-04-04) https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200404-sitrep-75-covid-19.pdf
5. How you can help with COVID-19 modelling
+
7. How you can help with COVID-19 modelling
Julia R. Gog
Nature Reviews Physics (2020-04-08) https://doi.org/ggrsq3
DOI: 10.1038/s42254-020-0175-7 · PMCID: PMC7144181
6. Open collaborative writing with Manubot
+
8. Open collaborative writing with Manubot
Daniel S. Himmelstein, Vincent Rubinetti, David R. Slochower, Dongbo Hu, Venkat S. Malladi, Casey S. Greene, Anthony Gitter
PLOS Computational Biology (2019-06-24) https://doi.org/c7np
DOI: 10.1371/journal.pcbi.1007128 · PMID: 31233491 · PMCID: PMC6611653
7. Cases, Data, and Surveillance
+
9. Cases, Data, and Surveillance
CDC
Centers for Disease Control and Prevention (2020-02-11) https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/about-epidemiology/index.html
8. IHME | COVID-19 Projections
+
10. IHME | COVID-19 Projections
Institute for Health Metrics and Evaluation
https://covid19.healthdata.org/
9. Managing epidemics: key facts about major deadly diseases.
+
11. Managing epidemics: key facts about major deadly diseases.
World Health Organization
(2018)
ISBN: 9789241565530
10. A Novel Coronavirus Genome Identified in a Cluster of Pneumonia Cases — Wuhan, China 2019−2020
+
12. A Novel Coronavirus Genome Identified in a Cluster of Pneumonia Cases — Wuhan, China 2019−2020
Wenjie Tan, Xiang Zhao, Xuejun Ma, Wenling Wang, Peihua Niu, Wenbo Xu, George F. Gao, Guizhen Wu, MHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, China, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Beijing, China
China CDC Weekly (2020) https://doi.org/gg8z47
DOI: 10.46234/ccdcw2020.017
11. A new coronavirus associated with human respiratory disease in China
+
13. A new coronavirus associated with human respiratory disease in China
Fan Wu, Su Zhao, Bin Yu, Yan-Mei Chen, Wen Wang, Zhi-Gang Song, Yi Hu, Zhao-Wu Tao, Jun-Hua Tian, Yuan-Yuan Pei, … Yong-Zhen Zhang
Nature (2020-02-03) https://doi.org/dk2w
DOI: 10.1038/s41586-020-2008-3 · PMID: 32015508 · PMCID: PMC7094943
12. A pneumonia outbreak associated with a new coronavirus of probable bat origin
+
14. A pneumonia outbreak associated with a new coronavirus of probable bat origin
Peng Zhou, Xing-Lou Yang, Xian-Guang Wang, Ben Hu, Lei Zhang, Wei Zhang, Hao-Rui Si, Yan Zhu, Bei Li, Chao-Lin Huang, … Zheng-Li Shi
Nature (2020-02-03) https://doi.org/ggj5cg
DOI: 10.1038/s41586-020-2012-7 · PMID: 32015507 · PMCID: PMC7095418
13. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding
+
15. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding
Roujian Lu, Xiang Zhao, Juan Li, Peihua Niu, Bo Yang, Honglong Wu, Wenling Wang, Hao Song, Baoying Huang, Na Zhu, … Wenjie Tan
The Lancet (2020-02) https://doi.org/ggjr43
DOI: 10.1016/s0140-6736(20)30251-8
14. On the origin and continuing evolution of SARS-CoV-2
+
16. On the origin and continuing evolution of SARS-CoV-2
Xiaolu Tang, Changcheng Wu, Xiang Li, Yuhe Song, Xinmin Yao, Xinkai Wu, Yuange Duan, Hong Zhang, Yirong Wang, Zhaohui Qian, … Jian Lu
National Science Review (2020-06) https://doi.org/ggndzn
DOI: 10.1093/nsr/nwaa036 · PMCID: PMC7107875
15. Pangolin homology associated with 2019-nCoV
+
17. Pangolin homology associated with 2019-nCoV
Tao Zhang, Qunfu Wu, Zhigang Zhang
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggpvpt
DOI: 10.1101/2020.02.19.950253
16. Emergence of SARS-CoV-2 through recombination and strong purifying selection
+
18. Emergence of SARS-CoV-2 through recombination and strong purifying selection
Xiaojun Li, Elena E. Giorgi, Manukumar Honnayakanahalli Marichannegowda, Brian Foley, Chuan Xiao, Xiang-Peng Kong, Yue Chen, S. Gnanakaran, Bette Korber, Feng Gao
Science Advances (2020-07) https://doi.org/gg6r93
DOI: 10.1126/sciadv.abb9153 · PMID: 32937441 · PMCID: PMC7458444
17. The proximal origin of SARS-CoV-2
+
19. The proximal origin of SARS-CoV-2
Kristian G. Andersen, Andrew Rambaut, W. Ian Lipkin, Edward C. Holmes, Robert F. Garry
Nature Medicine (2020-03-17) https://doi.org/ggn4dn
DOI: 10.1038/s41591-020-0820-9 · PMCID: PMC7095063
18. Coronavirus immunogens
+
20. Coronavirus immunogens
Linda J. Saif
Veterinary Microbiology (1993-11) https://doi.org/ckfn8b
DOI: 10.1016/0378-1135(93)90030-b · PMID: 8116187 · PMCID: PMC7117163
19. Origin and evolution of pathogenic coronaviruses
+
21. Origin and evolution of pathogenic coronaviruses
Jie Cui, Fang Li, Zheng-Li Shi
Nature Reviews Microbiology (2018-12-10) https://doi.org/ggh4vb
DOI: 10.1038/s41579-018-0118-9 · PMID: 30531947 · PMCID: PMC7097006
20. Human Coronaviruses: A Review of Virus–Host Interactions
+
22. Human Coronaviruses: A Review of Virus–Host Interactions
Yvonne Lim, Yan Ng, James Tam, Ding Liu
Diseases (2016-07-25) https://doi.org/ggjs23
DOI: 10.3390/diseases4030026 · PMID: 28933406 · PMCID: PMC5456285
21. A New Virus Isolated from the Human Respiratory Tract.
+
23. A New Virus Isolated from the Human Respiratory Tract.
D. Hamre, J. J. Procknow
Experimental Biology and Medicine (1966-01-01) https://doi.org/gg84fc
DOI: 10.3181/00379727-121-30734 · PMID: 4285768
22. Recovery in tracheal organ cultures of novel viruses from patients with respiratory disease.
+
24. Recovery in tracheal organ cultures of novel viruses from patients with respiratory disease.
K. McIntosh, J. H. Dees, W. B. Becker, A. Z. Kapikian, R. M. Chanock
Proceedings of the National Academy of Sciences (1967-04-01) https://doi.org/bhfd6w
DOI: 10.1073/pnas.57.4.933 · PMID: 5231356 · PMCID: PMC224637
23.:(unav)
+
25.:(unav)
Krzysztof Pyrc, Maarten F Jebbink, Ben Berkhout, Lia van der Hoek
Virology Journal (2004) https://doi.org/dnmj8m
DOI: 10.1186/1743-422x-1-7 · PMID: 15548333 · PMCID: PMC538260
24. Understanding Human Coronavirus HCoV-NL63.
+
26. Understanding Human Coronavirus HCoV-NL63.
Sahar Abdul-Rasool, Burtram C Fielding
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562. Synairgen to start trial of SNG001 in COVID-19 imminently
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635. The Lipid Mediator Protectin D1 Inhibits Influenza Virus Replication and Improves Severe Influenza
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Sesquile Ramon, Steven F. Baker, Julie M. Sahler, Nina Kim, Eric A. Feldsott, Charles N. Serhan, Luis Martínez-Sobrido, David J. Topham, Richard P. Phipps
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638. Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19?
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639. Pro resolving inflammatory effects of the lipid mediators of omega 3 fatty acids and its implication in SARS COVID-19
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640. Obesity-Driven Deficiencies of Specialized Pro-resolving Mediators May Drive Adverse Outcomes During SARS-CoV-2 Infection
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641. Obesity-Driven Deficiencies of Specialized Pro-resolving Mediators May Drive Adverse Outcomes During SARS-CoV-2 Infection
Anandita Pal, Kymberly M. Gowdy, Kenneth J. Oestreich, Melinda Beck, Saame Raza Shaikh
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641. Fish Oil-Fed Mice Have Impaired Resistance to Influenza Infection
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Nicole M. J. Schwerbrock, Erik A. Karlsson, Qing Shi, Patricia A. Sheridan, Melinda A. Beck
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643. Bioactive products formed in humans from fish oils
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644. Resolving Inflammatory Storm in COVID-19 Patients by Omega-3 Polyunsaturated Fatty Acids - A Single-blind, Randomized, Placebo-controlled Feasibility Study
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645. Resolving Inflammatory Storm in COVID-19 Patients by Omega-3 Polyunsaturated Fatty Acids - A Single-blind, Randomized, Placebo-controlled Feasibility Study
Magnus Bäck
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645. Stimulating the Resolution of Inflammation Through Omega-3 Polyunsaturated Fatty Acids in COVID-19: Rationale for the COVID-Omega-F Trial
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646. Stimulating the Resolution of Inflammation Through Omega-3 Polyunsaturated Fatty Acids in COVID-19: Rationale for the COVID-Omega-F Trial
Hildur Arnardottir, Sven-Christian Pawelzik, Ulf Öhlund Wistbacka, Gonzalo Artiach, Robin Hofmann, Ingalill Reinholdsson, Frieder Braunschweig, Per Tornvall, Dorota Religa, Magnus Bäck
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646. COVID-19 and its implications for thrombosis and anticoagulation
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Jean M. Connors, Jerrold H. Levy
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647. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up
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648. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up
Behnood Bikdeli, Mahesh V. Madhavan, David Jimenez, Taylor Chuich, Isaac Dreyfus, Elissa Driggin, Caroline Der Nigoghossian, Walter Ageno, Mohammad Madjid, Yutao Guo, … Gregory Y. H. Lip
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648. Thrombosis and COVID-19: The Potential Role of Nutrition
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649. Thrombosis and COVID-19: The Potential Role of Nutrition
Alexandros Tsoupras, Ronan Lordan, Ioannis Zabetakis
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649. Regulation of platelet function and thrombosis by omega-3 and omega-6 polyunsaturated fatty acids
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650. Regulation of platelet function and thrombosis by omega-3 and omega-6 polyunsaturated fatty acids
Reheman Adili, Megan Hawley, Michael Holinstat
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650. Platelet activation and prothrombotic mediators at the nexus of inflammation and atherosclerosis: Potential role of antiplatelet agents
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651. Platelet activation and prothrombotic mediators at the nexus of inflammation and atherosclerosis: Potential role of antiplatelet agents
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651. An Investigation on the Effects of Icosapent Ethyl (VascepaTM) on Inflammatory Biomarkers in Individuals With COVID-19 - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04412018
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652. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia
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653. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia
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653. A Randomised, Double-blind, Placebo Controlled Study of Eicosapentaenoic Acid (EPA-FFA) Gastro-resistant Capsules to Treat Hospitalised Subjects With Confirmed SARS-CoV-2
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654. A Randomised, Double-blind, Placebo Controlled Study of Eicosapentaenoic Acid (EPA-FFA) Gastro-resistant Capsules to Treat Hospitalised Subjects With Confirmed SARS-CoV-2
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654. Anti-inflammatory/Antioxidant Oral Nutrition Supplementation on the Cytokine Storm and Progression of COVID-19: A Randomized Controlled Trial
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655. Anti-inflammatory/Antioxidant Oral Nutrition Supplementation on the Cytokine Storm and Progression of COVID-19: A Randomized Controlled Trial
Mahmoud Abulmeaty FACN M. D.
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655. Functional Role of Dietary Intervention to Improve the Outcome of COVID-19: A Hypothesis of Work
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656. Functional Role of Dietary Intervention to Improve the Outcome of COVID-19: A Hypothesis of Work
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International Journal of Molecular Sciences (2020-04-28) https://doi.org/ggvb88
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656. Zinc and immunity: An essential interrelation
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658. Zinc activates NF-κB in HUT-78 cells
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659. Innate or Adaptive Immunity? The Example of Natural Killer Cells
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661. The Role of Zinc in Antiviral Immunity
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662. The Role of Zinc in Antiviral Immunity
Scott A Read, Stephanie Obeid, Chantelle Ahlenstiel, Golo Ahlenstiel
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662. Efficacy of Zinc Against Common Cold Viruses: An Overview
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663. Efficacy of Zinc Against Common Cold Viruses: An Overview
Darrell Hulisz
Journal of the American Pharmacists Association (2004-09) https://doi.org/cf6pmt
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663. Zinc Lozenges May Shorten the Duration of Colds: A Systematic Review
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664. COVID-19: Poor outcomes in patients with zinc deficiency
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665. COVID-19: Poor outcomes in patients with zinc deficiency
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International Journal of Infectious Diseases (2020-11) https://doi.org/ghr93t
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665. Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture
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666. Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture
Aartjan J. W. te Velthuis, Sjoerd H. E. van den Worm, Amy C. Sims, Ralph S. Baric, Eric J. Snijder, Martijn J. van Hemert
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666. The SARS-coronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds
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667. The SARS-coronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds
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667. A Randomized Study Evaluating the Safety and Efficacy of Hydroxychloroquine and Zinc in Combination With Either Azithromycin or Doxycycline for the Treatment of COVID-19 in the Outpatient Setting
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668. A Randomized Study Evaluating the Safety and Efficacy of Hydroxychloroquine and Zinc in Combination With Either Azithromycin or Doxycycline for the Treatment of COVID-19 in the Outpatient Setting
Avni Thakore MD
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668. A Study of Hydroxychloroquine and Zinc in the Prevention of COVID-19 Infection in Military Healthcare Workers - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04377646
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669. Therapies to Prevent Progression of COVID-19, Including Hydroxychloroquine, Azithromycin, Zinc, Vitamin D, Vitamin B12 With or Without Vitamin C, a Multi-centre, International, Randomized Trial: The International ALLIANCE Study
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670. Therapies to Prevent Progression of COVID-19, Including Hydroxychloroquine, Azithromycin, Zinc, Vitamin D, Vitamin B12 With or Without Vitamin C, a Multi-centre, International, Randomized Trial: The International ALLIANCE Study
National Institute of Integrative Medicine, Australia
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670. Early Intervention in COVID-19: Favipiravir Verses Standard Care - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04373733
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671. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19
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672. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19
Alexandre B. Cavalcanti, Fernando G. Zampieri, Regis G. Rosa, Luciano C. P. Azevedo, Viviane C. Veiga, Alvaro Avezum, Lucas P. Damiani, Aline Marcadenti, Letícia Kawano-Dourado, Thiago Lisboa, … Otavio Berwanger
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672. The efficacy and safety of hydroxychloroquine for COVID-19 prophylaxis: A systematic review and meta-analysis of randomized trials
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673. The efficacy and safety of hydroxychloroquine for COVID-19 prophylaxis: A systematic review and meta-analysis of randomized trials
Kimberley Lewis, Dipayan Chaudhuri, Fayez Alshamsi, Laiya Carayannopoulos, Karin Dearness, Zain Chagla, Waleed Alhazzani, for the GUIDE Group
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673. Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis
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674. Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis
Thibault Fiolet, Anthony Guihur, Mathieu Edouard Rebeaud, Matthieu Mulot, Nathan Peiffer-Smadja, Yahya Mahamat-Saleh
Clinical Microbiology and Infection (2021-01) https://doi.org/gg9jk2
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674. Zinc sulfate in combination with a zinc ionophore may improve outcomes in hospitalized COVID-19 patients
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675. Zinc sulfate in combination with a zinc ionophore may improve outcomes in hospitalized COVID-19 patients
Philip M. Carlucci, Tania Ahuja, Christopher Petrilli, Harish Rajagopalan, Simon Jones, Joseph Rahimian
Journal of Medical Microbiology (2020-10-01) https://doi.org/ghnws7
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675. The Minimal Effect of Zinc on the Survival of Hospitalized Patients With COVID-19
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676. The Minimal Effect of Zinc on the Survival of Hospitalized Patients With COVID-19
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676. Coronavirus Disease 2019- Using Ascorbic Acid and Zinc Supplementation (COVIDAtoZ) Research Study A Randomized, Open Label Single Center Study
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677. Coronavirus Disease 2019- Using Ascorbic Acid and Zinc Supplementation (COVIDAtoZ) Research Study A Randomized, Open Label Single Center Study
Milind Desai
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677. Vitamin B12 May Inhibit RNA-Dependent-RNA Polymerase Activity of nsp12 from the COVID-19 Virus
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678. Vitamin B12 May Inhibit RNA-Dependent-RNA Polymerase Activity of nsp12 from the COVID-19 Virus
Naveen Narayanan, Deepak T. Nair
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678. The Long History of Vitamin C: From Prevention of the Common Cold to Potential Aid in the Treatment of COVID-19
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679. The Long History of Vitamin C: From Prevention of the Common Cold to Potential Aid in the Treatment of COVID-19
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679. The Emerging Role of Vitamin C in the Prevention and Treatment of COVID-19
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681. Intravenous infusion of ascorbic acid decreases serum histamine concentrations in patients with allergic and non-allergic diseases
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686. Vitamin C and Infections
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687. Vitamin C and the common cold
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689. Serum Levels of Vitamin C and Vitamin D in a Cohort of Critically Ill COVID-19 Patients of a North American Community Hospital Intensive Care Unit in May 2020: A Pilot Study
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690. Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome
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691. Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome
Luis Chiscano-Camón, Juan Carlos Ruiz-Rodriguez, Adolf Ruiz-Sanmartin, Oriol Roca, Ricard Ferrer
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691. Targeting coagulation activation in severe COVID-19 pneumonia: lessons from bacterial pneumonia and sepsis
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Ricardo J. José, Andrew Williams, Ari Manuel, Jeremy S. Brown, Rachel C. Chambers
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692. Vitamin C and Microvascular Dysfunction in Systemic Inflammation
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Karel Tyml
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693. The use of IV vitamin C for patients with COVID-19: a case series
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Raul Hiedra, Kevin Bryan Lo, Mohammad Elbashabsheh, Fahad Gul, Robert Matthew Wright, Jeri Albano, Zurab Azmaiparashvili, Gabriel Patarroyo Aponte
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694. Vitamin C for preventing and treating the common cold
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Harri Hemilä, Elizabeth Chalker
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695. Vitamin C intake and susceptibility to pneumonia
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696. Vitamin C intake and susceptibility to pneumonia
HARRI HEMILÄ
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696. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure
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697. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure
Alpha A. Fowler, Jonathon D. Truwit, R. Duncan Hite, Peter E. Morris, Christine DeWilde, Anna Priday, Bernard Fisher, Leroy R. Thacker, Ramesh Natarajan, Donald F. Brophy, … Matthew Halquist
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697. Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial
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698. Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial
Fang Liu, Yuan Zhu, Jing Zhang, Yiming Li, Zhiyong Peng
BMJ Open (2020-07-08) https://doi.org/gg4sgj
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698. Pilot Trial of High-dose vitamin C in critically ill COVID-19 patients
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699. Pilot Trial of High-dose vitamin C in critically ill COVID-19 patients
Jing Zhang, Xin Rao, Yiming Li, Yuan Zhu, Fang Liu, Guangling Guo, Guoshi Luo, Zhongji Meng, Daniel De Backer, Hui Xiang, Zhi-Yong Peng
Research Square (2020-08-03) https://doi.org/ghr94x
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699. High-dose vitamin C infusion for the treatment of critically ill COVID-19
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700. High-dose vitamin C infusion for the treatment of critically ill COVID-19
Jing Zhang, Xin Rao, Yiming Li, Yuan Zhu, Fang Liu, Guangling Guo, Guoshi Luo, Zhongji Meng, Daniel De Backer, Hui Xiang, Zhi-Yong Peng
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700. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids
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701. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids
Panel on Dietary Antioxidants and Related Compounds, Subcommittee on Upper Reference Levels of Nutrients, Subcommittee on Interpretation and Uses of Dietary Reference Intakes, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine
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701. Vitamin D and Infectious Diseases: Simple Bystander or Contributing Factor?
