Impact of tocilizumab administration on mortality in severe COVID-19

  1. Andrew Tsai
  2. Oumou Diawara
  3. Ronald G. Nahass
  4. Luigi Brunetti

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Abstract

The novel coronavirus disease 2019 (COVID-19) worldwide pandemic has placed a significant burden on hospitals and healthcare providers. The immune response to this disease is thought to lead to an aberrant inflammatory response or cytokine storm, which contributes to the severity of illness. There is an urgent need to confirm whether the use of tocilizumab provides a benefit in individuals with COVID-19. A single-center propensity-score matched cohort study, including all consecutive COVID-19 patients, admitted to the medical center who were either discharged from the medical center or expired between March 1, 2020, and May 5, 2020, was performed. Patients were stratified according to the receipt of tocilizumab for cytokine storm and matched to controls using propensity scores. The primary outcome was in-hospital mortality. A total of 274 patients meeting inclusion and exclusion criteria were identified and 132 patients were included in the matched dataset (tocilizumab = 66; no tocilizumab = 66). Approximately 73% of the patients were male. Hypertension (55%), diabetes mellitus (31%), and chronic pulmonary disease (15%) were the most common comorbidities present. There were 18 deaths (27.3%) in the tocilizumab group and 18 deaths (27.3%) in the no tocilizumab group (odds ratio, 1.0; 95% confidence interval, 0.465 – 2.151; p = 1.00). Advanced age, history of myocardial infarction, dementia, chronic pulmonary disease, heart failure, and malignancy were significantly more common in patients who died. The current analysis does not support the use of tocilizumab for the management of cytokine storm in patients with COVID-19. Use of this therapeutic agent should be limited to the context of a clinical trial until more evidence is available.

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  1. ScreenIT

    SciScore for 10.1101/2020.07.30.20114959: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The study was granted expedited approval by the Institutional Review Board (IRB20-20).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Statistical Analysis: Propensity scores were generated using PS Match in SPSS v26.0 (IBM Corporation).
    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:
    There are several limitations to this study. Patients primarily received a single flat 400 mg dose of tocilizumab intravenously, with some receiving a second dose if an additional benefit was considered likely by the treating clinician. The current practice utilizes weight-based dosing for T-cell-induced cytokine release syndrome, and elevations in CRP have been noted to be inversely related to tocilizumab clearance from the body. Therefore, our patients may have been at risk of being underdosed. However, the fixed dosing strategy was based mainly on positive results recently published by Xu and colleagues.12 Additionally, serum CRP concentration was included in the propensity score matching. Furthermore, population pharmacokinetic analysis of tocilizumab supports a flat dosing approach due to reductions in the variability of drug exposure among patient weight categories.22 Other limitations of our study include the retrospective design, as it may have increased the risk of selection bias toward more severe patients in the tocilizumab arm. While propensity score matching was utilized and resulted in well-matched groups, residual confounding cannot be excluded. Finally, given the small sample size, a type II error is possible. Remarkably, the mortality was identical in both treatment and control groups, suggesting that even if there is a difference in mortality, it may be modest at best. While the results of the current study were unexpected, recent preliminary reports of rand...

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

    IdentifierStatusTitle
    NCT04331808Active, not recruitingCORIMUNO-19 - Tocilizumab Trial - TOCI (CORIMUNO-TOCI)
    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

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  2. Version published to 10.1038/s41598-020-76187-y
  3. Version published to 10.1101/2020.07.30.20114959v1 on medRxiv