SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis

  1. Muge Cevik
  2. Matthew Tate
  3. Ollie Lloyd
  4. Alberto Enrico Maraolo
  5. Jenna Schafers
  6. Antonia Ho

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Abstract

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  1. ScreenIT

    SciScore for 10.1101/2020.07.25.20162107: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Search Strategy: We retrieved all articles reporting viral dynamics and/or the duration of shedding of SARS-CoV-2, SARS-CoV-1 or MERS-CoV in various specimens through systematic searches of major databases including Medline, EMBASE, Europe PMC, pre-print databases (MedRxiv, BioRxiv) and the grey literature from 1 January 2003 to 6th June 2020 using Medical Subject Headings (MeSH) terms (Supplementary Material).
    Medline
    suggested: (MEDLINE, RRID:SCR_002185)
    EMBASE
    suggested: (EMBASE, RRID:SCR_001650)
    BioRxiv
    suggested: (bioRxiv, RRID:SCR_003933)
    MeSH
    suggested: (MeSH, RRID:SCR_004750)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Our study has limitations. First, some patients in the included studies received a range of treatments, including steroids and antivirals, which may have modified the shedding dynamics. Second, most of the included studies are case series, which are particularly vulnerable to selection bias. Third, our meta-analysis identified substantial study heterogeneity, likely due to differences in study population, follow up and management approaches. Further, shedding duration is reported as median ± IQR for most studies, but meta-analysis necessitates conversion to mean ± SD.6 The validity of this conversion is based on the assumption that duration of viral shedding is normally distributed, which may not apply to some studies. Lastly, although there is likely a broad overlap, the true clinical window of infectious shedding may not entirely align with viral culture duration. We identified a systematic review of SARS CoV-2 viral load kinetics that included studies published up until 12 May 2020.86 This review included many studies that did not meet our eligibility criteria, including 26 case reports and 13 case series involving <5 individuals; these are prone to significant selection bias, reporting atypical cases with prolonged viral shedding. Additionally, the review included studies that reported viral shedding duration from the time of hospital admission or initial PCR positivity, rather than symptom onset. Furthermore, no meta-analysis of the duration of viral shedding was perform...

    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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1016/s2666-5247(20)30172-5
  3. ScreenIT

    SciScore for 10.1101/2020.07.25.20162107: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.Randomizationnot detected.Blindingnot detected.Power Analysisnot detected.Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Flowchart describing study selection Records identified through MEDLINE and EMBASE (n = 948) Records identified through preprint servers (n = 373) Records screened based on title and abstract (n = 1486) Additional records i (n = 165) Records exclud (n = 1136) Articles exclude (n = 252) Records assessed for eligibility (n = 350) 206 not eligible 17 duplicates 29 removed after disc Studies included Studies included Studies included SARS-CoV-2 (n = 79) SARS-CoV-1 (n =8) MERS-CoV (n = 11) : Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009).
    MEDLINE
    suggested: (MEDLINE, RRID:SCR_002185)
    EMBASE
    suggested: (EMBASE, RRID:SCR_001650)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:

    Our study has limitations. First, some patients in the included studies received a range of treatments, including steroids and antivirals, which may have modified the shedding dynamics. Second, most of the included studies are case series, which are particularly vulnerable to selection bias. Third, our meta-analysis identified substantial study heterogeneity, likely due to differences in study population, follow up and management approaches. Further, shedding duration is reported as median ± IQR for most studies, but meta-analysis necessitates conversion to mean ± SD.6 The validity of this conversion is based on the assumption that duration of viral shedding is normally distributed, which may not apply to some studies. Lastly, although there is likely a broad overlap, the true clinical window of infectious shedding may not entirely align with viral culture duration. We identified a systematic review of SARS CoV-2 viral load kinetics that included studies published up until 12 May 2020.86 This review included many studies that did not meet our eligibility criteria, including 26 case reports and 13 case series involving <5 individuals; these are prone to significant selection bias, reporting atypical cases with prolonged viral shedding. Additionally, the review included studies that reported viral shedding duration from the time of hospital admission or initial PCR positivity, rather than symptom onset. Furthermore, no metaanalysis of the duration of viral shedding was performed. This review provides detailed understanding about the available evidence to date on viral dynamics of SARS-CoV-2 and has implications for pandemic control strategies and infection control practices. Although SARS-CoV-2 RNA shedding can be prolonged in respiratory and stool samples, the duration of viable virus is short-lived, with culture success associated with viral load levels. No study has reported live SARS-CoV-2 beyond day nine to date. Most studies detected the SARS-CoV-2 viral load peak within the first week of illness. These findings highlight that isolation practices should be commenced with the start of first symptoms including mild and atypical symptoms that precede more typical COVID-19 symptoms. This systematic review underscores the importance of early case finding and isolation, as well as public education on the spectrum of illness. However, given potential delays in the isolation of patients, effective containment of SARS-CoV-2 may be challenging even with an early detection and isolation strategy.87 Authors contributions: M. Cevik: conceptualisation, methodology, investigation, data curation, writing – original draft. M. Tate: investigation, data curation, writing – original draft; O Lloyd: investigation, data curation, writing – review and editing; A. E. Maraolo: formal analysis, writing – original draft; J. Schafers: investigation, data curation, writing – review and editing; A Ho: conceptualisation, methodology, data curation, writing – original draft, supervision. Financial support and sponsorship No financial support received

    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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.

