Prevalence of Asymptomatic SARS-CoV-2 Infection
Authors: Daniel P. Oran, Eric J. Topol
Journal: Annals of Internal Medicine (2021)

LettersFebruary 2021Prevalence of Asymptomatic SARS-CoV-2 InfectionFREEDaniel P. Oran, AM, Eric J. Topol, MDDaniel P. Oran, AMScripps Research Translational Institute, Scripps Research La Jolla, CaliforniaSearch for more papers by this author, Eric J. Topol, MDScripps Research Translational Institute, Scripps Research La Jolla, CaliforniaSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L20-1285 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:In our view, Dr. Halperin does not fairly characterize the evidence of asymptomatic transmission presented by Lavezzo and colleagues (1) concerning their research in Vo’, Italy. Lavezzo and colleagues state, “The presence of a significant number of asymptomatic SARS-CoV-2 infections raises questions about their ability to transmit the virus. To address this issue, we conducted an extensive contact tracing analysis of the 8 new infections.” After describing the various contacts of the infected persons, Lavezzo and colleagues conclude, “These results suggest that asymptomatic infections may play a key role in the transmission of SARS-CoV-2.”The following is the complete sentence from our review cited by Dr. Halperin: “The early data that we have assembled on the prevalence of asymptomatic SARS-CoV-2 infection suggest that this is a significant factor in the rapid progression of the COVID-19 pandemic.” From our perspective, it seems that Dr. Halperin has inferred a far more extreme interpretation than our actual words are meant to convey. We stress that the data are early, not definitive. We describe them as suggestive, not conclusive.We are puzzled by the critique of Dr. Cevik and associates. In the opening paragraphs of our review, we clearly state that most of the data sets were cross-sectional in nature. In our table, we took care in labeling the minority of data sets that included longitudinal data. We also clearly explained the ambiguity surrounding asymptomatic versus presymptomatic status.The “systematic review” preprint (2) that Dr. Cevik and associates cite appeared after our article was published. In our opinion, this review fails to adequately address the compelling study that it included from Vo’, Italy, which we also included. Not only does this study contain a large representative sample with longitudinal data, but its findings are supported by other data sets that we included. The study was completed over 14 days, and the investigators concluded that the proportion of asymptomatic persons was 42.2%. In addition, none of the participants who was asymptomatic at the beginning of the study had developed symptoms by the end.None of the sources cited by Drs. Han and Li present data that were collected from representative samples. In contrast, 3 of the studies that we included in our review are the result of representative samples, and 1 of these has the added benefit of longitudinal data from a 14-day period. We were impressed by the narrow range reported in these studies for the proportion of asymptomatic infected persons: between 42.2% and 44.8%. However, in the absence of longitudinal data for 2 of these studies and because of the resulting uncertainty concerning the possible admixture of presymptomatic persons, we suggested that 30% is a conservative estimate.Drs. Cohen and Kessel are concerned about a potentially high false-positive rate for RT-PCR testing for SARS-CoV-2. Large-scale testing programs in China would seem to be instructive. Between 14 May and 1 June 2020 in Wuhan, public health officials tested 9 899 828 persons, which represented 92.9% of those older than 6 years (3); a total of 300 persons received positive results. In October 2020 in Qingdao, 10.9 million persons were tested (4); of these, 9 persons received positive results.Even if one were to assume that all of these positive test results were erroneous, that would mean that, as a fraction of total tests performed, 0.003% of the tests in Wuhan and 0.00008% of those in Qingdao were false-positives. This real-world evidence seems to be at odds with the studies cited by Drs. Cohen and Kessel, which are based on considerably smaller