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
Authors: Amer Marwa , Bawazeer Mohammed , Maghrabi Khalid , Kamel Ahmed M. , Butt Abid , Dahhan Talal , Kseibi Eiad , Khurshid Syed Moazzum , Abujazar Mohammed , Alghunaim Razan , Rabee Muath , Abualkhair Maal , Al-Janoubi Ali , AlFirm Abeer Turki , Gajic Ognjen , Walkey Allan J. , Mosier Jarrod M , Zabolotskikh Igor Borisovich , Gavidia Oscar Y , Teruel Santiago Y. , Bernstein Michael A. , Boman Karen , Kumar Vishakha K. , Bansal Vikas , Kashyap Rahul 
Published: April 2021

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.