False-negative results of initial RT-PCR assays for COVID-19: A systematic review

Ingrid Arevalo-rodriguez, Diana Buitrago- García, Daniel Simancas- Racines, Paula Zambrano- Achig, Rosa del Campo, Agustin Ciapponi, Omar Sued, Laura Martinez-Garcıa, Anne W S Rutjes, Nicola Low, Patrick M. Bossuyt, Jose A Perez- Molina, Javier Zamora

Research output: Contribution to journalArticlepeer-review


A false-negative case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is defined as a person with suspected infection and an initial negative result by reverse transcription-polymerase chain reaction (RT-PCR) test, with a positive result on a subsequent test. False-negative cases have important implications for isolation and risk of transmission of infected people and for the management of coronavirus disease 2019 (COVID-19). We aimed to review and critically appraise evidence about the rate of RT-PCR false-negatives at initial testing for COVID-19.
We searched MEDLINE, EMBASE, LILACS, as well as COVID-19 repositories, including the EPPI-Centre living systematic map of evidence about COVID-19 and the Coronavirus Open Access Project living evidence database. Two authors independently screened and selected studies according to the eligibility criteria and collected data from the included studies. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. We calculated the proportion of false-negative test results using a multilevel mixed-effect logistic regression model. The certainty of the evidence about false-negative cases was rated using the GRADE approach for tests and strategies. All information in this article is current up to July 17, 2020.
PLOS ONE | https://doi.org/10.1371/journal.pone.0242958 December 10, 2020 1 / 19
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Citation:Arevalo-Rodriguez I, Buitrago-Garcia D, Simancas-Racines D, Zambrano-Achig P, Del Campo R, Ciapponi A, et al. (2020) False-negative results of initial RT-PCRassays for COVID-19:A systematic review. PLoSONE 15(12): e0242958. https://doi.org/10.1371/journal.pone.0242958
Editor:Daniela Flavia Hozbor, Universidad Nacional de la Plata, ARGENTINA
Received:May 14, 2020
Accepted:November 12, 2020
Published:December10, 2020 Copyright:©2020 Arevalo-Rodriguez et al. This is an open access article distributed under the terms of the Creative CommonsAttribution License, which permitsunrestricted use, distribution, and reproductionin any medium,provided the original author and source are credited.
Data AvailabilityStatement:All relevant data are within the manuscript and its Supporting informationfiles.
Funding:The author(s) receivedno specific fundingfor this work.
Competinginterests: The authorshave declared that no competing interests exist.
We included 34 studies enrolling 12,057 COVID-19 confirmed cases. All studies were affected by several risks of bias and applicability concerns. The pooled estimate of falsenegative proportion was highly affected by unexplained heterogeneity (tau-squared = 1.39; 90% prediction interval from 0.02 to 0.54). The certainty of the evidence was judged as very low due to the risk of bias, indirectness, and inconsistency issues.
There is substantial and largely unexplained heterogeneity in the proportion of false-negative RT-PCR results. The collected evidence has several limitations, including risk of bias issues, high heterogeneity, and concerns about its applicability. Nonetheless, our findings reinforce the need for repeated testing in patients with suspicion of SARS-Cov-2 infection given that up to 54% of COVID-19 patients may have an initial false-negative RT-PCR (very low certainty of evidence).
Systematic review registration
Protocol available on the OSF website: https://tinyurl.com/vvbgqya.
Original languageEnglish
JournalPLOS One
Publication statusPublished - 10 Dec 2020


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