key: cord-0727911-od6zj47a
authors: Koh, W. C.; Naing, L.; Rosledzana, M. A.; Alikhan, M. F.; Chaw, L.; Griffith, M.; Pastore, R.; Wong, J.
title: What do we know about SARS-CoV-2 transmission? A systematic review and meta-analysis of the secondary attack rate, serial interval, and asymptomatic infection
date: 2020-05-23
journal: nan
DOI: 10.1101/2020.05.21.20108746
sha: 71e70b5653d6340dd4872d069c63efa228ec4a5e
doc_id: 727911
cord_uid: od6zj47a

Background Current SARS-CoV-2 containment measures rely on the capacity to control person-to-person viral transmission. Effective prioritization of these measures can be determined by understanding SARS-CoV-2 transmission dynamics. We conducted a systematic review and meta-analyses of three parameters: (i) secondary attack rate (SAR) in various settings, (ii) clinical onset serial interval (SI), and (iii) the proportion of asymptomatic infection. Methods and Findings We searched PubMed, medRxiv, and bioRxiv databases between January 1, 2020, and May 15, 2020, for articles describing SARS-CoV-2 attack rate, SI, and asymptomatic infection. Studies were included if they presented original data for estimating point estimates and 95% confidence intervals of the three parameters. Random effects models were constructed to pool SAR, mean SI, and asymptomatic proportion. Risk ratios were used to examine differences in transmission risk by setting, type of contact, and symptom status of the index case. Publication and related bias were assessed by funnel plots and Egger's meta-regression test for small-study effects. Our search strategy for SAR, SI, and asymptomatic infection identified 459, 572, and 1624 studies respectively. Of these, 20 studies met the inclusion criteria for SAR, 18 studies for SI, and 66 studies for asymptomatic infection. We estimated the pooled household SAR at 15.4% (95% CI: 12.2%, 18.7%) compared to 4.0% (95% CI: 2.8%, 5.2%) in non-household settings. We observed variation across settings; however, the small number of studies limited power to detect associations and sources of heterogeneity. SAR of symptomatic index cases is significantly higher than cases that were symptom-free at diagnosis (RR 2.55, 95% CI: 1.47, 4.45). Adults appear to be more susceptible to transmission than children (RR 1.40, 95% CI: 1.00, 1.96). The pooled mean SI is estimated at 4.87 days (95% CI: 3.98, 5.77). The pooled proportion of cases who had no symptoms at diagnosis is 25.9% (95% CI: 18.8%, 33.1%). Conclusions Based our pooled estimates, 10 infected symptomatic persons living with 100 contacts would result in 15 additional cases in <5 days. To be effective, quarantine of contacts should occur within 3 days of symptom onset. If testing and tracing relies on symptoms, one-quarter of cases would be missed. As such, while aggressive contact tracing strategies may be appropriate early in an outbreak, as it progresses, control measures should transition to account for SAR variability across settings. Targeted strategies focusing on high-density enclosed settings may be effective without overly restricting social movement.

The ongoing pandemic caused by SARS-CoV-2 continues to escalate. Modeling studies have enhanced understanding of COVID-19 transmission dynamics and initial phylogenetic analysis of closely related viruses suggest highly linked person-to-person spread of SARS-CoV-2 originating from mid-November to early December 2019 (1) (2) (3) .

There are no known effective therapeutics or vaccines (4, 5) . As such, containment measures rely on the capacity to control viral transmission from person-to-person, such as case isolation, contact tracing and quarantine, and physical distancing (6) . Effective prioritization of these measures can be determined by understanding SARS-CoV-2 transmission patterns.

There is an abundance of literature on the biological mode of transmission of coronaviruses: through exhaled droplets, aerosol at close proximity, fomites, and possibly through fecal-oral contamination (7, 8) . However, few observational studies have assessed transmission patterns in populations, and what determines whether the infection is contained or spreads. Previous theoretical work by Fraser et al. proposed three transmission-related criteria that impact on outbreak control: (i) viral transmissibility; (ii) disease generation time; and (iii) the proportion of transmission occurring prior to symptoms (9) .

To better understand SARS-CoV-2 transmission, we conducted a systematic review and meta-analyses of these three parameters. Using publicly available articles, we estimated the (i) secondary attack rate (SAR) in various settings, (ii) clinical onset serial interval (SI) from studies that linked dates of symptom onset for infector-infectee pairs, and (iii) proportion of asymptomatic infection.

This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Definitions SAR is defined as the probability that an exposed susceptible person develops disease caused by an infected person (10) . It is calculated by dividing the number of exposed close contacts who tested positive (numerator) by the total number of close contacts of the index case (denominator). SI is defined as the time between disease symptom onset of a case and that of its infector (11) . It is used as a proxy for the generation interval-the time between the infection of the infectee and that of the infector, which is an unobservable duration.

Asymptomatic cases are defined as those with laboratory confirmation, but without clinical signs and symptoms at diagnosis. This definition therefore includes pre-symptomatic cases. The asymptomatic proportion is calculated as the number of asymptomatic cases divided by the total number of cases.