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702. Vitamin D and Infectious Diseases: Simple Bystander or Contributing Factor?
Pedro Gois, Daniela Ferreira, Simon Olenski, Antonio Seguro
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702. Vitamin D and Influenza—Prevention or Therapy?
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Beata M. Gruber–Bzura
International Journal of Molecular Sciences (2018-08-16) https://doi.org/ggndrj
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703. Immunologic Effects of Vitamin D on Human Health and Disease
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704. Immunologic Effects of Vitamin D on Human Health and Disease
Nipith Charoenngam, Michael F. Holick
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704. Vitamin D and respiratory health
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705. Vitamin D and respiratory health
D. A. Hughes, R. Norton
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705. Regulation of Immune Function by Vitamin D and Its Use in Diseases of Immunity
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706. Regulation of Immune Function by Vitamin D and Its Use in Diseases of Immunity
An-Sofie Vanherwegen, Conny Gysemans, Chantal Mathieu
Endocrinology and Metabolism Clinics of North America (2017-12) https://doi.org/gcm7h9
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706. Vitamin D and the Immune System
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707. Vitamin D and the Immune System
Cynthia Aranow
Journal of Investigative Medicine (2015-12-15) https://doi.org/f3wh87
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707. Vitamin D in the prevention of acute respiratory infection: Systematic review of clinical studies
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David A. Jolliffe, Christopher J. Griffiths, Adrian R. Martineau
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708. Vitamin D: modulator of the immune system
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Femke Baeke, Tatiana Takiishi, Hannelie Korf, Conny Gysemans, Chantal Mathieu
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709. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths
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710. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths
William B. Grant, Henry Lahore, Sharon L. McDonnell, Carole A. Baggerly, Christine B. French, Jennifer L. Aliano, Harjit P. Bhattoa
Nutrients (2020-04-02) https://doi.org/ggr2v5
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710. Perspective: Vitamin D deficiency and COVID‐19 severity – plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis
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711. Perspective: Vitamin D deficiency and COVID‐19 severity – plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis
J. M. Rhodes, S. Subramanian, E. Laird, G. Griffin, R. A. Kenny
Journal of Internal Medicine (2020-07-22) https://doi.org/ghc7dh
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711. COVID-19 fatalities, latitude, sunlight, and vitamin D
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712. COVID-19 fatalities, latitude, sunlight, and vitamin D
Paul B. Whittemore
American Journal of Infection Control (2020-09) https://doi.org/ghr93r
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712. Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity
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713. Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity
Jonathan M. Rhodes, Sreedhar Subramanian, Eamon Laird, Rose A. Kenny
Alimentary Pharmacology & Therapeutics (2020-06) https://doi.org/ggtw4b
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713. 25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2
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714. 25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2
Antonio D’Avolio, Valeria Avataneo, Alessandra Manca, Jessica Cusato, Amedeo De Nicolò, Renzo Lucchini, Franco Keller, Marco Cantù
Nutrients (2020-05-09) https://doi.org/ggvv76
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714. Vitamin D deficiency as risk factor for severe COVID-19: a convergence of two pandemics
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715. Vitamin D deficiency as risk factor for severe COVID-19: a convergence of two pandemics
D. De Smet, K. De Smet, P. Herroelen, S. Gryspeerdt, G. A. Martens
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715. Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection
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716. Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection
Zhila Maghbooli, Mohammad Ali Sahraian, Mehdi Ebrahimi, Marzieh Pazoki, Samira Kafan, Hedieh Moradi Tabriz, Azar Hadadi, Mahnaz Montazeri, Mehrad Nasiri, Arash Shirvani, Michael F. Holick
PLOS ONE (2020-09-25) https://doi.org/ghdzx8
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716. Role of vitamin D in preventing of COVID-19 infection, progression and severity
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717. Role of vitamin D in preventing of COVID-19 infection, progression and severity
Nurshad Ali
Journal of Infection and Public Health (2020-10) https://doi.org/ghdzw9
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717. Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: an Israeli population‐based study
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718. Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: an Israeli population‐based study
Eugene Merzon, Dmitry Tworowski, Alessandro Gorohovski, Shlomo Vinker, Avivit Golan Cohen, Ilan Green, Milana Frenkel‐Morgenstern
The FEBS Journal (2020-08-28) https://doi.org/gg7b5c
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718. Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results
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719. Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results
David O. Meltzer, Thomas J. Best, Hui Zhang, Tamara Vokes, Vineet Arora, Julian Solway
JAMA Network Open (2020-09-03) https://doi.org/ghdzw6
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719. Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection
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720. Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection
José L Hernández, Daniel Nan, Marta Fernandez-Ayala, Mayte García-Unzueta, Miguel A Hernández-Hernández, Marcos López-Hoyos, Pedro Muñoz-Cacho, José M Olmos, Manuel Gutiérrez-Cuadra, Juan J Ruiz-Cubillán, … Víctor M Martínez-Taboada
The Journal of Clinical Endocrinology & Metabolism (2020-10-27) https://doi.org/ghh737
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720. Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers
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721. Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers
Anshul Jain, Rachna Chaurasia, Narendra Singh Sengar, Mayank Singh, Sachin Mahor, Sumit Narain
Scientific Reports (2020-11-19) https://doi.org/ghm3zn
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721. Low 25-Hydroxyvitamin D Levels on Admission to the Intensive Care Unit May Predispose COVID-19 Pneumonia Patients to a Higher 28-Day Mortality Risk: A Pilot Study on a Greek ICU Cohort
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722. Low 25-Hydroxyvitamin D Levels on Admission to the Intensive Care Unit May Predispose COVID-19 Pneumonia Patients to a Higher 28-Day Mortality Risk: A Pilot Study on a Greek ICU Cohort
Alice G. Vassiliou, Edison Jahaj, Maria Pratikaki, Stylianos E. Orfanos, Ioanna Dimopoulou, Anastasia Kotanidou
Nutrients (2020-12-09) https://doi.org/ghr95d
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722. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19
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723. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19
G. E. Carpagnano, V. Di Lecce, V. N. Quaranta, A. Zito, E. Buonamico, E. Capozza, A. Palumbo, G. Di Gioia, V. N. Valerio, O. Resta
Journal of Endocrinological Investigation (2020-08-09) https://doi.org/gg7kqp
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723. Vitamin D Deficiency and Outcome of COVID-19 Patients
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724. Vitamin D Deficiency and Outcome of COVID-19 Patients
Aleksandar Radujkovic, Theresa Hippchen, Shilpa Tiwari-Heckler, Saida Dreher, Monica Boxberger, Uta Merle
Nutrients (2020-09-10) https://doi.org/ghgfmp
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724. Impact of Vitamin D Deficiency on COVID-19—A Prospective Analysis from the CovILD Registry
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725. Impact of Vitamin D Deficiency on COVID-19—A Prospective Analysis from the CovILD Registry
Alex Pizzini, Magdalena Aichner, Sabina Sahanic, Anna Böhm, Alexander Egger, Gregor Hoermann, Katharina Kurz, Gerlig Widmann, Rosa Bellmann-Weiler, Günter Weiss, … Judith Löffler-Ragg
Nutrients (2020-09-11) https://doi.org/ghr95b
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725. Does Serum Vitamin D Level Affect COVID-19 Infection and Its Severity?-A Case-Control Study
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726. Does Serum Vitamin D Level Affect COVID-19 Infection and Its Severity?-A Case-Control Study
Kun Ye, Fen Tang, Xin Liao, Benjamin A. Shaw, Meiqiu Deng, Guangyi Huang, Zhiqiang Qin, Xiaomei Peng, Hewei Xiao, Chunxia Chen, … Jianrong Yang
Journal of the American College of Nutrition (2020-10-13) https://doi.org/ghr935
DOI: 10.1080/07315724.2020.1826005 · PMID: 33048028
726. Lower levels of vitamin D are associated with SARS-CoV-2 infection and mortality in the Indian population: An observational study
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727. Lower levels of vitamin D are associated with SARS-CoV-2 infection and mortality in the Indian population: An observational study
Sunali Padhi, Subham Suvankar, Venketesh K. Panda, Abhijit Pati, Aditya K. Panda
International Immunopharmacology (2020-11) https://doi.org/ghr93w
DOI: 10.1016/j.intimp.2020.107001 · PMID: 33182040 · PMCID: PMC7489890
727. Vitamin D Deficiency Is Associated with COVID-19 Incidence and Disease Severity in Chinese People
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728. Vitamin D Deficiency Is Associated with COVID-19 Incidence and Disease Severity in Chinese People
Xia Luo, Qing Liao, Ying Shen, Huijun Li, Liming Cheng
The Journal of Nutrition (2021-01) https://doi.org/ghr939
DOI: 10.1093/jn/nxaa332 · PMID: 33188401
728. Vitamin D concentrations and COVID-19 infection in UK Biobank
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729. Vitamin D concentrations and COVID-19 infection in UK Biobank
Claire E. Hastie, Daniel F. Mackay, Frederick Ho, Carlos A. Celis-Morales, Srinivasa Vittal Katikireddi, Claire L. Niedzwiedz, Bhautesh D. Jani, Paul Welsh, Frances S. Mair, Stuart R. Gray, … Jill P. Pell
Diabetes & Metabolic Syndrome: Clinical Research & Reviews (2020-07) https://doi.org/ggvv72
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729. Vitamin D and COVID-19 infection and mortality in UK Biobank
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730. Vitamin D and COVID-19 infection and mortality in UK Biobank
Claire E. Hastie, Jill P. Pell, Naveed Sattar
European Journal of Nutrition (2020-08-26) https://doi.org/ghr93p
DOI: 10.1007/s00394-020-02372-4 · PMID: 32851419 · PMCID: PMC7449523
730. Low serum 25‐hydroxyvitamin D (25[OH]D) levels in patients hospitalized with COVID‐19 are associated with greater disease severity
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731. Low serum 25‐hydroxyvitamin D (25[OH]D) levels in patients hospitalized with COVID‐19 are associated with greater disease severity
Grigorios Panagiotou, Su Ann Tee, Yasir Ihsan, Waseem Athar, Gabriella Marchitelli, Donna Kelly, Christopher S. Boot, Nadia Stock, James Macfarlane, Adrian R. Martineau, … Richard Quinton
Clinical Endocrinology (2020-08-06) https://doi.org/gg5gbj
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731. Letter in response to the article: Vitamin D concentrations and COVID-19 infection in UK biobank (Hastie et al.)
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732. Letter in response to the article: Vitamin D concentrations and COVID-19 infection in UK biobank (Hastie et al.)
W. B. Grant, S. L. McDonnell
Diabetes & Metabolic Syndrome: Clinical Research & Reviews (2020-09) https://doi.org/ghc7p4
DOI: 10.1016/j.dsx.2020.05.046 · PMID: 32563941 · PMCID: PMC7293469
732. Vitamin D deficiency in African Americans is associated with a high risk of severe disease and mortality by SARS-CoV-2
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733. Vitamin D deficiency in African Americans is associated with a high risk of severe disease and mortality by SARS-CoV-2
Virna Margarita Martín Giménez, Felipe Inserra, León Ferder, Joxel García, Walter Manucha
Journal of Human Hypertension (2020-08-13) https://doi.org/ghr933
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733. Evidence for possible association of vitamin D status with cytokine storm and unregulated inflammation in COVID-19 patients
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734. Evidence for possible association of vitamin D status with cytokine storm and unregulated inflammation in COVID-19 patients
Ali Daneshkhah, Vasundhara Agrawal, Adam Eshein, Hariharan Subramanian, Hemant Kumar Roy, Vadim Backman
Aging Clinical and Experimental Research (2020-09-02) https://doi.org/ghr93q
DOI: 10.1007/s40520-020-01677-y · PMID: 32876941 · PMCID: PMC7465887
734. Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study)
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735. Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study)
Ashu Rastogi, Anil Bhansali, Niranjan Khare, Vikas Suri, Narayana Yaddanapudi, Naresh Sachdeva, GD Puri, Pankaj Malhotra
Postgraduate Medical Journal (2020-11-12) https://doi.org/ghnhpq
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735. “Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study”
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736. “Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study”
Marta Entrenas Castillo, Luis Manuel Entrenas Costa, José Manuel Vaquero Barrios, Juan Francisco Alcalá Díaz, José López Miranda, Roger Bouillon, José Manuel Quesada Gomez
The Journal of Steroid Biochemistry and Molecular Biology (2020-10) https://doi.org/ghd79r
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736. COVID-19 rapid evidence summary: vitamin D for COVID-19 | Advice | NICE https://www.nice.org.uk/advice/es28
+737. COVID-19 rapid evidence summary: vitamin D for COVID-19 | Advice | NICE https://www.nice.org.uk/advice/es28
737. Mathematical analysis of Córdoba calcifediol trial suggests strong role for Vitamin D in reducing ICU admissions of hospitalized COVID-19 patients
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738. Mathematical analysis of Córdoba calcifediol trial suggests strong role for Vitamin D in reducing ICU admissions of hospitalized COVID-19 patients
Irwin Jungreis, Manolis Kellis
Cold Spring Harbor Laboratory (2020-12-21) https://doi.org/ghr94h
DOI: 10.1101/2020.11.08.20222638
738. High-Dose Cholecalciferol Booster Therapy is Associated with a Reduced Risk of Mortality in Patients with COVID-19: A Cross-Sectional Multi-Centre Observational Study
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739. High-Dose Cholecalciferol Booster Therapy is Associated with a Reduced Risk of Mortality in Patients with COVID-19: A Cross-Sectional Multi-Centre Observational Study
Stephanie F. Ling, Eleanor Broad, Rebecca Murphy, Joseph M. Pappachan, Satveer Pardesi-Newton, Marie-France Kong, Edward B. Jude
Nutrients (2020-12-11) https://doi.org/ghr95f
DOI: 10.3390/nu12123799 · PMID: 33322317 · PMCID: PMC7763301
739. Effect of Vitamin D 3 Supplementation vs Placebo on Hospital Length of Stay in Patients with Severe COVID-19: A Multicenter, Double-blind, Randomized Controlled Trial
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740. Effect of Vitamin D 3 Supplementation vs Placebo on Hospital Length of Stay in Patients with Severe COVID-19: A Multicenter, Double-blind, Randomized Controlled Trial
Igor H. Murai, Alan L. Fernandes, Lucas P. Sales, Ana J. Pinto, Karla F. Goessler, Camila S. C. Duran, Carla B. R. Silva, André S. Franco, Marina B. Macedo, Henrique H. H. Dalmolin, … Rosa M. R. Pereira
Cold Spring Harbor Laboratory (2020-11-17) https://doi.org/ghr94j
DOI: 10.1101/2020.11.16.20232397
740. Effect of Vitamin D Administration on Prevention and Treatment of Mild Forms of Suspected Covid-19
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741. Effect of Vitamin D Administration on Prevention and Treatment of Mild Forms of Suspected Covid-19
Manuel Castillo Garzón
clinicaltrials.gov (2020-04-03) https://clinicaltrials.gov/ct2/show/NCT04334005
741. Improving Vitamin D Status in the Management of COVID-19
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742. Improving Vitamin D Status in the Management of COVID-19
Aldo Montano-Loza
clinicaltrials.gov (2020-06-03) https://clinicaltrials.gov/ct2/show/NCT04385940
742. Cholecalciferol to Improve the Outcomes of COVID-19 Patients - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04411446
+743. Cholecalciferol to Improve the Outcomes of COVID-19 Patients - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04411446
743. COvid-19 and Vitamin D Supplementation: a Multicenter Randomized Controlled Trial of High Dose Versus Standard Dose Vitamin D3 in High-risk COVID-19 Patients (CoVitTrial) - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04344041
+744. COvid-19 and Vitamin D Supplementation: a Multicenter Randomized Controlled Trial of High Dose Versus Standard Dose Vitamin D3 in High-risk COVID-19 Patients (CoVitTrial) - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04344041
744. The LEAD COVID-19 Trial: Low-risk, Early Aspirin and Vitamin D to Reduce COVID-19 Hospitalizations
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745. The LEAD COVID-19 Trial: Low-risk, Early Aspirin and Vitamin D to Reduce COVID-19 Hospitalizations
Louisiana State University Health Sciences Center in New Orleans
clinicaltrials.gov (2020-04-24) https://clinicaltrials.gov/ct2/show/NCT04363840
745. Randomized Double-Blind Placebo-Controlled Proof-of-Concept Trial of a Plant Polyphenol for the Outpatient Treatment of Mild Coronavirus Disease (COVID-19)
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746. Randomized Double-Blind Placebo-Controlled Proof-of-Concept Trial of a Plant Polyphenol for the Outpatient Treatment of Mild Coronavirus Disease (COVID-19)
Marvin McCreary MD
clinicaltrials.gov (2020-09-22) https://clinicaltrials.gov/ct2/show/NCT04400890
746. Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society
