Effect of Tocilizumab in Hospitalized Patients with Severe COVID-19 Pneumonia: A Case-Control Cohort Study

  1. Benjamin Rossi
  2. Lee S. Nguyen
  3. Philippe Zimmermann
  4. Faiza Boucenna
  5. Louis Dubret
  6. Louise Baucher
  7. Helene Guillot
  8. Marie-Anne Bouldouyre
  9. Yves Allenbach
  10. Joe-Elie Salem
  11. Paul Barsoum
  12. Arezki Oufella
  13. Helene Gros

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Abstract

Tocilizumab, an anti-interleukin-6 receptor, administrated during the right timeframe may be beneficial against coronavirus-disease-2019 (COVID-19) pneumonia. All patients admitted for severe COVID-19 pneumonia (SpO2 ≤ 96% despite O2-support ≥ 6 L/min) without invasive mechanical ventilation were included in a retrospective cohort study in a primary care hospital. The treatment effect of a single-dose, 400 mg, of tocilizumab was assessed by comparing those who received tocilizumab to those who did not. Selection bias was mitigated using three statistical methods. Primary outcome measure was a composite of mortality and ventilation at day 28. A total of 246 patients were included (106 were treated with tocilizumab). Overall, 105 (42.7%) patients presented the primary outcome, with 71 (28.9%) deaths during the 28-day follow-up. Propensity-score-matched 84 pairs of comparable patients. In the matched cohort (n = 168), tocilizumab was associated with fewer primary outcomes than the control group (hazard ratio (HR) = 0.49 (95% confidence interval (95%CI) = 0.3–0.81), p-value = 0.005). These results were similar in the overall cohort (n = 246), with Cox multivariable analysis yielding a protective association between tocilizumab and primary outcome (adjusted HR = 0.26 (95%CI = 0.135–0.51, p = 0.0001), confirmed by inverse probability score weighting (IPSW) analysis (p < 0.0001). Analyses on mortality only, with 28 days of follow-up, yielded similar results. In this study, tocilizumab 400 mg in a single-dose was associated with improved survival without mechanical ventilation in patients with severe COVID-19.

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  1. Version published to 10.3390/ph13100317
  2. ScreenIT

    SciScore for 10.1101/2020.06.06.20122341: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: This retrospective study was approved by research ethics committee and registered on clinicaltrials.gov (NCT04366206).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    All analyses were performed using SPSS (IBM, Armonk, USA) and R software.
    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:
    With 20/100, 17.5% patients who died by day 10, these results are akin to ours (with 28.9% deaths by day 28).(13) Interestingly, in that study, tocilizumab administration protocol mentioned 800 mg twice in 87 patients and 800 mg three times in 13 patients, similar to that of ongoing trials with two injections of up to 800 mg each, within a 3-days period.(14, 15) In comparison, in our study, dosage of tocilizumab was 400 mg, injected once, following previous reports of improved outcomes chimeric antigen receptor-T-cell-induced CRS with 8 mg/kg dosage.(4) Further confirming our results with the same dosage would improve the availability of this costly biotherapy for which access may become an issue.(16) We acknowledge several limitations. First, the single-center nature of this study requires external validation, however, it guarantees homogeneity in the care of all patients, in our non-ICU departments dedicated to treat COVID-19 patients, i.e. observed differences are more likely to be due to tocilizumab. Second, although we aimed to mitigate selection bias using three statistical methods, including propensity-score matching, Cox multivariable and IPSW analyses, residual confounders are plausible.(8, 9) Due to comorbidities and lack of beds in the context of Covid-19 pandemic, a significant proportion of patients were labeled as limited, regarding possibilities of being transferred in critical care medicine department, as well as invasive mechanical ventilation. However, these...

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

    IdentifierStatusTitle
    NCT04366206RecruitingFactors Associated With Clinical Outcomes in Patients Hospit…

    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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  3. Version published to 10.1101/2020.06.06.20122341v1 on medRxiv