We performed a literature search of published journal articles in PubMed and pre-print articles in medRxiv and bioRxiv from January 1, 2020. For SAR, we used the search terms ("SARS-CoV-2" OR "COVID-19") AND ("attack rate" OR "contact tracing"). We replaced the last search term with "serial interval" for SI, and "asymptomatic" for asymptomatic infection. The last search date was on May 15, 2020 . All studies that were written in English or have an abstract in English were included.

The articles were initially screened by title and abstract, and subsequently by review of selected full-text articles. Three reviewers selected the studies independently using predetermined inclusion criteria and differences in opinions were resolved through consensus. From the included articles, the same reviewers extracted the data for all parameter estimates: event counts, point estimates, confidence intervals (CI), and sample size. Whenever available, we also extracted data on setting, symptom status, age group, and relationship of cases and close contacts. Data were obtained directly from the reports, but when not explicitly stated, we derived the data from tables, charts, or supplementary materials.

Studies reporting SAR were included if they: (i) presented original data for estimating the SAR, such as from a contact tracing investigation; (ii) reported a numerator and denominator of close contacts, or at least two of numerator, denominator, and SAR; (iii) specified a particular setting; and (iv) cases were confirmed positive with SARS-CoV-2 through reverse transcription polymerase chain reaction (RT-PCR) test. Point-testing or prevalence studies to measure cumulative incidence of infection in a setting were excluded as the source of infection could not be traced, but we reported these studies as supplementary materials.

For SI, studies were included if they: (i) contained original parameter estimates of either mean or median SI; (ii) reported the associated 95% CI; and (iii) reported the number of infector-infectee pairs.

For asymptomatic infection, studies were included if they: (i) presented original data for estimating the proportion of asymptomatic cases at diagnosis, such as from a cross-sectional survey, cohort study, or case series; (ii) reported the number of asymptomatic cases and the number of total cases, or at least two of the asymptomatic proportion, number of asymptomatic cases, and number of total cases; and (iii) cases were confirmed positive by RT-PCR test. Studies with data on asymptomatic infection assessed at admission or throughout the follow-up period were included for comparison purposes.

We identified 20 studies that allowed direct estimation of the SAR (Table 1 ; Supplementary materials Figure S1a ). Fifteen of these were published articles (three in Chinese language) and the other five were pre-prints. Some studies identified close contacts through active surveillance systems while in others they were identified following an outbreak investigation. Testing protocols of close contacts also differed; in the United States, only those with symptoms or persons under investigation were tested whereas in others, particularly Asian countries, all close contacts were tested regardless of symptoms.

There was variation in the definition of household contacts; most used a traditional definition as those who resided with the index case but some studies broadened the scope to include others who spent at least a night in the same residence or a specified duration of at least 24 hours of living together.

From these studies, we estimated household SAR in 17 locations, and non-household SAR in different settings in 10 locations. The non-household settings were non-household family, meal, travel, workplace or school, healthcare, religious event, chalet, and choir. The sample size of the settings varied depending on the location and context studied. We also estimated the SAR by symptom status of the index case, adults vs. children, and in the household, spouse vs. child and other household members.

Description of study Figure 1 summarizes the estimated SARs. The estimated mean household SAR is 15.4% (95% CI: 12.2%, 18.7%) with significant heterogeneity (p <0.001). Household SAR ranged from 6.6% in Taiwan to more than 30% in Shandong, Wuhan, Zhejiang, and Zhuhai in mainland China. In non-household settings, the . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 23, 2020. Figure S2a , Table S1a ). Similar analyses could not be done for other settings due to the limited number of studies. ES is the estimated SAR, with 95% confidence intervals (CI). I-squared is the percentage of between-study heterogeneity that is attributable to variability in the true effect, rather than sampling variation.

The risk of infection also varies by the symptom status of the index case. Based on six studies, SARs of symptomatic index cases were 2.55 times of that of asymptomatic cases (including pre-symptomatic cases; Supplementary materials Figure S3 ). . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 23, 2020. . https://doi.org/10.1101/2020.05.21.20108746 doi: medRxiv preprint SARs from eight studies showed that close contacts who are adults were more likely to be infected compared to children, with a relative risk of 1.40 (95% CI: 1.00, 1.96) (Supplementary materials Figure  S4 ). SARs from several studies indicated a 3.23 (95% CI: 2.23, 4.68) times risk of infection for a spouse of an index case as compared to a child (Supplementary materials Figure S5 ), and 3.63 (95% CI: 1. 68, 7.87) times as compared to other household members (Supplementary materials Figure S6 ).

We included 18 studies (9 published articles, 9 pre-prints) in the meta-analysis of the mean SI (Table 2 ; Supplementary materials Figure S1b ). We found a pre-print rapid review of SI (38) and cross-checked their articles-they were all included in our full-text shortlist. Several studies used the same dataset of the infector-infectee pairs; we therefore selected those that were the most comprehensive from a single location. For studies with multiple locations, publicly available datasets were used and hence there is likely to be substantial overlaps; nonetheless, we reported these studies as a comparison instead of discarding them.

