key: cord-1054148-p2cta338
authors: Ravindra, Khaiwal; Malik, Vivek Singh; Padhi, Bijaya K.; Goel, Sonu; Gupta, Madhu
title: Asymptomatic infection and transmission of COVID-19 among clusters: Systematic Review and Meta-Analysis
date: 2021-12-09
journal: Public Health
DOI: 10.1016/j.puhe.2021.12.003
sha: 5b69c70b19c94c87a45477d7bb32402ca5964d6d
doc_id: 1054148
cord_uid: p2cta338

Objectives Countries throughout the world are experiencing COVID-19 viral load in their populations, leading to potential transmission and infectivity of asymptomatic COVID-19 cases. The current systematic review and meta-analysis aims to investigate the role of asymptomatic infection and transmission reported in family clusters, adults, children and healthcare workers, globally. Study design Systematic review and meta-analysis. Methods An online literature search of PubMed, Google Scholar, medRixv and BioRixv was performed using standard Boolean operators, and included studies published up to 17 August 2021. For the systematic review, case reports, short communications and retrospective studies were included to ensure sufficient asymptomatic COVID-19 transmission data were reported. For the quantitative synthesis (meta-analysis), participant data from a collection of cohort studies focusing on groups of familial clusters, adults, children and healthcare workers were included. Inconsistency among studies was assessed using I2 statistics. The data synthesis was computed using the STATA 16.0 software. Results This study showed asymptomatic transmission among familial clusters, adults, children and healthcare workers of 15.72%, 29.48%, 24.09% and 0%, respectively. Overall, asymptomatic transmission was 24.51% (95% confidence interval [CI]: 14.38, 36.02) among all studied population groups, with a heterogeneity of I2 = 95.30% (p <0.001). No heterogeneity was seen in the population subgroups of children and healthcare workers. The risk of bias in all included studies was assessed using the Newcastle Ottawa Scale. Conclusions To minimise the spread of COVID-19 within the community, this study found that following screening of asymptomatic cases and their close contacts for chest CT scan (for symptomatic patients), even after negative nucleic acid testing, it is essential to perform a rigorous epidemiological history, early isolation, social distancing and an increased quarantine period (a minimum of 14–28 days). This systematic review and meta-analysis supports the notion of asymptomatic COVID-19 infection and person-to-person transmission, and suggests that this is dependent on the varying viral incubation period among individuals. Children, especially those of school age (i.e. <18 years), need to be monitored carefully and follow mitigation strategies (e.g. social distancing, hand hygiene, wearing face masks) to prevent asymptomatic community transmission of COVID-19.

Symptomatic COVID-19 viral infections are a significant risk factor for transmission of disease within the general public. The major signs of COVID-19 infection include fever, dyspnoea, a dry cough and diarrhoea; these symptoms are reported to last up to 14 days, with a median incubation period of 9-12 days. Aerosol transmissions occur through sneezing or coughing and are reported to be the primary route of person-to-person infection 1 . However, simulation studies have also observed asymptomatic COVID-19 person-to-person transmission 2 Asymptomatic infection was reported as 'hidden coronavirus infections' ('infections' or 'covert coronavirus infections') 5 . The COVID-19 prevention and control protocol (6 th edition) states that asymptomatic COVID-19 cases should remain in quarantine for 14 days and that they should have two negative nucleic acid tests before being discharged. Worldwide, interest in asymptomatic COVID-19 infections and their transmission potential has increased 6 . In China, around 86% of asymptomatic COVID-19 transmission was undocumented before travel restrictions were introduced 6 .

To date, asymptomatic COVID-19 cases have been reported among family clusters 7-12 , pregnant women 13, 14 , adults [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] , children 1, 25, 26 , healthcare workers [27] [28] [29] and travellers [30] [31] [32] [33] [34] . Considering the potential transmission of asymptomatic COVID-19 within the community, this study aimed to collate data from the general population, as well as vulnerable groups from different backgrounds, and perform a meta-analysis. Previous studies have reported the proportion of COVID-19 infections attributable to asymptomatic transmission to be around 20%, with some variation depending on the population group. In this study, a meta-analysis was performed that considered different population groups.

