Abstract
Critically ill patients with acute respiratory distress syndrome (ARDS) and sepsis exhibit distinct inflammatory phenotypes with divergent clinical outcomes and apparent heterogeneity of treatment effects, but the underlying molecular mechanisms remain poorly understood. These phenotypes, derived from clinical data and protein biomarkers, were associated with metabolic differences in a prior pilot study. This study investigated the metabolomic and transcriptomic differences between Hyperinflammatory and Hypoinflammatory phenotypes through integrative multi-omics analysis of blood samples from ARDS patients in the ROSE trial. Multi-omics integration revealed three molecular signatures strongly associated with the Hyperinflammatory phenotype and with mortality: enhanced innate immune activation coupled with increased glycolysis, hepatic dysfunction and immune dysfunction paired with impaired fatty acid beta-oxidation, and interferon program suppression coupled with altered mitochondrial respiration. A fourth molecular signature, not associated with inflammatory phenotype, identified redox impairment and cell proliferation pathways associated with mortality. Integrated multi-omics analysis within each inflammatory phenotype revealed distinct pathways associated with mortality. All mortality-associated molecular signatures including those within phenotypes were validated in an independent cohort of critically ill patients with sepsis (EARLI). These findings reveal distinct molecular mechanisms underlying ARDS/sepsis phenotypes and suggest potential therapeutic targets for precise treatment strategies in critical illness.