Most of the studies were from Asian countries, particularly China, and two were from Italy. In multiplelocation studies, data from Germany and the United States were also used. The number of infectorinfectee pairs ranged from less than 10 in single-location studies to 689 in multiple-location ones. However, studies with a large sample size are not necessarily representative of the countries from which the data were drawn. For instance, in He et al. with 77 pairs used, only one was from the United States, 20 were from East Asian countries, and the rest from mainland China (39) . We evaluated the value of a larger sample size against the accuracy of the infector-infectee relationship, and decided to retain all small-sample studies.

The mean SI was more often reported compared to the median. Statistical distributions used were usually Gamma, Weibull, or lognormal. Negative serial intervals were reported in a few studies, and the authors suggested the Normal distribution as a more appropriate fit (31, 40, 41) . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The estimated mean SI are shown in Figure 2 . The mean SI of the single-location studies is estimated to be 4.87 days (95% CI: 3.98, 5.77). The shortest SI was observed in South Korea (3.6 days) and the longest in Wuhan (7.5 days). In the multiple-location studies, the shortest mean SI was 4.0 days and longest 7.0 days. There is wide heterogeneity in the multiple-location studies (p <0.001), but less in the singlelocation ones. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 23, 2020. . https://doi.org/10.1101/2020.05.21.20108746 doi: medRxiv preprint squared is the percentage of between-study heterogeneity that is attributable to variability in the true effect, rather than sampling variation.

We identified 66 studies that allowed estimation of the proportion of cases that were asymptomatic (Table 3 ; Supplementary materials Figure S1c ). 54 of these were published articles (5 in Chinese language) and the remainder pre-prints. Twelve studies focused on children. For studies with overlapping datasets, we selected the ones that were most comprehensive. We found a rapid review of asymptomatic infections (54) but it only included studies with cases that were asymptomatic throughout the duration of their illness; we cross-checked the articles and they were all covered in our full-text shortlist.

Most of the retrospective cohort studies were from China and those on point-testing and prevalence studies were outside China. In terms of symptom assessment, many of the retrospective studies followed up patients throughout whereas symptoms at diagnosis could be observed in cross-sectional surveys and in investigation of family clusters. There is wide variation in the sample size, from less than 10 in family clusters in China to 1, 192 in Japan's case series. We did not exclude studies based on an arbitrary sample size cut-off as we see value in assessing asymptomatic infection in different settings and study populations. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 23, 2020. Table 3 . Description of studies included in the review and analysis of asymptomatic infection Figure 3 summarizes the proportion of asymptomatic cases. The estimated mean asymptomatic proportion at diagnosis is 25.9% (95% CI: 18.8%, 33.1%). Unsurprisingly, this proportion is larger than that at admission (14.8%) and throughout the follow-up period (8.0%). In general, the asymptomatic proportion decreases with age-this is more evident in hospital-based studies that observe patients over a certain time period (Supplementary materials Figure S7 ). The mean asymptomatic proportion at diagnosis is higher in children at 41.8% but there is wide variation due to the limited number of studies (Supplementary materials Figure S8 ). The asymptomatic proportion in children seems to change little over the course of the follow-up period.

Among the studies with asymptomatic cases assessed at diagnosis, the asymptomatic proportion is notably high in the Diamond Princess cruise (58.9%), a nursing facility in the United States (56.3%), vulnerable population in France (51.0%), Japanese residents evacuated from China (33.3%), and healthcare workers in Italy (29.7%). Pregnant women also had a high asymptomatic proportion (49.3%). The proportion is also high in studies investigating family clusters (49.1%); we note that there is a systematic overestimation in such contact investigations since all clusters include at least one asymptomatic case.

The funnel plot for overall asymptomatic infection is asymmetric, suggesting the presence of small-study effects and confirmed by Egger's meta-regression test (including segregation by asymptomatic at diagnosis, admission, or throughout), as noted above (Supplementary materials Figure S2b and Table  S1b ). We therefore conducted an additional search but could not identify any other relevant articles.

There is no evidence of bias in studies on children (Supplementary materials Figure S2c and Table S1c ).

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The copyright holder for this preprint this version posted May 23, 2020. . https://doi.org/10.1101/2020.05.21.20108746 doi: medRxiv preprint Figure 3 . Forest plot of the proportion of asymptomatic cases. ES is the estimated asymptomatic proportion, with 95% confidence intervals (CI). I-squared is the percentage of between-study heterogeneity that is attributable to variability in the true effect, rather than sampling variation.

We estimated household SAR at 15.4% (95% CI: 12.2%, 18.7%), almost four times higher than nonhousehold SAR at 4.0% (95% CI: 2.8%, 5.2%). The mean SI was 4.87 days (95% CI: 3.98, 5.77) and the asymptomatic proportion at diagnosis was 25.9% (95% CI: 18.8%, 33.1%). Symptomatic persons had a 2.55 (95% 1.47, 4.45) times higher risk of infecting others.