data sets. Clearly, more research is needed on this topic.We assembled the data in our review in April and May 2020, beginning approximately 3 months after the first reports of illness caused by a novel coronavirus. Our review, which was published on 3 June, was our best effort to present and interpret those early data. We believe that it scrupulously adheres to the principles of “accurate reporting, prudence, and restraint” suggested by Dr. Elder.Like so much else associated with SARS-CoV-2, the finer points of infectiousness and asymptomatic transmission are still, as of this writing in October 2020, hardly settled matters. According to the Centers for Disease Control and Prevention, “Recovery of replication-competent virus between 10 and 20 days after symptom onset has been documented in some persons with severe COVID-19 that, in some cases, was complicated by immunocompromised state” (5). An analysis of the outbreak aboard the Diamond Princess cruise ship concluded, “Asymptomatic individuals were the source for 69% (20-85%) of all infections” (6).References1. Lavezzo E, Franchin E, Ciavarella C, et al. Suppression of COVID-19 outbreak in the municipality of Vo’, Italy. medRxiv. Preprint posted online 18 April 2020. doi:10.1101/2020.04.17.20053157 Google Scholar2. Buitrago-Garcia DC, Egli-Gany D, Counotte MJ, et al. The role of asymptomatic SARS-CoV-2 infections: rapid living systematic review and meta-analysis. medRxiv. Preprint posted online 28 July 2020. doi:10.1101/2020.04.25.20079103 Google Scholar3. Cao S, Gan Y, Wang C, et al. Post-lockdown SARS-CoV-2 nucleic acid screening in nearly ten million residents of Wuhan, China. Nat Commun. 2020;11:5917. [PMID: 33219229] doi:10.1038/s41467-020-19802-w CrossrefMedlineGoogle Scholar4. Xing Y, Wong GWK, Ni W, et al. Rapid response to an outbreak in Qingdao, China [Letter]. N Engl J Med. 2020;383:e129. [PMID: 33207089] doi:10.1056/NEJMc2032361 CrossrefMedlineGoogle Scholar5. Centers for Disease Control and Prevention. Duration of isolation and precautions for adults with COVID-19. 10 September 2020. Accessed at www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.html on 8 October 2020. Google Scholar6. Emery JC, Russell TW, Liu Y, et al; CMMID COVID-19 Working Group. The contribution of asymptomatic SARS-CoV-2 infections to transmission on the Diamond Princess cruise ship. Elife. 2020;9. [PMID: 32831176] doi:10.7554/eLife.58699 CrossrefMedlineGoogle Scholar Comments 0 Comments Sign In to Submit A Comment Author, Article, and Disclosure InformationAuthors: Daniel P. Oran, AM; Eric J. Topol, MDAffiliations: Scripps Research Translational Institute, Scripps Research La Jolla, CaliforniaDisclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-3012. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoPrevalence of Asymptomatic SARS-CoV-2 Infection Daniel P. Oran and Eric J. Topol Prevalence of Asymptomatic SARS-CoV-2 Infection Muge Cevik , Isaac I. Bogoch , Gail Carson , Eric D’Ortenzio , Krutika Kuppalli Prevalence of Asymptomatic SARS-CoV-2 Infection Andrew N. Cohen , Bruce Kessel Prevalence of Asymptomatic SARS-CoV-2 Infection Daniel T. Halperin Prevalence of Asymptomatic SARS-CoV-2 Infection N. 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Sax, MDAsymptomatic Cases, the Hidden Challenge in Predicting COVID-19 Caseload IncreasesComparison of forehead temperature screening with infra-red thermometer and thermal imaging scannerPitfall of Universal Pre-Admission Screening for SARS-CoV-2 in a Low Prevalence CountryEven vaccinated against COVID-19, we must continue to wear a maskExecutive summary: It's wrong not to test: The case for universal, frequent rapid COVID-19 testingTransmission of SARS-CoV2 and Strategies for Control of Infection: Lessons LearntAsymptomatic COVID-19 transmission: the importance of avoiding official miscommunication February 2021Volume 174, Issue 2 Page: 286-287 Keywords Conflicts of interest COVID-19 Disclosure Factor analysis Longitudinal studies Prevention, policy, and public health Reverse transcriptase polymerase chain reaction Systematic reviews ePublished: 16 February 2021 Issue Published: February 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. 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