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 infection or presymptomatic?

METHODS AND FINDINGS

We searched PubMed, Embase, bioRxiv, and medRxiv using a database of SARS-CoV-2 literature that is updated daily, on 25 March 2020, 20 April 2020, and 10 June 2020. Studies of people with SARS-CoV-2 diagnosed by reverse transcriptase PCR (RT-PCR) that documented follow-up and symptom status at the beginning and end of follow-up or modelling studies were included. One reviewer extracted data and a second verified the extraction, with disagreement resolved by discussion or a third reviewer. Risk of bias in empirical studies was assessed with an adapted checklist for case series, and the relevance and credibility of modelling studies were assessed using a published checklist. We included a total of 94 studies. 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 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.

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

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged from a zoonotic spill-over event and has led to a global pandemic. The public health response has been predominantly informed by surveillance of symptomatic individuals and contact tracing, with quarantine, and other preventive measures have then been applied to mitigate further spread. Non-traditional methods of surveillance such as genomic epidemiology and wastewater-based epidemiology (WBE) have also been leveraged during this pandemic. Genomic epidemiology uses high-throughput sequencing of SARS-CoV-2 genomes to inform local and international transmission events, as well as the diversity of circulating variants. WBE uses wastewater to analyse community spread, as it is known that SARS-CoV-2 is shed through bodily excretions. Since both symptomatic and asymptomatic individuals contribute to wastewater inputs, we hypothesized that the resultant pooled sample of population-wide excreta can provide a more comprehensive picture of SARS-CoV-2 genomic diversity circulating in a community than clinical testing and sequencing alone. In this study, we analysed 91 wastewater samples from 11 states in the USA, where the majority of samples represent Maricopa County, Arizona (USA). With the objective of assessing the viral diversity at a population scale, we undertook a single-nucleotide variant (SNV) analysis on data from 52 samples with >90% SARS-CoV-2 genome coverage of sequence reads, and compared these SNVs with those detected in genomes sequenced from clinical patients. We identified 7973 SNVs, of which 5680 were novel SNVs that had not yet been identified in the global clinical-derived data as of 17th June 2020 (the day after our last wastewater sampling date). However, between 17th of June 2020 and 20th November 2020, almost half of the SNVs have since been detected in clinical-derived data. Using the combination of SNVs present in each sample, we identified the more probable lineages present in that sample and compared them to lineages observed in North America prior to our sampling dates. The wastewater-derived SARS-CoV-2 sequence data indicates there were more lineages circulating across the sampled communities than represented in the clinical-derived data. Principal coordinate analyses identified patterns in population structure based on genetic variation within the sequenced samples, with clear trends associated with increased diversity likely due to a higher number of infected individuals relative to the sampling dates. We demonstrate that genetic correlation analysis combined with SNVs analysis using wastewater sampling can provide a comprehensive snapshot of the SARS-CoV-2 genetic population structure circulating within a community, which might not be observed if relying solely on clinical cases.

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High-throughput sequencing of SARS-CoV-2 in wastewater provides insights into circulating variants

The numbers of confirmed cases of SARS-CoV-2 infection are increasing in many places. Consequently, the number of individuals placed into quarantine is increasing too. The large number of individuals in quarantine has high societal and economical costs, as well as infringing on the freedom of the individual. This has led to a vigorous debate about the duration of quarantine, particularly in light of the potentially low specificity of quarantine (i.e. low probability of quarantined individuals indeed being infected). We present a mathematical model that leverages empirically determined distributions of incubation period, infectivity, and generation time to quantify how the duration of quarantine affects transmission. With this model we address the impact of shortening the quarantine for returning travellers and traced contacts of confirmed cases, both in terms of prevented transmission and the ratio of prevented transmission to days spent in quarantine. We also consider the impact of i) test-and-release strategies; ii) additional hygiene measures imposed upon release after a negative test; iii) the development of symptoms during quarantine; iv) the relationship between quarantine duration and adherence; and v) the specificity of quarantine. When considering the benefit versus cost utility of quarantine, we find that the diminishing impact of longer quarantine on transmission prevention may support a quarantine duration below 10 days, particularly for returning travellers. A greater gain of utility can be achieved through a test-and-release strategy, and this can be even further strengthened by imposed hygiene measures post-release. We also find that unless a test-and-release strategy is considered, the specificity of quarantine does not affect the optimal duration of quarantine. Therefore, the argument that we should shorten quarantine because of lack of specificity is misguided.

