Latent Class Analysis-Derived Subphenotypes are Generalizable to Observational Cohorts of Acute Respiratory Distress Syndrome: A Prospective Study

RATIONALE: Using latent class analysis (LCA), two subphenotypes of acute respiratory distress syndrome (ARDS) have consistently been identified in five randomized controlled trials (RCTs), with distinct biological characteristics, divergent outcomes and differential treatment responses to randomized interventions. Their existence in unselected populations of ARDS remains unknown. We sought to identify subphenotypes in observational cohorts of ARDS using LCA. METHODS: LCA was independently applied to ARDS patients from two prospective observational cohorts of patients admitted to the ICU, derived from the VALID (n=624), and EARLI (n=335) studies. Clinical and biological data were used as class-defining variables. To test for concordance with prior ARDS subphenotypes, the performance metrics of parsimonious classifier models (Interleukin-8, bicarbonate, Protein C and vasopressor-use), previously-developed in RCTs, were evaluated in EARLI and VALID with LCA-derived subphenotypes as the gold-standard. RESULTS: A two-class model best fit the population in VALID (p=0.0010) and in EARLI (p<0.0001). Class 2 comprised 26% and 37% of the populations in VALID and EARLI respectively. Consistent with the previously described “Hyperinflammatory” subphenotype, Class 2 was characterized by higher pro-inflammatory biomarkers, acidosis and increased shock and worse clinical outcomes. The similarities between these and prior RCT-derived subphenotypes were further substantiated by the performance of the parsimonious classifier models in both cohorts (AUCs 0.92–0.94). The Hyperinflammatory subphenotype was associated with increased prevalence of chronic liver disease and neutropenia and reduced incidence of chronic obstructive pulmonary disease. Measurement of novel biomarkers showed significantly higher levels of matrix metalloproteinase-8 and markers of endothelial injury in the Hyperinflammatory subphenotype, whereas, matrix metalloproteinase-9 was significantly lower. CONCLUSION: Previously described subphenotypes are generalizable to unselected populations of non-trauma ARDS.