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| ==2. Diagnostic testing of COVID-19== | | <div class="nonumtoc">__TOC__</div> |
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| | | ==Sandbox begins below== |
| ===2.1 Testing conducted on previous coronaviruses=== | |
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| ====2.1.1 Severe acute respiratory syndrome (SARS)====
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| [[Severe acute respiratory syndrome]], otherwise known as SARS, arose in South China in late 2002. Caused by the SARS caronavirus (SARS-CoV) and believed to have originated from horseshoe bats<ref name="McKieScientists17">{{cite web |url=https://www.theguardian.com/world/2017/dec/10/sars-virus-bats-china-severe-acute-respiratory-syndrome |title=Scientists trace 2002 Sars virus to colony of cave-dwelling bats in China |author=McKie, R. |work=The Guardian |date=09 December 2017 |accessdate=03 April 2020}}</ref>, SARS eventually was contained in the summer of 2003. The last known infection was in April 2004, due to a laboratory accident.<ref name="NormileMounting04">{{cite journal |title=Mounting Lab Accidents Raise SARS Fears |journal=Science |author=Normile, D. |volume304 |issue=5671 |pages=659–61 |year=2004 |doi=10.1126/science.304.5671.659 |pmid=15118129}}</ref> During that time, the following sample collection and test procedures evolved from the related outbreaks (note that this is only a summary; consult the cited literature directly for full details)<ref name="NYSDHLab04">{{cite web |url=https://www.health.ny.gov/diseases/communicable/sars/sars_reporting/attachment_6_dear_doctor_lab.htm |title=Laboratory Testing for SARS |author=New York State Department of Health |publisher=State of New York |date=February 2004 |accessdate=03 April 2020}}</ref><ref name="CDCSevere04">{{cite web |url=https://www.cdc.gov/sars/guidance/f-lab/downloads/F-lab-full.pdf |format=PDF |title=Public Health Guidance for Community-Level Preparedness and Response to Severe Acute Respiratory Syndrome (SARS), Version 2 - Supplement F: Laboratory Guidance |author=Centers for Disease Control and Prevention |publisher=Centers for Disease Control and Prevention |date=21 May 2004 |accessdate=03 April 2020}}</ref><ref name="KnoblerLearning04">{{cite book |chapter=Appendix C: In the absence of SARS-CoV transmission worldwide: Guidance for surveillance, clinical and laboratory evaluation, and reporting |title=Learning from SARS: Preparing for the Next Disease Outbreak |editor=Knobler, S.; Mahmoud, A.; Lemon, S. et al. |publisher=National Academies Press |pages=292–302 |year=2004 |isbn=9780309182157 |doi=10.17226/10915}}</ref><ref name="WHO_SARSInt04">{{cite web |url=http://www.who.int/csr/resources/publications/en/SARSReferenceLab.pdf |title=WHO SARS International Reference and Verification Laboratory Network: Policy and Procedures in the Inter-Epidemic Period |author=World Health Organization |publisher=World Health Organization |date=23 January 2004 |accessdate=03 April 2020}}</ref><ref name="LiangLab04">{{cite journal |title=Laboratory Diagnosis of Four Recent Sporadic Cases of Community-acquired SARS, Guangdong Province, China |journal=Emerging Infectious Diseases |author=Liang, G.; Chen, Q.; Xu, J. et al. |volume=10 |issue=10 |pages=1774–81 |year=2004 |doi=10.3201/eid1010.040445 |pmid=15504263 |pmc=PMC3323270}}</ref>:
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| * Determine that the patient is indicating clinical and/or epidemiological evidence of SARS. As Knobler ''et al.'' put it: "SARS-CoV testing should be considered if no alternative diagnosis is identified 72 hours after initiation of the clinical evaluation and the patient is thought to be at high risk for SARS-CoV disease (e.g., is part of a cluster of unexplained pneumonia cases)."<ref name="KnoblerLearning04" />
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| * Collect multiple specimen types at different time points of the patient's illness. Respiratory and plasma or serum specimens should be collected early into the first week of illness. Respiratory samples should be from [[Nasopharyngeal swab|nasopharyngeal aspirates and swabs]] in the upper respiratory tract, or in some cases fluids from the lower respiratory tract using [[bronchoalveolar lavage]], tracheal aspiration, or a pleural tap. Whole blood (5 to 10 ml) is collected into either a serum separator tube for blood serum or EDTA tube for blood plasma. Stool samples are also of import early on for virus isolation or detection and are useful in at least the first and second weeks of the illness. Blood serum is usefull in weeks two and three for detecting a rising titre. Additionally, the literature also makes reference to methods of collecting specimens post-mortum.
