Systematic review and meta-analysis of anakinra, sarilumab, siltuximab and tocilizumab for COVID-19

  1. Fasihul A Khan
  2. Iain Stewart
  3. Laura Fabbri
  4. Samuel Moss
  5. Karen Robinson
  6. Alan Robert Smyth
  7. Gisli Jenkins

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Abstract

There is accumulating evidence for an overly activated immune response in severe COVID-19, with several studies exploring the therapeutic role of immunomodulation. Through systematic review and meta-analysis, we assess the effectiveness of specific interleukin inhibitors for the treatment of COVID-19.

Methods

Electronic databases were searched on 7 January 2021 to identify studies of immunomodulatory agents (anakinra, sarilumab, siltuximab and tocilizumab) for the treatment of COVID-19. The primary outcomes were severity on an Ordinal Scale measured at day 15 from intervention and days to hospital discharge. Key secondary endpoints included overall mortality.

Results

71 studies totalling 22 058 patients were included, 6 were randomised trials. Most studies explored outcomes in patients who received tocilizumab (60/71). In prospective studies, tocilizumab was associated with improved unadjusted survival (risk ratio 0.83, 95% CI 0.72 to 0.96, I 2 =0.0%), but conclusive benefit was not demonstrated for other outcomes. In retrospective studies, tocilizumab was associated with less severe outcomes on an Ordinal Scale (generalised OR 1.34, 95% CI 1.10 to 1.64, I 2 =98%) and adjusted mortality risk (HR 0.52, 95% CI 0.41 to 0.66, I 2 =76.6%). The mean difference in duration of hospitalisation was 0.36 days (95% CI −0.07 to 0.80, I 2 =93.8%). There was substantial heterogeneity in retrospective studies, and estimates should be interpreted cautiously. Other immunomodulatory agents showed similar effects to tocilizumab, but insufficient data precluded meta-analysis by agent.

Conclusion

Tocilizumab was associated with a lower relative risk of mortality in prospective studies, but effects were inconclusive for other outcomes. Current evidence for the efficacy of anakinra, siltuximab or sarilumab in COVID-19 is insufficient, with further studies urgently needed for conclusive findings.

PROSPERO registration number

CRD42020176375.

Article activity feed

  1. Version published to 10.1136/thoraxjnl-2020-215266
  2. Version published to 10.1101/2020.04.23.20076612v5 on medRxiv
  3. Version published to 10.1101/2020.04.23.20076612v3 on medRxiv
  4. Version published to 10.1101/2020.04.23.20076612v4 on medRxiv
  5. Version published to 10.1101/2020.04.23.20076612v2 on medRxiv
  6. ScreenIT

    SciScore for 10.1101/2020.04.23.20076612: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    RandomizationThe GenOR provides a measure of the likelihood that the intervention leads to a better rather than worse outcome when compared to a randomly chosen control (17).
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Search strategy and study selection: Electronic database searches were carried out in MEDLINE (1946 to latest) and EMBASE (1974 to latest), and ongoing clinical trial registries (clinicaltrials.gov and EU Clinical Trials Register), with the last search carried out on 7th January 2021.
    MEDLINE
    suggested: (MEDLINE, RRID:SCR_002185)
    EMBASE
    suggested: (EMBASE, RRID:SCR_001650)
    Unpublished and ongoing studies were identified by searching pre-print servers including medRxiv and bioRxiv.
    bioRxiv
    suggested: (bioRxiv, RRID:SCR_003933)
    Randomised studies were assessed using the Cochrane risk-of-bias tool for randomised trials (RoB2)(15).
    Cochrane
    suggested: (Cochrane Library, RRID:SCR_013000)
    16 (StataCorp, College Station, TX, USA).
    StataCorp
    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:
    In this review we highlight multiple limitations and considerable sources of inter-study heterogeneity. The majority of included studies were non-randomised cohorts of relatively modest size. Although most studies necessitated respiratory failure requiring at least basic respiratory support, participant criteria were not entirely consistent across the studies. The dosage and delivery of therapy varied across many of the non-randomised studies, and in nearly all studies patients were on concomitant medications such as antivirals, hydroxychloroquine and steroids with administration at the discretion of the treating physician, precluding causal associations of specific interleukin inhibitors with outcomes. Study outcomes were heterogeneous and a combination of clinical, laboratory and radiological outcomes were reported, rather than a single consistent endpoint. Furthermore, there was inconsistency in the duration of follow up and timing of reported outcomes. Individual patient data (IPD) may have mitigated some of these limitations, but in a rapidly progressing area, seeking IPD was deemed to be unrealistic due to the associated delays. We also observed significant statistical heterogeneity as measured by I2, and therefore the findings of our meta-analysis should be interpreted with caution. We were unable to explain all the residual heterogeneity using the factors we assessed, although concomitant steroid use, route of drug administration and day outcome measured appeared to c...

    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.

  7. Version published to 10.1101/2020.04.23.20076612v1 on medRxiv