  4. ScreenIT

    SciScore for 10.1101/2020.07.25.20162107: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.Randomizationnot detected.Blindingnot detected.Power Analysisnot detected.Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Flowchart describing study selection Records identified through MEDLINE and EMBASE (n = 948) Records identified through preprint servers (n = 373) Records screened based on title and abstract (n = 1486) Additional records (n = 165) Records exclud (n = 1136) Articles exclude (n = 252) Records assessed for eligibility (n = 350) 206 not eligibl 17 duplicates 29 removed after dis Studies included Studies included Studies included SARS-CoV-2 (n = 79) SARS-CoV-1 (n =8) MERS-CoV (n = 11) : Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009).
    MEDLINE
    suggested: (MEDLINE, RRID:SCR_002185)
    EMBASE
    suggested: (EMBASE, RRID:SCR_001650)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:

    Our study has limitations. First, some patients in the included studies received a range of treatments, including steroids and antivirals, which may have modified the shedding dynamics. Second, most of the included studies are case series, which are particularly vulnerable to selection bias. Third, our meta-analysis identified substantial study heterogeneity, likely due to differences in study population, follow up and management approaches. Further, shedding duration is reported as median ± IQR for most studies, but meta-analysis necessitates conversion to mean ± SD.6 The validity of this conversion is based on the assumption that duration of viral shedding is normally distributed, which may not apply to some studies. Lastly, although there is likely a broad overlap, the true clinical window of infectious shedding may not entirely align with viral culture duration. We identified a systematic review of SARS CoV-2 viral load kinetics that included studies published up until 12 May 2020.86 This review included many studies that did not meet our eligibility criteria, including 26 case reports and 13 case series involving <5 individuals; these are prone to significant selection bias, reporting atypical cases with prolonged viral shedding. Additionally, the review included studies that reported viral shedding duration from the time of hospital admission or initial PCR positivity, rather than symptom onset. Furthermore, no metaanalysis of the duration of viral shedding was performed. This review provides detailed understanding about the available evidence to date on viral dynamics of SARS-CoV-2 and has implications for pandemic control strategies and infection control practices. Although SARS-CoV-2 RNA shedding can be prolonged in respiratory and stool samples, the duration of viable virus is short-lived, with culture success associated with viral load levels. No study has reported live SARS-CoV-2 beyond day nine to date. Most studies detected the SARS-CoV-2 viral load peak within the first week of illness. These findings highlight that isolation practices should be commenced with the start of first symptoms including mild and atypical symptoms that precede more typical COVID-19 symptoms. This systematic review underscores the importance of early case finding and isolation, as well as public education on the spectrum of illness. However, given potential delays in the isolation of patients, effective containment of SARS-CoV-2 may be challenging even with an early detection and isolation strategy.87 Authors contributions: M. Cevik: conceptualisation, methodology, investigation, data curation, writing – original draft. M. Tate: investigation, data curation, writing – original draft; O Lloyd: investigation, data curation, writing – review and editing; A. E. Maraolo: formal analysis, writing – original draft; J. Schafers: investigation, data curation, writing – review and editing; A Ho: conceptualisation, methodology, data curation, writing – original draft, supervision. Financial support and sponsorship No financial support received

    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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.

  5. ScreenIT

    SciScore for 10.1101/2020.07.25.20162107: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.Randomizationnot detected.Blindingnot detected.Power Analysisnot detected.Sex as a biological variableWhen adjusted for the proportion of male subjects in a multivariable analysis, mean age was positively associated with the mean duration of viral shedding in URT specimens (p = 0.003).

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Methods: Medline, EMBASE, Europe PMC, preprint servers and grey literature were searched to retrieve all articles reporting viral dynamics and duration of SARS-CoV-2, SARS-CoV-1 and MERS-CoV shedding.
    Medline
    suggested: (MEDLINE, SCR_002185)
    METHODS Search Strategy We retrieved all articles reporting viral dynamics and/or the duration of shedding of SARS-CoV-2, SARS-CoV-1 or MERS-CoV in various specimens through systematic searches of major databases including Medline, EMBASE, Europe PMC, pre-print databases (MedRxiv, BioRxiv) and the grey literature from 1 January 2003 to 6th June 2020 using Medical Subject Headings (MeSH) terms (Supplementary Material).
    EMBASE
    suggested: (EMBASE, SCR_001650)
          <div style="margin-bottom:8px">
        <div><b>BioRxiv</b></div>
        <div>suggested: (bioRxiv, <a href="https://scicrunch.org/resources/Any/search?q=SCR_003933">SCR_003933</a>)</div>
      </div>
    
      <div style="margin-bottom:8px">
        <div><b>MeSH</b></div>
        <div>suggested: (MeSH, <a href="https://scicrunch.org/resources/Any/search?q=SCR_004750">SCR_004750</a>)</div>
      </div>
    </td></tr></table>

    Data from additional tools added to each annotation on a weekly basis.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.

  6. Version published to 10.1101/2020.07.25.20162107 on medRxiv