Occurrence and transmission potential of asymptomatic and presymptomatic SARS-CoV-2 infections: A living systematic review and meta-analysis

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 presymptomatic?

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 (RT-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% confidence interval [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 presymptomatic could not be summarised, owing to heterogeneity. The secondary attack rate was 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 presymptomatic 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 the database does not include all sources.

Conclusions: The findings of this living systematic review suggest that most people who become infected with SARS-CoV-2 will not remain asymptomatic throughout the course of the infection. The contribution of presymptomatic 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.

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: GS has participated in two scientific meetings for Merck and Biogen. NL is a member of the PLOS Medicine editorial board.

Figures

Fig 1. Forest plot of proportion (‘Prop.’) of people with asymptomatic SARS-CoV-2 infection, stratified by setting.

In the setting 'Contact investigations', in which more than one cluster was reported, clusters are annotated with '[cluster]'. The diamond shows the summary estimate and its 95% CI. The red bar and red text show the prediction interval. CI, confidence interval; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Fig 2. Forest plot of proportion (‘Prop.’) of people with presymptomatic SARS-CoV-2 infection, stratified by setting.

CI, confidence interval; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Fig 3. Forest plot of the RR and 95% CI of the SAR, comparing infections in contacts of asymptomatic and presymptomatic index cases with infections in contacts of symptomatic cases.

The RR is on a logarithmic scale. CI, confidence interval; E, number of secondary transmission events; N, number of close contacts; RR, risk ratio; SAR, secondary attack rate.

Fig 4. Forest plot of proportion (‘Prop.’) of SARS-CoV-2 infection resulting from asymptomatic or presymptomatic transmission.

For studies that report outcomes in multiple settings, these are annotated in brackets. CI, confidence interval; GI, generation interval; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SI, serial interval.