Objectives: To compare the clinical characteristics and outcomes of
critically ill coronavirus disease MESHD (
COVID-19 MESHD) patients requiring mechanical ventilation (MV), receiving interleukin 6 receptor (
IL6R HGNC) antagonists, steroids, or a combination of both. Design: An international, multicenter, observational study derived from the COVID-2019 Viral Infection and Respiratory Illness University Study (VIRUS) registry and conducted through the Discovery Network, the Society of Critical Care Medicine. Marginal structural modeling was used to adjust for time-dependent confounders, and observations were weighted using the inverse probability of treatment weight. Sensitivity analysis was conducted to emulate a target trial design. Setting: 168 hospitals in 16 countries. Patients: adult ICU patients ( > 18 years) requiring MV for
COVID-19 MESHD between March 01, 2020, and January 10, 2021. Intervention: None. Measurements and Main Results: A total of 860 patients met eligibility criteria: 589 received steroids, 170
IL-6R HGNC antagonists, and 101 combination therapy, and the groups were balanced after adjustment. The median daily steroid dose was 7.5 mg dexamethasone or equivalent (IQR: 6 to 14 mg); 80.8% received low-dose and 19.2% high-dose steroids (> 15 mg/day of dexamethasone or equivalent). The median
C-reactive protein HGNC level was > 75 mg/L in majority of our cohort. The use of
IL6R HGNC antagonists alone or in combination was not associated with a significant difference in ventilator free days (
VFD MESHD) compared to steroids alone (adjusted incidence rate ratio [95% CI]):
IL6R HGNC 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 MESHD compared to
IL6R HGNC antagonists (beta= 0.62, 95% CI -1.54, 2.78 for low-dose steroid; beta= -1.19, 95% CI -3.85, 1.47 for high-dose steroid). The use of
IL6R HGNC antagonists alone or in combination was not associated with a significant difference in 28 day mortality compared to steroids alone (adjusted odds ratio [95% CI]):
IL6R HGNC antagonists alone (0.68 [0.44,1.07]), combination (1.07 [0.67,1.7]). There was no difference in hospital mortality compared to steroids alone (aOR 0.68, 95% CI 0.43,1.09 for
IL6R HGNC antagonist, aOR 1.23, 95 % CI 0.72,2.11 for combination). The findings of sensitivity analysis were consistent with the primary analysis. The rate of
liver dysfunction MESHD was higher in the
IL6R HGNC antagonist (p=0.038), while the rate of
bacteremia MESHD did not differ among the three groups. Conclusions: We observed no difference in outcomes between mechanically ventilated adult ICU patients who received
IL6R HGNC antagonists, steroids, or combination therapy and those who received
IL6R HGNC antagonists or low or high dose steroids. Further trials are needed to evaluate high-dose steroids as substitutes for
IL6R HGNC antagonists in resource-limited settings.