A systematic review and meta-analysis were performed. J o u r n a l P r e -p r o o f

For the meta-analysis, PRISMA guidelines were followed. 35, 36 The following Boolean operators were used to search the PubMed database, Google scholar, medRxiv and BioRixv: 'asymptomatic 

For the meta-analysis, the present study included cohort studies that reported asymptomatic person-to-person transmission among clusters. Studies that were published in the English language were included.

Details of authors, sample size and numbers reported for the asymptomatic infection of COVID-19 were extracted and recorded independently. Data extraction was done separately by two independent reviewers and disagreement was settled by joint discussion. To minimise the risk of duplication, the data were carefully checked.

The Newcastle Ottawa scale (cohort studies) was used to evaluate the selected studies in the current systematic review and meta-analysis 35,37 . J o u r n a l P r e -p r o o f

Possible publication bias in this study was assessed for the included cohort studies 38 .

After extracting the results, studies were pooled and the effect of asymptomatic COVID-19 transmission was examined through the random effects method. For continuous outcomes, the standard error (SE) with 95% confidence intervals (CIs) were calculated. Heterogeneity between studies was assessed using the I 2 statistic (I 2 values indicating the existence of heterogeneity were assessed according to Higgins and colleagues) 35, 39, 40 . Data for the meta-analysis were collated 35, 41 . Data synthesis was conducted using the STATA 16.0 software.

There was no direct patient or public involvement in this systematic review and meta-analysis.

The literature search and screening were performed according to the PRISMA chart ( Figure 1 ).

Initially, 4667 published research articles were identified using the online database search. After removing 4460 duplicate publications, 207 research articles were shortlisted. After screening the title and abstracts, 123 articles were excluded and 84 full-text articles were assessed for eligibility.

A further 48 studies were excluded because they were research highlight reports, review studies, had incomplete information, reported no age-specific data, were classified as 'other' non-relevant studies or had language issues. For the qualitative synthesis, 36 articles were selected and 23 studies were included in the meta-analysis. Studies were grouped into the following population subgroups: family clusters (n = 5), adults (n = 12), children (n = 4) and healthcare workers (n = 2).

The main components of the included studies are summarised in Table 1 

The Newcastle Ottawa Scale (for cohort studies) was used for qualitative evaluation of the studies included in the meta-analysis 35, 37 . The risk of bias was assessed based on three domains (selection, comparability and outcome), as highlighted in Table 2 .

The bubble plot (see Figure 4 ) shows the study-specific effect size, where the size of each bubble is proportional to the precision of each study. Asymptomatic participants' funnel plot (standard error) showed no obvious publication bias ( Figure 5 ).

The outcomes of the current meta-analysis (Table 3) Another study supports the possibility of asymptomatic transmission among familial clusters during the incubation period 12 . In addition, in a familial cluster of five COVID-19-positive patients, it was observed that they had contact with other asymptomatic family members who had returned from Wuhan, China, suggesting asymptomatic transmission 7 .

During any disease outbreak, the unborn babies of pregnant woman are at high risk. It has been reported that pregnant woman with asymptomatic COVID-19 infection have delivered babies who are negative for the COVID-19 nucleic acid test, suggesting no vertical transmission among neonates born to COVID-19-infected mothers 14, [42] [43] [44] [45] [46] [47] [48] [49] .

In Wuhan, a lower COVID-19 fatality rate and higher discharge rate were observed than in Beijing, China. It is essential to identify asymptomatic individuals and implement necessary control measures to prevent transmission 21 . In South Korea, 41 COVID-19 asymptomatic adults were identified (confirmed by RT-PCR) out of 213 individuals 17 . In another study among 100 asymptomatic cases, 60% developed delayed symptoms and none of the asymptomatic patients died, suggesting that asymptomatic transmission could take place during the incubation period 18 .

