icles selected at the title and abstract screen were obtained and reviewed for eligibility. The screening process was completed according to a predefined protocol (Supplemental Digital Content 1, http://links.lww.com/INF/E887 ). We included all studies reporting Proportion of asymptomatic persons among all SARS-CoV-2 infected persons. The numerator includes all SARS-CoV-2 positive persons who were asymptomatic. The denominator includes all SARS-CoV-2 positive persons who tested positive. Prevalence of asymptomatic SARS-CoV-2 positive persons among the defined general population. The numerator includes all SARS-CoV-2 positive persons who were asymptomatic. The denominator is the defined study population who were tested for SARS-CoV-2 (e.g., general population in the local community, healthcare workers, patients on hospital admission, nursing home residents). Asymptomatic infection: a person with confirmed SARS-CoV-2 infection, who has no symptoms at the time of screening (including the first clinical assessment or laboratory test) and had no symptoms throughout the follow-up period. We aimed to include all studies enrolling infected individuals who were symptomatic and asymptomatic. At the beginning of the COVID-19 pandemic, respiratory symptoms and fever were considered consistent with symptomatic SARS-CoV-2 infection. As the pandemic evolved, a broader spectrum of clinical manifestations associated with COVID-19 have been recognized such as loss of the senses of smell (anosmia) and taste (ageusia). In some countries, chest imaging has been used to diagnose and monitor the disease for patients without respiratory symptoms. Consequently, some studies defined asymptomatic infection as no clinical symptoms and absence of abnormal chest imaging findings. In this review, we did not limit studies using different definitions of symptomatic disease or asymptomatic infection as absence of these symptoms. We only attempted to exclude patients who were previously asymptomatic 1 , 3 – 21 Previous researchers attempted to synthesize the best available evidence in different age groups such as children, adults and elderly. 5 , 7 , 11 , 13 , 16 None, however, have investigated the proportion of asymptomatic SARS-CoV-2 infections throughout the course of infection by age. This review, therefore, aims to (1) identify, assess and synthesize the evidence on the proportion of people infected with SARS-CoV-2 who were asymptomatic throughout the course of infection, and (2) to estimate asymptomatic proportion by age. The screening process was completed according to a predefined protocol (Supplemental Digital Content 1, http://links.lww.com/INF/E887 ). We included all studies reporting Proportion of asymptomatic persons among all SARS-CoV-2 infected persons. The numerator includes all The denominator is the defined study population who were tested for SARS-CoV-2 (e.g., general population in the local community, healthcare workers, patients on hospital admission, nursing home residents). Asymptomatic infection: a person with confirmed SARS-CoV-2 infection, who has no symptoms at the time of screening (including the first clinical assessment or laboratory test) and had no symptoms throughout the follow-up period. We aimed to include all studies enrolling infected individuals who were symptomatic and asymptomatic. At the beginning of the COVID-19 pandemic, respiratory symptoms and fever were considered consistent with symptomatic SARS-CoV-2 infection. We included all studies aiming to enroll infected individuals who were symptomatic and asymptomatic. We excluded studies that purposely selected SARS-CoV-2 infected cases and did not enroll cases consecutively. We did not exclude any studies enrolling cases in specific study populations, and only excluded studies published in languages other than English. comments, letters, editorials, consensus reports and reviews. studies that did not report any age information (e.g., mean or median age) for asymptomatic infections. studies that clearly stated that the SARS-CoV-2 infected persons were included without any follow up and did not distinguish between asymptomatic and presymptomatic infections. studies that only tested and enrolled asymptomatic persons and mild cases. case studies, case reports and case series with fewer than 20 SARS-CoV-2 infected persons. case studies, case reports and case series that identified SARS-CoV-2 positive persons through contact tracing where only symptomatic persons were tested. serology studies that did not check history of symptoms compatible with SARS-CoV-2 infection and enrolled cases confirmed with SARS-CoV-2 infection by use of IgM only. The predicted asymptomatic proportion peaked (36.2%, 95% CI: 26.0%–46.5%) at 13.5 years of age, then gradually decreased, leveling out in adults 40–50 years old, before dropping to 8.1% (95% CI: 3.4%–12.7%) by 90.5 years (Fig. 2 ). FIGURE 2. Open in a new tab Predicted proportion of asymptomatic SARS-CoV-2 infection by age*. *The size of each circle is proportional to the total number of SARS-CoV-2 positive persons reported in each age group in individual studies, with larger circles indicating a larger sample size. In the sensitivity analysis, 3 studies with a very low or high proportion of asymptomatic infection were excluded to investigate the effect of outliers. Because we attempted to include all studies aiming to enroll infected individuals with or without symptoms, high heterogeneities were found in the studies included in our meta-analysis. Testing and isolation policies, study settings, follow-up period and definition of SARS-CoV-2 infection and asymptomatic cases varied between studies. The study settings ranged from hospital admission to universal screening. COVID-19 disease control policies varied between countries. In some countries such as China and Korea, most infected individuals were hospitalized for treatment or isolation regardless of being symptomatic or asymptomatic.

