Beneficial and harmful outcomes of tocilizumab in severe COVID‐19: A systematic review and meta‐analysis

  1. Manuel Rubio‐Rivas
  2. Carlos G. Forero
  3. José María Mora‐Luján
  4. Abelardo Montero
  5. Francesc Formiga
  6. Narcís A. Homs
  7. Joan Albà‐Albalate
  8. Laura Sánchez
  9. Jordi Rello
  10. Xavier Corbella

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Abstract

Introduction

The results of studies of tocilizumab (TCZ) in COVID‐19 are contradictory. Our study aims to update medical evidence from controlled observational studies and randomized clinical trials (RCTs) on the use of TCZ in hospitalized patients with COVID‐19.

Methods

We searched the following databases from January 1, 2020 to April 13, 2021 (date of the last search): MEDLINE database through the PubMed search engine and Scopus, using the terms (“COVID‐19" [Supplementary Concept]) AND "tocilizumab" [Supplementary Concept]).

Results

Sixty four studies were included in the present study: 54 were controlled observational studies (50 retrospective and 4 prospective) and 10 were RCTs. The overall results provided data from 20,616 hospitalized patients with COVID‐19: 7668 patients received TCZ in addition to standard of care (SOC) (including 1915 patients admitted to intensive care units (ICU) with reported mortality) and 12,948 patients only receiving SOC (including 4410 patients admitted to the ICU with reported mortality). After applying the random‐effects model, the hospital‐wide (including ICU) pooled mortality odds ratio (OR) of patients with COVID‐19 treated with TCZ was 0.73 (95% confidence interval (CI) = 0.56–0.93). The pooled hospital‐wide mortality OR was 1.25 (95% CI = 0.74–2.18) in patients admitted at conventional wards versus 0.66 (95% CI = 0.59–0.76) in patients admitted to the ICU. The pooled OR of hospital‐wide mortality (including ICU) of COVID‐19 patients treated with TCZ plus corticosteroids (CS) was 0.67 (95% CI = 0.54–0.84). The pooled in‐hospital mortality OR was 0.71 (95% CI = 0.35–1.42) when TCZ was early administered (≤10 days from symptom onset) versus 0.83 (95% CI 0.48–1.45) for late administration (>10 days from symptom onset). The meta‐analysis did not find significantly higher risk for secondary infections in COVID‐19 patients treated with TCZ.

Conclusions

TCZ prevented mortality in patients hospitalized for COVID‐19. This benefit was seen to a greater extent in patients receiving concomitant CS and when TCZ administration occurred within the first 10 days after symptom onset.

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  1. Version published to 10.1002/phar.2627
  2. ScreenIT

    SciScore for 10.1101/2020.09.05.20188912: (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
    We searched the following databases from 1 January to 21 August 2020: MEDLINE database through the PubMed search engine, Scopus, and the medRxiv repository, using the terms “COVID-19” [MesH]) AND “Tocilizumab” [MesH].
    MEDLINE
    suggested: (MEDLINE, RRID:SCR_002185)
    PubMed
    suggested: (PubMed, RRID:SCR_004846)
    MesH
    suggested: (MeSH, RRID:SCR_004750)
    Statistical analysis was performed by IBM SPSS Statistics for Windows, Version 26.0.
    SPSS
    suggested: (SPSS, RRID:SCR_002865)

    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:
    As mentioned, the first and major limitation of this SRMA is the lack of data from RCTs. In their absence, the present revision was based on observational studies; therefore, conclusions should be considered with caution. Moreover, a second limitation is the fact that most of the included studies were retrospective in nature. A third limitation is the heterogeneity regarding the study population (I2 index) and the potential risk of detected bias. Fourth, variations in criteria for prescribing TCZ may not be ruled out in the included studies, although most of them indicated TCZ use to treat those patients with severe COVID-19 with the systemic hyperinflammatory state. Fifth, important factors influencing the effect of TCZ on clinical outcomes such as the baseline characteristics of the patients included, the average time from symptoms onset to TCZ administration, the clinical severity of the disease at the time of TCZ administration, the doses and the form of administration used, the hospital site from where TCZ was indicated, or the use of concomitant drug regimens could not be evaluated in-depth, since they were not uniformly provided by the included studies. Sixth, in the vast majority of included studies, there is a lack of subgroup analyses according to age, sex or underlying conditions, concomitant treatments, the requirement of mechanical ventilation or ICU admission, and comparisons between ventilated and non-ventilated patients. Finally, there is a wide range in the m...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04320615CompletedA Study to Evaluate the Safety and Efficacy of Tocilizumab i…

    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 10.1101/2020.09.05.20188912 on medRxiv