Researchers conduct a living systematic review and meta-analysis on asymptomatic and pre-symptomatic SARS-CoV-2

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) related studies have been carried out since its emergence, the debate about the proportion of asymptomatic infections continues.

Previous studies have been found to either overestimate or underestimate the proportion of asymptomatic infections even when the patients are adequately followed-up.

An accurate estimation of the proportion of asymptomatic and pre-symptomatic infections is required for the determination of the balance and range of control measures. Previous systematic reviews reported high heterogeneity in the estimation of the proportion of asymptomatic and pre-symptomatic infections that may either be due to study difference or chance.

A new study published in the pre-print server medRxiv* aimed to understand and improve the changing evidence over time for three important review questions using a living systematic review.

The three questions were 1) What proportion of people infected with SARS-CoV-2 do not develop symptoms at all during infection? 2) What is the infectiousness of asymptomatic and pre-symptomatic individuals as compared to symptomatic individuals? 3) What proportion of SARS-CoV-2 transmission is caused by asymptomatic or pre-symptomatic individuals?

About the study

The study involved a live systematic review where the first research began on 25th March 2020 and was updated on 20th April 2020, 10th June 2020, and 2nd February 2021. Studies on asymptomatic and pre-symptomatic SARS-CoV-2 infections were identified with the help of a search string of medical subject headings and free-text keywords from four electronic databases (Medline, PubMed, Ovid Embase, bioRxiv, and medRxiv).

The studies could be in any language and included investigation of the symptom status for people who were diagnosed with SARS-CoV-2 by RT-PCR as well as contribution to SARS-CoV-2 transmission by asymptomatic or pre-symptomatic individuals. It also included cohort studies, contact tracing and outbreak investigations, case-control studies, and mathematical modeling studies. Studies that reported the proportion of only pre-symptomatic SARS-CoV-2 and those that dealt with mainly on people with symptoms were excluded.

Thereafter, data was extracted from the selected studies by reviewers. The extracted variables included study setting, study design, population, country and/or region, sex, age, length of follow-up, and primary outcomes. Finally, a tool was developed for the assessment of the risk of bias in the studies.

Findings

The results reported that the current study included a total of 107 selected studies out of which 94 estimated the proportion of people with asymptomatic SARS-CoV-2 infections, 5 reported secondary attacks and 11 reported contributions of asymptomatic or pre-symptomatic infection to SARS-CoV-2 transmission. Moreover, out of all the selected studies, 86 followed-up participants for seven days or more, 27 followed up until they had at least one negative RT-PCR test, 19 followed-up participants for at least 14 days after a known exposure, and 29 involved more than one method of follow-up.

The results indicated that most of the studies involved adults belonging to various age groups. Also, two types of study designs were generated, screening studies and contact and outbreak investigations. It was found that for contact and outbreak investigations the interquartile range (IQR) was 8-35 percent and the prediction interval from random-effects meta-analysis was 3-64 percent while for screening studies the IQR was 18-59 percent and prediction interval was 3-95 percent.

The contact and outbreak investigations were found to be associated with a significant risk of bias while screening studies were found to be associated with a low risk of bias. Furthermore, the estimated proportions with asymptomatic infection were found to be very similar to the overall estimates when restricted studies with more than ten SARS-CoV-2 infected people.

The risk ratio for secondary attack from asymptomatic to symptomatic infections was found to be 0.43 while from pre-symptomatic to symptomatic infections was found to be 0.71. Furthermore, the contribution of asymptomatic infection to SARS-CoV-2 transmission was found to be less than 10 percent while the contribution of pre-symptomatic infection was found to be 40 percent or higher.

The current study, therefore, indicated that the percentage of individuals with asymptomatic SARS-CoV-2 infection was quite low. Also, mostly half of all transmission was found to occur even before the symptoms develop. However, physical distancing measures and mask-wearing can prevent transmission from asymptomatic and presymptomatic individuals. The emergence of the Omicron variant whose clinical characteristics are not yet known along with vaccination can make the studying of asymptomatic infections more complicated. Further studies and systematic reviews must be carried out to know more about the effects of both variants of concern and vaccines on asymptomatic and pre-symptomatic SARS-CoV-2 infections.

Limitations

The study has certain limitations. First, the study only included published studies up to 2nd February 2021. Second, the pace of SARS-CoV-2 related publications exceeded the capacity of the reviewers. Third, although the number of studies is high, the yield is low. Fourth, the four databases involved in the study were not comprehensive. Fifth, the study did not consider the possible impact of false-negative RT-PCR results. Finally, no published studies on people infected with SARS-CoV-2 variants of concern or vaccination were found.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Suchandrima Bhowmik

Suchandrima has a Bachelor of Science (B.Sc.) degree in Microbiology and a Master of Science (M.Sc.) degree in Microbiology from the University of Calcutta, India. The study of health and diseases was always very important to her. In addition to Microbiology, she also gained extensive knowledge in Biochemistry, Immunology, Medical Microbiology, Metabolism, and Biotechnology as part of her master's degree.