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| * Conduct testing. At the time, the two primary test types used were enzyme immunoassay (EIA; today more commonly known as [[ELISA]]<ref name="LequinEnzyme05">{{cite journal |title=Enzyme Immunoassay (EIA)/Enzyme-Linked Immunosorbent Assay (ELISA) |journal=Clinical Chemistry |author=Lequin, R.M. |volume=51 |issue=12 |pages=2415–18 |year=2005 |doi=10.1373/clinchem.2005.051532 |pmid=16179424}}</ref>) for detection of serum antibody and reverse transcription [[polymerase chain reaction]] (RT-PCR) for detection of the virus' RNA. The U.S. Centers for Disease Control and Preventions had this to say about these tests in May 2004<ref name="CDCSevere04" />:
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| <blockquote>Both the EIA and the RT-PCR tests are sensitive and highly specific for SARS-CoV. The ability to diagnose SARS-CoV infection in a patient is often limited, however, by either the low concentration of virus in most clinical specimens (RT-PCR assays) or the time it takes a person to mount a measurable antibody response to SARS-CoV (serologic assays). The likelihood of detecting infection is increased if multiple specimens (e.g., stool, serum, respiratory tract specimens) are collected at several times during the course of illness.</blockquote>
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| :The literature also makes reference to an [[Immunofluorescence|immunofluorescence assay]] (IFA) for detecting antibody, with the CDC calling its results "essentially identical to those for the EIA for SARS antibody."<ref name="CDCSevere04" /> Tangentially, isolation of SARS-CoV in cell culture from a clinical specimen is also referenced, though such activity is reserved for [[Biosafety level|Biosafety Level 3]] (BSL-3) laboratories.
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| * Confirm the results. Laboratory confirmation is based on one of 1. initial local lab detection and subsequent national reference lab confirmation of a validated serology-based test detection; 2. isolation of SARS-CoV in cell culture with subsequent confirmation from a validated test; or 3. initial local lab detection and subsequent national reference lab confirmation of SARS-CoV RNA from a validated RT-PCR test which used either two clinical specimens from different sources or two same-source clinical specimens from two different days.
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| :Additionally, in the case of serology, one of the following must be true:
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| # SARS-CoV serum antibodies are detected in a single serum specimen; or,
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| # a "four-fold or greater increase in SARS-CoV antibody titer between acute- and convalescent-phase serum specimens tested in parallel"<ref name="CDCSevere04" /> is detected; or,
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| # a "negative SARS-CoV antibody test result on acute-phase serum and positive SARS-CoV antibody test result on convalescent-phase serum tested in parallel"<ref name="CDCSevere04" /> is detected.
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| :Of note is the WHO's January 2004 cautionary message about serological diagnostics in not only SARS-CoV but other types of coronaviruses. At that time, they showed a level of unsureness in regards to how coronaviruses elicited serological cross-reactions and generated antigenic recall. They also preached caution in interpreting serological results in non-epidemic periods and when no viral sequence data are available. Finally, they also mentioned the added difficulties of rate cases when coinfection with a related human coronavirus occurs, "although the use of expressed proteins in Western blots may help to sort this out."<ref name="WHO_SARSInt04" /> More than 15 years later, Loeffelholz and Tang put this concept into clearer terms, indicating that while "serological assays are not routinely used for diagnosis of [human coronavirus] infections due to the lack of commercial reagents," they still have important value "for understanding the epidemiology of emerging [human cornaviruses], including the burden and role of asymptomatic infections," as well as for antibody detection of novel and emerging coronaviruses.<ref name="LoeffelholzLab20">{{cite journal |title=Laboratory diagnosis of emerging human coronavirus infections – The state of the art |journal=Emerging Microbes & Infections |author=Loeffelholz, M.J.; Tang, T.-W. |volume=9 |issue=1 |pages=747–56 |year=2020 |doi=10.1080/22221751.2020.1745095 |pmid=32196430}}</ref>
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| * Arrange for confirmatory testing to be performed by an appropriate test site in the case of a positive RT-PCR test.
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| * Report to state or local health departments details of patients radiographically confirmed with pneumonia with at least one SARS-CoV risk factor for exposure, clusters of healthcare workers with unexplained pneumonia, and any positive SARS-CoV test results. Additional international reporting of SARS by WHO Member States in regards to probable and laboratory-confirmed cases is also requested.