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 infe 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 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 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 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. Accurate estimates of the proportions of true asymptomatic and presymptomatic infections are needed urgently because their contribution to overall SARS-CoV-2 transmission at the population level will determine the appropriate balance of control measures [ 3 ]. If the predominant route of transmission is from people who have symptoms, then strategies should focus on testing, followed by isolation of infected individuals and quarantine of their contacts. If, however, most transmission is from people without symptoms, social distancing measures that reduce contact with people who might be infectious should be prioritised, enhanced by active case-finding through testing of asymptomatic people. Sources of bias specific to studies in particular settings are discussed with the relevant results. The overall estimate of the proportion of people who become infected with SARS-CoV-2 and remain asymptomatic throughout the course of infection was 20% (95% CI 17%–25%, 79 studies), with a prediction interval of 3%–67% ( Fig 1 ). One statistical modelling study was based on data from all 634 passengers from the Diamond Princess cruise ship with RT-PCR positive test results [ 24 ]. The studies reporting on single-family clusters (21 estimates from 16 studies in China, n = 102 people with SARS-CoV-2) all included at least one asymptomatic person [ 17 , 18 , 21 – 23 , 26 , 44 , 49 , 50 , 70 , 73 – 76 , 85 , 110 ]. The summary estimate was 34% (95% CI 26%–44%, prediction interval 25%–45%). In nine studies that reported on close contacts of infected individuals and aggregated data from clusters of both asymptomatic and symptomatic people with SARS-CoV-2 the summary estimate was 14% (95% CI 8%–23%, prediction interval 2%–53%) [ 36 , 47 , 60 , 62 , 66 , 72 , 105 , 108 , 111 ]. The secondary attack rate from asymptomatic infections may be lower than that from symptomatic infections (relative risk 0.35, 95% CI 0.1–1.27). Modelling studies estimated a wide range of the proportion of all SARS-CoV-2 infections that result from transmission from asymptomatic and presymptomatic individuals. Strengths and weaknesses A strength of this review is that we used clear definitions and separated review questions to distinguish between SARS-CoV-2 infections that remain asymptomatic throughout their course from those that become symptomatic and to separate proportions of people with infection from their contribution to transmission in a population. Since all people infected with SARS-CoV-2 are initially asymptomatic, the proportion that Age might play a role as children appear more likely than adults to have an asymptomatic course of infection ( Fig 1 ) [ 126 ]; age was poorly reported in studies included in this review ( Table 1 ). SARS-CoV-2 transmission from people who are either asymptomatic or presymptomatic has implications for prevention. Social distancing measures will need to be sustained at some level because droplet transmission from close contact with people with asymptomatic and presymptomatic infection occurs. Easing of restrictions will, however, only be possible with wide access to testing, contact tracing, and rapid isolation of infected individuals.