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747. Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society
Paul Lips, Kevin D Cashman, Christel Lamberg-Allardt, Heike Annette Bischoff-Ferrari, Barbara Obermayer-Pietsch, Maria Luisa Bianchi, Jan Stepan, Ghada El-Hajj Fuleihan, Roger Bouillon
European Journal of Endocrinology (2019-04) https://doi.org/ggr42p
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872. DAMP-Inducing Adjuvant and PAMP Adjuvants Parallelly Enhance Protective Type-2 and Type-1 Immune Responses to Influenza Split Vaccination
Tomoya Hayashi, Masatoshi Momota, Etsushi Kuroda, Takato Kusakabe, Shingo Kobari, Kotaro Makisaka, Yoshitaka Ohno, Yusuke Suzuki, Fumika Nakagawa, Michelle S. J. Lee, … Hidetoshi Arima
Frontiers in Immunology (2018-11-20) https://doi.org/gfqq89
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872. Better Adjuvants for Better Vaccines: Progress in Adjuvant Delivery Systems, Modifications, and Adjuvant–Antigen Codelivery
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873. Better Adjuvants for Better Vaccines: Progress in Adjuvant Delivery Systems, Modifications, and Adjuvant–Antigen Codelivery
Zhi-Biao Wang, Jing Xu
Vaccines (2020-03-13) https://doi.org/gg35vj
DOI: 10.3390/vaccines8010128 · PMID: 32183209 · PMCID: PMC7157724
873. Defining trained immunity and its role in health and disease
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874. Defining trained immunity and its role in health and disease
Mihai G. Netea, Jorge Domínguez-Andrés, Luis B. Barreiro, Triantafyllos Chavakis, Maziar Divangahi, Elaine Fuchs, Leo A. B. Joosten, Jos W. M. van der Meer, Musa M. Mhlanga, Willem J. M. Mulder, … Eicke Latz
Nature Reviews Immunology (2020-03-04) https://doi.org/gg28pr
DOI: 10.1038/s41577-020-0285-6 · PMID: 32132681 · PMCID: PMC7186935
874. Trained Immunity: a Tool for Reducing Susceptibility to and the Severity of SARS-CoV-2 Infection
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875. Trained Immunity: a Tool for Reducing Susceptibility to and the Severity of SARS-CoV-2 Infection
Mihai G. Netea, Evangelos J. Giamarellos-Bourboulis, Jorge Domínguez-Andrés, Nigel Curtis, Reinout van Crevel, Frank L. van de Veerdonk, Marc Bonten
Cell (2020-05) https://doi.org/gg2584
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875. BCG Vaccination to Protect Healthcare Workers Against COVID-19 - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04327206
+876. BCG Vaccination to Protect Healthcare Workers Against COVID-19 - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04327206
876. Reducing Health Care Workers Absenteeism in Covid-19 Pandemic Through BCG Vaccine - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04328441
+877. Reducing Health Care Workers Absenteeism in Covid-19 Pandemic Through BCG Vaccine - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04328441
877. BCG Vaccine for Health Care Workers as Defense Against COVID 19 - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04348370
+878. BCG Vaccine for Health Care Workers as Defense Against COVID 19 - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04348370
878. Application of BCG Vaccine for Immune-prophylaxis Among Egyptian Healthcare Workers During the Pandemic of COVID-19
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879. Application of BCG Vaccine for Immune-prophylaxis Among Egyptian Healthcare Workers During the Pandemic of COVID-19
Adel Khattab
clinicaltrials.gov (2020-04-17) https://clinicaltrials.gov/ct2/show/NCT04350931
879. Performance Evaluation of BCG Vaccination in Healthcare Personnel to Reduce the Severity of SARS-COV-2 Infection in Medellín, Colombia, 2020
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880. Performance Evaluation of BCG Vaccination in Healthcare Personnel to Reduce the Severity of SARS-COV-2 Infection in Medellín, Colombia, 2020
Universidad de Antioquia
clinicaltrials.gov (2020-11-24) https://clinicaltrials.gov/ct2/show/NCT04362124
880. COVID-19: BCG As Therapeutic Vaccine, Transmission Limitation, and Immunoglobulin Enhancement - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04369794
+881. COVID-19: BCG As Therapeutic Vaccine, Transmission Limitation, and Immunoglobulin Enhancement - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04369794
881. Using BCG Vaccine to Protect Health Care Workers in the COVID-19 Pandemic - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04373291
+882. Using BCG Vaccine to Protect Health Care Workers in the COVID-19 Pandemic - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04373291
882. Reducing Morbidity and Mortality in Health Care Workers Exposed to SARS-CoV-2 by Enhancing Non-specific Immune Responses Through Bacillus Calmette-Guérin Vaccination, a Randomized Controlled Trial
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883. Reducing Morbidity and Mortality in Health Care Workers Exposed to SARS-CoV-2 by Enhancing Non-specific Immune Responses Through Bacillus Calmette-Guérin Vaccination, a Randomized Controlled Trial
TASK Applied Science
clinicaltrials.gov (2020-05-06) https://clinicaltrials.gov/ct2/show/NCT04379336
883. Randomized Controlled Trial Evaluating the Efficacy of Vaccination With Bacillus Calmette and Guérin (BCG) in the Prevention of COVID-19 Via the Strengthening of Innate Immunity in Health Care Workers
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884. Randomized Controlled Trial Evaluating the Efficacy of Vaccination With Bacillus Calmette and Guérin (BCG) in the Prevention of COVID-19 Via the Strengthening of Innate Immunity in Health Care Workers
Assistance Publique - Hôpitaux de Paris
clinicaltrials.gov (2020-08-17) https://clinicaltrials.gov/ct2/show/NCT04384549
884. Study to Assess VPM1002 in Reducing Healthcare Professionals’ Absenteeism in COVID-19 Pandemic - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04387409
+885. Study to Assess VPM1002 in Reducing Healthcare Professionals’ Absenteeism in COVID-19 Pandemic - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04387409
885. A Randomized Clinical Trial for Enhanced Trained Immune Responses Through Bacillus Calmette-Guérin Vaccination to Prevent Infections by COVID-19: The ACTIVATE II Trial
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886. A Randomized Clinical Trial for Enhanced Trained Immune Responses Through Bacillus Calmette-Guérin Vaccination to Prevent Infections by COVID-19: The ACTIVATE II Trial
Hellenic Institute for the Study of Sepsis
clinicaltrials.gov (2020-07-10) https://clinicaltrials.gov/ct2/show/NCT04414267
886. Reducing Hospital Admission of Elderly in SARS-CoV-2 Pandemic Via the Induction of Trained Immunity by Bacillus Calmette-Guérin Vaccination, a Randomized Controlled Trial
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887. Reducing Hospital Admission of Elderly in SARS-CoV-2 Pandemic Via the Induction of Trained Immunity by Bacillus Calmette-Guérin Vaccination, a Randomized Controlled Trial
Radboud University
clinicaltrials.gov (2020-06-03) https://clinicaltrials.gov/ct2/show/NCT04417335
887. Study to Assess VPM1002 in Reducing Hospital Admissions and/or Severe Respiratory Infectious Diseases in Elderly in COVID-19 Pandemic - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04435379
+888. Study to Assess VPM1002 in Reducing Hospital Admissions and/or Severe Respiratory Infectious Diseases in Elderly in COVID-19 Pandemic - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04435379
888. Efficacy and Safety of VPM1002 in Reducing SARS-CoV-2 (COVID-19) Infection Rate and Severity - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04439045
+889. Efficacy and Safety of VPM1002 in Reducing SARS-CoV-2 (COVID-19) Infection Rate and Severity - Full Text View - ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04439045
889. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure
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890. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure
Evangelos J. Giamarellos-Bourboulis, Mihai G. Netea, Nikoletta Rovina, Karolina Akinosoglou, Anastasia Antoniadou, Nikolaos Antonakos, Georgia Damoraki, Theologia Gkavogianni, Maria-Evangelia Adami, Paraskevi Katsaounou, … Antonia Koutsoukou
Cell Host & Microbe (2020-06) https://doi.org/ggthxs
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890. Type I and Type III Interferons – Induction, Signaling, Evasion, and Application to Combat COVID-19
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891. Type I and Type III Interferons – Induction, Signaling, Evasion, and Application to Combat COVID-19
Annsea Park, Akiko Iwasaki
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891. Pfizer and BioNTech to Submit Emergency Use Authorization Request Today to the U.S. FDA for COVID-19 Vaccine | Pfizer https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-submit-emergency-use-authorization
+892. Pfizer and BioNTech to Submit Emergency Use Authorization Request Today to the U.S. FDA for COVID-19 Vaccine | Pfizer https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-submit-emergency-use-authorization
892. Moderna Announces First Participants Dosed in Phase 2/3 Study of COVID-19 Vaccine Candidate in Adolescents | Moderna, Inc. https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-first-participants-dosed-phase-23-study-covid/
+893. Moderna Announces First Participants Dosed in Phase 2/3 Study of COVID-19 Vaccine Candidate in Adolescents | Moderna, Inc. https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-first-participants-dosed-phase-23-study-covid/
893. Association of Race With Mortality Among Patients Hospitalized With Coronavirus Disease 2019 (COVID-19) at 92 US Hospitals
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894. Association of Race With Mortality Among Patients Hospitalized With Coronavirus Disease 2019 (COVID-19) at 92 US Hospitals
Baligh R. Yehia, Angela Winegar, Richard Fogel, Mohamad Fakih, Allison Ottenbacher, Christine Jesser, Angelo Bufalino, Ren-Huai Huang, Joseph Cacchione
JAMA Network Open (2020-08-18) https://doi.org/ghcspt
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894. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China
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895. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China
Zunyou Wu, Jennifer M. McGoogan
JAMA (2020-04-07) https://doi.org/ggmq43
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895. Critical Care Utilization for the COVID-19 Outbreak in Lombardy, Italy
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896. Critical Care Utilization for the COVID-19 Outbreak in Lombardy, Italy
Giacomo Grasselli, Antonio Pesenti, Maurizio Cecconi
JAMA (2020-04-28) https://doi.org/ggqf6g
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896. Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 — COVID-NET, 14 States, March 1–30, 2020
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897. Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 — COVID-NET, 14 States, March 1–30, 2020
Shikha Garg, Lindsay Kim, Michael Whitaker, Alissa O’Halloran, Charisse Cummings, Rachel Holstein, Mila Prill, Shua J. Chai, Pam D. Kirley, Nisha B. Alden, … Alicia Fry
MMWR. Morbidity and Mortality Weekly Report (2020-04-17) https://doi.org/ggsppz
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897. COVID-19 and Your Health
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898. COVID-19 and Your Health
CDC
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898. Disparities In Outcomes Among COVID-19 Patients In A Large Health Care System In California
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899. Disparities In Outcomes Among COVID-19 Patients In A Large Health Care System In California
Kristen M. J. Azar, Zijun Shen, Robert J. Romanelli, Stephen H. Lockhart, Kelly Smits, Sarah Robinson, Stephanie Brown, Alice R. Pressman
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899. Characteristics Associated with Hospitalization Among Patients with COVID-19 — Metropolitan Atlanta, Georgia, March–April 2020
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900. Characteristics Associated with Hospitalization Among Patients with COVID-19 — Metropolitan Atlanta, Georgia, March–April 2020
Marie E. Killerby, Ruth Link-Gelles, Sarah C. Haight, Caroline A. Schrodt, Lucinda England, Danica J. Gomes, Mays Shamout, Kristen Pettrone, Kevin O’Laughlin, Anne Kimball, … CDC COVID-19 Response Clinical Team
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900. Demographic science aids in understanding the spread and fatality rates of COVID-19
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901. Demographic science aids in understanding the spread and fatality rates of COVID-19
Jennifer Beam Dowd, Liliana Andriano, David M. Brazel, Valentina Rotondi, Per Block, Xuejie Ding, Yan Liu, Melinda C. Mills
Proceedings of the National Academy of Sciences (2020-05-05) https://doi.org/ggsd5b
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901. ‐19 and Older Adults: What We Know
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902. ‐19 and Older Adults: What We Know
Zainab Shahid, Ricci Kalayanamitra, Brendan McClafferty, Douglas Kepko, Devyani Ramgobin, Ravi Patel, Chander Shekher Aggarwal, Ramarao Vunnam, Nitasa Sahu, Dhirisha Bhatt, … Rohit Jain
Journal of the American Geriatrics Society (2020-04-20) https://doi.org/ggxgsb
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902. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study
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903. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study
Annemarie B Docherty, Ewen M Harrison, Christopher A Green, Hayley E Hardwick, Riinu Pius, Lisa Norman, Karl A Holden, Jonathan M Read, Frank Dondelinger, Gail Carson, … Malcolm G Semple
BMJ (2020-05-22) https://doi.org/ggw4nh
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903. Impact of sex and gender on COVID-19 outcomes in Europe
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904. Impact of sex and gender on COVID-19 outcomes in Europe
Catherine Gebhard, Vera Regitz-Zagrosek, Hannelore K. Neuhauser, Rosemary Morgan, Sabra L. Klein
Biology of Sex Differences (2020-05-25) https://doi.org/ghbvck
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904. The Sex, Gender and COVID-19 Project | Global Health 50/50 https://globalhealth5050.org/the-sex-gender-and-covid-19-project/
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905. Biological sex impacts COVID-19 outcomes
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906. Biological sex impacts COVID-19 outcomes
Sabra L. Klein, Santosh Dhakal, Rebecca L. Ursin, Sharvari Deshpande, Kathryn Sandberg, Franck Mauvais-Jarvis
PLOS Pathogens (2020-06-22) https://doi.org/gg3hwv
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906. Sex-specific clinical characteristics and prognosis of coronavirus disease-19 infection in Wuhan, China: A retrospective study of 168 severe patients
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907. Sex-specific clinical characteristics and prognosis of coronavirus disease-19 infection in Wuhan, China: A retrospective study of 168 severe patients
Yifan Meng, Ping Wu, Wanrong Lu, Kui Liu, Ke Ma, Liang Huang, Jiaojiao Cai, Hong Zhang, Yu Qin, Haiying Sun, … Peng Wu
PLOS Pathogens (2020-04-28) https://doi.org/ggv3zn
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907. Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17β-oestradiol-dependent and sex chromosome-independent
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908. Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17β-oestradiol-dependent and sex chromosome-independent
Jun Liu, Hong Ji, Wei Zheng, Xie Wu, Janet J Zhu, Arthur P Arnold, Kathryn Sandberg
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908. COVID-19 in nursing homes
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909. COVID-19 in nursing homes
A Fallon, T Dukelow, SP Kennelly, D O’Neill
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909. Vulnerabilities to COVID-19 Among Transgender Adults in the U.S.
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910. Vulnerabilities to COVID-19 Among Transgender Adults in the U.S.
Jody L. Herman, Kathryn O’Neill
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910. Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes
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911. Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes
Lihua Zhu, Zhi-Gang She, Xu Cheng, Juan-Juan Qin, Xiao-Jing Zhang, Jingjing Cai, Fang Lei, Haitao Wang, Jing Xie, Wenxin Wang, … Hongliang Li
Cell Metabolism (2020-06) https://doi.org/ggvcc9
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911. Diabetes increases the mortality of patients with COVID-19: a meta-analysis
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912. Diabetes increases the mortality of patients with COVID-19: a meta-analysis
Zeng-hong Wu, Yun Tang, Qing Cheng
Acta Diabetologica (2020-06-24) https://doi.org/gg3k55
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912. COVID-19 infection may cause ketosis and ketoacidosis
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913. COVID-19 infection may cause ketosis and ketoacidosis
Juyi Li, Xiufang Wang, Jian Chen, Xiuran Zuo, Hongmei Zhang, Aiping Deng
Diabetes, Obesity and Metabolism (2020-05-18) https://doi.org/ggv4tm
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913. COVID-19 pandemic, coronaviruses, and diabetes mellitus
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914. COVID-19 pandemic, coronaviruses, and diabetes mellitus
Ranganath Muniyappa, Sriram Gubbi
American Journal of Physiology-Endocrinology and Metabolism (2020-05-01) https://doi.org/ggq79v
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914. Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, New York
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915. Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, New York
Leonidas Palaiodimos, Damianos G. Kokkinidis, Weijia Li, Dimitrios Karamanis, Jennifer Ognibene, Shitij Arora, William N. Southern, Christos S. Mantzoros
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915. Features of 16,749 hospitalised UK patients with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol
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916. Features of 16,749 hospitalised UK patients with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol
AB Docherty, EM Harrison, CA Green, H Hardwick, R Pius, L Norman, KA Holden, JM Read, F Dondelinger, G Carson, … ISARIC4C Investigators
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916. When Two Pandemics Meet: Why Is Obesity Associated with Increased COVID-19 Mortality?
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917. When Two Pandemics Meet: Why Is Obesity Associated with Increased COVID-19 Mortality?