We estimated SAR across various settings as a measure of viral transmissibility. While a number of studies have estimated the basic reproductive number (R0) at 2-4, (111) (112) (113) (114) in isolation it is a suboptimal gauge of infectious disease dynamics as it does not account for variability in specific situations and settings (115, 116) .

The significant heterogeneity in SAR across the different settings is unsurprising given that SAR depends not only on the causative agent but also on socio-demographic, environmental, and behavioral factors in . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 23, 2020. . https://doi.org/10.1101/2020.05.21.20108746 doi: medRxiv preprint study populations (117) . Variation in methods for case ascertainment and then subsequent detection of infected cases among contacts likely contributed to the heterogeneity across studies.

Household SAR at 15.4% was higher than in non-household settings at 4.0%. Reports suggest that familial transmission account for the majority of transmissions (25, 118) . The household is thought to be a fundamental unit of SARS-CoV-2 transmission because of the high frequency and intensity of contacts that occur between family members, and because transmission has continued in places with movement restriction (31) . We found the household SAR for COVID-19 approaches the upper range of estimates of the household SAR for the 2009 H1N1 pandemic influenza (5-15%) (119) (120) (121) , and higher than that observed for both SARS (5-10%) (122) (123) (124) and MERS (4-5%) (125, 126) . This suggests relatively higher SARS-CoV-2 transmissibility in the household setting. SARS-CoV-2 also has a higher R0 when compared to MERS-CoV and SARS-CoV-1 (127) . This finding highlights the necessity of case isolation, immediate tracing, and quarantine of household contacts (128) .

The relatively lower SAR in non-household settings may mask variation between setting types. Some studies reported significantly higher SAR in mass gatherings and other enclosed settings with potential for prolonged physical contact, such as at the ski chalet in France (73.3%), at a choir in the United States (53.3%), and a religious gathering in Brunei (14.8%) (31, 36, 37) . In contrast, SAR in workplace/school and in healthcare settings ranged between 1-2%, suggesting a gradation of risk outside the household (19, 28, 31) . As an aggregate, we found that the transmission risk was significantly reduced outside the household.

Our meta-analysis excluded studies that solely reported attack rates (AR) without identification of an index case and their transmission generations within the cluster. However, such studies may be important in understanding the role of super-spreading events (SSEs) in driving SARS-CoV-2 transmission (116) . Specific settings where high ARs have been observed were in a nursing home in Kings County, Washington (64%), a call centre in South Korea (43.5%), a church in Arkansas (38%), a homeless shelter in Boston (36%), a fitness dance class (26.3%), and the Diamond Princess cruise ship in Japan (18.8%) (Supplementary materials Table S2 ).

Reflecting on the high household SAR and high AR in some settings, we suggest that several common environmental factors potentially account for the rapid person-to-person transmission observed: closed environments, population density, and shared eating environments. This is supported by environmental sampling studies (129) and ecological observations on the declining incidence of COVID-19 cases in areas with restrictions on indoor mass gatherings (130) .

There are implications for mass gatherings and certain religious events, particularly as countries begin to relax physical distancing measures. Non-household residential settings such as long-term care facilities, dormitories, and detention facilities pose specific challenges where additional prevention measures merit consideration, including staff screening, enhanced testing, and strict visitor policies (67) .

Certainly, across all settings, the longer the duration and the greater the degree of physical contact with an index case, the higher the risk of transmission. However, we find that the risk model for transmission of SARS-CoV-2 is nuanced-while the highest risk of transmission is in crowded and enclosed settings, social interaction in public settings has a lower risk. This suggests that socially disruptive large-scale community lockdowns can be avoided if case isolation, tracing, and physical distancing measures that target higher risk activities can be implemented effectively (131) . This combination of measures is . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 23, 2020. . https://doi.org/10.1101/2020.05.21.20108746 doi: medRxiv preprint dependent upon the stage of the epidemic in a particular area and may be more feasible in areas with imported cases or limited local transmission.

In addition, as anxiety with physical distancing measures (so-called "quarantine fatigue") gain momentum (132) , public communications surrounding these measures should convey this continuum of risk based on the transmission dynamics across different settings, supporting sustainable longer-term behavior changes.

The SI depends upon the temporal relation between infectiousness and clinical onset of a source case and the incubation period of the receiving case (133) . We estimated the mean SI at 4.87 days, with studies reporting the SI ranging from 3.58 to 7.5 days, which is considerably shorter than observed for SARS (8.4 days) and MERS (14.6 days). The variation between studies is expected, as the interval between symptoms in an infector-infectee pair is influenced by the level of close contact, varying widely between different countries and in different settings.

