Profile of Circulatory Cytokines and Chemokines in Human Coronaviruses: A Systematic Review and Meta-Analysis

  1. Ayat Zawawi
  2. Abdallah Y. Naser
  3. Hassan Alwafi
  4. Faisal Minshawi

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Abstract

SARS, MERS, and COVID-19 share similar characteristics. For instance, the genetic homology of SARS-CoV-2 compared to SARS-CoV and MERS-CoV is 80% and 50%, respectively, which may cause similar clinical features. Moreover, uncontrolled release of proinflammatory mediators (also called a cytokine storm) by activated immune cells in SARS, MERS, and COVID-19 patients leads to severe phenotype development.

Aim

This systematic review and meta-analysis aimed to evaluate the inflammatory cytokine profile associated with three strains of severe human coronavirus diseases (MERS-CoV, SARS-CoV, and SARS-CoV-2).

Method

The PubMed, Embase, and Cochrane Library databases were searched for studies published until July 2020. Randomized and observational studies reporting the inflammatory cytokines associated with severe and non-severe human coronavirus diseases, including MERS-CoV, SARS-CoV, and SARS-CoV-2, were included. Two reviewers independently screened articles, extracted data, and assessed the quality of the included studies. Meta-analysis was performed using a random-effects model with a 95% confidence interval to estimate the pooled mean of inflammatory biomarkers.

Results

A high level of circulating IL-6 could be associated with the severity of infection of the three coronavirus strains. TNF, IL-10, and IL-8 are associated with the severity of COVID-19. Increased circulating levels of CXCL10/IP10 and CCL2/MCP-1 might also be related to the severity of MERS.

Conclusion

This study suggests that the immune response and immunopathology in the three severe human coronavirus strains are somewhat similar. The findings highlight that nearly all studies reporting severe cases of SARS, MERS, and COVID-19 have been associated with elevated levels of IL-6. This could be used as a potential therapeutic target to improve patients’ outcomes in severe cases.

Systematic Review Registration

PROSPERO registration 94 number: CRD42020209931.

Article activity feed

  1. Version published to 10.3389/fimmu.2021.666223
  2. ScreenIT

    SciScore for 10.1101/2021.02.16.21251673: (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
    A detailed electronic search on bibliographic databases including Medline, Embase, and Cochrane Library databases was performed from inception to July 2020.
    Medline
    suggested: (MEDLINE, RRID:SCR_002185)
    Embase
    suggested: (EMBASE, RRID:SCR_001650)
    Cochrane Library
    suggested: (Cochrane Library, RRID:SCR_013000)
    Keywords, Emtree and MeSH terms were used with both English and American spellings.
    MeSH
    suggested: (MeSH, RRID:SCR_004750)
    All analysis was performed using STATA 15.0.
    STATA
    suggested: (Stata, RRID:SCR_012763)

    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:
    Limitation of the study: Several limitations exist within our study; the most important is the observational nature of studies and significant heterogeneity in study results. However, high statistical heterogeneity is more frequent in meta-analyses of prevalence and descriptive studies (79). This can be explained because of the different patient populations, underlying comorbidities and coinfections, variant treatments and follow-up. The different time of blood collections, control donors, and cytokine detection assays can also explain the heterogenicity. Another significant limitation is the variability in laboratory assays used to measure the level of serum cytokines, as local laboratories have different normal ranges based on local data. This confounding variable can somewhat undermine our results and thus, our data should be interpreted as such, keeping in mind this important limitation. The number of studies included on SARS and MERS compared to COVID-19 were low. However, this can be explained as the COVID-19 infection caused a major threat to the whole population compared to SARS and MERS.

    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.

  3. Version published to 10.1101/2021.02.16.21251673v1 on medRxiv