Sam M. Lockhart, Stephen O’Rahilly
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917. Besides population age structure, health and other demographic factors can contribute to understanding the COVID-19 burden
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918. Besides population age structure, health and other demographic factors can contribute to understanding the COVID-19 burden
Marília R. Nepomuceno, Enrique Acosta, Diego Alburez-Gutierrez, José Manuel Aburto, Alain Gagnon, Cássio M. Turra
Proceedings of the National Academy of Sciences (2020-06-23) https://doi.org/gg33qx
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919. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure
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920. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure
J. -L. Vincent, R. Moreno, J. Takala, S. Willatts, A. De Mendonça, H. Bruining, C. K. Reinhart, P. M. Suter, L. G. Thijs
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920. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)
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921. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)
Mervyn Singer, Clifford S. Deutschman, Christopher Warren Seymour, Manu Shankar-Hari, Djillali Annane, Michael Bauer, Rinaldo Bellomo, Gordon R. Bernard, Jean-Daniel Chiche, Craig M. Coopersmith, … Derek C. Angus
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921. COVID-19 and African Americans
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922. COVID-19 and African Americans
Clyde W. Yancy
JAMA (2020-05-19) https://doi.org/ggv494
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922. COVID-19 and Racial/Ethnic Disparities
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923. COVID-19 and Racial/Ethnic Disparities
Monica Webb Hooper, Anna María Nápoles, Eliseo J. Pérez-Stable
JAMA (2020-06-23) https://doi.org/ggvzqn
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923. Covid-19: Black people and other minorities are hardest hit in US
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924. Covid-19: Black people and other minorities are hardest hit in US
Owen Dyer
BMJ (2020-04-14) https://doi.org/ggv5br
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924. Susceptibility of Southwestern American Indian Tribes to Coronavirus Disease 2019 (COVID‐19)
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925. Susceptibility of Southwestern American Indian Tribes to Coronavirus Disease 2019 (COVID‐19)
Monika Kakol, Dona Upson, Akshay Sood
The Journal of Rural Health (2020-06) https://doi.org/ggtzkq
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925. The Fullest Look Yet at the Racial Inequity of Coronavirus
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926. The Fullest Look Yet at the Racial Inequity of Coronavirus
Richard A. Oppel Jr, Robert Gebeloff, K. K. Rebecca Lai, Will Wright, Mitch Smith
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926. Addressing inequities in COVID-19 morbidity and mortality: research and policy recommendations
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927. Addressing inequities in COVID-19 morbidity and mortality: research and policy recommendations
Monica L Wang, Pamela Behrman, Akilah Dulin, Monica L Baskin, Joanna Buscemi, Kassandra I Alcaraz, Carly M Goldstein, Tiffany L Carson, Megan Shen, Marian Fitzgibbon
Translational Behavioral Medicine (2020-06) https://doi.org/gg3389
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927. Historical Environmental Racism, Structural Inequalities, and Dik’os Ntsaaígíí-19 (COVID-19) on Navajo Nation
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928. Historical Environmental Racism, Structural Inequalities, and Dik’os Ntsaaígíí-19 (COVID-19) on Navajo Nation
Nicholet A. Deschine Parkhurst, Kimberly R. Huyser, Aggie J. Yellow Horse
Journal of Indigenous Social Development (2020-11-02) https://journalhosting.ucalgary.ca/index.php/jisd/article/view/70753
928. Protect Indigenous peoples from COVID-19
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929. Protect Indigenous peoples from COVID-19
Lucas Ferrante, Philip M. Fearnside
Science (2020-04-16) https://doi.org/gg3k6f
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929. Factors associated with COVID-19-related death using OpenSAFELY
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930. Factors associated with COVID-19-related death using OpenSAFELY
Elizabeth J. Williamson, Alex J. Walker, Krishnan Bhaskaran, Seb Bacon, Chris Bates, Caroline E. Morton, Helen J. Curtis, Amir Mehrkar, David Evans, Peter Inglesby, … Ben Goldacre
Nature (2020-07-08) https://doi.org/gg39n7
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930. Implications of biogeography of human populations for “race” and medicine
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931. Implications of biogeography of human populations for “race” and medicine
Sarah A Tishkoff, Kenneth K Kidd
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931. African Genetic Diversity: Implications for Human Demographic History, Modern Human Origins, and Complex Disease Mapping
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932. African Genetic Diversity: Implications for Human Demographic History, Modern Human Origins, and Complex Disease Mapping
Michael C. Campbell, Sarah A. Tishkoff
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932. NIH must confront the use of race in science
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933. NIH must confront the use of race in science
Michael Yudell, Dorothy Roberts, Rob DeSalle, Sarah Tishkoff, 70 signatories
Science (2020-09-10) https://doi.org/ghcm7s
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933. Interferon-Induced Transmembrane Protein 3 Genetic Variant rs12252-C Associated With Disease Severity in Coronavirus Disease 2019
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934. Interferon-Induced Transmembrane Protein 3 Genetic Variant rs12252-C Associated With Disease Severity in Coronavirus Disease 2019
Yonghong Zhang, Ling Qin, Yan Zhao, Ping Zhang, Bin Xu, Kang Li, Lianchun Liang, Chi Zhang, Yanchao Dai, Yingmei Feng, … Ronghua Jin
The Journal of Infectious Diseases (2020-07-01) https://doi.org/ggv3tj
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934. Genomewide Association Study of Severe Covid-19 with Respiratory Failure
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935. Genomewide Association Study of Severe Covid-19 with Respiratory Failure
The Severe Covid-19 GWAS Group
New England Journal of Medicine (2020-10-15) https://doi.org/gg2pqx
DOI: 10.1056/nejmoa2020283 · PMID: 32558485 · PMCID: PMC7315890
935. APOE e4 Genotype Predicts Severe COVID-19 in the UK Biobank Community Cohort
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936. APOE e4 Genotype Predicts Severe COVID-19 in the UK Biobank Community Cohort
Chia-Ling Kuo, Luke C Pilling, Janice L Atkins, Jane AH Masoli, João Delgado, George A Kuchel, David Melzer
The Journals of Gerontology: Series A (2020-11) https://doi.org/ggx4ng
DOI: 10.1093/gerona/glaa131 · PMID: 32451547 · PMCID: PMC7314139
936. Genome-wide CRISPR screen reveals host genes that regulate SARS-CoV-2 infection
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937. Genome-wide CRISPR screen reveals host genes that regulate SARS-CoV-2 infection
Jin Wei, Mia Madel Alfajaro, Ruth E. Hanna, Peter C. DeWeirdt, Madison S. Strine, William J. Lu-Culligan, Shang-Min Zhang, Vincent R. Graziano, Cameron O. Schmitz, Jennifer S. Chen, … Craig B. Wilen
Cold Spring Harbor Laboratory (2020-06-17) https://doi.org/dzz3
DOI: 10.1101/2020.06.16.155101 · PMID: 32869025 · PMCID: PMC7457610
937. New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis
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938. New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis
Yuan Hou, Junfei Zhao, William Martin, Asha Kallianpur, Mina K. Chung, Lara Jehi, Nima Sharifi, Serpil Erzurum, Charis Eng, Feixiong Cheng
BMC Medicine (2020-07-15) https://doi.org/gg445n
DOI: 10.1186/s12916-020-01673-z · PMID: 32664879 · PMCID: PMC7360473
938. Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Kenyan blood donors
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939. Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Kenyan blood donors
Sophie Uyoga, Ifedayo M.O. Adetifa, Henry K. Karanja, James Nyagwange, James Tuju, Perpetual Wanjiku, Rashid Aman, Mercy Mwangangi, Patrick Amoth, Kadondi Kasera, … George M. Warimwe
Cold Spring Harbor Laboratory (2020-07-29) https://doi.org/ghcm7p
DOI: 10.1101/2020.07.27.20162693
939. High SARS-CoV-2 seroprevalence in Health Care Workers but relatively low numbers of deaths in urban Malawi
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940. High SARS-CoV-2 seroprevalence in Health Care Workers but relatively low numbers of deaths in urban Malawi
Marah G. Chibwana, Khuzwayo C. Jere, Raphael Kamn’gona, Jonathan Mandolo, Vincent Katunga-Phiri, Dumizulu Tembo, Ndaona Mitole, Samantha Musasa, Simon Sichone, Agness Lakudzala, … Kondwani C. Jambo
Cold Spring Harbor Laboratory (2020-08-01) https://doi.org/ghcm7q
DOI: 10.1101/2020.07.30.20164970 · PMID: 32766597 · PMCID: PMC7402052
940. Africa’s pandemic puzzle: why so few cases and deaths?
+
941. Africa’s pandemic puzzle: why so few cases and deaths?
Linda Nordling
Science (2020-08-13) https://doi.org/ghcm7r
DOI: 10.1126/science.369.6505.756 · PMID: 32792376
941. Are some ethnic groups more vulnerable to COVID-19 than others? https://www.ifs.org.uk/inequality/chapter/are-some-ethnic-groups-more-vulnerable-to-covid-19-than-others/
+942. Are some ethnic groups more vulnerable to COVID-19 than others? https://www.ifs.org.uk/inequality/chapter/are-some-ethnic-groups-more-vulnerable-to-covid-19-than-others/
942. Quantifying the social distancing privilege gap: a longitudinal study of smartphone movement
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943. Quantifying the social distancing privilege gap: a longitudinal study of smartphone movement
Nabarun Dasgupta, Michele Jonsson Funk, Allison Lazard, Benjamin Eugene White, Stephen W. Marshall
Cold Spring Harbor Laboratory (2020-05-08) https://doi.org/gg79qk
DOI: 10.1101/2020.05.03.20084624
943. Uncovering socioeconomic gaps in mobility reduction during the COVID-19 pandemic using location data
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944. Uncovering socioeconomic gaps in mobility reduction during the COVID-19 pandemic using location data
Samuel P. Fraiberger, Pablo Astudillo, Lorenzo Candeago, Alex Chunet, Nicholas K. W. Jones, Maham Faisal Khan, Bruno Lepri, Nancy Lozano Gracia, Lorenzo Lucchini, Emanuele Massaro, Aleister Montfort
arXiv (2020-07-28) https://arxiv.org/abs/2006.15195
944. Mobility network models of COVID-19 explain inequities and inform reopening
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945. Mobility network models of COVID-19 explain inequities and inform reopening
Serina Chang, Emma Pierson, Pang Wei Koh, Jaline Gerardin, Beth Redbird, David Grusky, Jure Leskovec
Nature (2020-11-10) https://doi.org/ghjmt2
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945. A Basic Demographic Profile of Workers in Frontline Industries
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946. A Basic Demographic Profile of Workers in Frontline Industries
Hye Jin Rho;Shawn Fremstad;Hayley Brown
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946. Differential occupational risk for COVID‐19 and other infection exposure according to race and ethnicity
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947. Differential occupational risk for COVID‐19 and other infection exposure according to race and ethnicity
Devan Hawkins
American Journal of Industrial Medicine (2020-06-15) https://doi.org/gg3rb2
DOI: 10.1002/ajim.23145 · PMID: 32539166 · PMCID: PMC7323065
947. Estimating the burden of United States workers exposed to infection or disease: A key factor in containing risk of COVID-19 infection
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948. Estimating the burden of United States workers exposed to infection or disease: A key factor in containing risk of COVID-19 infection
Marissa G. Baker, Trevor K. Peckham, Noah S. Seixas
PLOS ONE (2020-04-28) https://doi.org/ggtx7c
DOI: 10.1371/journal.pone.0232452 · PMID: 32343747 · PMCID: PMC7188235
948. Coronavirus (COVID-19) related deaths by occupation, England and Wales: deaths registered up to and including 20 April 2020
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949. Coronavirus (COVID-19) related deaths by occupation, England and Wales: deaths registered up to and including 20 April 2020
Ben Windsor-Shellard, Jasveer Kaur
(2020-05-11) https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/causesofdeath/bulletins/coronaviruscovid19relateddeathsbyoccupationenglandandwales/deathsregistereduptoandincluding20april2020
949. Which occupations have the highest potential exposure to the coronavirus (COVID-19)?
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950. Which occupations have the highest potential exposure to the coronavirus (COVID-19)?
Office for National Statistics
(2020-05-11) https://www.ons.gov.uk/employmentandlabourmarket/peopleinwork/employmentandemployeetypes/articles/whichoccupationshavethehighestpotentialexposuretothecoronaviruscovid19/2020-05-11
950. Disparities in the risk and outcomes from COVID-19
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951. Disparities in the risk and outcomes from COVID-19
Public Health England
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951. Exclusive: deaths of NHS staff from covid-19 analysed
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952. Exclusive: deaths of NHS staff from covid-19 analysed
Tim Cook, Emira Kursumovic, Simon Lennane2020-04-22T12:42:00+01:00
Health Service Journal https://www.hsj.co.uk/exclusive-deaths-of-nhs-staff-from-covid-19-analysed/7027471.article
953. Racial Disparity in COVID-19 Deaths: Seeking Economic Roots with Census data.
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954. Racial Disparity in COVID-19 Deaths: Seeking Economic Roots with Census data.
John McLaren
National Bureau of Economic Research (2020-06-22) https://www.nber.org/papers/w27407
954. Mortality, Admissions, and Patient Census at SNFs in 3 US Cities During the COVID-19 Pandemic
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955. Mortality, Admissions, and Patient Census at SNFs in 3 US Cities During the COVID-19 Pandemic
Michael L. Barnett, Lissy Hu, Thomas Martin, David C. Grabowski
JAMA (2020-08-04) https://doi.org/gg3387
DOI: 10.1001/jama.2020.11642 · PMID: 32579161 · PMCID: PMC7315390
955. COVID-19 in Prisons and Jails in the United States
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956. COVID-19 in Prisons and Jails in the United States
Laura Hawks, Steffie Woolhandler, Danny McCormick
JAMA Internal Medicine (2020-08-01) https://doi.org/ggtxw6
DOI: 10.1001/jamainternmed.2020.1856 · PMID: 32343355
956. COVID-19 Cases and Deaths in Federal and State Prisons
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957. COVID-19 Cases and Deaths in Federal and State Prisons
Brendan Saloner, Kalind Parish, Julie A. Ward, Grace DiLaura, Sharon Dolovich
JAMA (2020-08-11) https://doi.org/gg4dcv
DOI: 10.1001/jama.2020.12528 · PMID: 32639537 · PMCID: PMC7344796
957. State Rates of Incarceration Race & Ethnicity_updated2
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958. State Rates of Incarceration Race & Ethnicity_updated2
nlizanna
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958. Under One Roof: A Review of Research on Intergenerational Coresidence and Multigenerational Households in the United States
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959. Under One Roof: A Review of Research on Intergenerational Coresidence and Multigenerational Households in the United States
Jennifer Reid Keene, Christie D. Batson
Sociology Compass (2010-08) https://doi.org/fsrcr7
DOI: 10.1111/j.1751-9020.2010.00306.x
959. Chaos and the macrosetting: The role of poverty and socioeconomic status.
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960. Chaos and the macrosetting: The role of poverty and socioeconomic status.
Gary W. Evans, John Eckenrode, Lyscha A. Marcynyszyn
American Psychological Association (APA) (2010-01-12) https://doi.org/c76n3g
DOI: 10.1037/12057-014
960. Housing insecurity among urban fathers
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961. Housing insecurity among urban fathers
Marah A. Curtis, Amanda B. Geller
Columbia University (2010) https://doi.org/ghdjn2
DOI: 10.7916/d8wh2w9t
961. Housing and Employment Insecurity among the Working Poor
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962. Housing and Employment Insecurity among the Working Poor
Matthew Desmond, Carl Gershenson
Social Problems (2016-02) https://doi.org/f8crm2
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962. Obesity and its comorbid conditions
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963. Obesity and its comorbid conditions
Lalita Khaodhiar, Karen C. McCowen, George L. Blackburn
Clinical Cornerstone (1999-01) https://doi.org/bpp37d
DOI: 10.1016/s1098-3597(99)90002-9
963. Aging, Male Sex, Obesity, and Metabolic Inflammation Create the Perfect Storm for COVID-19
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964. Aging, Male Sex, Obesity, and Metabolic Inflammation Create the Perfect Storm for COVID-19
Franck Mauvais-Jarvis
Diabetes (2020-09) https://doi.org/gg47zk
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964. Non-communicable disease syndemics: poverty, depression, and diabetes among low-income populations
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965. Non-communicable disease syndemics: poverty, depression, and diabetes among low-income populations
Emily Mendenhall, Brandon A Kohrt, Shane A Norris, David Ndetei, Dorairaj Prabhakaran
The Lancet (2017-03) https://doi.org/gddg84
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965. Obesity and poverty paradox in developed countries
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966. Obesity and poverty paradox in developed countries
Wioletta Żukiewicz-Sobczak, Paula Wróblewska, Jacek Zwoliński, Jolanta Chmielewska-Badora, Piotr Adamczuk, Ewelina Krasowska, Jerzy Zagórski, Anna Oniszczuk, Jacek Piątek, Wojciech Silny
Annals of Agricultural and Environmental Medicine (2014-09-04) https://doi.org/f6jhzc
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966. Impact of the COVID‐19 Pandemic on Unhealthy Eating in Populations with Obesity
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967. Impact of the COVID‐19 Pandemic on Unhealthy Eating in Populations with Obesity
Nathaniel J. S. Ashby
Obesity (2020-08-20) https://doi.org/ghd6qc
DOI: 10.1002/oby.22940 · PMID: 32589788 · PMCID: PMC7361200
967. Fast Food Patronage and Obesity Prevalence During the COVID‐19 Pandemic: An Alternative Explanation
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968. Fast Food Patronage and Obesity Prevalence During the COVID‐19 Pandemic: An Alternative Explanation
Candice A. Myers, Stephanie T. Broyles
Obesity (2020-09-03) https://doi.org/gg6v84
DOI: 10.1002/oby.22993 · PMID: 32741130 · PMCID: PMC7435526
968. The global food syndemic: The impact of food insecurity, Malnutrition and obesity on the healthspan amid the COVID-19 pandemic
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969. The global food syndemic: The impact of food insecurity, Malnutrition and obesity on the healthspan amid the COVID-19 pandemic
Martha I. Huizar, Ross Arena, Deepika R. Laddu
Progress in Cardiovascular Diseases (2020-07) https://doi.org/gg4r3h
DOI: 10.1016/j.pcad.2020.07.002 · PMID: 32653438 · PMCID: PMC7347484
969. Stress, chronic inflammation, and emotional and physical well-being: Concurrent effects and chronic sequelae
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970. Stress, chronic inflammation, and emotional and physical well-being: Concurrent effects and chronic sequelae
George P. Chrousos
Journal of Allergy and Clinical Immunology (2000-11) https://doi.org/bgx7hn
DOI: 10.1067/mai.2000.110163 · PMID: 11080744
970. Chronic psychological stress and the regulation of pro-inflammatory cytokines: A glucocorticoid-resistance model.
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971. Chronic psychological stress and the regulation of pro-inflammatory cytokines: A glucocorticoid-resistance model.
Gregory E. Miller, Sheldon Cohen, A. Kim Ritchey
Health Psychology (2002) https://doi.org/dj5r8b
DOI: 10.1037/0278-6133.21.6.531
971. Chronic stress, daily stressors, and circulating inflammatory markers.
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972. Chronic stress, daily stressors, and circulating inflammatory markers.