Negative serial intervals were reported in several studies indicating that the infectee had symptoms earlier than the infector, thereby strengthening the evidence for pre-symptomatic transmission (98) . Using a mean SI of 5.21 days obtained from the Grace Assembly of God cluster in Singapore, Ganyani et al. conducted a sensitivity analysis suggesting that the proportion of pre-symptomatic transmission increased from 48% to 66% when negative SI values were taken into account (41) . Other studies have estimated that persons can potentially be transmitting up to 2 days prior to symptom onset (28, 39) . Taken together, our findings suggest that for quarantine to be effective, cases have to be identified and contacts traced and quarantined within 2.87 days of the onset of symptoms of the index case. Quarantine after this period potentially results in transmission from secondary to tertiary cases.

If significant transmission were occurring prior to symptoms, this could pose challenges for symptombased public health control measures, such as clinical criteria for testing, and early case isolation (9) . We estimated that 25.9% of COVID-19 cases were asymptomatic at time of diagnosis. Of these, more than two-thirds went on to develop symptoms over the course of their disease with a 'true asymptomatic' proportion of 8.4%. Our study does not support claims that the majority of SARS-CoV-2 infections are asymptomatic (134) . Questions remain as to the role of asymptomatic carriers in the transmission of SARS-CoV-2. A number of studies have described familial clusters resulting from asymptomatic carrier transmission (55, 135) . From the observational studies included in our analysis, we found a significantly higher risk of transmission where the index case was symptomatic with a relative risk of 2.55, suggesting that testing strategies should prioritize symptomatic persons (9) particularly where resources are finite.

Nonetheless, the proportion of asymptomatic infection combined with a relatively short SI warrant caution as there is potential for silent transmission (98) . Even with a highly effective case isolation and quarantine system, asymptomatic infections are difficult to detect rapidly and may give rise to transmission chains within community settings. Therefore, some degree of physical distancing is likely to be needed to account for this (131) .

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The copyright holder for this preprint this version posted May 23, 2020. . https://doi.org/10.1101/2020.05.21.20108746 doi: medRxiv preprint For many infectious diseases, such as seasonal and pandemic influenza, children are known be drivers of transmission in households and communities (136) . Case series data on SARS-CoV-2 suggests that children are less likely to be affected than adults. A national analysis of the first 72,314 cases in China reported only 2.1% of all cases were in children aged 0-19 years old (137) . Other studies show similarly low proportions (138) .

To better understand their relative susceptibility of infection, we compared the SAR between adults and children and found adults at 1.40 times higher risk of infection than children. The lower rate of susceptibility in children could be explained by differences in symptomatic infection rates and subsequent issues with case ascertainment (139) . The estimated mean asymptomatic proportion among children is 41.8%, about 1.6 times the proportion in the general population.

The literature surrounding infectivity in children is scarce. In household transmission studies, children are usually identified through contact tracing of adult cases, although a number of case reports have documented transmission from children to adults (140) . There is also insufficient knowledge on transmissibility of SARS-CoV-2 from children to other children. In addition, age may be important to determine dynamics of interactions among children but inadequate data hampered our efforts at risk stratification by age.

While there are still important unknowns with respect to SARS-CoV-2 in children, these early findings may assist health authorities in determining proportionate thresholds for school closures in future waves of the pandemic.

Our analysis has important limitations. The studies selected were based on field investigation; variability was noted with respect to study design, the number of individuals assessed, clinical definitions, the extent to which confirmatory laboratory tests were used, the methods of clinical data collection, and the duration of follow-up. Studies may have different definitions of household and contacts and are subject to recall and observer bias (141) . Moreover, without accounting for outside sources of infection, settingspecific SARs are likely to be overestimated (117) . In fact, none of the reviewed studies addressed the composition of secondary vs. community infections when estimating the SAR or used viral sequencing to confirm homology between the strains infecting the index and secondary cases in the household.

All studies on SAR were retrospective transmission studies based on contact tracing datasets where the index case determination or the direction of transmission may be uncertain, particularly in diseases such as COVID-19 where a substantial proportion of cases are asymptomatic or mild. An additional challenge concerns the timing of recruitment of cases and their contacts during the course of an epidemic. Studies conducted in early stages can provide timely SAR estimates; however, this may be influenced by behavioral factors and other non-pharmaceutical interventions (e.g. community quarantine) that alter over the course of the epidemic (117) .

Studies reporting SI face have similar limitations. Most do not account for incomplete reporting over the course of the epidemic and hence have incomplete transmission networks (41) . Changes in social contacts and other behavioral changes, such as mask-wearing, may also alter the SI (133) . Akin to contact tracing-based transmission studies, the order of transmission in clusters can easily be mistaken.

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The copyright holder for this preprint this version posted May 23, 2020. . https://doi.org/10.1101/2020.05. 21.20108746 doi: medRxiv preprint Moreover, given the potential for pre-symptomatic and asymptomatic transmission, it can be difficult to determine the source of infection with certainty.

