Tocilizumab efficacy in COVID-19 patients is associated with respiratory severity-based stages

  1. Melchor Alvarez-Mon
  2. Angel Asunsolo
  3. José Sanz
  4. Benjamin Muñoz
  5. José Alberto Arranz-Caso
  6. Maria Novella Mena
  7. Cristina Hernández-Gutiérrez
  8. Jorge Navarro
  9. Maria Cristina Lozano Duran
  10. Juan Arévalo Serrano
  11. Rocío Henche Sanchez
  12. Lara Bravo Quiroga
  13. Julio Flores Segovia
  14. Marta Garcia Sanchez
  15. Aida Gutierrez Garcia
  16. Ana Pérez
  17. Marta Herrero
  18. Nieves Plana
  19. Daniel Troncoso
  20. Gorjana Rackov
  21. Carlos Martinez-A
  22. Dimitrios Balomenos
  23. for The Medicine-COVID19 HUPA group

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Abstract

Background

Tocilizumab treatment is investigated, and effectiveness in ICU-admitted COVID-19 patients has been reported. Although controversy exists regarding the efficacy of tocilizumab treatment, it has been suggested that tocilizumab might show positive results depending on patient severity status. We examined an association between tocilizumab and distinct disease severity stages.

Methods and Findings

From March 3 to March 23 2020, 494 consecutively admitted COVID-19 patients received tocilizumab or standard treatment alone. Data were obtained retrospectively. Clinical respiratory severity (CRS) stages were defined by patient oxygenation status and were also associated to scores of WHO clinical progression scale. We categorized patients in three stages, mild/moderate CRS1 (FiSpO 2 <0.35; WHO score 5), moderate/severe CRS2 (FiO 2 =0.5/high flow mask; WHO score 6) and severe/critical CRS3 (FiO 2 <80%/high flow/prone position or mechanical ventilation; score>6). The primary outcome was the composite of death or ICU admission in patients of stages CRS1, CRS2, and CRS3, as well as in total patients. We also addressed mortality alone in total patients. Kaplan-Maier curves, Cox proportional regression and inverse probability weighting marginal structural models were used. We conducted the study from March 3 to April 7 2020 with broad-ranged severity patients; 167 tocilizumab-treated and 327 untreated. CRS1 patients showed no apparent benefit after treatment, while the risk of the primary outcome was greatly reduced in CRS2 treated participants ((HR=0.22; 95% CI (0.16-0.44)). Moreover, tocilizumab treatment was associated with significantly decreased CRS2 patient proportion that reached the outcome compared to non-treated controls (27.8.0% vs. 65.4%; p<0.001). Severe/critical CRS3 patients, also showed benefit after treatment (HR=0.38; 95% CI (0.16-90)), although not as robust as was that of CRS2 treated individuals. Tocilizumab was associated with reduced outcome risk in total patients (HR=0.42; 95% CI (0.26-0.66)) after CRS adjustment, but not if CRS classification was not accounted as confounding factor (HR=1.19; 95% CI (0.84-1.69)). The outcome of mortality alone upon tocilizumab treatment was significant (HR=0.58; 95% CI (0.35-0.96)) after accounting for CRS classification.

Conclusions

Tocilizumab treatment is associated with reduced COVID-19 escalation in CRS2 patients, suggesting efficacy in moderate/severe non-ICU-admitted patients. CRS classification could represent an essential confounding factor in evaluating tocilizumab in studies of broad-ranged severity patients.

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    SciScore for 10.1101/2021.03.04.21252167: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The study was approved by the institutional review board of the University Hospital Prince of Asturias (HUPA0406/20).
    Consent: All patients provided informed consent before starting treatment.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    All statistical analyses were performed using STATA v14 SE or SPSSv26.
    STATA
    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:
    Our study has the following limitations. First, the study was performed in one hospital and was not randomized as tocilizumab treatment was prioritized for worsening patients within the same CRS stage. Second, CRS3 stage patient population did not get the support of MV due to the near collapse conditions in Spain at the time of the study. Third, our study was not blinded and therefore a bias for ICU admission could favor untreated patients; this limitation was minimized as analysis of overall hospital mortality as an endpoint showed benefit after tocilizumab treatment. The strengths of this study include the newly applied patient classification in CRS stages. This later point is crucial since previous studies mostly found no tocilizumab effect when considering patients of wide range disease severity. Several analyses were performed, with consistent results across the models. Oxygen supplementation was uniform especially for the CRS2 stage, as the vast majority of the patients were managed on the floor (i.e. not in the ICU) on steady FiO2, avoiding the bias of oxygen supplementation in influencing the outcome. Finally, although differences in tocilizumab efficacy have been suggested to depend on disease stage, here we show this in a single study that encompassed three disease stages.

    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

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  2. Version published to 10.1101/2021.03.04.21252167 on medRxiv