Jean-Philippe Gouin, Ronald Glaser, William B. Malarkey, David Beversdorf, Janice Kiecolt-Glaser
Health Psychology (2012-03) https://doi.org/dkz9tr
DOI: 10.1037/a0025536 · PMID: 21928900 · PMCID: PMC3253267
972. Turning Up the Heat
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973. Turning Up the Heat
Gregory E. Miller, Ekin Blackwell
Current Directions in Psychological Science (2016-06-24) https://doi.org/bft9mv
DOI: 10.1111/j.1467-8721.2006.00450.x
973. Sick of Poverty
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974. Sick of Poverty
Robert Sapolsky
Scientific American (2005-12) https://doi.org/fxf5kp
DOI: 10.1038/scientificamerican1205-92 · PMID: 16323696
974. Exposure to air pollution and COVID-19 mortality in the United States: A nationwide cross-sectional study
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975. Exposure to air pollution and COVID-19 mortality in the United States: A nationwide cross-sectional study
Xiao Wu, Rachel C Nethery, M Benjamin Sabath, Danielle Braun, Francesca Dominici
Cold Spring Harbor Laboratory (2020-04-27) https://doi.org/ggrpcj
DOI: 10.1101/2020.04.05.20054502 · PMID: 32511651 · PMCID: PMC7277007
975. Global estimates of mortality associated with long-term exposure to outdoor fine particulate matter
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976. Global estimates of mortality associated with long-term exposure to outdoor fine particulate matter
Richard Burnett, Hong Chen, Mieczysław Szyszkowicz, Neal Fann, Bryan Hubbell, C. Arden Pope, Joshua S. Apte, Michael Brauer, Aaron Cohen, Scott Weichenthal, … Joseph V. Spadaro
Proceedings of the National Academy of Sciences (2018-09-18) https://doi.org/gfgbcx
DOI: 10.1073/pnas.1803222115 · PMID: 30181279 · PMCID: PMC6156628
976. Early-Life Air Pollution Exposure, Neighborhood Poverty, and Childhood Asthma in the United States, 1990–2014
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977. Early-Life Air Pollution Exposure, Neighborhood Poverty, and Childhood Asthma in the United States, 1990–2014
Nicole Kravitz-Wirtz, Samantha Teixeira, Anjum Hajat, Bongki Woo, Kyle Crowder, David Takeuchi
International Journal of Environmental Research and Public Health (2018-05-30) https://doi.org/gdvwp9
DOI: 10.3390/ijerph15061114 · PMID: 29848979 · PMCID: PMC6025399
977. Early life stress, air pollution, inflammation, and disease: An integrative review and immunologic model of social-environmental adversity and lifespan health
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978. Early life stress, air pollution, inflammation, and disease: An integrative review and immunologic model of social-environmental adversity and lifespan health
Hector A. Olvera Alvarez, Laura D. Kubzansky, Matthew J. Campen, George M. Slavich
Neuroscience & Biobehavioral Reviews (2018-09) https://doi.org/gd46bm
DOI: 10.1016/j.neubiorev.2018.06.002 · PMID: 29874545 · PMCID: PMC6082389
978. Covid-19 and Disparities in Nutrition and Obesity
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979. Covid-19 and Disparities in Nutrition and Obesity
Matthew J. Belanger, Michael A. Hill, Angeliki M. Angelidi, Maria Dalamaga, James R. Sowers, Christos S. Mantzoros
New England Journal of Medicine (2020-09-10) https://doi.org/gg475x
DOI: 10.1056/nejmp2021264 · PMID: 32668105
979. Systemic racism, chronic health inequities, and ‐19: A syndemic in the making?
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980. Systemic racism, chronic health inequities, and ‐19: A syndemic in the making?
Clarence C. Gravlee
American Journal of Human Biology (2020-08-04) https://doi.org/ghcxwk
DOI: 10.1002/ajhb.23482 · PMID: 32754945 · PMCID: PMC7441277
980. Coronavirus Disease (COVID-19): A primer for emergency physicians
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981. Coronavirus Disease (COVID-19): A primer for emergency physicians
Summer Chavez, Brit Long, Alex Koyfman, Stephen Y. Liang
The American Journal of Emergency Medicine (2020-03) https://doi.org/ggr22z
DOI: 10.1016/j.ajem.2020.03.036 · PMID: 32265065 · PMCID: PMC7102516
981. Insurers May Only Pay For Coronavirus Tests When They’re “Medically Necessary”
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982. Insurers May Only Pay For Coronavirus Tests When They’re “Medically Necessary”
NPR.org
https://www.npr.org/sections/health-shots/2020/06/19/880543755/insurers-may-only-pay-for-coronavirus-tests-when-theyre-medically-necessary
982. Private Health Insurance Coverage in the COVID-19 Public Health Emergency | Commonwealth Fund https://www.commonwealthfund.org/blog/2020/private-health-insurance-coverage-covid-19-public-health-emergency
+983. Private Health Insurance Coverage in the COVID-19 Public Health Emergency | Commonwealth Fund https://www.commonwealthfund.org/blog/2020/private-health-insurance-coverage-covid-19-public-health-emergency
983. COVID-19 and racial disparities
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984. COVID-19 and racial disparities
Monica Shah, Muskaan Sachdeva, Roni P. Dodiuk-Gad
Journal of the American Academy of Dermatology (2020-07) https://doi.org/ggtwm7
DOI: 10.1016/j.jaad.2020.04.046 · PMID: 32305444 · PMCID: PMC7162783
984. FAQs for COVID-19 Claims Reimbursement to Health Care Providers and Facilities for Testing, Treatment and Vaccine Administration
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985. FAQs for COVID-19 Claims Reimbursement to Health Care Providers and Facilities for Testing, Treatment and Vaccine Administration
Official web site of the U.S. Health Resources & Services Administration
https://www.hrsa.gov/coviduninsuredclaim/frequently-asked-questions
985. Potential association between COVID-19 mortality and health-care resource availability
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986. Potential association between COVID-19 mortality and health-care resource availability
Yunpeng Ji, Zhongren Ma, Maikel P Peppelenbosch, Qiuwei Pan
The Lancet Global Health (2020-04) https://doi.org/ggqscd
DOI: 10.1016/s2214-109x(20)30068-1 · PMID: 32109372 · PMCID: PMC7128131
986. Combating COVID-19: health equity matters
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987. Combating COVID-19: health equity matters
Zhicheng Wang, Kun Tang
Nature Medicine (2020-03-26) https://doi.org/ggs4p6
DOI: 10.1038/s41591-020-0823-6 · PMID: 32284617
987. lockup black
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988. lockup black
chen0307
(2020-10-14) https://www.census.gov/content/dam/Census/library/publications/2019/demo/p60-267.pdf
988. An Ethical Dilemma in SARS-Cov-2 Pandemic : Who Gets the Ventilator?
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989. An Ethical Dilemma in SARS-Cov-2 Pandemic : Who Gets the Ventilator?
Dumache Raluca, Ciocan Veronica, Muresan Camelia Oana, Enache Alexandra
European Scientific Journal ESJ (2020-07-31) https://doi.org/ghfprk
DOI: 10.19044/esj.2020.v16n21p24
989. Planning Hospital Needs for Ventilators and Respiratory Therapists in the COVID-19 Crisis
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990. Planning Hospital Needs for Ventilators and Respiratory Therapists in the COVID-19 Crisis
John Raffensperger, Marygail Brauner, R. Briggs
Rand Corporation (2020) https://doi.org/ghfprp
DOI: 10.7249/pea228-1
990. Fair Allocation of Vaccines, Ventilators and Antiviral Treatments: Leaving No Ethical Value Behind in Health Care Rationing
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991. Fair Allocation of Vaccines, Ventilators and Antiviral Treatments: Leaving No Ethical Value Behind in Health Care Rationing
Parag A. Pathak, Tayfun Sönmez, M. Utku Ünver, M. Bumin Yenmez
arXiv (2021-01-21) https://arxiv.org/abs/2008.00374
991. Reallocating ventilators during the coronavirus disease 2019 pandemic: Is it ethical?
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992. Reallocating ventilators during the coronavirus disease 2019 pandemic: Is it ethical?
Quyen Chu, Ricardo Correa, Tracey L. Henry, Kyle A. McGregor, Hanni Stoklosa, Loren Robinson, Sachin Jha, Alagappan Annamalai, Benson S. Hsu, Rohit Gupta, … SreyRam Kuy
Surgery (2020-09) https://doi.org/ghfprb
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992. Ethics Lessons From Seattle’s Early Experience With COVID-19
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993. Ethics Lessons From Seattle’s Early Experience With COVID-19
Denise M. Dudzinski, Benjamin Y. Hoisington, Crystal E. Brown
The American Journal of Bioethics (2020-06-18) https://doi.org/ghfprc
DOI: 10.1080/15265161.2020.1764137 · PMID: 32552455
993. Rationing Limited Healthcare Resources in the COVID‐19 Era and Beyond: Ethical Considerations Regarding Older Adults
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994. Rationing Limited Healthcare Resources in the COVID‐19 Era and Beyond: Ethical Considerations Regarding Older Adults
Timothy W. Farrell, Leslie Francis, Teneille Brown, Lauren E. Ferrante, Eric Widera, Ramona Rhodes, Tony Rosen, Ula Hwang, Leah J. Witt, Niranjan Thothala, … Debra Saliba
Journal of the American Geriatrics Society (2020-06-14) https://doi.org/ggvt7z
DOI: 10.1111/jgs.16539 · PMID: 32374466 · PMCID: PMC7267288
994. Paediatric ethical issues during the COVID‐19 pandemic are not just about ventilator triage
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995. Paediatric ethical issues during the COVID‐19 pandemic are not just about ventilator triage
Marlyse F. Haward, Gregory P. Moore, John Lantos, Annie Janvier
Acta Paediatrica (2020-05-20) https://doi.org/ggv24n
DOI: 10.1111/apa.15334 · PMID: 32364256 · PMCID: PMC7267437
995. Ethical Challenges Arising in the COVID-19 Pandemic: An Overview from the Association of Bioethics Program Directors (ABPD) Task Force
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996. Ethical Challenges Arising in the COVID-19 Pandemic: An Overview from the Association of Bioethics Program Directors (ABPD) Task Force
Amy L. McGuire, Mark P. Aulisio, F. Daniel Davis, Cheryl Erwin, Thomas D. Harter, Reshma Jagsi, Robert Klitzman, Robert Macauley, Eric Racine, Susan M. Wolf, … The COVID-19 Task Force of the Association of Bioethics Program Directors (ABPD)
The American Journal of Bioethics (2020-06-08) https://doi.org/gg6c5k
DOI: 10.1080/15265161.2020.1764138 · PMID: 32511078
996. Disability, Ethics, and Health Care in the COVID-19 Pandemic
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997. Disability, Ethics, and Health Care in the COVID-19 Pandemic
Maya Sabatello, Teresa Blankmeyer Burke, Katherine E. McDonald, Paul S. Appelbaum
American Journal of Public Health (2020-10) https://doi.org/ghfprm
DOI: 10.2105/ajph.2020.305837 · PMID: 32816541 · PMCID: PMC7483109
997. Allocating Ventilators During the COVID-19 Pandemic and Conscientious Objection
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998. Allocating Ventilators During the COVID-19 Pandemic and Conscientious Objection
Mark Wicclair
The American Journal of Bioethics (2020-07-27) https://doi.org/gg6nk4
DOI: 10.1080/15265161.2020.1777347 · PMID: 32716798
998. Colorblind Algorithms: Racism in the Era of COVID-19
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999. Colorblind Algorithms: Racism in the Era of COVID-19
J. Corey Williams, Nientara Anderson, Myra Mathis, Ezelle Sanford, Jeffrey Eugene, Jessica Isom
Journal of the National Medical Association (2020-10) https://doi.org/ghfpq8
DOI: 10.1016/j.jnma.2020.05.010 · PMID: 32563687
999. Structural Racism, Social Risk Factors, and Covid-19 — A Dangerous Convergence for Black Americans
+
1000. Structural Racism, Social Risk Factors, and Covid-19 — A Dangerous Convergence for Black Americans
Leonard E. Egede, Rebekah J. Walker
New England Journal of Medicine (2020-09-17) https://doi.org/gg56nc
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1000. Allocating Remdesivir Under Scarcity: Social Justice or More Systemic Racism
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1001. Allocating Remdesivir Under Scarcity: Social Justice or More Systemic Racism
Eli Weber, Mark J. Bliton
The American Journal of Bioethics (2020-08-25) https://doi.org/ghfprf
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1001. Revisiting the equity debate in COVID-19: ICU is no panacea
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1002. Revisiting the equity debate in COVID-19: ICU is no panacea
Angela Ballantyne, Wendy A Rogers, Vikki Entwistle, Cindy Towns
Journal of Medical Ethics (2020-10) https://doi.org/gg33nq
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1002. Ethical Dilemmas in Covid-19 Medical Care: Is a Problematic Triage Protocol Better or Worse than No Protocol at All?
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1003. Ethical Dilemmas in Covid-19 Medical Care: Is a Problematic Triage Protocol Better or Worse than No Protocol at All?
Sheri Fink
The American Journal of Bioethics (2020-07-27) https://doi.org/gg6nqn
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1003. Developing an Ethics Framework for Allocating Remdesivir in the COVID-19 Pandemic
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1004. Developing an Ethics Framework for Allocating Remdesivir in the COVID-19 Pandemic
Sarah Lim, Debra A. DeBruin, Jonathon P. Leider, Nneka Sederstrom, Ruth Lynfield, Jason V. Baker, Susan Kline, Sarah Kesler, Stacey Rizza, Joel Wu, … Susan M. Wolf
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1004. Ethically Allocating COVID-19 Drugs Via Pre-approval Access and Emergency Use Authorization
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1005. Ethically Allocating COVID-19 Drugs Via Pre-approval Access and Emergency Use Authorization
Jamie Webb, Lesha D. Shah, Holly Fernandez Lynch
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1006. Adopting an Anti-Racist Model of COVID-19 Drug Allocation and Prioritization
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1007. Adopting an Anti-Racist Model of COVID-19 Drug Allocation and Prioritization
Akilah A. Jefferson
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1007. Equitably Sharing the Benefits and Burdens of Research: Covid‐19 Raises the Stakes
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1008. Equitably Sharing the Benefits and Burdens of Research: Covid‐19 Raises the Stakes
Carl H. Coleman
Ethics & Human Research (2020-05-14) https://doi.org/ghgg2q
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1008. Ensuring global access to COVID-19 vaccines
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1009. Ensuring global access to COVID-19 vaccines
Gavin Yamey, Marco Schäferhoff, Richard Hatchett, Muhammad Pate, Feng Zhao, Kaci Kennedy McDade
The Lancet (2020-05) https://doi.org/ggq7mf
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1009. The Equitable Distribution of COVID-19 Therapeutics and Vaccines
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1010. The Equitable Distribution of COVID-19 Therapeutics and Vaccines
Thomas J. Bollyky, Lawrence O. Gostin, Margaret A. Hamburg
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1010. Recruitment and participation in clinical trials: Socio-demographic, rural/urban, and health care access predictors
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Claudia R. Baquet, Patricia Commiskey, C. Daniel Mullins, Shiraz I. Mishra
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1011. COVID-19 vaccine trials in Africa
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1012. COVID-19 vaccine trials in Africa
Munyaradzi Makoni
The Lancet Respiratory Medicine (2020-11) https://doi.org/fgzk
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1012. Racial/ethnic differences in clinical trial enrollment, refusal rates, ineligibility, and reasons for decline among patients at sites in the National Cancer Institute’s Community Cancer Centers Program
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1013. Racial/ethnic differences in clinical trial enrollment, refusal rates, ineligibility, and reasons for decline among patients at sites in the National Cancer Institute’s Community Cancer Centers Program
Aisha T. Langford, Ken Resnicow, Eileen P. Dimond, Andrea M. Denicoff, Diane St. Germain, Worta McCaskill-Stevens, Rebecca A. Enos, Angela Carrigan, Kathy Wilkinson, Ronald S. Go
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1014. Participation in Surgical Oncology Clinical Trials: Gender-, Race/Ethnicity-, and Age-based Disparities
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1015. Participation in Surgical Oncology Clinical Trials: Gender-, Race/Ethnicity-, and Age-based Disparities
John H. Stewart, Alain G. Bertoni, Jennifer L. Staten, Edward A. Levine, Cary P. Gross
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1015. Inclusion, Analysis, and Reporting of Sex and Race/Ethnicity in Clinical Trials: Have We Made Progress?
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1016. Inclusion, Analysis, and Reporting of Sex and Race/Ethnicity in Clinical Trials: Have We Made Progress?
