Tocilizumab in hospitalized patients with COVID‐19: Clinical outcomes, inflammatory marker kinetics, and safety

  1. Joshua A. Hill
  2. Manoj P. Menon
  3. Shireesha Dhanireddy
  4. Mark M. Wurfel
  5. Margaret Green
  6. Rupali Jain
  7. Jeannie D. Chan
  8. Joanne Huang
  9. Danika Bethune
  10. Cameron Turtle
  11. Christine Johnston
  12. Hu Xie
  13. Wendy M. Leisenring
  14. H. Nina Kim
  15. Guang‐Shing Cheng

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Abstract

Coronavirus disease 2019 (COVID‐19) due to infection with severe acute respiratory syndrome coronavirus 2 causes substantial morbidity. Tocilizumab, an interleukin‐6 receptor antagonist, might improve outcomes by mitigating inflammation. We conducted a retrospective study of patients admitted to the University of Washington Hospital system with COVID‐19 and requiring supplemental oxygen. Outcomes included clinical improvement, defined as a two‐point reduction in severity on a six‐point ordinal scale or discharge, and mortality within 28 days. We used Cox proportional‐hazards models with propensity score inverse probability weighting to compare outcomes in patients who did and did not receive tocilizumab. We evaluated 43 patients who received tocilizumab and 45 who did not. Patients receiving tocilizumab were younger with fewer comorbidities but higher baseline oxygen requirements. Tocilizumab treatment was associated with reduced C‐reactive protein, fibrinogen, and temperature, but there were no meaningful differences in time to clinical improvement (adjusted hazard ratio [aHR], 0.92; 95% confidence interval [CI], 0.38–2.22) or mortality (aHR, 0.57; 95% CI, 0.21–1.52). A numerically higher proportion of tocilizumab‐treated patients had subsequent infections, transaminitis, and cytopenias. Tocilizumab did not improve outcomes in hospitalized patients with COVID‐19. However, this study was not powered to detect small differences, and there remains the possibility for a survival benefit.

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  1. Version published to 10.1002/jmv.26674
  2. ScreenIT

    SciScore for 10.1101/2020.08.05.20169060: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: This study was approved by the UW Institutional Review
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    SAS version 9.4 (SAS Institute, Cary, NC) and RStudio were used for analyses.
    SAS Institute
    suggested: (Statistical Analysis System, RRID:SCR_008567)
    Literature review: A literature search was conducted on July 10, 2020 via PubMed using the following search terms: (
    PubMed
    suggested: (PubMed, RRID:SCR_004846)

    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 primary limitations of our study include those inherent to a retrospective, non-randomized design. Higher baseline severity status in the tocilizumab cohort, as well as other differences in patient characteristics, resulted in imbalances in the patient cohorts. To control for some of these differences, we compared outcomes within baseline severity categories and performed IPTW adjusted analyses. For most comparisons, we were limited to detecting relatively large differences. Strengths of this study include the relatively large cohort of patients requiring noninvasive and invasive oxygenation, along with careful adjustment for differences in patient characteristics and other confounders. We performed an RMST analysis for time to clinical improvement that is novel to studies of tocilizumab for COVID-19 and provide a tangible measure of treatment effect.(32) We performed comprehensive chart review and data abstraction to describe and analyze a variety of clinical and laboratory outcomes to evaluate the potential benefits and side effects of tocilizumab therapy, including novel comparisons of thrombotic events and resolution of sepsis physiology. Our data were not confounded by steroids, and most patients did not receive remdesivir. In conclusion, there was no clear evidence of improved clinical outcomes among hospitalized patients with COVID-19 who received one dose of 400 mg of tocilizumab without concurrent steroids or effective antivirals. Tocilizumab was associated with ...

    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 10.1101/2020.08.05.20169060v1 on medRxiv