Clinical Characteristics and Outcomes of Critically ill Mechanically Ventilated COVID-19 Patients Receiving interleukin-6 Receptor Antagonists and Corticosteroid Therapy: A Multicenter International Observational Study

  1. Marwa Amer
  2. Mohammed Bawazeer
  3. Khalid Maghrabi
  4. Ahmed M. Kamel
  5. Abid Butt
  6. Talal Dahhan
  7. Eiad Kseibi
  8. Syed Moazzum Khurshid
  9. Mohammed Abujazar
  10. Razan Alghunaim
  11. Muath Rabee
  12. Maal Abualkhair
  13. Ali Al-Janoubi
  14. Abeer Turki AlFirm
  15. Ognjen Gajic
  16. Allan J. Walkey
  17. Jarrod M Mosier
  18. Igor Borisovich Zabolotskikh
  19. Oscar Y Gavidia
  20. Santiago Y. Teruel
  21. Michael A. Bernstein
  22. Karen Boman
  23. Vishakha K. Kumar
  24. Vikas Bansal
  25. Rahul Kashyap

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Abstract

Objectives

The interest in interleukin-6 receptor antagonists (IL-6RA) and steroids have increased recently due to their potential role as immunomodulatory effect in critically ill coronavirus disease (COVID-19). The magnitude of this therapy in subgroups of patients with invasive mechanical ventilation (MV) remains to be fully clarified. We compared the clinical characteristics and outcomes of patients requiring iMV, and receiving IL-6RA and steroids with different steroids regimens.

Design

International, multicenter, observational study derived from Viral Infection and Respiratory Illness University Study registry and conducted through Discovery Network, Society of Critical Care Medicine. Marginal structural modeling was used to adjust time-dependent confounders; observations were weighted using inverse probability of treatment weight. A sensitivity analysis was conducted for target trial design.

Setting

168 hospitals, 16 countries.

Patients

Covid-19 ICU patients (≥18 years) requiring MV between March 01,2020, and January 10,2021.

Intervention

None.

Measurements and Main Results

Of 860 patients met eligibility criteria, 589 received steroids, 170 IL-6RA, and 101 combinations; groups were balanced after adjustment. Median daily steroid dose was 7.5 mg dexamethasone or equivalent (IQR:6-14 mg); 80.8% and 19.2% received low-dose and high-dose steroids, respectively. The median C-reactive protein level was >75 mg/L in majority of our cohort. The use of IL-6R antagonists alone or in combination was not associated with a significant difference in ventilator-free days (VFD) compared to steroids alone with different steroids regimens (adjusted incidence rate ratio [95% CI]): IL-6R antagonists (1.12 [0.88,1.4]), combination (0.83 [0.6,1.14]). Patients treated with low or high-dose steroids had non-significant differences in VFD compared to IL-6RA (ß=0.62, 95% CI −1.54,2.78 for low-dose steroid; ß=-1.19, 95% CI −3.85,1.47 for high-dose steroid). There was no difference in 28-day mortality and hospital mortality with IL-6RA alone or in combination compared to steroids alone (28-day mortality adjusted odds ratio [95% CI]): IL-6RA (0.68[0.44,1.07]), combination (1.07[0.67,1.70]). Sensitivity analysis findings were consistent with primary analysis. Liver dysfunction was higher in IL-6RA (p=0.04) while rate of bacteremia did not differ among groups.

Conclusions

In adult ICU COVID-19 patients on iMV, we found no difference in outcomes between those who received IL-6RA, steroids, or combination therapy and those who received IL-6RA or low-or high-dose steroids. Further randomized trials are needed to enhance our understanding for IL-6RA safety with different steroids regimen and the magnitude of benefit in those subgroups of patients.

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  1. Version published to 10.1101/2021.04.12.21255323v2 on medRxiv
  2. ScreenIT

    SciScore for 10.1101/2021.04.12.21255323: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The study is approved by the Ethics Committee (Project ID 2201053), SCCM Scientific Review Committee, and SCCM Discovery Steering Committee.
    Consent: In some participating hospitals, verbal consent was obtained whereas in other countries the requirement for patient consent was waived by local research ethics committees.
    RandomizationThose who get a treatment of interest after day 1 would be classified by the treatment they got in the first 48 hours (as in an intention-to-treat analysis in a randomized trial) [22].
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Data were collected online and stored on a secure data server that runs the Mayo Clinic Research Electronic Data Capture (REDCap) web application.
    REDCap
    suggested: (REDCap, RRID:SCR_003445)

    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:
    We acknowledge several limitations. First, randomized controlled trial are critical for exploring the causal effect of treatments and clinical outcomes and accurately quantifying the risks. Second, our sample size was limited, indicating that there were risks of type II errors. Although we used the best available method to compare well-balanced groups, controlling for confounders in observational study may be incomplete despite all efforts. Moreover, there was a large proportion of incomplete data for SOFA and APACHE II scores, because of the heavy burden experienced by participating clinicians during the pandemic. We also did not report the steroid and IL-6R antagonist administration time from symptom onset and we did not address the potential role of IL-6R antagonists in preventing MV or the role of IL-6 level (available only in 24 patients of our cohort) in predicting IL-6R antagonist responses, all of which are important questions that warrant further investigation. In addition, the standard treatment protocol for COVID-19 evolved since the analysis of this study, which may have impacted the clinical characteristics and outcomes for patients who presented in the later phase of the pandemic. The steroid duration was highly variable, and data entry was inconsistent. Thus, we were unable to completely minimize the effect of this important variable. We also did not have detailed documentation on the AEs and we were unable to collect data on the time to viral clearance. Finall...

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

    IdentifierStatusTitle
    NCT04486521RecruitingAnti-IL6 and Corticosteroid Monotherapy vs Combination in CO…

    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 10.1101/2021.04.12.21255323v1 on medRxiv