Interleukin‐6 in Covid‐19: A systematic review and meta‐analysis

  1. Eric A. Coomes
  2. Hourmazd Haghbayan

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Abstract

Coronaviruses may activate dysregulated host immune responses. As exploratory studies have suggested that interleukin‐6 (IL‐6) levels are elevated in cases of complicated Covid‐19, we undertook a systematic review and meta‐analysis to assess the evidence in this field. We systematically searched MEDLINE and EMBASE for studies investigating the immunological response in Covid‐19; additional grey literature searches were undertaken. Study selection and data abstraction was undertaken independently by two authors. Meta‐analysis was undertaken using random effects models to compute ratios of means with 95% confidence intervals (95%CIs). Eight published studies and two preprints (n = 1798) were eligible for inclusion. Meta‐analysis of mean IL‐6 concentrations demonstrated 2.9‐fold higher levels in patients with complicated Covid‐19 compared with patients with noncomplicated disease (six studies; n = 1302; 95%CI, 1.17‐7.19; I 2 = 100%). Consistent results were found in sensitivity analyses exclusively restricted to studies comparing patients requiring ICU admission vs no ICU admission (two studies; n = 540; ratio of means = 3.24; 95%CI, 2.54‐4.14; P  < .001; I 2 = 87%). Nine of ten studies were assessed to have at least moderate risk of bias. In patients with Covid‐19, IL‐6 levels are significantly elevated and associated with adverse clinical outcomes. Inhibition of IL‐6 may be a novel target for therapeutics for the management of dysregulated host responses in patients with Covid‐19 and high‐quality studies of intervention in this field are urgently required.

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  1. Version published to 10.1002/rmv.2141
  2. ScreenIT

    SciScore for 10.1101/2020.03.30.20048058: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    RandomizationArticles eligible for inclusion were observational cohort, case-control, or randomized controlled trials (RCTs) characterizing either serum IL-6 dynamics or therapeutic response to tocilizumab in adult or pediatric patients diagnosed with COVID-19.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    This systematic review was undertaken with methodology in accordance with Cochrane Handbook,25 and reporting consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
    Cochrane
    suggested: (Cochrane Library, RRID:SCR_013000)
    , pre-publication manuscripts in pre-print servers (Biorxiv, Medrxiv, and Chinxiv), and Google Scholar, and for planned trials in clinical trial registries (clinicaltrials
    Biorxiv
    suggested: (bioRxiv, RRID:SCR_003933)
    Google Scholar
    suggested: (Google Scholar, RRID:SCR_008878)
    We then conducted an expanded Ovid Medline and Embase database search from January 1, 2020 to March 15, 2020 for all published cohort studies reporting COVID-19 patient characteristics and outcomes (see Appendix for full search strategy) to ensure all studies reporting IL-6 levels in COVID-19 were identified.
    Embase
    suggested: (EMBASE, RRID:SCR_001650)
    Data analysis was undertaken utilizing Microsoft Excel version 16.35 (
    Microsoft Excel
    suggested: (Microsoft Excel, RRID:SCR_016137)
    (Microsoft, Redmond, United States, 2020) and Review Manager version 5.3.5 (Cochrane Collaboration, Copenhagen, Denmark, 2014).
    Review Manager
    suggested: None
    Cochrane Collaboration
    suggested: None

    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:
    The results of the preliminary investigation of tocilizumab in severe COVID-19 are promising, but also suffer from important limitations.43 In patients receiving tocilizumab, all experienced rapid resolution of fever, symptomatic improvement, and the majority had early reductions in oxygen requirements and radiographic abnormalities. In contrast to other cohorts, which have demonstrated mortality rates of up to 61.5% amongst critically ill patients (and the pooled mortality of 22% among all hospitalized patients seen in our meta-analysis), no patients died in this study after administration of tocilizumab.48 Further, despite intensive immunosuppression, no patients developed superimposed nosocomial pulmonary infections nor significant adverse drug reactions. This study is limited by its small sample size, non-randomised intervention, lack of comparator arm, and retrospective design, but the results are biologically plausible as the included patients all had elevated IL-6 levels which decreased progressively in parallel to clinical and radiographical improvement.43 Despite these early signals of benefit, the results of several ongoing clinical studies should be awaited to better define the role of tocilizumab in the therapy of COVID-19.49-53 Such studies benefit from larger sample sizes, prospective recruitment of patients with a wide spectrum of disease severity, and in some protocols, the use of active controls. Further, sarilumab, another monoclonal antibody blocking the IL...

    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 10.1101/2020.03.30.20048058v1 on medRxiv