Derivation, validation, and clinical relevance of a pediatric sepsis phenotype with persistent hypoxemia and shock

Background Untangling the heterogeneity of sepsis in children and identifying clinically relevant phenotypes could lead to the development of enrichment strategies and targeted therapies. In this study, our aim was to analyze the organ dysfunction-based trajectories of children with sepsis-associated multiple organ dysfunction syndrome (MODS) to identify and characterize reproducible and clinically relevant sepsis phenotypes using a data-driven approach. Methods We collected data from patients admitted with suspected infections to 13 pediatric intensive care units (PICUs) in the U.S. between 2012-2018. We used subgraph-augmented nonnegative matrix factorization to identify candidate trajectory-driven phenotypes based on the type, severity, and progression of organ dysfunction in the first 72 hours of PICU admission. We analyzed the candidate phenotypes to determine reproducibility as well as prognostic, therapeutic, and biological relevance. Results Overall, 38,732 children had suspected infection, of which 15,246 (39.4%) had sepsis-associated MODS. Amongst patients with sepsis-associated MODS, 1,537 (10.1%) died in the hospital. We identified an organ dysfunction trajectory-based phenotype (which we termed persistent hypoxemia and shock) that was highly reproducible, had features of systemic inflammation and coagulopathy, and was independently associated with higher mortality. In a propensity score matched analysis, patients with the persistent hypoxemia and shock phenotype appeared to have a higher likelihood to benefit from adjuvant therapy with hydrocortisone and albumin than other patients. When compared to other high-risk clinical syndromes, the persistent hypoxemia and shock phenotype only overlapped with 50 to 60% of patients with septic shock, those with moderate-to-severe pediatric acute respiratory distress syndrome, or those in the top tertile of organ dysfunction burden, suggesting that it represents a distinct clinical phenotype of sepsis-associated MODS with a disproportionately high risk of mortality. Conclusions We derived and validated the persistent hypoxemia and shock phenotype, a trajectory-based organ dysfunction phenotype which is highly reproducible, clinically relevant, and associated with heterogeneity of treatment effect to common adjuvant therapies. Further validation is warranted. Future studies are needed to validate this phenotype, assess whether it can be predicted earlier in the course, study possible biological mechanisms underlying it, and investigate candidate therapeutic targets.