Estimates of the asymptomatic proportion should be interpreted with caution as they are approximated from studies that lack a standardized case definition for asymptomatic infections. The collection of acute and convalescent serology from household contacts in household transmission studies could provide key information on asymptomatic cases, which is essential to forecasting the course of the pandemic. We cannot exclude publication bias for studies reporting on asymptomatic proportion given the media attention surrounding this particular topic.

The major strength of our study is that it comprehensively covers several key parameters of SARS-CoV-2 transmission-related dynamics, thus facilitating discussion and allowing for triangulation of these different parameters to identify the key drivers of transmission.

Our estimates of SAR, SI, and asymptomatic infection demonstrate the challenges in controlling SARS-CoV-2 transmission. Based on our pooled estimates of these three parameters, 10 infected symptomatic persons living with 100 contacts would result in 15 additional symptomatic infected persons in <5 days and 39 in <15 days. If the testing and tracing strategy is based on symptoms, we would further miss 25% of infected individuals, who are asymptomatic and could potentially be transmitting.

Overall, these findings suggest that aggressive contact-tracing strategies based on suspect cases may be appropriate early in an outbreak but as it progresses, control measures should transition to a combination of approaches that account for setting-specific transmission risk. Quarantine may need to cover entire communities such as dormitories, workplaces, or other institutional and residential settings, while contact tracing should shift to identifying hotspots of transmission and vulnerable populations. The variability in SAR across settings suggests targeted strategies may allow for reducing infections while not overly restricting social movement.

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The copyright holder for this preprint this version posted May 23, 2020. Funnel plot with pseudo 95% confidence limits . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 23, 2020. . https://doi.org/10.1101/2020.05.21.20108746 doi: medRxiv preprint Figure S2c . Funnel plot of the 12 studies on asymptomatic infection in children. Figure S3 . Forest plot of secondary attack rate by symptom status of index case. RR is the estimated relative risk ratio, with 95% confidence intervals (CI). I-squared is the percentage of between-study heterogeneity that is attributable to variability in the true effect, rather than sampling variation. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 23, 2020. . https://doi.org/10.1101/2020.05.21.20108746 doi: medRxiv preprint Figure S4 . Forest plot of secondary attack rate in adults and children. RR is the estimated relative risk ratio, with 95% confidence intervals (CI). I-squared is the percentage of between-study heterogeneity that is attributable to variability in the true effect, rather than sampling variation. Figure S5 . Forest plot of secondary attack rate in spouse and child of an index case. RR is the estimated relative risk ratio, with 95% confidence intervals (CI). I-squared is the percentage of between-study heterogeneity that is attributable to variability in the true effect, rather than sampling variation. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 23, 2020. . https://doi.org/10.1101/2020.05.21.20108746 doi: medRxiv preprint Figure S6 . Forest plot of secondary attack rate in spouse and other household members (excluding child) of an index case. RR is the estimated relative risk ratio, with 95% confidence intervals (CI). I-squared is the percentage of between-study heterogeneity that is attributable to variability in the true effect, rather than sampling variation. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 23, 2020. Asymptomatic throughout . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 23, 2020. . https://doi.org/10.1101/2020.05.21.20108746 doi: medRxiv preprint Figure S8 . Forest plot of the proportion of asymptomatic cases in children at diagnosis, admission, and throughout the follow-up period. ES is the estimated asymptomatic proportion, with 95% confidence intervals (CI). I-squared is the percentage of between-study heterogeneity that is attributable to variability in the true effect, rather than sampling variation. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

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The copyright holder for this preprint this version posted May 23, 2020. . https://doi.org/10.1101/2020.05.21.20108746 doi: medRxiv preprint

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

Early dynamics of transmission and control of COVID-19: a mathematical modelling study

Phylogenetic network analysis of SARS-CoV-2 genomes

Developing Covid-19 Vaccines at Pandemic Speed

Emerging pharmacotherapies for COVID-19

Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period

Epidemiological research priorities for public health control of the ongoing global novel coronavirus (2019-nCoV) outbreak

Quantifying SARS-CoV-2 transmission suggests epidemic control with digital contact tracing

Factors that make an infectious disease outbreak controllable

Secondary attack rate and superspreading events for SARS-CoV-2

Serial intervals of respiratory infectious diseases: a systematic review and analysis

Meta-analysis in clinical trials

Measuring inconsistency in meta-analyses

Bias in meta-analysis detected by a simple, graphical test

Funnel Plots in Meta-analysis

metan: fixed-and random-effects meta-analysis

Updated tests for small-study effects in meta-analyses

Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study

The epidemiological characteristics of infection in close contacts of COVID-19 in Ningbo city

Household secondary attack rate of COVID-19 and associated determinants

Modes of contact and risk of transmission in COVID-19 among close contacts

The characteristics of household transmission of COVID-19

Transmission potential of asymptomatic and paucisymptomatic SARS-CoV-2 infections: a three-family cluster study in China

Investigation of a cluster epidemic of COVID-19 in a supermarket in Liaocheng, Shandong province