Stacie E. Geller, Abby Koch, Beth Pellettieri, Molly Carnes
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1016. The Representation of Gender and Race/Ethnic Groups in Randomized Clinical Trials of Individuals with Systemic Lupus Erythematosus
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1017. The Representation of Gender and Race/Ethnic Groups in Randomized Clinical Trials of Individuals with Systemic Lupus Erythematosus
Titilola Falasinnu, Yashaar Chaichian, Michelle B. Bass, Julia F. Simard
Current Rheumatology Reports (2018-03-17) https://doi.org/ghjmpz
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1017. Racial Disproportionality in Covid Clinical Trials
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Daniel B. Chastain, Sharmon P. Osae, Andrés F. Henao-Martínez, Carlos Franco-Paredes, Joeanna S. Chastain, Henry N. Young
New England Journal of Medicine (2020-08-27) https://doi.org/gg7vcf
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1018. Othering and Being Othered in the Context of Health Care Services
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Joy L. Johnson, Joan L. Bottorff, Annette J. Browne, Sukhdev Grewal, B. Ann Hilton, Heather Clarke
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1019. A decade of studying implicit racial/ethnic bias in healthcare providers using the implicit association test
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Ivy W. Maina, Tanisha D. Belton, Sara Ginzberg, Ajit Singh, Tiffani J. Johnson
Social Science & Medicine (2018-02) https://doi.org/gdfwd9
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1020. A Systematic Review of the Impact of Physician Implicit Racial Bias on Clinical Decision Making
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Erin Dehon, Nicole Weiss, Jonathan Jones, Whitney Faulconer, Elizabeth Hinton, Sarah Sterling
Academic Emergency Medicine (2017-08) https://doi.org/gbw5pk
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1021. Aversive racism and medical interactions with Black patients: A field study
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Louis A. Penner, John F. Dovidio, Tessa V. West, Samuel L. Gaertner, Terrance L. Albrecht, Rhonda K. Dailey, Tsveti Markova
Journal of Experimental Social Psychology (2010-03) https://doi.org/dc5342
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1022. Intersection of Bias, Structural Racism, and Social Determinants With Health Care Inequities
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Tiffani J. Johnson
Pediatrics (2020-08) https://doi.org/ghjmqz
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1023. A Systematic Review Of The Food And Drug Administration’s “Exception From Informed Consent” Pathway
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1024. A Systematic Review Of The Food And Drug Administration’s “Exception From Informed Consent” Pathway
William B. Feldman, Spencer Phillips Hey, Aaron S. Kesselheim
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1024. The legacy of the tuskegee syphilis experiments for emergency exception from informed consent
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1025. The legacy of the tuskegee syphilis experiments for emergency exception from informed consent
Terri A. Schmidt
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1025. CDC officials are considering a plan to distribute COVID-19 vaccines to the most vulnerable first — including people of color
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1026. CDC officials are considering a plan to distribute COVID-19 vaccines to the most vulnerable first — including people of color
Sarah Al-Arshani
Business Insider https://www.businessinsider.com/cdc-official-considering-giving-covid-19-vaccine-most-vulnerable-first-2020-10
1026. Racial Differences in T-Lymphocyte Response to Glucocorticoids
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1027. Racial Differences in T-Lymphocyte Response to Glucocorticoids
Monica J. Federico, Ronina A. Covar, Eleanor E. Brown, Donald Y. M. Leung, Joseph D. Spahn
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1027. ENDOCRINOLOGY OF THE STRESS RESPONSE
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1028. ENDOCRINOLOGY OF THE STRESS RESPONSE
Evangelia Charmandari, Constantine Tsigos, George Chrousos
Annual Review of Physiology (2005-03-17) https://doi.org/brcm9n
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1028. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk
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S. Cohen, D. Janicki-Deverts, W. J. Doyle, G. E. Miller, E. Frank, B. S. Rabin, R. B. Turner
Proceedings of the National Academy of Sciences (2012-04-02) https://doi.org/f4n6r8
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1029. Opportunities and obstacles for deep learning in biology and medicine
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1030. Opportunities and obstacles for deep learning in biology and medicine
Travers Ching, Daniel S. Himmelstein, Brett K. Beaulieu-Jones, Alexandr A. Kalinin, Brian T. Do, Gregory P. Way, Enrico Ferrero, Paul-Michael Agapow, Michael Zietz, Michael M. Hoffman, … Casey S. Greene
Journal of The Royal Society Interface (2018-04-04) https://doi.org/gddkhn
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1030. Opportunities and obstacles for deep learning in biology and medicine [update in progress]
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1031. Opportunities and obstacles for deep learning in biology and medicine [update in progress]
Casey S. Greene, Daniel S. Himmelstein, Daniel C. Elton, Brock C. Christensen, Anthony Gitter, Alexander J. Titus, Joshua J. Levy
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1031. ismms-himc/covid-19_sinai_reviews
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1032. ismms-himc/covid-19_sinai_reviews
Human Immune Monitoring Center at Mount Sinai
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1032. Advancing scientific knowledge in times of pandemics
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1033. Advancing scientific knowledge in times of pandemics
Nicolas Vabret, Robert Samstein, Nicolas Fernandez, Miriam Merad, The Sinai Immunology Review Project, Trainees, Faculty
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1033. Undergraduate Mentoring - American Physician Scientists Association https://www.physicianscientists.org/page/summer-research-pilot-program
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1034. greenelab/covid19-review
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1035. greenelab/covid19-review
Greene Laboratory
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1035. SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics
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1036. SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics
Halie M. Rando, Casey S. Greene, Michael P. Robson, Simina M. Boca, Nils Wellhausen, Ronan Lordan, Christian Brueffer, Sandipan Ray, Lucy D\’Agostino McGowan, Anthony Gitter, … Rishi Raj Goel
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1036. Matplotlib: A 2D Graphics Environment
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1037. Matplotlib: A 2D Graphics Environment
John D. Hunter
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1037. Using the MAARIE Framework To Read the Research Literature
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1038. Using the MAARIE Framework To Read the Research Literature
M. Corcoran
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1038. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody
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1039. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody
Xiaolong Tian, Cheng Li, Ailing Huang, Shuai Xia, Sicong Lu, Zhengli Shi, Lu Lu, Shibo Jiang, Zhenlin Yang, Yanling Wu, Tianlei Ying
Cold Spring Harbor Laboratory (2020-01-28) https://doi.org/ggjqfd
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1039. Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of 2019-nCoV
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1040. Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of 2019-nCoV
Xiang He, Lei Zhang, Qin Ran, Junyi Wang, Anying Xiong, Dehong Wu, Feng Chen, Guoping Li
Cold Spring Harbor Laboratory (2020-02-05) https://doi.org/ggrbd8
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1040. Diarrhea may be underestimated: a missing link in 2019 novel coronavirus
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1041. Diarrhea may be underestimated: a missing link in 2019 novel coronavirus
Weicheng Liang, Zhijie Feng, Shitao Rao, Cuicui Xiao, Ze-Xiao Lin, Qi Zhang, Qi Wei
Cold Spring Harbor Laboratory (2020-02-17) https://doi.org/ggrbdw
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1041. Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection
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1042. Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection
Xiaoqiang Chai, Longfei Hu, Yan Zhang, Weiyu Han, Zhou Lu, Aiwu Ke, Jian Zhou, Guoming Shi, Nan Fang, Jia Fan, … Fei Lan
Cold Spring Harbor Laboratory (2020-02-04) https://doi.org/ggq626
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1042. Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids
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1043. Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids
Bing Zhao, Chao Ni, Ran Gao, Yuyan Wang, Li Yang, Jinsong Wei, Ting Lv, Jianqing Liang, Qisheng Zhang, Wei Xu, … Xinhua Lin
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq648
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1043. ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism
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1044. ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism
Jun Wang, Shanmeizi Zhao, Ming Liu, Zhiyao Zhao, Yiping Xu, Ping Wang, Meng Lin, Yanhui Xu, Bing Huang, Xiaoyu Zuo, … Yuxia Zhang
Cold Spring Harbor Laboratory (2020-02-07) https://doi.org/ggrfbx
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1044. The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice
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1045. The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice
Linlin Bao, Wei Deng, Baoying Huang, Hong Gao, Jiangning Liu, Lili Ren, Qiang Wei, Pin Yu, Yanfeng Xu, Feifei Qi, … Chuan Qin
Cold Spring Harbor Laboratory (2020-02-28) https://doi.org/dph2
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1045. Caution on Kidney Dysfunctions of COVID-19 Patients
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1046. Caution on Kidney Dysfunctions of COVID-19 Patients
Zhen Li, Ming Wu, Jiwei Yao, Jie Guo, Xiang Liao, Siji Song, Jiali Li, Guangjie Duan, Yuanxiu Zhou, Xiaojun Wu, … Junan Yan
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1046. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome
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1047. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome
Kwok Hong Chu, Wai Kay Tsang, Colin S. Tang, Man Fai Lam, Fernand M. Lai, Ka Fai To, Ka Shun Fung, Hon Lok Tang, Wing Wa Yan, Hilda W. H. Chan, … Kar Neng Lai
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1047. Single-cell Analysis of ACE2 Expression in Human Kidneys and Bladders Reveals a Potential Route of 2019-nCoV Infection
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1048. Single-cell Analysis of ACE2 Expression in Human Kidneys and Bladders Reveals a Potential Route of 2019-nCoV Infection
Wei Lin, Longfei Hu, Yan Zhang, Joshua D. Ooi, Ting Meng, Peng Jin, Xiang Ding, Longkai Peng, Lei Song, Zhou Xiao, … Yong Zhong
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1048. The immune vulnerability landscape of the 2019 Novel Coronavirus, SARS-CoV-2
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1049. The immune vulnerability landscape of the 2019 Novel Coronavirus, SARS-CoV-2
James Zhu, Jiwoong Kim, Xue Xiao, Yunguan Wang, Danni Luo, Shuang Jiang, Ran Chen, Lin Xu, He Zhang, Lenny Moise, … Yang Xie
Cold Spring Harbor Laboratory (2020-09-04) https://doi.org/ggq628
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1049. Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection
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1050. Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection
Yaseen M. Arabi, Ahmed A. Arifi, Hanan H. Balkhy, Hani Najm, Abdulaziz S. Aldawood, Alaa Ghabashi, Hassan Hawa, Adel Alothman, Abdulaziz Khaldi, Basel Al Raiy
Annals of Internal Medicine (2014-03-18) https://doi.org/ggptxw
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1050. Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage
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1051. Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage
Jingyuan Liu, Yao Liu, Pan Xiang, Lin Pu, Haofeng Xiong, Chuansheng Li, Ming Zhang, Jianbo Tan, Yanli Xu, Rui Song, … Xianbo Wang
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1051. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China
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1052. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China
Chuan Qin, Luoqi Zhou, Ziwei Hu, Shuoqi Zhang, Sheng Yang, Yu Tao, Cuihong Xie, Ke Ma, Ke Shang, Wei Wang, Dai-Shi Tian
Clinical Infectious Diseases (2020-08-01) https://doi.org/ggpxcf
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1052. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)
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1053. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)
Suxin Wan, Qingjie Yi, Shibing Fan, Jinglong Lv, Xianxiang Zhang, Lian Guo, Chunhui Lang, Qing Xiao, Kaihu Xiao, Zhengjun Yi, … Yongping Chen
Cold Spring Harbor Laboratory (2020-02-12) https://doi.org/ggq63b
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1053. Longitudinal Characteristics of Lymphocyte Responses and Cytokine Profiles in the Peripheral Blood of SARS-CoV-2 Infected Patients
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1054. Longitudinal Characteristics of Lymphocyte Responses and Cytokine Profiles in the Peripheral Blood of SARS-CoV-2 Infected Patients
Jing Liu, Sumeng Li, Jia Liu, Boyun Liang, Xiaobei Wang, Wei Li, Hua Wang, Qiaoxia Tong, Jianhua Yi, Lei Zhao, … Xin Zheng
SSRN Electronic Journal (2020) https://doi.org/ggq655
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1054. Epidemiological and Clinical Characteristics of 17 Hospitalized Patients with 2019 Novel Coronavirus Infections Outside Wuhan, China
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1055. Epidemiological and Clinical Characteristics of 17 Hospitalized Patients with 2019 Novel Coronavirus Infections Outside Wuhan, China
Jie Li, Shilin Li, Yurui Cai, Qin Liu, Xue Li, Zhaoping Zeng, Yanpeng Chu, Fangcheng Zhu, Fanxin Zeng
Cold Spring Harbor Laboratory (2020-02-12) https://doi.org/ggq63c
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1055. ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection
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1056. ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection
Caibin Fan, Kai Li, Yanhong Ding, Wei Lu, Jianqing Wang
Cold Spring Harbor Laboratory (2020-02-13) https://doi.org/ggq63d
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1056. Aberrant pathogenic GM-CSF + T cells and inflammatory CD14 + CD16 + monocytes in severe pulmonary syndrome patients of a new coronavirus
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1057. Aberrant pathogenic GM-CSF + T cells and inflammatory CD14 + CD16 + monocytes in severe pulmonary syndrome patients of a new coronavirus
Yonggang Zhou, Binqing Fu, Xiaohu Zheng, Dongsheng Wang, Changcheng Zhao, Yingjie qi, Rui Sun, Zhigang Tian, Xiaoling Xu, Haiming Wei
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggq63f
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1057. Clinical Characteristics of 2019 Novel Infected Coronavirus Pneumonia: A Systemic Review and Meta-analysis
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1058. Clinical Characteristics of 2019 Novel Infected Coronavirus Pneumonia: A Systemic Review and Meta-analysis
Kai Qian, Yi Deng, Yong-Hang Tai, Jun Peng, Hao Peng, Li-Hong Jiang
Cold Spring Harbor Laboratory (2020-02-17) https://doi.org/ggrgbq
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1058. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients
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1059. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients
Jing Liu, Sumeng Li, Jia Liu, Boyun Liang, Xiaobei Wang, Hua Wang, Wei Li, Qiaoxia Tong, Jianhua Yi, Lei Zhao, … Xin Zheng
Cold Spring Harbor Laboratory (2020-02-22) https://doi.org/ggq63g
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1059. Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019
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1060. Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019
Guang Chen, Di Wu, Wei Guo, Yong Cao, Da Huang, Hongwu Wang, Tao Wang, Xiaoyun Zhang, Huilong Chen, Haijing Yu, … Qin Ning
Cold Spring Harbor Laboratory (2020-02-19) https://doi.org/ggq63h
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1060. SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development
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1061. SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development
Chunyun Sun, Long Chen, Ji Yang, Chunxia Luo, Yanjing Zhang, Jing Li, Jiahui Yang, Jie Zhang, Liangzhi Xie
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggq63j
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1061. Protection of Rhesus Macaque from SARS-Coronavirus challenge by recombinant adenovirus vaccine
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1062. Protection of Rhesus Macaque from SARS-Coronavirus challenge by recombinant adenovirus vaccine
Yiyou Chen, Qiang Wei, Ruobing Li, Hong Gao, Hua Zhu, Wei Deng, Linlin Bao, Wei Tong, Zhe Cong, Hong Jiang, Chuan Qin
Cold Spring Harbor Laboratory (2020-02-21) https://doi.org/ggq63k
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1062. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)
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1063. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)
Bo Diao, Chenhui Wang, Yingjun Tan, Xiewan Chen, Ying Liu, Lifen Ning, Li Chen, Min Li, Yueping Liu, Gang Wang, … Yongwen Chen
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggq63m
DOI: 10.1101/2020.02.18.20024364
1063. Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China
+
1064. Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China
Xun Li, Luwen Wang, Shaonan Yan, Fan Yang, Longkui Xiang, Jiling Zhu, Bo Shen, Zuojiong Gong
Cold Spring Harbor Laboratory (2020-02-25) https://doi.org/ggq63n
DOI: 10.1101/2020.02.19.20025239
1064. SARS-CoV-2 infection does not significantly cause acute renal injury: an analysis of 116 hospitalized patients with COVID-19 in a single hospital, Wuhan, China
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1065. SARS-CoV-2 infection does not significantly cause acute renal injury: an analysis of 116 hospitalized patients with COVID-19 in a single hospital, Wuhan, China
Luwen Wang, Xun Li, Hui Chen, Shaonan Yan, Yan Li, Dong Li, Zuojiong Gong
Cold Spring Harbor Laboratory (2020-02-23) https://doi.org/ggq63p
DOI: 10.1101/2020.02.19.20025288
1065. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China
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1066. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China
Dawei Wang, Bo Hu, Chang Hu, Fangfang Zhu, Xing Liu, Jing Zhang, Binbin Wang, Hui Xiang, Zhenshun Cheng, Yong Xiong, … Zhiyong Peng
JAMA (2020-03-17) https://doi.org/ggkh48
DOI: 10.1001/jama.2020.1585 · PMID: 32031570 · PMCID: PMC7042881
1066. Clinical characteristics of 2019 novel coronavirus infection in China
+
1067. Clinical characteristics of 2019 novel coronavirus infection in China
Wei-jie Guan, Zheng-yi Ni, Yu Hu, Wen-hua Liang, Chun-quan Ou, Jian-xing He, Lei Liu, Hong Shan, Chun-liang Lei, David S. C. Hui, … Nan-shan Zhong
Cold Spring Harbor Laboratory (2020-02-09) https://doi.org/ggkj9s
DOI: 10.1101/2020.02.06.20020974
1067. Potential T-cell and B-cell Epitopes of 2019-nCoV
+
1068. Potential T-cell and B-cell Epitopes of 2019-nCoV
Ethan Fast, Russ B. Altman, Binbin Chen
Cold Spring Harbor Laboratory (2020-03-18) https://doi.org/ggq63q
DOI: 10.1101/2020.02.19.955484
1068. Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein
+
1069. Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein
Alexandra C. Walls, Young-Jun Park, M. Alexandra Tortorici, Abigail Wall, Andrew T. McGuire, David Veesler
Cold Spring Harbor Laboratory (2020-02-20) https://doi.org/ggrgbr
DOI: 10.1101/2020.02.19.956581
1069. Breadth of concomitant immune responses underpinning viral clearance and patient recovery in a non-severe case of COVID-19
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1070. Breadth of concomitant immune responses underpinning viral clearance and patient recovery in a non-severe case of COVID-19
Irani Thevarajan, Thi HO Nguyen, Marios Koutsakos, Julian Druce, Leon Caly, Carolien E van de Sandt, Xiaoxiao Jia, Suellen Nicholson, Mike Catton, Benjamin Cowie, … Katherine Kedzierska
Cold Spring Harbor Laboratory (2020-02-23) https://doi.org/ggq63r
DOI: 10.1101/2020.02.20.20025841
1070. The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing
+
1071. The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing
Minfeng Liao, Yang Liu, Jin Yuan, Yanling Wen, Gang Xu, Juanjuan Zhao, Lin Chen, Jinxiu Li, Xin Wang, Fuxiang Wang, … Zheng Zhang
Cold Spring Harbor Laboratory (2020-02-26) https://doi.org/ggq63s
DOI: 10.1101/2020.02.23.20026690
1071. Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells
+
1072. Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells
Marlena Scharenberg, Sindhu Vangeti, Eliisa Kekäläinen, Per Bergman, Mamdoh Al-Ameri, Niclas Johansson, Klara Sondén, Sara Falck-Jones, Anna Färnert, Hans-Gustaf Ljunggren, … Nicole Marquardt
Frontiers in Immunology (2019-05-17) https://doi.org/ggq656
DOI: 10.3389/fimmu.2019.01116 · PMID: 31156653 · PMCID: PMC6534051
1072. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
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1073. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
Chaolin Huang, Yeming Wang, Xingwang Li, Lili Ren, Jianping Zhao, Yi Hu, Li Zhang, Guohui Fan, Jiuyang Xu, Xiaoying Gu, … Bin Cao
The Lancet (2020-02) https://doi.org/ggjfnn
DOI: 10.1016/s0140-6736(20)30183-5
1073. Alveolar Macrophages in the Resolution of Inflammation, Tissue Repair, and Tolerance to Infection
+
1074. Alveolar Macrophages in the Resolution of Inflammation, Tissue Repair, and Tolerance to Infection
Benoit Allard, Alice Panariti, James G. Martin
Frontiers in Immunology (2018-07-31) https://doi.org/gd3bnz
DOI: 10.3389/fimmu.2018.01777 · PMID: 30108592 · PMCID: PMC6079255
1074. PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery following Respiratory Viral Infection
+
1075. PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery following Respiratory Viral Infection
Su Huang, Bibo Zhu, In Su Cheon, Nick P. Goplen, Li Jiang, Ruixuan Zhang, R. Stokes Peebles, Matthias Mack, Mark H. Kaplan, Andrew H. Limper, Jie Sun
Journal of Virology (2019-04-17) https://doi.org/ggq652
DOI: 10.1128/jvi.00030-19 · PMID: 30787149 · PMCID: PMC6475778
1075. Can routine laboratory tests discriminate 2019 novel coronavirus infected pneumonia from other community-acquired pneumonia?
+
1076. Can routine laboratory tests discriminate 2019 novel coronavirus infected pneumonia from other community-acquired pneumonia?
