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: 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 PaO₂/FiO₂ 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.