Novel Phenotypes of Acute Respiratory Failure and Differential Response to Awake Prone Positioning: A Multi-Cohort...

The heterogeneity of acute respiratory failure (ARF) in non-intubated patients remains poorly defined. This study aimed to identify novel phenotypes in non-intubated ARF patients and evaluate their prognostic and predictive ability. We analyzed data from three cohorts: a training cohort from the Chinese Database in Intensive Care, validation cohort A from a randomized controlled trial, and validation cohort B from a multicenter dataset. Latent class analysis and k-means clustering were applied independently across cohorts to identify phenotypes. A two-class model demonstrated the optimal fit in the training cohort (n = 706). Compared to Phenotype 1, Phenotype 2 exhibited worse oxygenation, higher lactate concentrations, and more severe coagulation dysfunction, along with significantly higher intubation (56.7 vs. 28.7%, p < 0.001) and mortality rates within 28 days (22.0 vs. 9.7%, p < 0.001). Similar phenotypes were verified in validation cohorts A (n = 409) and B (n = 609). Notably, Phenotype 1 patients benefited most from prolonged awake prone positioning (APP), with a significant interaction observed (p = 0.035; adjusted p = 0.048). Two parsimonious models were further developed for phenotype assignment prediction. The two novel phenotypes with both prognostic and predictive ability may help tailor APP to individual non-intubated ARF patients.