International Validation of Temperature-Trajectory Sepsis Subphenotypes With Longitudinal Immune and Coagulation Patterns and Its Implications for Immunoglobulin Therapy

OBJECTIVES: Sepsis remains a major challenge in the ICU. Given the limitations of the one-size-fits-all strategy, precision medicine approaches are needed to identify distinct sepsis subtypes that may respond to different treatments. This study aimed to validate a temperature-trajectory model of sepsis developed in U.S. centers in a non-U.S. cohort from China, to characterize longitudinal immune and coagulation profiles, and to explore their potential value in guiding immunotherapy. DESIGN: This study validated a previously developed sepsis temperature-trajectory model, delineated longitudinal immune and coagulation dynamics across distinct subphenotypes, and, after propensity score matching, examined the heterogeneous effects of immunoglobulin treatment. SETTING: Retrospective data from a tertiary-care hospital ICU in China. PATIENTS: Adult ICU patients with suspected infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical and microbiological characteristics were compared across subphenotypes, and the interaction between subphenotype and immunoglobulin therapy on 30-day mortality was assessed. In total, 2478 patients were included and classified into four subphenotypes: hyperthermic slow resolvers (567; 23%), hyperthermic fast resolvers (397; 16%), normothermic (780; 31%), and hypothermic (HT, 734; 30%). The HT subphenotype exhibited the highest mortality rate (25%), consistent with previous findings. In longitudinal immune and coagulation profiling, the HT subphenotype exhibited the lowest inflammatory response (low and rapidly declining C-reactive protein and rapidly declining interleukin-6), suppressed immunity (persistently low lymphocyte counts and monocyte human leukocyte antigen-DR), and coagulation abnormalities (persistently prolonged prothrombin time and activated partial thromboplastin time; the lowest platelet counts, fibrinogen, and hemoglobin; and the highest rate and dose of RBC transfusion). Immunoglobulin therapy showed heterogeneous effects across different subphenotypes, with patients in the HT subphenotype showing a consistent direction of benefit (primary subtyping: hazard ratio, 0.47; p = 0.03). CONCLUSIONS: The temperature-trajectory subphenotypes were validated in an international cohort. Patients in the HT subphenotype exhibited the highest mortality and showed persistent immune dysfunction and coagulopathy. Furthermore, different subphenotypes demonstrated distinct responses to immunoglobulin therapy.