Rapid Diagnostic Testing for SARS-CoV-2

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To the Editor

The review by Drain (Jan. 20 issue) 1 about rapid diagnostic testing for SARS-CoV-2 raises important questions. First, Drain states that persons who are not fully vaccinated and who have had exposure to an infected contact should quarantine while awaiting test results. Why would this not also apply to fully vaccinated persons, since they appear to be as potentially contagious? 2,3 Why would the pretest probability of infection be higher among unvaccinated persons than among fully vaccinated persons?

Second, Drain highlights that nucleic acid amplification tests (NAATs) may remain positive for weeks or months after infection, as opposed to antigen-based tests, which are positive essentially during the period that the person may be contagious. Yet, in the algorithms provided by the author, a positive test in an asymptomatic person, regardless of vaccine status, who has a moderate pretest probability of infection is considered to indicate confirmed Covid-19. If this test was a NAAT, should not such a person undergo an antigen-based test, which could be used as triage information regarding transmissibility? Third, if the approved tests have 98 to 100% specificity, why is repeat testing frequently recommended when an initial test is positive?

Peter Bogaty, MDLaval University, Quebec, QC, Canada [email protected]

No potential conflict of interest relevant to this letter was reported.

This letter was published on April 13, 2022, at NEJM.org.

3 References

1. Drain PK. Rapid diagnostic testing for SARS-CoV-2. N Engl J Med 2022; 386: 264-272.

2. Kissler SM, Fauver JR, Mack C, et al. Viral dynamics of SARS-CoV-19 variants in vaccinated and unvaccinated persons. N Engl J Med 2021; 385: 2489-2491.

3. Singanayagam A, Hakki S, Dunning J, et al. Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study. Lancet Infect Dis 2022; 22: 183-195.

Response

The author replies: Understanding the clinical indications and interpretation of rapid diagnostic tests for SARS-CoV-2 is critical for successful implementation, and Bogaty raises several important questions. First, vaccinated persons with breakthrough infection clear the virus more quickly than unvaccinated persons, which leads to a shorter duration of infection. 1 Although data comparing infectivity and transmission are limited, the Centers for Disease Control and Prevention recommends that asymptomatic persons with SARS-CoV -2 exposure who are not fully vaccinated quarantine for at least 5 full days after exposure and then undergo testing.

Second, viral RNA can be detected in nasal specimens for prolonged periods, 2,3 and rapid antigen-based tests may correlate better with replication-competent virus and transmissibility. 4 Although rapid antigen-based tests could be used to monitor viral clearance, the clinical data to support this approach, particularly with regard to early termination of the isolation period, are still being evaluated.

Third, it is appropriate for fully vaccinated, asymptomatic persons who have a low pretest probability of infection and a positive rapid diagnostic test to consider repeat testing. In areas with a low prevalence of SARS-CoV-2 infection, most rapid diagnostic tests have a high negative predictive value but a low positive predictive value. At the minimal Food and Drug Administration criteria for Emergency Use Authorization (80% sensitivity and 98% specificity), SARS-CoV-2 test-positivity rates of 5%, 3%, and 1% correspond to positive predictive values ​​of 68%, 55%, and 29%, respectively. Fortunately, a meta-analysis of rapid diagnostic tests showed high overall specificity (99.6%), even when the tests are used in asymptomatic persons. 5

Paul K. Drain, MD, MPH University of Washington, Seattle, WA [email protected]

Since publication of his article, the author reports no further potential conflict of interest.

This letter was published on April 13, 2022, at NEJM.org.

5 References

1. Kissler SM, Fauver JR, Mack C, et al. Viral dynamics of SARS-CoV-2 variants in vaccinated and unvaccinated persons. N Engl J Med 2021; 385: 2489-2491.

2. Lee S, Kim T, Lee E, et al. Clinical course and molecular viral shedding among asymptomatic and symptomatic patients with SARS-CoV-2 infection in a community treatment center in the Republic of Korea. JAMA Intern Med 2020; 180: 1447-1452.

3. Hay JA, Kissler SM, Fauver JR, et al. Viral dynamics and duration of PCR positivity of the SARS-CoV-2 omicron variant. January 14, 2022 (https://www.medrxiv.org/content/10.1101/2022.01.13.22269257v1). preprint.

4. Pekosz A, Parvu V, Li M, et al. Antigen-based testing but not real-time polymerase chain reaction correlates with severe acute respiratory syndrome coronavirus 2 viral culture. Clin Infect Dis 2021; 73 (9): e2861-e2866.

5. Brümmer LE, Katzenschlager S, Gaeddert M, et al. Accuracy of novel antigen rapid diagnostics for SARS-CoV-2: a living systematic review and meta-analysis. PLoS Med 2021; 18 (8): e1003735-e1003735.

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