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

BACKGROUND Debate about the level of asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues. The amount of evidence is increasing and study designs have changed over time. We conducted a living systematic review 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) What is the infectiousness of asymptomatic and presymptomatic, compared with symptomatic, SARS-CoV-2 infection? (3) What proportion of SARS-CoV-2 transmission in a population is accounted for by people who are asymptomatic or presymptomatic? METHODS AND FINDINGS The protocol was first published on 1 April 2020 and last updated on 18 June 2020. We searched PubMed, Embase, bioRxiv and medRxiv, aggregated in a database of SARS-CoV-2 literature, most recently on 2 February 2021. Studies of people with PCR-diagnosed SARS-CoV-2, which documented symptom status at the beginning and end of follow-up, or mathematical modelling studies were included. Studies restricted to people already diagnosed, of single individuals or families, or without sufficient follow-up were excluded. 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 a bespoke checklist and modelling studies with a published checklist. All data syntheses were done using random effects models. Review question (1): We included 94 studies. Heterogeneity was high and we could not reliably estimate values for the proportion of asymptomatic infections overall (interquartile range 13-45%, prediction interval 2-89%), or in studies based on screening of defined populations (interquartile range 18-59%, prediction interval 3-95%). In screening studies at low risk of information bias, the prediction interval was 4-69% (summary proportion 23%, 95% CI 14-35%). In 40 studies based on contact or outbreak investigations, the summary proportion asymptomatic was 18% (95% CI 14-24%, prediction interval 3-64%) and, in studies at low risk of selection bias, 25% (95% CI 18-33%, prediction interval 5-66%). (2) The secondary attack rate in contacts of people with asymptomatic infection compared with symptomatic infection was 0.43 (95% CI 0.05-3.44, 5 studies). (3) In 11 modelling studies fit to data, the proportion of all SARS-CoV-2 transmission from presymptomatic individuals was higher than from asymptomatic individuals. Limitations of the evidence include high heterogeneity in studies that were not designed to measure persistently asymptomatic infection, high risks of selection and information bias, and the absence of studies about variants of concern or in people who have been vaccinated. CONCLUSIONS This review does not provide a summary estimate of the proportion of asymptomatic SARS-CoV-2 across all study designs. In studies based on contact and outbreak investigation, most SARS-CoV-2 infections were not persistently asymptomatic. Summary estimates from meta-analysis may be misleading when variability between studies is extreme. Without prospective longitudinal studies with methods that minimise selection and measurement biases, further updates with the study types included in this living systematic review are unlikely to be able to provide a reliable summary estimate of the proportion of asymptomatic infections caused by wild-type SARS-CoV-2.