Asymptomatic SARS-CoV-2 infections: a living systematic review and meta-analysis

ABSTRACTBACKGROUNDThere 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 FINDINGSWe 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.CONCLUSIONSThe 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.AUTHOR SUMMARYWhy was this study done?▪The proportion of people who will remain asymptomatic throughout the course of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (covid-19), is not known.▪Studies that assess people at just one time point will overestimate the proportion of true asymptomatic infection because those who go on to develop covid-19 symptoms will be wrongly classified as asymptomatic, rather than pre-symptomatic.▪The amount, and infectiousness, of asymptomatic SARS-CoV-2 infection will determine what kind of measures will prevent transmission most effectively.What did the researchers do and find?▪We did a living systematic review through 10 June 2020, using automated workflows that speed up the review processes, and allow the review to be updated when relevant new evidence becomes available.▪Overall, in 79 studies in a range of different settings, 20% (95% confidence interval, CI 17–25%) of people with SARS-CoV-2 infection remained asymptomatic during follow-up, but biases in study designs limit the certainty of this estimate.▪We found some evidence that SARS-CoV-2 infection in contacts of people with asymptomatic infection is less likely than in contacts of people with symptomatic infection (relative risk 0.35, 95% CI 0.10-1.27).What do these findings mean?▪The findings of this living systematic review suggest that most SARS-CoV-2 infections are not asymptomatic throughout the course of infection.▪Future studies should be designed specifically to determine the true proportion of asymptomatic SARS-CoV-2 infections, using methods to minimise biases in the selection of study participants and ascertainment of symptom status during follow up.▪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.Changes from version 2▪Search updated 10.06.2020, total number of included studies increased from 37 to 94▪Protocol updated at https://osf.io/9ewys/▪New analysesReview question 1, prediction intervals added for each study settingMeta-analysis of secondary attack rate from asymptomatic and pre-symptomatic index cases compared with symptomaticSensitivity analysis for review question 1, omitting preprints▪Conclusions unchanged