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 updated a living systematic review to address 3 questions: (1) Among 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 10.1371/journal.pmed.1003987 10.1371/journal.pmed.1003987 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 updated a living systematic review to address 3 questions: (1) Among 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? In 46 studies based on contact or outbreak investigations, the summary proportion asymptomatic was 19% (95% confidence interval (CI) 15% to 25%, prediction interval 2% to 70%). (2) The secondary attack rate in contacts of people with asymptomatic infection compared with symptomatic infection was 0.32 (95% CI 0.16 to 0.64, prediction interval 0.11 to 0.95, 8 studies). (3) In 13 modelling studies fit to data, the proportion of all SARS-CoV-2 transmission from presymptomatic individuals was higher than from asymptomatic individuals. Review protocol Open Science Framework ( https://osf.io/9ewys/ ) Diana Buitrago-Garcia and co-workers update a living systematic review and meta-analysis on occurrence and transmission of asymptomatic SARS-CoV-2 infections. Author summary Why 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 debated. Outbreaks COVID-19 Data Availability All data and code used to display and synthesise the results are available at https://github.com/leonieheron/LSR_Asymp_v5 . Introduction There is ongoing debate about the true proportion of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection that remains asymptomatic [ 1 ]. A well-recognised source of overestimation arises when people without symptoms at the time of testing are reported as having asymptomatic infection, with such cross-sectional studies often reporting percentages of 80% or more [ 2 , 3 ]. In this fifth version of our living systematic review [ 21 ], we aimed to improve and understand the changing evidence over time for 3 review questions: (1) Among 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 people with asymptomatic and presymptomatic, compared with symptomatic SARS-CoV-2 infection? (3) What proportion of SARS-CoV-2 transmission is accounted for by people who are either asymptomatic throughout infection or presymptomatic? To compare our findings with other studies, we extracted the raw data from 5 systematic reviews [ 11 , 13 – 16 ] and calculated prediction intervals [ 17 ]. For review question 2, as a measure of infectiousness, we calculated the secondary attack rate as the number of SARS-CoV-2-infected contacts as a proportion of all close contacts ascertained. For each included study, we compared the secondary attack rate from asymptomatic or presymptomatic index cases with that from symptomatic cases in the same study. If there were no events in a group, we added 0.5 to each cell in the 2 × 2 table. The RR is on a logarithmic scale. The diamonds show the summary estimate and its 95% CI. The red bar shows the prediction interval. CI, confidence interval; E, number of secondary transmission events; N, number of close contacts; RR, risk ratio; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; Symp., symptomatic individuals. Contribution of asymptomatic and presymptomatic infection to SARS-CoV-2 transmission We included 13 mathematical modelling studies ( Fig 3 and S5 Table ) [ 7 , 165 , 169 – 179 ]. Comparison with other reviews and interpretation The type of studies that provide estimates of the proportion of asymptomatic SARS-CoV-2 infections and heterogeneity between them has changed over the course of the pandemic. In our living systematic review, the prediction interval has widened from 23% to 37% in studies published up to 25 March 2020 [ 23 ], to 3% to 67% up to June 2020 [ 12 ], 2% to 89% up to 2 February 2021 [ 21 ] and remains at 2% to 90% up to 6 July. We found 3 systematic reviews, in which authors reported In particular, we expected that studies that detect SARS-CoV-2 through screening of defined populations and follow up of those infected would be less affected by biases in study methodology [ 30 ] and would provide a more accurate estimate of persistently asymptomatic SARS-CoV-2, which should be influenced mainly by properties of the virus and the host response to infection [ 182 ]. Study design was the factor that explained the largest proportion of variability in this review ( S2 Appendix ). In meta-analyses of 2 proportions, the direct comparison within studies reduces heterogeneity and is less biased [ 34 ]. Since SARS-CoV-2 can be transmitted a few days before the onset of symptoms [ 185 ], presymptomatic transmission likely contributes substantially to overall SARS-CoV-2 epidemics. If both the proportion and transmissibility of asymptomatic infection are relatively low, people with asymptomatic SARS-CoV-2 infection should account for a smaller proportion of overall transmission than presymptomatic individuals.

