Targeting specific biomarker-defined subgroups of heterogeneous syndromes, such as cancer or asthma, has fundamentally changed approaches to clinical management. For example, subphenotypes based on Th2-type inflammation have been identified in asthma, leading to new targeted treatment approaches such as monoclonal antibodies against interleukin-13 ( ). Acute respiratory distress syndrome (ARDS) is an acute, diffuse, inflammatory lung injury that is associated with a variety of etiologies and leads to severe respiratory failure refractory to conventional oxygen therapy ( ). Lung protective ventilation strategies including low tidal volume and positive end-expiratory pressure (PEEP) are well-established treatments ( , ), although numerous pharmacotherapies that seemed to show promise in preclinical studies have failed in clinical trials. ARDS is diagnosed based on clinical criteria rather than laboratory or pathophysiological criteria ( ). ARDS cases may be very heterogenous with different responses to therapy. Calfee . identified two distinct ARDS subphenotypes in two randomized controlled trials (ARMA and ALVEOLI) ( , ) using latent class analysis ( ). Subphenotype 2 (a hyper-inflammatory ARDS) was associated with increased levels of inflammatory biomarkers, acidosis, shock, and mortality. In the ALVEOLI cohort, higher PEEP was beneficial in subphenotype 2 but harmful in subphenotype 1. In subsequent studies, using latent class analysis in the FACTT and HARP-2 study populations ( , ), the same group observed a survival benefit in the hyper-inflammatory subphenotype with conservative fluid management and simvastatin, respectively ( , ). Interestingly, extrapulmonary factors seemed to contribute more to subphenotype classification than did pulmonary-specific variables (PaO /FiO and ventilator parameters).
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