Longitudinal multi-omic signatures of ARDS and sepsis inflammatory phenotypes identify pathways associated with mortality.

Summary

Integrating plasma metabolomics and whole-blood transcriptomics from 160 ARDS patients in the ROSE trial, the authors identified four mortality-linked molecular signatures spanning innate activation/glycolysis, hepatic-immune dysfunction with impaired beta-oxidation, interferon suppression with altered mitochondrial respiration, and redox/cell-cycle programs. Mitochondrial dysfunction emerged as a unifying feature across phenotypes, and all signatures were validated in an independent sepsis cohort.

Key Findings

• Four mortality-associated multi-omic signatures span innate activation/glycolysis, hepatic-immune dysfunction with impaired beta-oxidation, interferon suppression with altered mitochondrial respiration, and redox/cell proliferation pathways.
• Mitochondrial dysfunction is a convergent hallmark across inflammatory phenotypes and persists to Day 2.
• All signatures validated in an independent critically ill sepsis cohort (EARLI), supporting generalizability.

Clinical Implications

Biomarker-guided stratification and trials targeting mitochondrial bioenergetics, interferon programs, and redox balance could personalize ARDS/sepsis therapies and improve survival.

Limitations

• Secondary analysis with moderate sample size; blood-based signatures may not capture organ-level heterogeneity
• Causality cannot be inferred; therapeutic targeting remains to be prospectively tested

Future Directions

Biomarker-driven interventional trials targeting mitochondrial bioenergetics and immune-metabolic programs; expansion to multi-organ omics and tissue-level validation.