The acute respiratory distress syndrome (ARDS), a process of nonhydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies, carries a high morbidity, mortality (10 to 90%), and financial cost. The reported annual incidence in the United States is 150,000 cases, but this figure has been challenged, and it may be different in Europe. Part of the reason for these uncertainties are the heterogeneity of diseases underlying ARDS and the lack of uniform definitions for ARDS. Thus, those who wish to know the true incidence and outcome of this clinical syndrome are stymied. The American-European Consensus Committee on ARDS was formed to focus on these issues and on the pathophysiologic mechanisms of the process. It was felt that international coordination between North America and Europe in clinical studies of ARDS was becoming increasingly important in order to address the recent plethora of potential therapeutic agents for the prevention and treatment of ARDS.

The acute respiratory distress syndrome (ARDS), a process of non-hydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies carries a high morbidity, mortality (10-90%) and financial cost. The reported annual incidence in the United States is 150,000 cases, but this figure has been challenged and may be different in Europe. Part of the reason for these uncertainties is the heterogeneity of diseases underlying ARDS and the lack of uniform definitions for ARDS. Thus, those whose wish to know the true incidence and outcome on this clinical syndrome are stymied. The European American Consensus Committee on ARDS was formed to focus on these issues and on the pathophysiologic mechanisms of the process. It was felt that international coordination between North America and Europe in clinical studies of ARDS was becoming increasingly important in order to address the recent plethora of potential therapeutic agents for the prevention and treatment of ARDS.

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Rationale We hypothesized that acute respiratory distress syndrome (ARDS) patients can be clustered based on concentrations of plasma biomarkers and that the thereby identified biological phenotypes are associated with mortality. Methods Consecutive patients with ARDS were included in this prospective observational cohort study. Cluster analysis of 20 biomarkers of inflammation, coagulation and endothelial activation provided the phenotypes in a training cohort, not taking any outcome data into account. Logistic regression with backward selection was used to select the most predictive biomarkers, and these predicted phenotypes were validated in a separate cohort. Multivariable logistic regression was used to quantify the independent association with mortality. Results Two phenotypes were identified in 454 patients, which we named ‘uninflamed’ (N=218) and ‘reactive’ (N=236). A selection of four biomarkers (IL-6, interferon gamma, angiopoetin 1/2 and PAI-1) could be used to accurately predict the phenotype in the training cohort (area under the receiver operating characteristics curve: 0.98 [95%-confidence interval: 0.97–0.99]). Mortality rates were 15.6% and 36.4% (P<0.001) in the training cohort and 13.6% and 37.5% (P<0.001) in the validation cohort (N=207). The ‘reactive phenotype’ was independent from confounders associated with ICU mortality (training cohort: OR 1.13 [95%-CI: 1.04–1.23]; validation cohort: OR 1.18 [95%-CI: 1.06–1.31]). Conclusions ARDS patients can be clustered into two biological phenotypes, with different mortality rates. Four biomarkers can be used to predict the phenotype with high accuracy. The phenotypes were very similar to those found in cohorts derived from randomized controlled trials, and these results may improve patient selection for future clinical trials targeting host response in patients with ARDS.