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

Summary

In 160 ARDS patients from the ROSE trial, integrated longitudinal plasma metabolomics and whole-blood transcriptomics identified four mortality-associated molecular signatures spanning innate immunity-glycolysis, hepatic/immune dysfunction with impaired beta-oxidation, interferon suppression with altered mitochondrial respiration, and redox/cell proliferation pathways. Signatures persisted to Day 2 and were validated in the EARLI sepsis cohort, highlighting mitochondrial dysfunction as a unifying feature.

Key Findings

• Four mortality-associated multi-omic signatures were identified, three linked to the Hyperinflammatory phenotype and one phenotype-independent.
• All signatures persisted to Day 2 after enrollment and were validated in an independent sepsis cohort (EARLI).
• A unifying theme of mitochondrial dysfunction characterized all mortality-associated signatures.
• Within-phenotype analyses revealed distinct mortality pathways in Hyperinflammatory vs Hypoinflammatory groups.

Clinical Implications

Findings support phenotype-guided trials testing metabolic/mitochondrial modulators and biomarker panels for risk stratification. Mitochondrial dysfunction emerges as a cross-phenotype target.

Limitations

• Moderate sample size (N=160) and blood-based omics may not fully capture lung-specific biology
• Observational associations limit causal inference; no interventional testing of targets

Future Directions

Prospective interventional trials targeting mitochondrial bioenergetics and metabolic pathways stratified by inflammatory phenotype; validation in larger, diverse cohorts with lung-specific sampling.