Household transmission of SARS-CoV-2

Household Transmission of SARS-CoV-2

Contact Tracing Assessment of COVID-19 Transmission Dynamics in Taiwan and Risk at Different Exposure Periods Before and After Symptom Onset

Coronavirus Disease Outbreak in Call Center

Coronavirus Disease-19: Summary of 2,370 Contact Investigations of the First 30 Cases in the Republic of Korea

SARS-CoV-2 transmission in different settings: Analysis of cases and close contacts from the Tablighi cluster in Brunei Darussalam

Investigation of a COVID-19 outbreak in Germany resulting from a single travel-associated primary case: a case series

Enhanced Contact Investigations for Nine Early Travel-Related Cases of SARS-CoV-2 in the United States

Transmission risk of SARS-CoV-2 to healthcare workers -observational results of a primary care hospital contact tracing

Community Transmission of SARS-CoV-2 at Two Family Gatherings

Cluster of coronavirus disease 2019 (Covid-19) in the French Alps

High SARS-CoV-2 Attack Rate Following Exposure at a Choir Practice -Skagit County

Estimating presymptomatic transmission of COVID-19: a secondary analysis using published data

Temporal dynamics in viral shedding and transmissibility of COVID-19

Serial Interval of COVID-19 among Publicly Reported Confirmed Cases

Estimating the generation interval for coronavirus disease (COVID-19) based on symptom onset data

Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia

Epidemiological and clinical characteristics of COVID-19 in adolescents and young adults

Epidemiological characteristics of the first 53 laboratory-confirmed cases of COVID-19 epidemic in Hong Kong

High transmissibility of COVID-19 near symptom onset

Clinical onset serial interval and diagnostic serial interval of SARS-CoV-2/COVID-19 in South Korea

The early phase of the COVID-19 outbreak in

Suppression of COVID-19 outbreak in the municipality of

Serial interval of novel coronavirus (COVID-19) infections

Estimating clinical severity of COVID-19 from the transmission dynamics in Wuhan, China

Epidemiological parameters of coronavirus disease 2019: a pooled analysis of publicly reported individual data of 1155 cases from seven countries

Evolving epidemiology and transmission dynamics of coronavirus disease 2019 outside Hubei province, China: a descriptive and modelling study

COVID-19 serial interval estimates based on confirmed cases in public reports from 86 Chinese cities

Presumed Asymptomatic Carrier Transmission of COVID-19

A confirmed asymptomatic carrier of 2019 novel coronavirus

Familial cluster of COVID-19 infection from an asymptomatic

Asymptomatic cases in a family cluster with SARS-CoV-2 infection

Characteristics of a family cluster of Severe Acute Respiratory Syndrome Coronavirus 2 in Henan

Delivery of infection from asymptomatic carriers of COVID-19 in a familial cluster

A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster

Asymptomatic SARS-CoV-2 Infection in Household Contacts of a Healthcare Provider

A COVID-19 Transmission within a family cluster by presymptomatic infectors in China

Preparation for Quarantine on the Cruise Ship Diamond Princess in Japan due to COVID-19

Characteristics of 1,573 healthcare workers who underwent nasopharyngeal swab for SARS-CoV-2 in Milano

Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility

Among Residents and Staff Members of an Independent and Assisted Living Community for Older Adults

Severe Acute Respiratory Syndrome Coronavirus 2 Infection among Returnees to Japan from Wuhan

Screening of SARS-CoV-2 among homeless people, asylum seekers and other people living in precarious conditions in Marseille

COVID-19 infection among asymptomatic and symptomatic pregnant women: Two weeks of confirmed presentations to an affiliated pair of New York City hospitals

Radiological findings and clinical characteristics of pregnant women with COVID-19 pneumonia

Clinical Manifestation and Laboratory Characteristics of SARS-CoV-2 Infection in Pregnant Women

Rapid asymptomatic transmission of COVID-19 during the incubation period demonstrating strong infectivity in a cluster of youngsters aged 16-23 years outside Wuhan and characteristics of young patients with COVID-19: A prospective contacttracing study

Characteristics of COVID-19 infection in Beijing

Epidemiological and clinical characteristics of 136 cases of COVID-19 in main district of Chongqing

Associations of clinical characteristics and antiviral drugs with viral RNA clearance in patients with COVID-19 in Guangzhou, China: a retrospective cohort study

Viral kinetics of SARS-CoV-2 in asymptomatic carriers and presymptomatic patients

Evidence from two cases of asymptomatic infection with SARS-CoV-2: Are 14 days of isolation sufficient?