Asymptomatic cases of SARS-CoV-2 can be unknown carriers magnifying the transmission of COVID-19. This study appraised the frequency of asymptomatic individuals and estimated occurrence by age group and gender by reviewing the existing published data on asymptomatic people with COVID-19. Three electronic databases, PubMed, Embase, and Web of Science (WoS), were used to search the literature following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). The study population for this review included asymptomatic individuals infected with SARS-CoV-2 reported in original articles published up to 30 April 2020. A random effects model was applied to analyze pooled data on the prevalence of asymptomatic cases among all COVID-19 patients and also by age and gender. From the meta-analysis of 16 studies, comprising 2,788 SARS-CoV-2 infected patients, the pooled prevalence according to the random effect size of asymptomatic cases was 48.2% (95% CI, 30-67%). Of the asymptomatic cases, 55.5% (95% CI, 43.6-66.8%) were female and 49.6% (95% CI, 20.5-79.1%) were children. Children and females were more likely to present as asymptomatic COVID-19 cases and could act as unknown carriers of SARS-CoV-2. Symptom-based screening might fail to identify all SARS-CoV-2 infections escalating the threat of global spread and impeding containment. Therefore, a mass surveillance system to track asymptomatic cases is critical, with special attention to females and children. This study appraised the frequency of asymptomatic individuals and estimated occurrence by age group and gender by reviewing the existing published data on asymptomatic people with COVID-19. Three electronic databases, PubMed, Embase, and Web of Science (WoS), were used to search the literature following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). The study population for this review included asymptomatic individuals infected with SARS-CoV-2 reported in original articles published up to 30 April 2020. Study ID Study period Country of study Total number of confirmed cases of COVID-19 Asymptomatic cases among confirmed cases [ N (%)] 1 ( 25 ) April 2020 Homeless Shelter in Boston, USA 147 129 (87.8%) 2 ( 26 ) January 16 to February 8, 2020 China 728 Kendall's tau with continuity correction in the Begg and Mazumdar rank Correlation [ p (2-tailed) = 0.0884] and Egger's regression intercept [ p (2-tailed) = 0.7472] were insignificant. ( Supplementary Table 4 ). Discussion The pooled prevalence of asymptomatic cases of COVID-19 from this meta-analysis of 2,788 infected patients was 48.2% as estimated by random effect size. In a case series of 78 patients from 26 transmission clusters in Wuhan, China, a similar estimate (42.3%) of asymptomatic carriers in SARS-CoV-2 infected individuals was reported ( 22 ). However, considering the basic reproduction number ( R 0 ) of 2.5, a slightly lower asymptomatic SARS-CoV-2 infection rate of 35% was estimated by the US Centers for Disease Control and Prevention (CDC) ( 47 ). This indicates a large number of asymptomatic cases of COVID-19 are in the community seeding potential outbreaks which requires vigilant control strategies to prevent future outbreaks. Thus, mask wearing, hand washing, physical distancing, and extensive testing, followed by quarantine of infected asymptomatic individuals, are essential to contain the rapid spread of SARS-CoV-2 locally and globally ( 48 ). Due to the high prevalence of asymptomatic cases, it is important to seek reasons for SARS-CoV-2 infection in people without visible symptoms ( 49 ). Some studies have highlighted that the cross-reactive T-cell response with exposure to other coronaviruses might have contributed to the asymptomatic phenotype in SARS-CoV-2 infected individuals ( 50 – 53 ). This is supported by the 67% homology in the sequences of epitope between common cold coronaviruses and SARS-CoV-2, and an increased number of CD4+ T cells in asymptomatic patients compared to symptomatic patients ( 54 , 55 ). However, children often experience numerous viral infections, and their repeated viral exposure is anticipated to aid their immune response to SARS-CoV-2 ( 76 ). Meanwhile, elderly people with a weakened immune system ( 77 , 78 ) are less likely to be asymptomatic carriers. In contrast, adults who most likely have a stronger immune system can be infected and remain asymptomatic carriers ( 79 ). However, a detailed mechanism for the differences in asymptomatic manifestation of SARS-CoV-2 among these three age groups (children, adults and the elderly) is yet to be explored. A recent review reported that as the surveillance and contact tracing of MERS progressed over time, the rate of asymptomatic MERS infected patients increased to 28.6% ( 60 ). The increase in asymptomatic infection of MERS was inversely proportional to the case fatality rate ( 82 ). This clearly demonstrates the importance of mass surveillance and contact tracing in the detection of asymptomatic SARS-CoV-2 infected individuals in the community and hospitals to reduce the disease fatality rate and dissemination of COVID-19. Transmission of COVID-19 by asymptomatic people is the weakness of COVID-19 control and prevention strategies ( 17 ). However, in general, asymptomatic infections can occur in any age range and either gender. As asymptomatic carriers play a critical role in the spread of the COVID-19 pandemic, understanding the actual prevalence of asymptomatic cases is important for setting control measures in both the community and health care centers. The high prevalence of asymptomatic COVID-19 cases suggests that screening based only on symptoms might fail to identify a large proportion of SARS-CoV-2 infections, escalating the threat of rapid spread. Thus, mask wearing, extensive testing for identification, and the quarantine of infected asymptomatic individuals are essential to curb this pandemic.

Asymptomatic infections are actually 'healthy' people