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Repeated Testing in SARS-CoV-2 Infection

      To the Editor:
      In a recently published article in the journal, Challener et al
      • Challener D.W.
      • Shah A.
      • O’Horo J.C.
      • Berbari E.
      • Binnicker M.J.
      • Tande A.J.
      Low utility of repeat real-time PCR testing for SARS-CoV-2 in clinical specimens.
      showed that 2.0% of participants (ie, 22 of 1113) tested positive within 1 week of the first negative nasopharyngeal swab for identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This evidence persuaded the authors to conclude that repeating an identical test in a low-prevalence environment is unlikely to generate added clinical value. However, some important considerations would lead us to disagree with this conclusion.
      The fact that the SARS-CoV-2 identification is directly related to the number of subsequent nasopharyngeal swabs collected is now widely acknowledged. Zhang et al
      • Zhang J.-J.
      • Cao Y.-Y.
      • Dong X.
      • et al.
      Distinct characteristics of COVID-19 patients with initial rRT-PCR-positive and rRT-PCR-negative results for SARS-CoV-2.
      found that 99% diagnostic sensitivity could be achieved after the fourth consecutive specimen collection. This suboptimal accuracy is attributable to a vast number of preanalytical and analytical issues, which have been comprehensively reviewed elsewhere.
      • Lippi G.
      • Simundic A.M.
      • Plebani M.
      Potential preanalytical and analytical vulnerabilities in the laboratory diagnosis of coronavirus disease 2019 (COVID-19).
      Besides these technical aspects, our perception is that a 2% rate of false-negative results on initial testing is not a negligible value and is not reassuring even (or especially) in a low-prevalence environment.
      The underdiagnosis or delayed diagnosis of SARS-CoV-2 infection has been highlighted as an important reason for rapid spread of infection in the community. It has now been clearly established that the viral load of asymptomatic patients, which represent most SARS-CoV-2 infections in low-prevalence areas, is almost identical to that of symptomatic patients.
      • Long Q.-X.
      • Tang X.-J.
      • Shi Q.-L.
      • et al.
      Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections.
      This would imply that underdiagnosing these asymptomatic individuals would lead to a substantial risk of contagion and generation of new local outbreaks, especially in a low-prevalence scenario, where a perception of scarce virus circulation may have attenuated the degree of vigilance (ie, social distancing, use of face masks, quarantine, and so forth). From this perspective, a recent analysis by Li et al
      • Li R.
      • Pei S.
      • Chen B.
      • et al.
      Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV-2).
      highlighted that asymptomatic cases may have been responsible for nearly 80% of SARS-CoV-2 contagions to date, thus further emphasizing the need for timely identification and immediate isolation of positive cases to prevent further spread of the virus. Notably, with an estimated basic reproduction number (ie, R0) of 3.3 for SARS-CoV-2, even a single presymptomatic infected individual may rapidly contribute to infect nearly 270 people within 5 days, which is the typical incubation time of SARS-CoV-2 infection.
      • Alimohamadi Y.
      • Taghdir M.
      • Sepandi M.
      Estimate of the basic reproduction number for COVID-19: a systematic review and meta-analysis.
      Moreover, although we agree that collection of alternative specimens (eg, broncholavage fluid or sputum) may potentially yield higher diagnostic accuracy, it must also be acknowledged that this approach is impractical, or even unfeasible, as a screening strategy for outpatients, especially when these are asymptomatic, presymptomatic, or mildly to moderately symptomatic.
      Unlike what has been concluded by Challener and colleagues, we believe that short-interval repeated collection and testing of nasopharyngeal swabs in individuals with high baseline clinical and environmental risk of being infected by SARS-CoV-2 (eg, those with a high likelihood calculated using the so-called Corona Score)
      • Kurstjens S.
      • van der Horst A.
      • Herpers R.
      • et al.
      Rapid identification of SARS-CoV-2-infected patients at the emergency department using routine testing.
      should be regarded as an essential containment measure.

      References

        • Challener D.W.
        • Shah A.
        • O’Horo J.C.
        • Berbari E.
        • Binnicker M.J.
        • Tande A.J.
        Low utility of repeat real-time PCR testing for SARS-CoV-2 in clinical specimens.
        Mayo Clin Proc. 2020; 00
        • Zhang J.-J.
        • Cao Y.-Y.
        • Dong X.
        • et al.
        Distinct characteristics of COVID-19 patients with initial rRT-PCR-positive and rRT-PCR-negative results for SARS-CoV-2.
        Allergy. 2020; 75: 1809-1812
        • Lippi G.
        • Simundic A.M.
        • Plebani M.
        Potential preanalytical and analytical vulnerabilities in the laboratory diagnosis of coronavirus disease 2019 (COVID-19).
        Clin Chem Lab Med. 2020; 58: 1070-1076
        • Long Q.-X.
        • Tang X.-J.
        • Shi Q.-L.
        • et al.
        Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections.
        Nat Med. 2020; 26: 1200-1204
        • Li R.
        • Pei S.
        • Chen B.
        • et al.
        Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV-2).
        Science. 2020; 368: 489-493
        • Alimohamadi Y.
        • Taghdir M.
        • Sepandi M.
        Estimate of the basic reproduction number for COVID-19: a systematic review and meta-analysis.
        J Prev Med Public Health. 2020; 53: 151-157
        • Kurstjens S.
        • van der Horst A.
        • Herpers R.
        • et al.
        Rapid identification of SARS-CoV-2-infected patients at the emergency department using routine testing.
        ([published online June 29, 2020]. Clin Chem Lab Med)

      Linked Article

      • In Reply—Repeated Testing in SARS-CoV-2 Infection
        Mayo Clinic ProceedingsVol. 95Issue 10
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          We appreciate the points raised by Lippi et al regarding our article describing repeated testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.1 In summary, the authors emphasize that repeated testing may be helpful in improving the negative predictive value of testing and ensuring that cases of COVID-19 are identified. The authors include evidence supporting the conclusion that identification of the SARS-CoV-2 virus is directly related to the number of nasopharyngeal swabs that are collected and also emphasize the importance of case-finding in control of the pandemic.
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      • Low Utility of Repeat Real-Time PCR Testing for SARS-CoV-2 in Clinical Specimens
        Mayo Clinic ProceedingsVol. 95Issue 9
        • Preview
          In a multicenter cohort of 22,315 patients tested for COVID-19, 1676 (7.5%) had repeat testing via real-time polymerase chain reaction following an initial negative test. Of those retested within 7 days of their first negative test, only 2.0% had a positive result. This suggests that repeat testing from the same source is unlikely to provide additional information.
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