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| * Send off for an additional verification by an external member of the WHO's SARS Reference and Verification Laboratory Network before internationally announcing results as a laboratory-confirmed case.
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| ====2.1.2 Middle East respiratory syndrome (MERS)====
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| ====2.1.3 The common cold====
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| Approximately 10 to 15 percent of cases of what we call the "common cold" are associated with an endemic coronavirus, of which are two distinct groups: HCoV-229E and HCoV-OC43.<ref name="WatTheCommon04">{{cite journal |title=The common cold: A review of the literature |journal=European Jouranl of Internal Medicine |author=Wat, D. |volume=15 |issue=2 |pages=79–88 |year=2004 |doi=10.1016/j.ejim.2004.01.006 |pmid=15172021}}</ref> Disease symptoms associated with these coronaviruses—typically in the form of respiratory infection and the symptoms that come with it—by themselves are typically mild<ref name="LoeffelholzLab20" />, and laboratory testing isn't necessarily indicated for those immunocompetent individuals capable of self-limiting.<ref name="BabadyMulti18">{{cite journal |title=Multicenter Evaluation of the ePlex Respiratory Pathogen Panel for the Detection of Viral and Bacterial Respiratory Tract Pathogens in Nasopharyngeal Swabs |journal=Journal of Clinical Microbiology |author=Babady, N.E.; England, M.R.; Jurcic Smith, K.L. et al. |volume=56 |issue=2 |at=e01658-17 |year=2018 |doi=10.1128/JCM.01658-17 |pmid=29212701 |pmc=PMC5786739}}</ref> However, symptom overlap with pharyngitis and bronchitis, as well as the complication of pharyngitis and sinusitis also potentially having bacterial origin, can complicate clinical diagnosis. Additionally, as more antivirals that target a specific virus are created, and as concerns of unnecessarily using antibiotics to treat viral diseases grows<ref name="JenisonRapid16">{{cite web |url=https://www.statnews.com/2016/11/30/antibiotic-resistance-molecular-diagnostics/ |title=Rapid lab tests can help reduce antibiotic resistance |author=Jenison, R. |work=STAT |date=30 November 2016 |accessdate=03 April 2020}}</ref><ref name="RoyRapid18">{{cite web |url=https://www.healio.com/infectious-disease/antimicrobials/news/online/%7B226c31f3-1d8e-4ffe-82b1-654cb37303c4%7D/rapid-test-for-viral-infections-reduces-unnecessary-antibiotic-prescribing |title=Rapid test for viral infections reduces unnecessary antibiotic prescribing |author=Roy, K. |work=Healio |date=26 September 2018 |accessdate=03 April 2020}}</ref>, laboratory methods of respiratory virus diagnosis—particularly for those who are immunocompromised—have value.<ref name="WatTheCommon04" /><ref name="BabadyMulti18" /> RT-PCR, a molecular method, have been used for over a decade for detecting coronaviruses.<ref name="MahonyDetect08">{{cite journal |title=Detection of Respiratory Viruses by Molecular Methods |journal=Clinical Microbiology Reviews |author=Mahoney, J.B. |volume=21 |issue=4 |pages=716–47 |year=2008 |doi=10.1128/CMR.00037-07 |pmid=18854489 |pmc=PMC2570148}}</ref> As molecular methods of analysis have expanded, however, more rapid solutions for testing have been developed. For example, the GenMark ePlex rapid multiplex molecular diagnostics instrument and the ePlex Respiratory Pathogen Panel were evaluated in a multicenter trial by Babady ''et al.'' in 2017.<ref name="BabadyMulti18" /> The panel is capable of testing for the presence of 15 viral types—including the -229E, -OC43, and two other coronaviruses—and two bacterial types in nasopharyngeal swab specimens, with results in typically less than two hours.<ref name="BabadyMulti18" /> The costs associated with these sorts of tests, compared to their benefits, likely limits ubiquitous use at the first sign of a cold<ref name="BabadyMulti18" />, but as molecular diagnostic technologies become more compact and easy-to-use, testing for infection by endemic human coronaviruses may become more commonplace, at least in the hospital setting.
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| ===2.2 Organizational and agency guidance on COVID-19 testing===
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| ===2.3 Current test kits and their differences===
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| ===2.4 Regulatory and recommended requirements for reporting test results===
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| ==References==
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| {{Reflist|colwidth=30em}}
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