Another study did not observe any difference in the symptomatic and asymptomatic COVID-19 transmission rates among patients 22 . In adults, CT imaging of asymptomatic COVID-19 individuals has advantages in highly suspicious cases with negative nucleic acid test results 17 15 . Theoretically, the quantified infection transmission rate shows the estimated risk ratio (RR) of infectivity of symptomatic against asymptomatic to be 3.9% (95% CI: 1.5, 11.8). In asymptomatic adults, transmission was significantly smaller than in symptomatic cases 16 . No gender difference was observed for asymptomatic transmission 20 .

Further longitudinal surveillance using nucleic acid testing is warranted to identify and assess viral load among asymptomatic COVID-19 adults 24 . In one study, four asymptomatic cases were quarantined for 14 days; thus, these individuals were unable to transmit the infection due to proper isolation management 19 .

Asymptomatic COVID-19 transmission has been observed in children 26 . In one study, 24 asymptomatic cases were identified from close contacts of asymptomatic COVID-19 patients 25 .

Another study supports multiple-site sampling of close contacts 1 among children. In a review, it was observed that adults with COVID-19 infection are more likely to show clinical symptoms and radiological manifestations than children, which is in line with previous reports for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses 50 .

In a study investigating healthcare workers in a nursing facility, rapid transmission of COVID-19 was reported in 76 residents; 23 (30.3%) had positive test results and 13 were asymptomatic on the day of testing, suggesting the possibility of asymptomatic transmission of COVID-19 27 .

Establishing effective infection control strategies to prevent COVID-19 transmission among frontline healthcare workers and patients should be addressed urgently and as a priority. In another study including 48 participants, two asymptomatic cases become positive, suggesting appropriate testing strategies are essential to prevent outbreaks of COVID-19 within hospital settings 29 . In the US, healthcare workers who were not wearing respirators were exposed to an asymptomatic COVID-19 patient without developing clinical illness 28 .

In Korea, COVID-19 was transmitted by 16 infected travellers from other countries; the disease was infectious at this stage, which resulted from close contact with asymptomatic carriers 30 

This is the first study to review the possibility of asymptomatic COVID-19 transmission among different population subgroups in the community. This study also identifies the potential role of isolation, identification of close contacts, social distancing, and testing asymptomatic COVID-19 cases with chest CT scan and nucleic acid testing to minimise the spread of the virus in the community.

Currently, there is no evidence that COVID-19 can be transmitted in the asymptomatic stage; however, results suggest that asymptomatic infections are not limited to one population group (e.g.

neonates, children, adults). In young people, it has been suggested that their strong immune status protects against COVID-19 severity. We hypothesise that asymptomatic carriers, either children or adults, should be vigilant as they are capable of transmitting COVID-19 during the incubation period without showing any signs or symptoms. As previous reports support the involvement of lung function in asymptomatic COVID-19 cases, we recommend chest CT scans among symptomatic cases, which is a convenient tool to monitor and trace patients in their incubation period.

Bijaya K Padhi: Interpretation, internal review of data, review and editing. Dr Sonu Goel:

Discussion, review and editing. Dr Madhu Gupta: Internal review of data, review and editing. 

J o u r n a l P r e -p r o o f 

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The authors thank the Department of Community Medicine and School of Public Health, PGIMER, and the Indian Council of Medical Research, New Delhi.

Not required.

Note: Selection; 1) Representativeness of the exposed cohort, 2) Selection of the non-exposed cohort, 3) Ascertain exposure, 4) Demonstration that outcome of interest was not present at the start of the study; Comparability; 5) Comparability of cohorts based on the design or analysis controlled for confounders; Outcome: 6) Assessment of outcome, 7) Was follow-up long enough for outcomes to occur, 8) Adequacy of follow-up of cohorts. Records screened for title