COVID-19, the disease caused by the novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV-2), has rapidly grown into a worldwide pandemic. There are over 1.3 million confirmed cases and over 74,000 reported deaths in 212 countries, areas or territories as of April 8th, 2020.1 It is the third coronavirus circulating in humans in the past two decades, following the severe acute respiratory syndrome coronavirus (SARS-CoV) outbreak in 2002 and the Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak in 2012.2 Compared with SARS-CoV and MERS-CoV, SARS-CoV-2 has demonstrated a lower mortality rate with higher transmissibility.3
Diagnostic testing is playing significant roles in COVID-19 case identification, infection control, and disease management. Traditional viral culture requires days’ turnaround time and biosafety level-3 facilities that are not available in many healthcare institutions. Real-time reverse transcription-polymerase chain reaction (rRT-PCR) is currently the gold standard for COVID-19 diagnosis. After the complete genome of SARS-CoV-2 was published,4 public health laboratories, clinical laboratories, and diagnostic companies from different countries developed numerous rRT-PCR methods for SARS-CoV-2 detection, targeting different genes and genomic regions (n, e, orf1ab, RdRp etc.) in the viral genome. Some of these tests target point-of-care use with turnaround time less than 45 min. The U.S. Food and Drug Administration (FDA) currently allows CLIA high-complexity laboratories to develop and offer laboratory-developed tests (LDTs) while pursuing emergency use authorization (EUA). There is limited data comparing the performance of various rRT-PCR tests. Some studies suggest limited clinical sensitivity and potential false negatives for some rRT-PCR tests.5 False negatives might be due to low viral load at time of testing, inappropriate sample collection, processing or transportation. For patients with typical clinical presentations or clear epidemic indications, clinical treatment and case management is necessary even with negative molecular testing results. Most molecular tests use nasopharyngeal or oropharyngeal swabs as acceptable sample types, but active development is ongoing exploring the use of sputum and saliva as sample types. Efforts are also ongoing exploring self-swabbing, self-testing and viral antigen testing. Another challenge faced by testing laboratories is the severe supply chain shortage, including for swabs and testing kits.
Serology testing has also been used to some extent for various indications, including infection status determination in combination with molecular results, seroprevalence, and immune protection status for healthcare workers. There is no clear and strong evidence correlating seropositivity with immune protection at this point. Asymptomatic carriers of SARS-CoV-2 contributing to “silent” transmission has been reported but the prevalence is not clearly characterized.6 Wide use of serology testing is thought to be useful in detecting and determining prevalence of “silent” carriers. Serology tests use various antigens (S1, S2, RBD, N etc.) to detect either IgM or IgG in the blood. Development efforts targeting IgA detection in saliva are also ongoing. Assay formats include traditional ELISA, lateral flow assays, and neutralization assays, with some tests multiplexing IgM and IgG. Major diagnostic companies are working on developing high-throughput serology tests. EUA by FDA has been granted to the first serology test on April 1st, 2020, while FDA allows clinical laboratories and commercial manufacturers to launch serology tests without an EUA. It is worthwhile to note that only a subset of patients with positive molecular results are seropositive, due to both physiological delay in antibody production and assay sensitivity issues. Due to the immunoassay nature, assay specificity also needs to be evaluated carefully.
Another biomarker of interest is IL-6. Tocilizumab is a humanized monoclonal antibody against the interleukin-6 receptor, and is used in ongoing clinical trials to treat severe COVID-19 diseases with cytokine release syndromes. Although there is limited evidence at this point, the measurement of IL-6 may be useful in guiding tocilizumab therapy. There is currently no FDA-approved or -cleared test for IL-6, and clinical laboratories need to develop LDTs to implement it.
A list of commercially-available COVID-19 diagnostic tests, including molecular and serology tests in the US, European and Asian markets can be viewed at https://www.360dx.com/coronavirus-test-tracker-launched-covid-19-tests. FDA also has a public list on its website for COVID-19 diagnostic testing: https://www.fda.gov/medical-devices/emergency-situations-medical-devices/faqs-diagnostic-testing-sars-cov-2. Note that this is a rapidly changing landscape, and some statements and conclusions in this Scientific Short may not be valid anymore as the pandemic and the diagnostic strategies evolve.
- Coronavirus disease (COVID-19) Pandemic. https://www.who.int/emergencies/diseases/novel-coronavirus-2019 (accessed April 8, 2020).
- de Wit, E.; van Doremalen, N.; Falzarano, D.; Munster, V. J., SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol 2016, 14 (8), 523-534.
- Munster, V. J.; Koopmans, M.; van Doremalen, N.; van Riel, D.; de Wit, E., A Novel Coronavirus Emerging in China - Key Questions for Impact Assessment. N Engl J Med 2020, 382 (8), 692-694.
- Zhou, P.; Yang, X. L.; Wang, X. G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H. R.; Zhu, Y.; Li, B.; Huang, C. L.; Chen, H. D.; Chen, J.; Luo, Y.; Guo, H.; Jiang, R. D.; Liu, M. Q.; Chen, Y.; Shen, X. R.; Wang, X.; Zheng, X. S.; Zhao, K.; Chen, Q. J.; Deng, F.; Liu, L. L.; Yan, B.; Zhan, F. X.; Wang, Y. Y.; Xiao, G. F.; Shi, Z. L., A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020, 579 (7798), 270-273.
- Ai, T.; Yang, Z.; Hou, H.; Zhan, C.; Chen, C.; Lv, W.; Tao, Q.; Sun, Z.; Xia, L., Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology 2020, 200642.
- Bai, Y.; Yao, L.; Wei, T.; Tian, F.; Jin, D. Y.; Chen, L.; Wang, M., Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA 2020.