Yunbao Pan, Guangming Ye, Xiantao Zeng, Guohong Liu, Xiaojiao Zeng, Xianghu Jiang, Jin Zhao, Liangjun Chen, Shuang Guo, Qiaoling Deng, … Xinghuan Wang
Cold Spring Harbor Laboratory (2020-02-25) https://doi.org/ggq63t
DOI: 10.1101/2020.02.25.20024711
1076. Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia
+
1077. Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia
Jing Gong, Hui Dong, Qingsong Xia, Zhaoyi Huang, Dingkun Wang, Yan Zhao, Wenhua Liu, Shenghao Tu, Mingmin Zhang, Qi Wang, Fuer Lu
Cold Spring Harbor Laboratory (2020-02-26) https://doi.org/ggq63v
DOI: 10.1101/2020.02.25.20025643
1077. An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors’ CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design
+
1078. An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors’ CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design
CV Herst, S Burkholz, J Sidney, A Sette, PE Harris, S Massey, T Brasel, E Cunha-Neto, DS Rosa, WCH Chao, … R Rubsamen
Cold Spring Harbor Laboratory (2020-04-06) https://doi.org/ggq63x
DOI: 10.1101/2020.02.25.963546
1078. Epitope-based peptide vaccine design and target site characterization against novel coronavirus disease caused by SARS-CoV-2
+
1079. Epitope-based peptide vaccine design and target site characterization against novel coronavirus disease caused by SARS-CoV-2
Lin Li, Ting Sun, Yufei He, Wendong Li, Yubo Fan, Jing Zhang
Cold Spring Harbor Laboratory (2020-02-27) https://doi.org/ggnqwt
DOI: 10.1101/2020.02.25.965434
1079. The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and Retrospective Analysis
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1080. The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and Retrospective Analysis
Wang Wenjun, Liu Xiaoqing, Wu Sipei, Lie Puyi, Huang Liyan, Li Yimin, Cheng Linling, Chen Sibei, Nong Lingbo, Lin Yongping, He Jianxing
Cold Spring Harbor Laboratory (2020-02-27) https://doi.org/ggrgbs
DOI: 10.1101/2020.02.26.20026989
1080. Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China
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1081. Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China
Ying Huang, Rui Yang, Ying Xu, Ping Gong
Cold Spring Harbor Laboratory (2020-03-05) https://doi.org/ggq63z
DOI: 10.1101/2020.02.27.20029009
1081. Risk factors related to hepatic injury in patients with corona virus disease 2019
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1082. Risk factors related to hepatic injury in patients with corona virus disease 2019
Lu Li, Shuang Li, Manman Xu, Pengfei Yu, Sujun Zheng, Zhongping Duan, Jing Liu, Yu Chen, Junfeng Li
Cold Spring Harbor Laboratory (2020-03-10) https://doi.org/ggq632
DOI: 10.1101/2020.02.28.20028514
1082. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients
+
1083. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients
Xiaohua Chen, Binghong Zhao, Yueming Qu, Yurou Chen, Jie Xiong, Yong Feng, Dong Men, Qianchuan Huang, Ying Liu, Bo Yang, … Feng Li
Cold Spring Harbor Laboratory (2020-03-03) https://doi.org/ggq633
DOI: 10.1101/2020.02.29.20029520
1083. Prognostic factors in the acute respiratory distress syndrome
+
1084. Prognostic factors in the acute respiratory distress syndrome
Wei Chen, Lorraine B Ware
Clinical and Translational Medicine (2015-07-02) https://doi.org/ggq653
DOI: 10.1186/s40169-015-0065-2 · PMID: 26162279 · PMCID: PMC4534483
1084. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study
+
1085. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study
Li Tan, Qi Wang, Duanyang Zhang, Jinya Ding, Qianchuan Huang, Yi-Quan Tang, Qiongshu Wang, Hongming Miao
Cold Spring Harbor Laboratory (2020-03-03) https://doi.org/ggq634
DOI: 10.1101/2020.03.01.20029074
1085. The potential role of IL-6 in monitoring severe case of coronavirus disease 2019
+
1086. The potential role of IL-6 in monitoring severe case of coronavirus disease 2019
Tao Liu, Jieying Zhang, Yuhui Yang, Hong Ma, Zhengyu Li, Jiaoyu Zhang, Ji Cheng, Xiaoyun Zhang, Yanxia Zhao, Zihan Xia, … Jianhua Yi
Cold Spring Harbor Laboratory (2020-03-10) https://doi.org/ggq635
DOI: 10.1101/2020.03.01.20029769
1086. Clinical and Laboratory Profiles of 75 Hospitalized Patients with Novel Coronavirus Disease 2019 in Hefei, China
+
1087. Clinical and Laboratory Profiles of 75 Hospitalized Patients with Novel Coronavirus Disease 2019 in Hefei, China
Zonghao Zhao, Jiajia Xie, Ming Yin, Yun Yang, Hongliang He, Tengchuan Jin, Wenting Li, Xiaowu Zhu, Jing Xu, Changcheng Zhao, … Xiaoling Ma
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq636
DOI: 10.1101/2020.03.01.20029785
1087. Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome
+
1088. Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome
Yang Yang, Chenguang Shen, Jinxiu Li, Jing Yuan, Minghui Yang, Fuxiang Wang, Guobao Li, Yanjie Li, Li Xing, Ling Peng, … Yingxia Liu
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq637
DOI: 10.1101/2020.03.02.20029975
1088. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019
+
1089. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019
Juanjuan Zhao, Quan Yuan, Haiyan Wang, Wei Liu, Xuejiao Liao, Yingying Su, Xin Wang, Jing Yuan, Tingdong Li, Jinxiu Li, … Zheng Zhang
Cold Spring Harbor Laboratory (2020-03-02) https://doi.org/ggrbj6
DOI: 10.1101/2020.03.02.20030189
1089. Restoration of leukomonocyte counts is associated with viral clearance in COVID-19 hospitalized patients
+
1090. Restoration of leukomonocyte counts is associated with viral clearance in COVID-19 hospitalized patients
Xiaoping Chen, Jiaxin Ling, Pingzheng Mo, Yongxi Zhang, Qunqun Jiang, Zhiyong Ma, Qian Cao, Wenjia Hu, Shi Zou, Liangjun Chen, … Yong Xiong
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq639
DOI: 10.1101/2020.03.03.20030437
1090. Effects of Systemically Administered Hydrocortisone on the Human Immunome
+
1091. Effects of Systemically Administered Hydrocortisone on the Human Immunome
Matthew J. Olnes, Yuri Kotliarov, Angélique Biancotto, Foo Cheung, Jinguo Chen, Rongye Shi, Huizhi Zhou, Ena Wang, John S. Tsang, Robert Nussenblatt, The CHI Consortium
Scientific Reports (2016-03-14) https://doi.org/f8dmvw
DOI: 10.1038/srep23002 · PMID: 26972611 · PMCID: PMC4789739
1091. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis
+
1092. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis
Giuseppe Lippi, Mario Plebani
Clinica Chimica Acta (2020-06) https://doi.org/ggpxp7
DOI: 10.1016/j.cca.2020.03.004 · PMID: 32145275 · PMCID: PMC7094472
1092. Clinical findings in critically ill patients infected with SARS-CoV-2 in Guangdong Province, China: a multi-center, retrospective, observational study
+
1093. Clinical findings in critically ill patients infected with SARS-CoV-2 in Guangdong Province, China: a multi-center, retrospective, observational study
Yonghao Xu, Zhiheng Xu, Xuesong Liu, Lihua Cai, Haichong Zheng, Yongbo Huang, Lixin Zhou, Linxi Huang, Yun Lin, Liehua Deng, … Yimin Li
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq64b
DOI: 10.1101/2020.03.03.20030668
1093. Multi-epitope vaccine design using an immunoinformatics approach for 2019 novel coronavirus (SARS-CoV-2)
+
1094. Multi-epitope vaccine design using an immunoinformatics approach for 2019 novel coronavirus (SARS-CoV-2)
Ye Feng, Min Qiu, Liang Liu, Shengmei Zou, Yun Li, Kai Luo, Qianpeng Guo, Ning Han, Yingqiang Sun, Kui Wang, … Fan Mo
Cold Spring Harbor Laboratory (2020-06-30) https://doi.org/ggq64c
DOI: 10.1101/2020.03.03.962332
1094. Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19) in Shanghai, China
+
1095. Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19) in Shanghai, China
Min Cao, Dandan Zhang, Youhua Wang, Yunfei Lu, Xiangdong Zhu, Ying Li, Honghao Xue, Yunxiao Lin, Min Zhang, Yiguo Sun, … Hongzhou Lu
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq64d
DOI: 10.1101/2020.03.04.20030395 · PMID: 32511465
1095. Serological detection of 2019-nCoV respond to the epidemic: A useful complement to nucleic acid testing
+
1096. Serological detection of 2019-nCoV respond to the epidemic: A useful complement to nucleic acid testing
Jin Zhang, Jianhua Liu, Na Li, Yong Liu, Rui Ye, Xiaosong Qin, Rui Zheng
Cold Spring Harbor Laboratory (2020-03-06) https://doi.org/ggq64f
DOI: 10.1101/2020.03.04.20030916
1096. Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection
+
1097. Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection
Bo Diao, Chenhui Wang, Rongshuai Wang, Zeqing Feng, Yingjun Tan, Huiming Wang, Changsong Wang, Liang Liu, Ying Liu, Yueping Liu, … Yongwen Chen
Cold Spring Harbor Laboratory (2020-04-10) https://doi.org/ggq64g
DOI: 10.1101/2020.03.04.20031120
1097. COVID-19 early warning score: a multi-parameter screening tool to identify highly suspected patients
+
1098. COVID-19 early warning score: a multi-parameter screening tool to identify highly suspected patients
Cong-Ying Song, Jia Xu, Jian-Qin He, Yuan-Qiang Lu
Cold Spring Harbor Laboratory (2020-03-08) https://doi.org/ggq64h
DOI: 10.1101/2020.03.05.20031906
1098. LY6E impairs coronavirus fusion and confers immune control of viral disease
+
1099. LY6E impairs coronavirus fusion and confers immune control of viral disease
Stephanie Pfaender, Katrina B. Mar, Eleftherios Michailidis, Annika Kratzel, Dagny Hirt, Philip V’kovski, Wenchun Fan, Nadine Ebert, Hanspeter Stalder, Hannah Kleine-Weber, … Volker Thiel
Cold Spring Harbor Laboratory (2020-03-07) https://doi.org/dpvn
DOI: 10.1101/2020.03.05.979260 · PMID: 32511345
1099. A preliminary study on serological assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 238 admitted hospital patients
+
1100. A preliminary study on serological assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 238 admitted hospital patients
Lei Liu, Wanbing Liu, Yaqiong Zheng, Xiaojing Jiang, Guomei Kou, Jinya Ding, Qiongshu Wang, Qianchuan Huang, Yinjuan Ding, Wenxu Ni, … Shangen Zheng
Cold Spring Harbor Laboratory (2020-03-08) https://doi.org/ggq64j
DOI: 10.1101/2020.03.06.20031856
1100. Monoclonal antibodies for the S2 subunit of spike of SARS-CoV cross-react with the newly-emerged SARS-CoV-2
+
1101. Monoclonal antibodies for the S2 subunit of spike of SARS-CoV cross-react with the newly-emerged SARS-CoV-2
Zhiqiang Zheng, Vanessa M. Monteil, Sebastian Maurer-Stroh, Chow Wenn Yew, Carol Leong, Nur Khairiah Mohd-Ismail, Suganya Cheyyatraivendran Arularasu, Vincent Tak Kwong Chow, Raymond Lin Tzer Pin, Ali Mirazimi, … Yee-Joo Tan
Cold Spring Harbor Laboratory (2020-03-07) https://doi.org/ggrbj7
DOI: 10.1101/2020.03.06.980037
1101. Mortality of COVID-19 is Associated with Cellular Immune Function Compared to Immune Function in Chinese Han Population
+
1102. Mortality of COVID-19 is Associated with Cellular Immune Function Compared to Immune Function in Chinese Han Population
Qiang Zeng, Yong-zhe Li, Gang Huang, Wei Wu, Sheng-yong Dong, Yang Xu
Cold Spring Harbor Laboratory (2020-03-13) https://doi.org/ggq64k
DOI: 10.1101/2020.03.08.20031229
1102. Retrospective Analysis of Clinical Features in 101 Death Cases with COVID-19
+
1103. Retrospective Analysis of Clinical Features in 101 Death Cases with COVID-19
Hua Fan, Lin Zhang, Bin Huang, Muxin Zhu, Yong Zhou, Huan Zhang, Xiaogen Tao, Shaohui Cheng, Wenhu Yu, Liping Zhu, Jian Chen
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq64n
DOI: 10.1101/2020.03.09.20033068
1103. Relationship between the ABO Blood Group and the COVID-19 Susceptibility
+
1104. Relationship between the ABO Blood Group and the COVID-19 Susceptibility
Jiao Zhao, Yan Yang, Hanping Huang, Dong Li, Dongfeng Gu, Xiangfeng Lu, Zheng Zhang, Lei Liu, Ting Liu, Yukun Liu, … Peng George Wang
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggpn3d
DOI: 10.1101/2020.03.11.20031096
1104. The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15
+
1105. The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15
Shutoku Matsuyama, Miyuki Kawase, Naganori Nao, Kazuya Shirato, Makoto Ujike, Wataru Kamitani, Masayuki Shimojima, Shuetsu Fukushi
Cold Spring Harbor Laboratory (2020-03-12) https://doi.org/ggq64p
DOI: 10.1101/2020.03.11.987016
1105. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19
+
1106. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19
Bicheng Zhang, Xiaoyang Zhou, Chengliang Zhu, Fan Feng, Yanru Qiu, Jia Feng, Qingzhu Jia, Qibin Song, Bo Zhu, Jun Wang
Cold Spring Harbor Laboratory (2020-03-16) https://doi.org/ggq64q
DOI: 10.1101/2020.03.12.20035048
1106. Lack of Reinfection in Rhesus Macaques Infected with SARS-CoV-2
+
1107. Lack of Reinfection in Rhesus Macaques Infected with SARS-CoV-2
Linlin Bao, Wei Deng, Hong Gao, Chong Xiao, Jiayi Liu, Jing Xue, Qi Lv, Jiangning Liu, Pin Yu, Yanfeng Xu, … Chuan Qin
Cold Spring Harbor Laboratory (2020-05-01) https://doi.org/ggn8r8
DOI: 10.1101/2020.03.13.990226
1107. A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV
+
1108. A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV
Meng Yuan, Nicholas C. Wu, Xueyong Zhu, Chang-Chun D. Lee, Ray T. Y. So, Huibin Lv, Chris K. P. Mok, Ian A. Wilson
Cold Spring Harbor Laboratory (2020-03-14) https://doi.org/ggq64s
DOI: 10.1101/2020.03.13.991570
1108. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein
+
1109. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein
Ke Wang, Wei Chen, Yu-Sen Zhou, Jian-Qi Lian, Zheng Zhang, Peng Du, Li Gong, Yang Zhang, Hong-Yong Cui, Jie-Jie Geng, … Zhi-Nan Chen
