Prevalence of Asymptomatic SARS-CoV-2 Infection
Authors: Andrew N. Cohen, Bruce Kessel
Journal: Annals of Internal Medicine (2021)

LettersFebruary 2021Prevalence of Asymptomatic SARS-CoV-2 InfectionFREEAndrew N. Cohen, PhD, Bruce Kessel, MDAndrew N. Cohen, PhDCenter for Research on Aquatic Bioinvasions, Richmond, California, Bruce Kessel, MDJohn A. Burns School of Medicine, University of Hawaii, Honolulu, HawaiiAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L20-1284 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Oran and Topol (1) reviewed 16 studies that provide data on asymptomatic persons who tested positive for SARS-CoV-2 infection by real-time reverse transcriptase polymerase chain reaction (RT-PCR) assays. On the basis of 3 representative studies, they concluded that 40% to 45% of infected persons are asymptomatic. From this, they made several policy recommendations. However, their calculations did not take into account the tests' sensitivity or specificity.We found 20 studies that reported false-negative rates of 0% to 52% (that is, sensitivities of 48% to 100%) using RT-PCR assays for SARS-CoV-2 (2). Though these tests typically have 100% analytical specificity, their clinical specificity—which includes false-positive results due to contamination and other human error—is lower. In a review of 37 large external quality assessments of PCR assays of RNA viruses between 2004 and 2019, false-positive rates ranged from less than 0.6% to 8.1%; a total of 7 external quality assessments of RT-PCR assays for SARS-CoV-2 yielded false-positive rates of less than 0.4% to 0.9%; and 3 studies of RT-PCR assays for SARS-CoV-2 used in clinical settings reported false-positive rates of 0.5% to 3.0% (2). These data show that false-positive rates vary with circumstances and that a low rate in 1 institution, state, or country does not mean that the rate is low everywhere.The 3 representative studies cited by Oran and Topol had positivity rates of 0.8% to 2.0%. With a false-negative rate of 0% to 52%, false positive-rates of 0.3% to 0.9% would yield enough false-positive results to account for all the asymptomatic infected persons reported. In other words, these persons may not actually have been infected.They also may not have been asymptomatic. Oran and Topol note that asymptomatic persons—that is, those who are infected but never develop symptoms—must be distinguished from presymptomatic ones. Doing so requires checking for symptoms over the period of time in which symptoms could potentially appear: the maximum reported incubation period starting from the person's date of infection (if known) or the first positive result on PCR testing. Oran and Topol acknowledge that longitudinal observations were made in only 5 of the 16 studies they reviewed. However, in 4 of those 5 studies, the actual or median observation periods were 2 days (obstetric patients), 7 days (nursing home residents), 0 to approximately 14 days (persons in Italy), and approximately 14 days (Greek evacuees). In contrast, the maximum incubation period for COVID-19 is reported as more than 14 days (3). In the 3 representative studies specifically, there was no effort made to determine symptoms over time (Iceland and Indiana) or the effort was insufficient (Italy).We do not contend that there are no asymptomatic carriers of SARS-CoV-2. Rather, we suggest that the data reviewed do not support the review's conclusion that a large proportion of infected persons are asymptomatic.References1. Oran DP, Topol EJ. Prevalence of asymptomatic SARS-CoV-2 infection. A narrative review. Ann Intern Med. 2020;173:362-7. doi:10.7326/M20-3012 LinkGoogle Scholar2. Cohen AN, Kessel B. False positives in reverse transcription PCR testing for SARS-CoV-2. medRxiv. Preprint posted online 28 September 2020. doi:10.1101/2020.04.26.20080911v4 Google Scholar3. Linton NM, Kobayashi T, Yang Y, et al. Incubation period and other epidemiological characteristics of 2019 novel coronavirus infections with right truncation: a statistical analysis of publicly available case data. J Clin Med. 2020;9. [PMID: 32079150] doi:10.3390/jcm9020538 CrossrefGoogle Scholar Comments 0 Comments Sign In to Submit A Comment Author, Article, and Disclosure InformationAuthors: Andrew N. Cohen, PhD; Bruce Kessel, MDAffiliations: Center for Research on Aquatic Bioinvasions, Richmond, CaliforniaJohn A. Burns School of Medicine, University of Hawaii, Honolulu, HawaiiDisclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L20-1284. 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