Identifying molecular phenotypes in sepsis: an analysis of two prospective observational cohorts and secondary analysis of two randomised controlledtrials

Background In sepsis and acute respiratory distress syndrome (ARDS), heterogeneity has contributed to difficulty identifying effective pharmacotherapies. In ARDS, two molecular phenotypes (hypoinflammatory and hyper inflammatory) have consistently been identified, with divergent outcomes and treatment responses. In this study, we sought to derive molecular phenotypes in critically ill adults with sepsis, determine their overlap with previous ARDS phenotypes, and evaluate whether they respond differently to treatment in completed sepsis trials. Methods We used clinical data and plasma biomarkers from two prospective sepsis cohorts, the Validating Acute Lung Injury biomarkers for Diagnosis (VALID) study (N=1140) and the Early Assessment of Renal and Lung Injury (EARLI) study (N=818), in latent class analysis (LCA) to identify the optimal number of classes in each cohort independently. We used validated models trained to classify ARDS phenotypes to evaluate concordance of sepsis and ARDS phenotypes. We applied these models retrospectively to the previously published Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis and Septic Shock (PROWESSSHOCK) trial and Vasopressin and Septic Shock Trial (VASST) to assign phenotypes and evaluate heterogeneity of treatment effect. Findings A twoclass model best fit both VALID and EARLI (p<0<middle dot>0001). In VALID, 804 (70<middle dot>5%) of the 1140 patients were classified as hypoinflammatory and 336 (29<middle dot>5%) as hyperinflammatory; in EARLI, 530 (64<middle dot>8%) of 818 were hypoinflammatory and 288 (35<middle dot>2%) hyperinflammatory. We observed higher plasma proinflammatory cytokines, more vasopressor use, more bacteraemia, lower protein C, and higher mortality in the hyperinflammatory than in the hypoinflammatory phenotype (p<0<middle dot>0001 for all). Classifier models indicated strong concordance between sepsis phenotypes and previously identified ARDS phenotypes (area under the curve 0<middle dot>87-0<middle dot>96, depending on the model). Findings were similar excluding participants with both sepsis and ARDS. In PROWESSSHOCK, 1142 (68<middle dot>0%) of 1680 patients had the hypoinflammatory phenotype and 538 (32<middle dot>0%) had the hyperinflammatory phenotype, and response to activated protein C differed by phenotype (p=0<middle dot>0043). In VASST, phenotype proportions were similar to other cohorts; however, no treatment interaction with the type of vasopressor was observed (p=0<middle dot>72). Interpretation Molecular phenotypes previously identified in ARDS are also identifiable in multiple sepsis cohorts and respond differently to activated protein C. Molecular phenotypes could represent a treatable trait in critical illness beyond the patient's syndromic diagnosis.