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Quantifying the impact of quarantine duration on COVID-19 transmission

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 by people who are asymptomatic or presymptomatic? Methods and findings The protocol was first published on 1 April 2020 and last updated on 18 June 2021. We searched PubMed, Embase, bioRxiv, and medRxiv, aggregated in a database of SARS-CoV-2 literature, most recently on 6 July 2021. Studies of people with PCR-diagnosed SARS-CoV-2, which documented symptom status at the beginning and end of follow-up, or mathematical modelling studies were included. Studies restricted to people already diagnosed, of single individuals or families, or without sufficient follow-up were excluded. One reviewer extracted data and a second verified the extraction, with disagreement resolved by discussion or a third reviewer. Risk of bias in empirical studies was assessed with a bespoke checklist and modelling studies with a published checklist. All data syntheses were done using random effects models. Review question (1): We included 130 studies. Heterogeneity was high so we did not estimate a mean proportion of asymptomatic infections overall (interquartile range (IQR) 14% to 50%, prediction interval 2% to 90%), or in 84 studies based on screening of defined populations (IQR 20% to 65%, prediction interval 4% to 94%). 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. Limitations of the evidence include high heterogeneity and high risks of selection and information bias in studies that were not designed to measure persistently asymptomatic infection, and limited information about variants of concern or in people who have been vaccinated. Conclusions Based on studies published up to July 2021, most SARS-CoV-2 infections were not persistently asymptomatic, and asymptomatic infections were less infectious than symptomatic infections. Summary estimates from meta-analysis may be misleading when variability between studies is extreme and prediction intervals should be presented. Future studies should determine the asymptomatic proportion of SARS-CoV-2 infections caused by variants of concern and in people with immunity following vaccination or previous infection. Without prospective longitudinal studies with methods that minimise selection and measurement biases, further updates with the study types included in this living systematic review are unlikely to be able to provide a reliable summary estimate of the proportion of asymptomatic infections caused by SARS-CoV-2. Review protocol Open Science Framework (https://osf.io/9ewys/)

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

Abstract Objectives To evaluate the potential for long distance airborne transmission of SARS-CoV-2 in indoor community settings and to investigate factors that might influence transmission. Design Rapid systematic review and narrative synthesis. Data sources Medline, Embase, medRxiv, Arxiv, and WHO COVID-19 Research Database for studies published from 27 July 2020 to 19 January 2022; existing relevant rapid systematic review for studies published from 1 January 2020 to 27 July 2020; and citation analysis in Web of Science and Cocites. Eligibility criteria for study selection Observational studies reporting on transmission events in indoor community (non-healthcare) settings in which long distance airborne transmission of SARS-CoV-2 was the most likely route. Studies such as those of household transmission where the main transmission route was likely to be close contact or fomite transmission were excluded. Data extraction and synthesis Data extraction was done by one reviewer and independently checked by a second reviewer. Primary outcomes were SARS-CoV-2 infections through long distance airborne transmission (>2 m) and any modifying factors. Methodological quality of included studies was rated using the quality criteria checklist, and certainty of primary outcomes was determined using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. Narrative synthesis was themed by setting. Results 22 reports relating to 18 studies were identified (methodological quality was high in three, medium in five, and low in 10); all the studies were outbreak investigations. Long distance airborne transmission was likely to have occurred for some or all transmission events in 16 studies and was unclear in two studies (GRADE: very low certainty). In the 16 studies, one or more factors plausibly increased the likelihood of long distance airborne transmission, particularly insufficient air replacement (very low certainty), directional air flow (very low certainty), and activities associated with increased emission of aerosols, such as singing or speaking loudly (very low certainty). In 13 studies, the primary cases were reported as being asymptomatic, presymptomatic, or around symptom onset at the time of transmission. Although some of the included studies were well conducted outbreak investigations, they remain at risk of bias owing to study design and do not always provide the level of detail needed to fully assess transmission routes. Conclusion This rapid systematic review found evidence suggesting that long distance airborne transmission of SARS-CoV-2 might occur in indoor settings such as restaurants, workplaces, and venues for choirs, and identified factors such as insufficient air replacement that probably contributed to transmission. These results strengthen the need for mitigation measures in indoor settings, particularly the use of adequate ventilation. Systematic review registration PROSPERO CRD42021236762.

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Muhammad Irfanul Alam

Papers

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