Abstract
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: In this retrospective cohort study, we included patients with COVID-19-related ARDS admitted to the intensive care unit (ICU) of an academic hospital in Rotterdam, the Netherlands between March 2020 and June 2022. High-dose corticosteroids were defined as > 6 mg of dexamethasone/day or equivalent. Biomarkers included C-reactive protein (CRP), d-dimer, ferritin, leukocyte count, interleukin-6 (IL-6), lactate dehydrogenase, and neutrophil-to-lymphocyte ratio (NLR). Using a causal mediation framework, we estimated the average mediation effect (AME) and % mediation for each biomarker, allowing to quantify the degree to which continuous levels of inflammatory markers mediate the association between receiving high-dose corticosteroids and mortality. The models used in this framework accounted for time-varying treatment/mediation with inverse probability of treatment weights, determined from the covariates PaO(2)/FiO(2) 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.