Identifying Novel Sepsis Subphenotypes Using Temperature Trajectories

Abstract

Rationale: Sepsis is a heterogeneous syndrome, and identifying clinically relevant subphenotypes is essential.Objectives: To identify novel subphenotypes in hospitalized patients with infection using longitudinal temperature trajectories.Methods: In the model development cohort, inpatient admissions meeting criteria for infection in the emergency department and receiving antibiotics within 24 hours of presentation were included. Temperature measurements within the first 72 hours were compared between survivors and nonsurvivors. Group-based trajectory modeling was performed to identify temperature trajectory groups, and patient characteristics and outcomes were compared between the groups. The model was then externally validated at a second hospital using the same inclusion criteria.Measurements and Main Results: A total of 12,413 admissions were included in the development cohort, and 19,053 were included in the validation cohort. In the development cohort, four temperature trajectory groups were identified: "hyperthermic, slow resolvers" (n = 1,855; 14.9% of the cohort); "hyperthermic, fast resolvers" (n = 2,877; 23.2%); "normothermic" (n = 4,067; 32.8%); and "hypothermic" (n = 3,614; 29.1%). The hypothermic subjects were the oldest and had the most comorbidities, the lowest levels of inflammatory markers, and the highest in-hospital mortality rate (9.5%). The hyperthermic, slow resolvers were the youngest and had the fewest comorbidities, the highest levels of inflammatory markers, and a mortality rate of 5.1%. The hyperthermic, fast resolvers had the lowest mortality rate (2.9%). Similar trajectory groups, patient characteristics, and outcomes were found in the validation cohort.Conclusions: We identified and validated four novel subphenotypes of patients with infection, with significant variability in inflammatory markers and outcomes.

Keywords: group-based trajectory modeling; infection; sepsis; temperature.

Figure 1.

Consolidated Standards of Reporting Trials diagram of patient selection for the study population in the development cohort.

Figure 2.

Body temperature trajectory over time in survivors and nonsurvivors in the development cohort. Trajectory width represents the 95% confidence interval of temperature measurements.

Figure 3.

Group-based trajectory model in the development and validation cohorts. Using group-based trajectory modeling, four temperature trajectory group subphenotypes were identified: “hyperthermic, fast resolvers”; “hyperthermic, slow resolvers”; “normothermic”; and “hypothermic.” Temperature measurements were standardized to the hospital’s mean temperature to remove the effect of facility-specific factors (e.g., measurement devices). For the development cohort, standardized temperatures from −1.0 to +1.0 represent temperature measurements from 35.6°C to 37.4°C. For the validation cohort, standardized temperatures from −1.0 to +1.0 represent a range from 36.3°C to 37.7°C.