Cold Spring Harbor Laboratory (2020-03-14) https://doi.org/ggq64t
DOI: 10.1101/2020.03.14.988345
1109. CD147 (EMMPRIN/Basigin) in kidney diseases: from an inflammation and immune system viewpoint
+
1110. CD147 (EMMPRIN/Basigin) in kidney diseases: from an inflammation and immune system viewpoint
Tomoki Kosugi, Kayaho Maeda, Waichi Sato, Shoichi Maruyama, Kenji Kadomatsu
Nephrology Dialysis Transplantation (2015-07) https://doi.org/ggq624
DOI: 10.1093/ndt/gfu302 · PMID: 25248362
1110. The roles of CyPA and CD147 in cardiac remodelling
+
1111. The roles of CyPA and CD147 in cardiac remodelling
Hongyan Su, Yi Yang
Experimental and Molecular Pathology (2018-06) https://doi.org/ggq622
DOI: 10.1016/j.yexmp.2018.05.001 · PMID: 29772453
1111. Cancer-related issues of CD147.
+
1112. Cancer-related issues of CD147.
Ulrich H Weidle, Werner Scheuer, Daniela Eggle, Stefan Klostermann, Hannes Stockinger
Cancer genomics & proteomics https://www.ncbi.nlm.nih.gov/pubmed/20551248
PMID: 20551248
1112. Blood single cell immune profiling reveals the interferon-MAPK pathway mediated adaptive immune response for COVID-19
+
1113. Blood single cell immune profiling reveals the interferon-MAPK pathway mediated adaptive immune response for COVID-19
Lulin Huang, Yi Shi, Bo Gong, Li Jiang, Xiaoqi Liu, Jialiang Yang, Juan Tang, Chunfang You, Qi Jiang, Bo Long, … Zhenglin Yang
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq64v
DOI: 10.1101/2020.03.15.20033472
1113. Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections
+
1114. Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections
Huibin Lv, Nicholas C. Wu, Owen Tak-Yin Tsang, Meng Yuan, Ranawaka A. P. M. Perera, Wai Shing Leung, Ray T. Y. So, Jacky Man Chun Chan, Garrick K. Yip, Thomas Shiu Hong Chik, … Chris K. P. Mok
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq64w
DOI: 10.1101/2020.03.15.993097 · PMID: 32511317
1114. The feasibility of convalescent plasma therapy in severe COVID- 19 patients: a pilot study
+
1115. The feasibility of convalescent plasma therapy in severe COVID- 19 patients: a pilot study
Kai Duan, Bende Liu, Cesheng Li, Huajun Zhang, Ting Yu, Jieming Qu, Min Zhou, Li Chen, Shengli Meng, Yong Hu, … Xiaoming Yang
Cold Spring Harbor Laboratory (2020-03-23) https://doi.org/dqrs
DOI: 10.1101/2020.03.16.20036145
1115. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial
+
1116. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial
Philippe Gautret, Jean-Christophe Lagier, Philippe Parola, Van Thuan Hoang, Line Meddeb, Morgane Mailhe, Barbara Doudier, Johan Courjon, Valérie Giordanengo, Vera Esteves Vieira, … Didier Raoult
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/dqbv
DOI: 10.1101/2020.03.16.20037135
1116. Chloroquine: Modes of action of an undervalued drug
+
1117. Chloroquine: Modes of action of an undervalued drug
Rodolfo Thomé, Stefanie Costa Pinto Lopes, Fabio Trindade Maranhão Costa, Liana Verinaud
Immunology Letters (2013-06) https://doi.org/f5b5cr
DOI: 10.1016/j.imlet.2013.07.004 · PMID: 23891850
1117. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy
+
1118. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy
B. Lo, K. Zhang, W. Lu, L. Zheng, Q. Zhang, C. Kanellopoulou, Y. Zhang, Z. Liu, J. M. Fritz, R. Marsh, … M. B. Jordan
Science (2015-07-23) https://doi.org/f7kc8d
DOI: 10.1126/science.aaa1663 · PMID: 26206937
1118. The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2
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1119. The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2
Erik Procko
Cold Spring Harbor Laboratory (2020-05-11) https://doi.org/ggrbj8
DOI: 10.1101/2020.03.16.994236 · PMID: 32511321
1119. Comparative Pathogenesis Of COVID-19, MERS And SARS In A Non-Human Primate Model
+
1120. Comparative Pathogenesis Of COVID-19, MERS And SARS In A Non-Human Primate Model
Barry Rockx, Thijs Kuiken, Sander Herfst, Theo Bestebroer, Mart M. Lamers, Dennis de Meulder, Geert van Amerongen, Judith van den Brand, Nisreen M. A. Okba, Debby Schipper, … Bart L. Haagmans
Cold Spring Harbor Laboratory (2020-03-17) https://doi.org/ggq649
DOI: 10.1101/2020.03.17.995639
1120. Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus
+
1121. Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus
Paul B. McCray, Lecia Pewe, Christine Wohlford-Lenane, Melissa Hickey, Lori Manzel, Lei Shi, Jason Netland, Hong Peng Jia, Carmen Halabi, Curt D. Sigmund, … Stanley Perlman
Journal of Virology (2007-01-15) https://doi.org/b2dr3s
DOI: 10.1128/jvi.02012-06 · PMID: 17079315 · PMCID: PMC1797474
1121. Modeling the Impact of Asymptomatic Carriers on COVID-19 Transmission Dynamics During Lockdown
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1122. Modeling the Impact of Asymptomatic Carriers on COVID-19 Transmission Dynamics During Lockdown
Jacob B. Aguilar, Jeremy Samuel Faust, Lauren M. Westafer, Juan B. Gutierrez
Cold Spring Harbor Laboratory (2020-08-11) https://doi.org/ggqnvp
DOI: 10.1101/2020.03.18.20037994
1122. Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice
+
1123. Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice
Quan-xin Long, Hai-jun Deng, Juan Chen, Jie-li Hu, Bei-zhong Liu, Pu Liao, Yong Lin, Li-hua Yu, Zhan Mo, Yin-yin Xu, … Ai-long Huang
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggpvz3
DOI: 10.1101/2020.03.18.20038018
1123. Heat inactivation of serum interferes with the immunoanalysis of antibodies to SARS-CoV-2
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1124. Heat inactivation of serum interferes with the immunoanalysis of antibodies to SARS-CoV-2
Xiumei Hu, Taixue An, Bo Situ, Yuhai Hu, Zihao Ou, Qiang Li, Xiaojing He, Ye Zhang, Peifu Tian, Dehua Sun, … Lei Zheng
Cold Spring Harbor Laboratory (2020-03-16) https://doi.org/ggq646
DOI: 10.1101/2020.03.12.20034231
1124. SARS-CoV-2 specific antibody responses in COVID-19 patients
+
1125. SARS-CoV-2 specific antibody responses in COVID-19 patients
Nisreen M. A. Okba, Marcel A. Müller, Wentao Li, Chunyan Wang, Corine H. GeurtsvanKessel, Victor M. Corman, Mart M. Lamers, Reina S. Sikkema, Erwin de Bruin, Felicity D. Chandler, … Bart L. Haagmans
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggpvz2
DOI: 10.1101/2020.03.18.20038059
1125. A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19
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1126. A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19
Drifa Belhadi, Nathan Peiffer-Smadja, François-Xavier Lescure, Yazdan Yazdanpanah, France Mentré, Cédric Laouénan
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65b
DOI: 10.1101/2020.03.18.20038190
1126. ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19
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1127. ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19
Janice M. Leung, Chen X. Yang, Anthony Tam, Tawimas Shaipanich, Tillie-Louise Hackett, Gurpreet K. Singhera, Delbert R. Dorscheid, Don D. Sin
Cold Spring Harbor Laboratory (2020-03-23) https://doi.org/dqx2
DOI: 10.1101/2020.03.18.20038455
1127. Dynamic profile of severe or critical COVID-19 cases
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1128. Dynamic profile of severe or critical COVID-19 cases
Yang Xu
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggrbj9
DOI: 10.1101/2020.03.18.20038513
1128. Association between Clinical, Laboratory and CT Characteristics and RT-PCR Results in the Follow-up of COVID-19 patients
+
1129. Association between Clinical, Laboratory and CT Characteristics and RT-PCR Results in the Follow-up of COVID-19 patients
Hang Fu, Huayan Xu, Na Zhang, Hong Xu, Zhenlin Li, Huizhu Chen, Rong Xu, Ran Sun, Lingyi Wen, Linjun Xie, … Yingkun Guo
Cold Spring Harbor Laboratory (2020-03-23) https://doi.org/ggq65c
DOI: 10.1101/2020.03.19.20038315
1129. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus
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1130. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus
Timothy P. Sheahan, Amy C. Sims, Shuntai Zhou, Rachel L. Graham, Collin S. Hill, Sarah R. Leist, Alexandra Schäfer, Kenneth H. Dinnon, Stephanie A. Montgomery, Maria L. Agostini, … Ralph S. Baric
Cold Spring Harbor Laboratory (2020-03-20) https://doi.org/ggrbkb
DOI: 10.1101/2020.03.19.997890
1130. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs
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1131. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs
Sangeun Jeon, Meehyun Ko, Jihye Lee, Inhee Choi, Soo Young Byun, Soonju Park, David Shum, Seungtaek Kim
Cold Spring Harbor Laboratory (2020-03-28) https://doi.org/ggq65h
DOI: 10.1101/2020.03.20.999730
1131. Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2
+
1132. Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2
Vincent J. Munster, Friederike Feldmann, Brandi N. Williamson, Neeltje van Doremalen, Lizzette Pérez-Pérez, Jonathan Schulz, Kimberly Meade-White, Atsushi Okumura, Julie Callison, Beniah Brumbaugh, … Emmie de Wit
Cold Spring Harbor Laboratory (2020-03-21) https://doi.org/ggq65j
DOI: 10.1101/2020.03.21.001628 · PMID: 32511299
1132. Ocular conjunctival inoculation of SARS-CoV-2 can cause mild COVID-19 in Rhesus macaques
+
1133. Ocular conjunctival inoculation of SARS-CoV-2 can cause mild COVID-19 in Rhesus macaques
Wei Deng, Linlin Bao, Hong Gao, Zhiguang Xiang, Yajin Qu, Zhiqi Song, Shunran Gong, Jiayi Liu, Jiangning Liu, Pin Yu, … Chuan Qin
Cold Spring Harbor Laboratory (2020-03-30) https://doi.org/ggq64r
DOI: 10.1101/2020.03.13.990036
1133. ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19
+
1134. ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19
Bruna G. G. Pinto, Antonio E. R. Oliveira, Youvika Singh, Leandro Jimenez, Andre N A. Gonçalves, Rodrigo L. T. Ogava, Rachel Creighton, Jean Pierre Schatzmann Peron, Helder I. Nakaya
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65k
DOI: 10.1101/2020.03.21.20040261 · PMID: 32511627
1134. Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial
+
1135. Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial
Huijie Bian, Zhao-Hui Zheng, Ding Wei, Zheng Zhang, Wen-Zhen Kang, Chun-Qiu Hao, Ke Dong, Wen Kang, Jie-Lai Xia, Jin-Lin Miao, … Ping Zhu
Cold Spring Harbor Laboratory (2020-07-15) https://doi.org/ggq65m
DOI: 10.1101/2020.03.21.20040691
1135. CD147 facilitates HIV-1 infection by interacting with virus-associated cyclophilin A
+
1136. CD147 facilitates HIV-1 infection by interacting with virus-associated cyclophilin A
T. Pushkarsky, G. Zybarth, L. Dubrovsky, V. Yurchenko, H. Tang, H. Guo, B. Toole, B. Sherry, M. Bukrinsky
Proceedings of the National Academy of Sciences (2001-05-15) https://doi.org/cc4c7p
DOI: 10.1073/pnas.111583198 · PMID: 11353871 · PMCID: PMC33473
1136. CD147/EMMPRIN Acts as a Functional Entry Receptor for Measles Virus on Epithelial Cells
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1137. CD147/EMMPRIN Acts as a Functional Entry Receptor for Measles Virus on Epithelial Cells
Akira Watanabe, Misako Yoneda, Fusako Ikeda, Yuri Terao-Muto, Hiroki Sato, Chieko Kai
Journal of Virology (2010-05-01) https://doi.org/dpcsqg
DOI: 10.1128/jvi.02168-09 · PMID: 20147391 · PMCID: PMC2863760
1137. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum
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1138. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum
Cécile Crosnier, Leyla Y. Bustamante, S. Josefin Bartholdson, Amy K. Bei, Michel Theron, Makoto Uchikawa, Souleymane Mboup, Omar Ndir, Dominic P. Kwiatkowski, Manoj T. Duraisingh, … Gavin J. Wright
Nature (2011-11-09) https://doi.org/dm59hf
DOI: 10.1038/nature10606 · PMID: 22080952 · PMCID: PMC3245779
1138. Function of HAb18G/CD147 in Invasion of Host Cells by Severe Acute Respiratory Syndrome Coronavirus
+
1139. Function of HAb18G/CD147 in Invasion of Host Cells by Severe Acute Respiratory Syndrome Coronavirus
Zhinan Chen, Li Mi, Jing Xu, Jiyun Yu, Xianhui Wang, Jianli Jiang, Jinliang Xing, Peng Shang, Airong Qian, Yu Li, … Ping Zhu
The Journal of Infectious Diseases (2005-03) https://doi.org/cd8snd
DOI: 10.1086/427811 · PMID: 15688292 · PMCID: PMC7110046
1139. CD147 mediates intrahepatic leukocyte aggregation and determines the extent of liver injury
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1140. CD147 mediates intrahepatic leukocyte aggregation and determines the extent of liver injury
Christine Yee, Nathan M. Main, Alexandra Terry, Igor Stevanovski, Annette Maczurek, Alison J. Morgan, Sarah Calabro, Alison J. Potter, Tina L. Iemma, David G. Bowen, … Nicholas A. Shackel
PLOS ONE (2019-07-10) https://doi.org/ggq654
DOI: 10.1371/journal.pone.0215557 · PMID: 31291257 · PMCID: PMC6619953
1140. Characterisation of the transcriptome and proteome of SARS-CoV-2 using direct RNA sequencing and tandem mass spectrometry reveals evidence for a cell passage induced in-frame deletion in the spike glycoprotein that removes the furin-like cleavage site
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1141. Characterisation of the transcriptome and proteome of SARS-CoV-2 using direct RNA sequencing and tandem mass spectrometry reveals evidence for a cell passage induced in-frame deletion in the spike glycoprotein that removes the furin-like cleavage site
Andrew D. Davidson, Maia Kavanagh Williamson, Sebastian Lewis, Deborah Shoemark, Miles W. Carroll, Kate Heesom, Maria Zambon, Joanna Ellis, Phillip A. Lewis, Julian A. Hiscox, David A. Matthews
Cold Spring Harbor Laboratory (2020-03-24) https://doi.org/ggq65n
DOI: 10.1101/2020.03.22.002204
1141. Modifications to the Hemagglutinin Cleavage Site Control the Virulence of a Neurotropic H1N1 Influenza Virus
+
1142. Modifications to the Hemagglutinin Cleavage Site Control the Virulence of a Neurotropic H1N1 Influenza Virus
Xiangjie Sun, Longping V. Tse, A Damon Ferguson, Gary R. Whittaker
Journal of Virology (2010-09-01) https://doi.org/drs2zt
DOI: 10.1128/jvi.00797-10 · PMID: 20554779 · PMCID: PMC2919019
1142. The architecture of SARS-CoV-2 transcriptome
+
1143. The architecture of SARS-CoV-2 transcriptome
Dongwan Kim, Joo-Yeon Lee, Jeong-Sun Yang, Jun Won Kim, V. Narry Kim, Hyeshik Chang
Cold Spring Harbor Laboratory (2020-03-14) https://doi.org/ggpx9q
DOI: 10.1101/2020.03.12.988865
1143. First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naïve and Experienced COVID-19 Patients
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1144. First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naïve and Experienced COVID-19 Patients
Hongyi Chen, Zhicheng Zhang, Li Wang, Zhihua Huang, Fanghua Gong, Xiaodong Li, Yahong Chen, Jinzi J. Wu
Cold Spring Harbor Laboratory (2020-03-24) https://doi.org/ggrgbt
DOI: 10.1101/2020.03.22.20034041
1144. Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)
+
1145. Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)
Scott D. Seiwert, Steven W. Andrews, Yutong Jiang, Vladimir Serebryany, Hua Tan, Karl Kossen, P. T. Ravi Rajagopalan, Shawn Misialek, Sarah K. Stevens, Antitsa Stoycheva, … Lawrence M. Blatt
Antimicrobial Agents and Chemotherapy (2008-12) https://doi.org/btpg52
DOI: 10.1128/aac.00699-08 · PMID: 18824605 · PMCID: PMC2592891
1145. Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China
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1146. Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China
Xiaoyuan Xu, Bo Feng, Yujuan Guan, Sujun Zheng, Jifang Sheng, Xingxiang Yang, Yuanji Ma, Yan Huang, Yi Kang, Xiaofeng Wen, … Lai Wei
Journal of Clinical and Translational Hepatology (2019-09-30) https://doi.org/ggrbkd
DOI: 10.14218/jcth.2019.00033 · PMID: 31608212 · PMCID: PMC6783683
1146. Potentially highly potent drugs for 2019-nCoV
+
1147. Potentially highly potent drugs for 2019-nCoV
Duc Duy Nguyen, Kaifu Gao, Jiahui Chen, Rui Wang, Guo-Wei Wei
Cold Spring Harbor Laboratory (2020-02-13) https://doi.org/ggrbj5
DOI: 10.1101/2020.02.05.936013 · PMID: 32511344
1147. Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset
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1148. Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset
Bin Lou, Ting-Dong Li, Shu-Fa Zheng, Ying-Ying Su, Zhi-Yong Li, Wei Liu, Fei Yu, Sheng-Xiang Ge, Qian-Da Zou, Quan Yuan, … Yu Chen
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggrbkc
DOI: 10.1101/2020.03.23.20041707
1148. SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems
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1149. SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems
Daniel Blanco-Melo, Benjamin E. Nilsson-Payant, Wen-Chun Liu, Rasmus Møller, Maryline Panis, David Sachs, Randy A. Albrecht, Benjamin R. tenOever
Cold Spring Harbor Laboratory (2020-03-24) https://doi.org/ggq65q
DOI: 10.1101/2020.03.24.004655
1149. A New Predictor of Disease Severity in Patients with COVID-19 in Wuhan, China
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1150. A New Predictor of Disease Severity in Patients with COVID-19 in Wuhan, China
Ying Zhou, Zhen Yang, Yanan Guo, Shuang Geng, Shan Gao, Shenglan Ye, Yi Hu, Yafei Wang
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65r
DOI: 10.1101/2020.03.24.20042119
1150. Metabolic disturbances and inflammatory dysfunction predict severity of coronavirus disease 2019 (COVID-19): a retrospective study
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1151. Metabolic disturbances and inflammatory dysfunction predict severity of coronavirus disease 2019 (COVID-19): a retrospective study
Shuke Nie, Xueqing Zhao, Kang Zhao, Zhaohui Zhang, Zhentao Zhang, Zhan Zhang
Cold Spring Harbor Laboratory (2020-03-26) https://doi.org/ggq65s
DOI: 10.1101/2020.03.24.20042283
1151. Viral Kinetics and Antibody Responses in Patients with COVID-19
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1152. Viral Kinetics and Antibody Responses in Patients with COVID-19
Wenting Tan, Yanqiu Lu, Juan Zhang, Jing Wang, Yunjie Dan, Zhaoxia Tan, Xiaoqing He, Chunfang Qian, Qiangzhong Sun, Qingli Hu, … Guohong Deng
Cold Spring Harbor Laboratory (2020-03-26) https://doi.org/ggq65t
DOI: 10.1101/2020.03.24.20042382
1152. Global profiling of SARS-CoV-2 specific IgG/ IgM responses of convalescents using a proteome microarray
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1153. Global profiling of SARS-CoV-2 specific IgG/ IgM responses of convalescents using a proteome microarray
He-wei Jiang, Yang Li, Hai-nan Zhang, Wei Wang, Dong Men, Xiao Yang, Huan Qi, Jie Zhou, Sheng-ce Tao
Cold Spring Harbor Laboratory (2020-03-27) https://doi.org/ggq65g
DOI: 10.1101/2020.03.20.20039495
1153. COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome
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1154. COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome
Dan Zhang, Rui Guo, Lei Lei, Hongjuan Liu, Yawen Wang, Yili Wang, Hongbo Qian, Tongxin Dai, Tianxiao Zhang, Yanjun Lai, … Jinsong Hu
Cold Spring Harbor Laboratory (2020-03-26) https://doi.org/ggq65v
DOI: 10.1101/2020.03.24.20042655
1154. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study
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1155. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study
Aaron Miller, Mac Josh Reandelar, Kimberly Fasciglione, Violeta Roumenova, Yan Li, Gonzalo H. Otazu
Cold Spring Harbor Laboratory (2020-03-28) https://doi.org/ggq65w
DOI: 10.1101/2020.03.24.20042937
1155. Non-specific effects of BCG vaccine on viral infections
+
1156. Non-specific effects of BCG vaccine on viral infections
S. J. C. F. M. Moorlag, R. J. W. Arts, R. van Crevel, M. G. Netea
Clinical Microbiology and Infection (2019-12) https://doi.org/ggq62z
DOI: 10.1016/j.cmi.2019.04.020 · PMID: 31055165
1156. BCG vaccination to reduce the impact of COVID-19 in healthcare workers (The BRACE Trial)
+
1157. BCG vaccination to reduce the impact of COVID-19 in healthcare workers (The BRACE Trial)
Murdoch Children’s Research Institute
https://www.mcri.edu.au/BRACE
1157. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia
+
1158. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia
David H. Brann, Tatsuya Tsukahara, Caleb Weinreb, Marcela Lipovsek, Koen Van den Berge, Boying Gong, Rebecca Chance, Iain C. Macaulay, Hsin-jung Chou, Russell Fletcher, … Sandeep Robert Datta
Cold Spring Harbor Laboratory (2020-05-18) https://doi.org/ggqr4m
DOI: 10.1101/2020.03.25.009084
1158. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract
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1159. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract
Joan C. Smith, Erin L. Sausville, Vishruth Girish, Monet Lou Yuan, Kristen M. John, Jason M. Sheltzer
Cold Spring Harbor Laboratory (2020-04-26) https://doi.org/ggq65x
DOI: 10.1101/2020.03.28.013672
1159. The comparative superiority of IgM-IgG antibody test to real-time reverse transcriptase PCR detection for SARS-CoV-2 infection diagnosis
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1160. The comparative superiority of IgM-IgG antibody test to real-time reverse transcriptase PCR detection for SARS-CoV-2 infection diagnosis
Rui Liu, Xinghui Liu, Huan Han, Muhammad Adnan Shereen, Zhili Niu, Dong Li, Fang Liu, Kailang Wu, Zhen Luo, Chengliang Zhu
Cold Spring Harbor Laboratory (2020-03-30) https://doi.org/ggqtp5
DOI: 10.1101/2020.03.28.20045765