Temporal stability of phenotypes of acute respiratory distress syndrome: clinical implications for early corticosteroid therapy and mortality

Purpose: Inflammatory phenotypes of acute respiratory distress syndrome (ARDS) can predict patient outcomes and potentially response to treatment. The aim was to assess whether inflammatory phenotypes can be characterized over time using clinical surrogate data and used to guide therapy with corticosteroids. Methods: Individual patient data and biomarkers from six multicenter randomized controlled trials (development, n = 1207; validation, n = 2751) were analyzed to establish an open-source AI Clinical Classifier (https://bostonmontpelliercare.shinyapps.io/AIClarity) for inflammatory phenotypes of ARDS using routine clinical data. Then, patients from a retrospective cohort (investigation, n = 5578) underwent classification from baseline to day 30. A discrete-time Bayesian Markov model assessed temporal stability at 3-day intervals. A target trial emulation and longitudinal logistic regression assessed corticosteroid effect on 30-day mortality depending on phenotype. Results: The AI Clinical Classifier identified 2169 (39%) hyperinflammatory and 3409 (61%) hypoinflammatory patients. 1053 (49%) and 826 (24%) patients died within 30 days, respectively (p < 0.001). Over 30 days, 49%(1072/2169) of hyperinflammatory patients at baseline transitioned to hypoinflammatory, and 7%(229/3409) of hypoinflammatory patients at baseline transitioned to hyperinflammatory (p < 0.001). Phenotypes predicted response to corticosteroids, with lower mortality in hyperinflammatory patients (IPW-weighted hazard ratio [HR]: 0.81 [0.67–0.98], p = 0.033), and higher mortality in hypoinflammatory patients (IPW-weighted HR: 1.26 [1.06–1.50], p = 0.009). At day 3, a positive response to corticosteroids only persisted among patients who remained hyperinflammatory (adjusted odds ratio = 0.51, 95% CI 0.32–0.80, p = 0.004). Conclusion: Characterization of inflammatory ARDS phenotypes using clinical surrogate data allows physicians to monitor patients throughout the course of the disease and guide clinical treatment. Corticosteroids may be beneficial in hyperinflammatory ARDS and harmful in hypoinflammatory ARDS.