Merge pull request #735 from rando2/split-general

Split general content (intro, discussion) across sections

content/07.pathogenesis.md

@@ -4,6 +4,21 @@
 
 ### Introduction
 
+On January 21, 2020, the World Health Organization (WHO) released its first report concerning what is now known as the Coronavirus Disease 2019 (COVID-19) [@url:https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200121-sitrep-1-2019-ncov.pdf].
+This infectious disease came to international attention on December 31, 2019 following an announcement by national officials in China describing 44 cases of a respiratory infection of unknown cause.
+The first known cases were located in Wuhan City within the Hubei province of China, but the disease spread rapidly throughout China and subsequently around the world.
+At the time of the WHO's first situation report [@url:https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200121-sitrep-1-2019-ncov.pdf], 282 confirmed cases had been identified.
+Most of these cases were in China, but one to two exported cases had also been identified in each of several neighboring countries (Thailand, Japan, and the Republic of Korea).
+One week later, 4,593 confirmed cases had been identified, spanning not only Asia, but also Australia, North America, and Europe [@url:https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200128-sitrep-8-ncov-cleared.pdf].
+On March 11, 2020, the WHO formally classified the situation as a pandemic [@url:https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200311-sitrep-51-covid-19.pdf].
+On April 4, 2020, the WHO reported that the global number of confirmed cases had surpassed one million [@url:https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200404-sitrep-75-covid-19.pdf].
+{{csse_deaths}} COVID-19 deaths had been reported worldwide as of {{csse_date_pretty}} (Figure @fig:csse-deaths).
+
+![
+**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 [@https://github.com/CSSEGISandData/COVID-19/tree/master/csse_covid_19_data/csse_covid_19_time_series].
+]({{csse_deaths_figure}} "Global COVID-19 deaths"){#fig:csse-deaths secno=1}
+
 The current COVID-19 pandemic, caused by the SARS-CoV-2 virus, represents an acute global health crisis where symptoms can range from mild to severe or fatal [@url:https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html], can affect a variety of organs and systems, and includes outcomes such as acute respiratory distress and acute lung injury, among other complications.
 Viral pathogenesis is typically broken down into three major components: entry, replication, and spread [@isbn:0-9631172-1-1 {chap. 45}].
 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.
@@ -510,3 +525,7 @@ Thus, the current evidence suggests that the apparent correlations between ances
 
 ### Conclusions
 
+As with other HCoV, the immune response to SARS-CoV-2 is likely driven by detection of its spike protein, which allows it to enter cells through the ACE2 receptor.
+Epithelial cells have also emerged as the major cellular target of the virus, contextualizing the respiratory and gastrointestinal symptoms that are frequently observed in COVID-19.
+
+Characterizing the rate of infection and fatality rates hinges on the availability of rapid and accurate diagnostic testing.

content/09.evolution.md

@@ -31,29 +31,6 @@ CoV-HKU1 was identified in samples collected from a 71-year-old pneumonia patien
 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 [@doi:10.1086/377612].
 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) [@doi:10.1038/nrmicro.2016.81; @doi:10.1038/s41579-018-0118-9; @doi:10.1016/bs.aivir.2018.01.001].
 
-At the time that SARS-CoV-1 emerged in the early 2000s, no HCoV had been identified in almost 40 years [@doi:10.1038/nrmicro.2016.81].
-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 [@doi:10.1093/ajcp/aqaa029; @doi:10.1038/nrmicro.2016.81].
-Unlike previously identified HCoV, SARS was much more severe, with an estimated death rate of 9.5% [@doi:10.1093/ajcp/aqaa029].
-It was also highly contagious via droplet transmission, with a basic reproduction number (R~0~) of 4 (i.e., each person infected was estimated to infect four other people) [@doi:10.1093/ajcp/aqaa029].
-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 [@doi:10.1038/nrmicro.2016.81].
-SARS-CoV-1 belonged to a distinct lineage from the two other HCoV known at the time [@doi:10.1093/ajcp/aqaa029].
-By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices [@doi:10.1038/nrmicro.2016.81].
-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 R~0~ of 1 [@doi:10.1093/ajcp/aqaa029].
-Although MERS is still circulating, its low reproduction number has allowed for its spread to be contained [@doi:10.1093/ajcp/aqaa029].
-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 [@doi:10.1038/nrmicro.2016.81; @doi:10.1093/ajcp/aqaa029].
-Vaccines were not used to control either virus, although vaccine development programs were established for SARS-CoV-1 [@doi:10.3390/v11010059].
-In general, care for SARS and MERS patients focuses on supportive care and symptom management [@doi:10.1093/ajcp/aqaa029].
-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 [@doi:10.1038/nrmicro.2016.81].
-However, retrospective and _in vitro_ analyses have reported inconclusive results of these treatments on SARS and the SARS-CoV-1 virus, respectively [@doi:10.1038/nrmicro.2016.81].
-IFNs and Ribavirin have shown promise in _in vitro_ analyses of MERS, but their clinical effectiveness remains unknown [@doi:10.1038/nrmicro.2016.81].
-Therefore, only limited strategy for the pharmaceutical management of COVID-19 can be adopted 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.
-
 ### Conclusions
 
 As of October 2020 the SARS-CoV-2 virus remains a serious worldwide threat.

content/10.diagnostics.md

@@ -15,6 +15,18 @@ While serological tests may be of interest to individuals who wish to confirm th
 However, serological tests provide population-level information for epidemiological analysis, as they can be used to estimate the extent of the infection in a given area.
 Thus, they may be useful in efforts to better understand the percent of cases that manifest as severe versus mild and for guiding public health and economic decisions regarding resource allocation and counter-disease measures.
 
+Understanding the fundamental organization of the human immune response to viral threats is critical to understanding the varied response to SARS-CoV-2.
+The human immune system utilizes a variety of innate and adaptive responses to protect against the pathogens it encounters.
+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 [@doi:10.1016/j.jaci.2005.09.034].
+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 [@doi:10.1016/j.jpha.2020.03.001].
+
 ### 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.
@@ -221,3 +233,15 @@ Technological advancements that facilitate widespread, rapid testing will theref
 
 ### Conclusions
 
+Major advancements have been made in identifying diagnostic approaches.
+The development of diagnostic technologies have been rapid, beginning with the release of the SARS-CoV-2 viral genome sequence in January.
+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 [@doi:10.1001/jama.2020.8259].
+Other strategies for testing can also influence the tests' accuracy, such as the use of nasopharyngeal swabs versus BALF [@doi:10.1001/jama.2020.8259], 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., [@doi:10/ghfgkt]), 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.
+