View ORCID ProfileDiana C Buitrago-Garcia, View ORCID ProfileDianne Egli-Gany, View ORCID ProfileMichel J Counotte, View ORCID ProfileStefanie Hossmann, View ORCID ProfileHira Imeri, View ORCID ProfileAziz Mert Ipekci, View ORCID ProfileGeorgia Salanti, View ORCID ProfileNicola Low
doi: https://doi.org/10.1101/2020.04.25.20079103
Abstract
BACKGROUND There is disagreement about the level of asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We conducted a living systematic review and meta-analysis to address three questions: 1. amongst people who become infected with SARS-CoV-2, what proportion does not experience symptoms at all during their infection? 2. Amongst people with SARS-CoV-2 infection who are asymptomatic when diagnosed, what proportion will develop symptoms later? 3. What proportion of SARS-CoV-2 transmission is accounted for by people who are either asymptomatic throughout infection, or pre-symptomatic? METHODS AND FINDINGS We searched PubMed, Embase, bioRxiv and medRxiv using a database of SARS-CoV-2 literature that is updated daily, on 25 March 2020, 20 April 2020 and 10 June 2020. Studies of people with SARS-CoV-2 diagnosed by reverse transcriptase PCR that documented follow-up and symptom status at the beginning and end of follow-up, or modelling studies were included. One reviewer extracted data and a second verified the extraction, with disagreement resolved by discussion or a third reviewer. Risk of bias in empirical studies was assessed with an adapted checklist for case series and the relevance and credibility of modelling studies were assessed using a published checklist. We included a total of 94 studies. The overall estimate of the proportion of people who become infected with SARS-CoV-2 and remain asymptomatic throughout infection was 20% (95% CI 17-25) with a prediction interval of 3-67% in 79 studies that addressed this review question. There was some evidence that biases in the selection of participants influence the estimate. In seven studies of defined populations screened for SARS-CoV-2 and then followed, 31% (95% CI 26-37%, prediction interval 24-38%) remained asymptomatic. The proportion of people that is pre-symptomatic could not be summarised, owing to heterogeneity. The secondary attack rate was slightly lower in contacts of people with asymptomatic infection than those with symptomatic infection (relative risk 0.35, 95% CI 0.10-1.27). Modelling studies fit to data found a higher proportion of all SARS-CoV-2 infections resulting from transmission from pre-symptomatic individuals than from asymptomatic individuals. Limitations of the review include that most included studies were not designed to estimate the proportion of asymptomatic SARS-CoV-2 infections and were at risk of selection biases, we did not consider the possible impact of false negative RT-PCR results, which would underestimate the proportion of asymptomatic infections, and that the database does not include all sources. CONCLUSIONS The findings of this living systematic review of publications early in the pandemic suggest that most SARS-CoV-2 infections are not asymptomatic throughout the course of infection. The contribution of pre-symptomatic and asymptomatic infections to overall SARS-CoV-2 transmission means that combination prevention measures, with enhanced hand hygiene, masks, testing tracing and isolation strategies and social distancing, will continue to be needed.
Competing Interest Statement
All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf and declare: GS has participated in two scientific meetings for Merck and Biogen. NL discloses support from the Swiss National Science Foundation and the European Union Horizon 2020 research and innovation programme. All other authors declare no competing interests, or activities that could appear to have influenced the submitted work.
Clinical Protocols
Funding Statement
Swiss National Science Foundation, project number 320030_176233; European Union Horizon 2020 research and innovation programme, project EpiPose (No 101003688).
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