Transmission and clinical characteristics of coronavirus disease 2019 in 104 outside-Wuhan patients

The implications of preliminary screening and diagnosis: Clinical characteristics of 33 mild patients with SARS-CoV-2 infection in Hunan

Epidemiological and clinical features of asymptomatic patients with SARS-CoV-2 infection

Characteristics of asymptomatic patients with SARS-CoV-2 infection in Jinan, China. Microbes Infect

Comparison of transmissibility of coronavirus between symptomatic and asymptomatic patients: Reanalysis of the Ningbo Covid-19 data

Clinical characteristics of COVID-19 in children compared with adults in Shandong Province

Follow-up of asymptomatic patients with SARS-CoV-2 infection

A considerable proportion of individuals with asymptomatic SARS-CoV-2 infection in Tibetan population

The clinical feature of silent infections of novel coronavirus infection (COVID-19) in Wenzhou

High incidence of asymptomatic SARS-CoV-2 infection

Clinical characteristics of non-critically ill patients with novel coronavirus infection (COVID-19) in a Fangcang Hospital

Clinical Characteristics of SARS-CoV-2 Pneumonia Compared to Controls in Chinese Han Population

CT features of SARS-CoV-2 pneumonia according to clinical presentation: a retrospective analysis of 120 consecutive patients from Wuhan city

A territory-wide study of early COVID-19 outbreak in Hong Kong community: A clinical, epidemiological and phylogenomic investigation

Analysis of Imported Cases of COVID-19 in Taiwan: A Nationwide Study

Epidemiological and Clinical Characteristics of 28 Cases of Coronavirus Disease in South Korea

Clinical characteristics of asymptomatic and symptomatic patients with mild COVID-19

Early epidemiological and clinical manifestations of COVID-19 in Japan

High proportion of asymptomatic and presymptomatic COVID-19 infections in travelers and returning residents to Brunei

Clinical Characteristics of Patients Hospitalized with Coronavirus Disease

Severe Acute Respiratory Syndrome Coronavirus 2 Shedding by Travelers

Radiological and Therapeutic Characteristics of Patients with COVID-19 in Saudi Arabia

Epidemiologic and clinical characteristics of 10 children with coronavirus disease 2019 in Changsha

Clinical features of pediatric patients with coronavirus disease (COVID-19)

SARS-CoV-2 Infection in Children

Clinical and CT features in pediatric patients with COVID-19 infection: Different points from adults

Chest computed tomography in children with COVID-19 respiratory infection

Preliminary estimation of the basic reproduction number of novel coronavirus (2019-nCoV) in China, from 2019 to 2020: A data-driven analysis in the early phase of the outbreak

The reproductive number of COVID-19 is higher compared to SARS coronavirus

Covid-19 Outbreak Progression in Italian Regions: Approaching the Peak by the End of March in Northern Italy and First Week of April in Southern Italy

Effective Reproductive Number estimation for initial stage of COVID-19 pandemic in Latin American Countries

Superspreading and the effect of individual variation on disease emergence

Identifying and Interrupting Superspreading Events-Implications for Control of Severe Acute Respiratory Syndrome Coronavirus 2

Household Transmission of Influenza Virus

Report of the WHO-China Joint Mission on Coronavirus Disease (COVID-19)

Secondary attack rate of pandemic influenza A(H1N1) 2009 in Western Australian households

Household transmission of influenza A(H1N1)pdm09 in the pandemic and post-pandemic seasons

Transmission dynamics and risk factors for pandemic H1N1-related illness: outbreak investigation in a rural community of British Columbia, Canada. Influenza Other Respir Viruses

Secondary household transmission of SARS

Probable secondary infections in households of SARS patients in Hong Kong

Household transmission of SARS

Transmission of MERS-coronavirus in household contacts

Transmissibility of MERS-CoV Infection in Closed Setting

COVID-19, SARS and MERS: are they closely related?

COVID-19 epidemic in Switzerland: on the importance of testing, contact tracing and isolation

Environmental sampling for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during a coronavirus disease (COVID-19) outbreak aboard a commercial cruise ship

Epidemiology of 2019 novel coronavirus in Jiangsu Province, China after wartime control measures: A population-level retrospective study

Effectiveness of isolation, testing, contact tracing and physical distancing on reducing transmission of SARS-CoV-2 in different settings

Shelter-in-place and mental health: an analogue study of well-being and distress

The interval between successive cases of an infectious disease

Covid-19: four fifths of cases are asymptomatic, China figures indicate

COVID-19 transmission through asymptomatic carriers is a challenge to containment. Influenza Other Respir Viruses2020

Attack rates assessment of the 2009 pandemic H1N1 influenza A in children and their contacts: a systematic review and meta-analysis

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

Epidemiological characteristics of 1212 COVID-19 patients in Henan, China

SARS-CoV-2 (COVID-19): What do we know about children? A systematic review

A Case Series of children with 2019 novel coronavirus infection: clinical and epidemiological features

Estimating the secondary attack rate and serial interval of influenza-like illnesses using social media. Influenza Other Respir Viruses

Prevalence of SARS-CoV-2 Infection in Residents of a Large Homeless Shelter in Boston

High COVID-19 Attack Rate Among Attendees at Events at a Church -Arkansas

Cluster of Coronavirus Disease Associated with Fitness Dance Classes

COVID-19 Among Workers in Meat and Poultry Processing Facilities -19 States