Plasma metabolic profiling implicates dysregulated lipid metabolism and glycolytic shift in hyperinflammatory ARDS

Using latent class analysis (LCA) of clinical and protein biomarkers, researchers have identified two phenotypes of the acute re-spiratory distress syndrome (ARDS) with divergent clinical trajectories and treatment responses. We investigated whether plasma metabolites differed among patients with LCA-derived hyperinflammatory and hypoinflammatory ARDS, and we tested the prog-nostic utility of adding metabolic clusters to LCA phenotypes. We analyzed data from 93 patients with ARDS and sepsis enrolled in a multicenter prospective cohort of critically ill patients, comparing 970 metabolites between the two LCA-derived phenotypes. In all, 188 metabolites were differentially abundant between the two LCA-derived phenotypes. After adjusting for age, sex, con-founding medications, and comorbid liver and kidney disease, 82 metabolites remained significantly different. Patients with hyperinflammatory ARDS had reduced circulating lipids but high levels of pyruvate, lactate, and malate. Metabolic cluster and LCA-derived phenotypes were each significantly and independently associated with survival. Patients with hyperinflammatory ARDS may be experiencing a glycolytic shift leading to dysregulated lipid metabolism. Metabolic profiling offers prognostic infor-mation beyond what is captured by LCA phenotypes alone. Deeper biological profiling may identify key differences in pathoge-nesis among patients with ARDS and may lead to novel targeted therapies.