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 stratified by inflammatory phenotype, the authors defined four mortality-associated molecular signatures that largely converged on mitochondrial dysfunction. These longitudinal signatures persisted to Day 2 and were validated in an independent critically ill sepsis cohort, revealing phenotype-specific and phenotype-independent pathways that may inform precision therapies.

Key Findings

• Four mortality-associated molecular signatures were identified, including innate immune activation with glycolysis, hepatic/immune dysfunction with impaired fatty acid β-oxidation, interferon suppression with altered mitochondrial respiration, and redox/proliferation pathways.
• Signatures persisted from Day 0 to Day 2 and were validated in an independent critically ill sepsis cohort (EARLI).
• Within-phenotype analyses revealed distinct mortality-associated pathways, indicating both phenotype-specific and phenotype-independent biology centered on mitochondrial dysfunction.

Clinical Implications

Supports endotype-based risk stratification and prioritizes mitochondrial bioenergetics, fatty acid oxidation, interferon signaling, and redox pathways as therapeutic targets; enables longitudinal biomarker panels for early prognosis.

Limitations

• Secondary analysis of trial biospecimens with modest sample size (n=160) may limit generalizability.
• Causal inference is limited; therapeutic targets require interventional validation.

Future Directions

Prospective, multi-center validation of signature-based risk models and interventional trials targeting mitochondrial bioenergetics, fatty acid oxidation, and interferon/redox pathways in endotype-enriched populations.