Inflammatory Biomarkers as Mediators of the Effect Between High‐Dose Corticosteroid Therapy and Mortality in COVID‐19‐Related ARDS: A Causal Mediation Analysis

BACKGROUND: Treatment guidelines for acute respiratory distress syndrome (ARDS) recommend the use of high-dose corticosteroids based on their anti-inflammatory effects, yet the efficacy of this therapeutic strategy in patients with COVID-19 related ARDS is inconclusive. To more thoroughly understand the mechanism of action for high-dose corticosteroids in patients with COVID-19-related ARDS, we hypothesized that the reduction of inflammatory markers induced by high-dose corticosteroids would reduce mortality (i.e., inflammation as a mediator). DESIGN AND METHODS: ratio, sex at birth, age, NLR, and ICU length of stay. RESULTS: Of the 327 patients included, 122 (37.3%) received high-dose corticosteroids. The risk of death was higher in patients who did vs. did not receive high-dose corticosteroids [incidence rate = 0.54, 95% confidence interval (CI) = 0.42-0.71 and 0.21, 95% CI = 0.15-0.29/person-month, respectively; p < 0.001]. This effect remained in most analyses accounting for time-varying treatment/mediation. The association between high-dose corticosteroids and mortality was reduced (i.e., mediated) with lower levels of CRP (AME = -0.006, 95% CI = -0.011, -0.002; %-mediation = -82.0%), d-dimer (AME = -0.002, 95% CI = -0.005, -0.001; %-mediation = -33.1%), and IL-6 (AME = -0.002, 95% CI = -0.004, -0.001; %-mediation = -25.5%). There was no evidence of mediation for other biomarkers. CONCLUSION: CRP, d-dimer, and IL-6 mediated the association between high-dose corticosteroids and mortality. When inflammation was reduced, the deleterious effect of high-dose corticosteroids was eliminated.