Subphenotypes in Acute Respiratory Distress Syndrome: Universal Steps Toward Treatable Traits

Patients with acute respiratory distress syndrome (ARDS) have severe respiratory impairment requiring mechanical ventilation resulting in high mortality. Despite extensive research, no effective pharmacological interventions have been identified in unselected ARDS, which has been attributed to the considerable heterogeneity. The identification of more homogeneous subgroups through phenotyping has provided a novel method to improve our pathophysiological understanding, trial design, and, most importantly, patient care through targeted interventions. The objective of this article is to outline a structured, stepwise approach toward identifying and classifying heterogeneity within ARDS and subsequently derive, validate, and integrate targeted treatment options. We present a 6-step roadmap toward the identification of effective phenotype-targeted treatments: development of distinct and reproducible subphenotypes, derivation of a possible parsimonious bedside classification method, identification of possible interventions, prospective validation of subphenotype classification, testing of subphenotype-targeted intervention prospectively in randomized clinical trial (RCT), and finally implementation of subphenotype classification and intervention in guidelines and clinical practice. Based on this framework, the current literature was reviewed. Respiratory physiology, lung morphology, and systemic inflammatory biology subphenotypes were identified. Currently, lung morphology and systemic inflammatory biology subphenotypes are being tested prospectively in RCTs.