Identification and validation of robust hospital-acquired pneumonia subphenotypes associated with all-cause mortality: a multi-cohort derivation and validation.

Summary

Across four derivation cohorts and an independent RCT dataset, a two-subphenotype model of HAP was reproducible. The higher-risk subphenotype had worse oxygenation and consistently higher 28-day mortality and treatment failure, showed microbiome dysbiosis and elevated cytokines, and demonstrated differential response to tedizolid.

Key Findings

• A two-cluster HAP model generalized across four derivation cohorts with consistent performance.
• Subphenotype 2 showed worse PaO2/FiO2, lower temperature, and higher 28-day mortality and test-of-cure failure (p<0.01).
• Subphenotype 2 was linked to respiratory microbiome dysbiosis, higher proinflammatory cytokines, and differential tedizolid effect in VITAL.

Clinical Implications

Clinicians can use the simplified classifier to identify high-risk HAP patients for closer monitoring and consider phenotype-guided antibiotic strategies in future trials. The findings support designing prospective, phenotype-enriched randomized studies.

Limitations

• Observational design limits causal inference about treatment effects.
• Heterogeneity in cohort characteristics and subphenotype prevalence across datasets.

Future Directions

Prospective randomized trials that stratify by HAP subphenotypes to test phenotype-guided therapies and validate predictive enrichment.