Longitudinal multiomic signatures of ARDS and sepsis inflammatory phenotypes identify pathways associated with mortality.

Pubmed ID: 41329523

Pubmed Central ID: PMC12867137

Journal: The Journal of clinical investigation

Publication Date: Dec. 2, 2025

MeSH Terms: Humans, Male, Female, Aged, Middle Aged, Longitudinal Studies, Phenotype, Inflammation, Sepsis, Biomarkers, Metabolomics, Respiratory Distress Syndrome, Transcriptome

Grants: T32 HL007185, R35 HL140026, R35 GM142992, R35 HL177135, R01 HL173531, R35 GM136312

Authors: Liu K, Matthay MA, Calfee CS, Lee D, Zhuo H, Sullivan K, Sinha P, Lin C, Rogers AJ, Sarma A, Alipanah-Lechner N, Neyton L, Leroux C, Bardillon K, Carrillo SA, Chak S, Chao O, Hariharan T, Hendrickson C, Kangelaris K, Langelier CR, Magee L, Ringor A, Schmiege E, Spottiswoode N, Weingart MF, Willmore A, Stringer KA

Cite As: Alipanah-Lechner N, Neyton L, Sinha P, Leroux C, Bardillon K, Carrillo SA, Chak S, Chao O, Hariharan T, Hendrickson C, Kangelaris K, Langelier CR, Lee D, Lin C, Liu K, Magee L, Ringor A, Sarma A, Schmiege E, Spottiswoode N, Sullivan K, Weingart MF, Willmore A, Zhuo H, Rogers AJ, Stringer KA, Matthay MA, Calfee CS. Longitudinal multiomic signatures of ARDS and sepsis inflammatory phenotypes identify pathways associated with mortality. J Clin Invest 2025 Dec 2;136. (3). doi: 10.1172/JCI196290. eCollection 2026 Feb 2.

Studies:

Abstract

BACKGROUNDCritically ill patients with acute respiratory distress syndrome (ARDS) and sepsis exhibit distinct inflammatory phenotypes with divergent clinical outcomes, but the underlying molecular mechanisms remain poorly understood. These phenotypes, derived from clinical data and protein biomarkers, were associated with metabolic differences in a pilot study.METHODSWe performed integrative multiomics analysis of blood samples from 160 patients with ARDS in the ROSE trial, randomly selecting 80 patients from each latent class analysis-defined inflammatory phenotype (hyperinflammatory and hypoinflammatory) with phenotype probability greater than 0.9. Untargeted plasma metabolomics and whole-blood transcriptomics at day 0 and day 2 were analyzed using multimodal factor analysis (MEFISTO). The primary outcome was 90-day mortality, with validation in an independent critically ill sepsis cohort (EARLI).RESULTSMultiomics integration revealed 4 molecular signatures associated with mortality: (a) enhanced innate immune activation coupled with increased glycolysis (associated with hyperinflammatory phenotype), (b) hepatic dysfunction and immune dysfunction paired with impaired fatty acid β-oxidation (associated with hyperinflammatory phenotype), (c) interferon program suppression coupled with altered mitochondrial respiration (associated with hyperinflammatory phenotype), and (d) redox impairment and cell proliferation pathways (not associated with inflammatory phenotype). These signatures persisted through day 2 of trial enrollment. Within-phenotype analysis revealed distinct mortality-associated pathways in each group. All molecular signatures were validated in the independent EARLI cohort.CONCLUSIONInflammatory phenotypes of ARDS reflect distinct underlying biological processes with both phenotype-specific and phenotype-independent pathways influencing patient outcomes, all characterized by mitochondrial dysfunction. These findings suggest potential therapeutic targets for precise treatment strategies in critical illness.FUNDINGNIH National Heart, Lung, and Blood Institute and National Institute of General Medical Sciences.