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

  1. Diana Buitrago-Garcia
  2. Aziz Mert Ipekci
  3. Leonie Heron
  4. Hira Imeri
  5. Lucia Araujo-Chaveron
  6. Ingrid Arevalo-Rodriguez
  7. Agustín Ciapponi
  8. Muge Cevik
  9. Anthony Hauser
  10. Muhammad Irfanul Alam
  11. Kaspar Meili
  12. Eric A. Meyerowitz
  13. Nirmala Prajapati
  14. Xueting Qiu
  15. Aaron Richterman
  16. William Gildardo Robles-Rodriguez
  17. Shabnam Thapa
  18. Ivan Zhelyazkov
  19. Georgia Salanti
  20. Nicola Low

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Abstract

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/ )

Article activity feed

  1. Version published to 10.1371/journal.pmed.1003987
  2. Version published to 10.1101/2022.01.20.22269581v2 on medRxiv
  3. ScreenIT

    SciScore for 10.1101/2022.01.20.22269581: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: Ethics committee review was not required for this review.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    We searched the COVID-19 living evidence database [20], which uses automated workflow processes to: (1) provide daily updates of searches of four electronic databases (Medline, PubMed,
    Medline
    suggested: (MEDLINE, RRID:SCR_002185)
    PubMed
    suggested: (PubMed, RRID:SCR_004846)
    , Ovid Embase, bioRxiv and medRxiv), using medical subject headings and free-text keywords for SARS-CoV-2 infection and COVID-19; (2) de-duplicate the records; (3) tag records that are preprints; and (4) allow searches of titles and abstracts using Boolean operators.
    bioRxiv
    suggested: (bioRxiv, RRID:SCR_003933)
    Two authors independently assessed the risk of bias, using a customised online tool, which saved responses into the REDCap database.
    REDCap
    suggested: (REDCap, RRID:SCR_003445)
    We used the metaprop and metabin functions from the meta package (version 4.11-0) [26] and the ggplot2 package (version 3.3.5) in R (version 3.5.1) to display the study findings in forest plots and synthesise their results, where appropriate.
    ggplot2
    suggested: (ggplot2, RRID:SCR_014601)

    Results from OddPub: Thank you for sharing your code and data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Strengths and weaknesses of the living systematic review methods: A strength of the methodology of this review is the transparent reporting, with openly available data and changes over different versions reported in the protocol. Our inclusion criteria attempted to reduce risks of bias and we developed a new tool to address potential biases in the studies included in this review. In contact investigations, we subtracted index cases from the total number of people with SARS-CoV-2 to avoid underestimation of the proportion asymptomatic [14]. We examined heterogeneity in detail and, as a result of the wide prediction interval, we chose not to report an overall summary estimate [19, 146]. A limitation of the methods for this living systematic review is that this update only includes published studies up to 2 February 2021. Although we made extensive efforts to comply with the planned 3-monthly updates, with weekly searches and a continuous process of screening, data extraction and risk of bias assessment, the pace of publications about SARS-CoV-2 exceeds the capacity of our crowd of reviewers [8, 20]. In reviews of observational epidemiological studies, search terms are broad so the number of studies that needs to be screened is high, but the yield of included studies is low. We are in the process of updating our findings and preliminary analyses show that the main findings do not change when including studies published up to April 2021. The four databases that we searched are no...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  4. Version published to 10.1101/2022.01.20.22269581v1 on medRxiv