Background Subphenotypes have been identified within heterogeneous syndromes such as asthma and breast cancer, with important therapeutic implications. Whether subphenotypes exist within the acute respiratory distress syndrome (ARDS), another heterogeneous syndrome, is unknown. Methods We applied latent class modeling to identify subphenotypes using clinical and biological data from two NHLBI ARDS randomized controlled trials; modeling was conducted independently in each cohort. We then tested the association of subphenotypes with clinical outcomes in both cohorts and with the response to positive end-expiratory pressure (PEEP) in the second cohort. Findings Independent latent class models indicated that a two-class (i.e. two subphenotype) model was optimal for both cohorts. In both cohorts, we identified a hyperinflammatory subphenotype (Phenotype 2) that was characterized by higher plasma levels of inflammatory biomarkers, a higher prevalence of vasopressor use, lower serum bicarbonate, and a higher prevalence of sepsis, compared to Phenotype 1. Subjects in Phenotype 2 had higher mortality and fewer ventilator-free and organ failure-free days in both cohorts. In the second cohort, the effects of ventilation strategy on mortality, ventilator and organ failure-free days differed significantly by phenotype (p=0.003–0.049 for interactions). Interpretation Latent class models identify two subphenotypes within ARDS, one of which is characterized by more severe inflammation, shock, and metabolic acidosis and by significantly worse clinical outcomes. Response to treatment in a randomized trial of PEEP strategies differed based on subphenotype. Identification of ARDS subphenotypes may be useful in selecting patients for clinical trials. Funding National Institutes of Health

In patients with acute lung injury, plasma interleukin-6 and interleukin-8 levels are associated with morbidity and mortality. The severity of inflammation varies with clinical risk factor, suggesting that clinical risk factor should be considered when both developing and testing therapeutic interventions. Low tidal volume ventilation is associated with a more rapid attenuation of the inflammatory response.