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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the NIH (R21HD096402, Sanchez-Pinto). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The institutional review board (IRB) at Ann and Robert H. Lurie Children's Hospital of Chicago served as the central IRB for this study and provided a waiver of consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors