Rationale: Despite etiologic and severity heterogeneity in neutropenic sepsis, management is often uniform. Understanding host response clinical subphenotypes might inform treatment strategies for neutropenic sepsis. Objectives: In this retrospective two-hospital study, we analyzed whether temperature trajectory modeling could identify distinct, clinically relevant subphenotypes among oncology patients with neutropenia and suspected infection. Methods: Among adult oncologic admissions with neutropenia and blood cultures within 24 hours, a previously validated model classified patients' initial 72-hour temperature trajectories into one of four subphenotypes. We analyzed subphenotypes' independent relationships with hospital mortality and bloodstream infection using multivariable models. Measurements and Main Results: Patients (primary cohort n = 1,145, validation cohort n = 6,564) fit into one of four temperature subphenotypes. "Hyperthermic slow resolvers" (pooled n = 1,140 [14.8%], mortality n = 104 [9.1%]) and "hypothermic" encounters (n = 1,612 [20.9%], mortality n = 138 [8.6%]) had higher mortality than "hyperthermic fast resolvers" (n = 1,314 [17.0%], mortality n = 47 [3.6%]) and "normothermic" (n = 3,643 [47.3%], mortality n = 196 [5.4%]) encounters (P < 0.001). Bloodstream infections were more common among hyperthermic slow resolvers (n = 248 [21.8%]) and hyperthermic fast resolvers (n = 240 [18.3%]) than among hypothermic (n = 188 [11.7%]) or normothermic (n = 418 [11.5%]) encounters (P < 0.001). Adjusted for confounders, hyperthermic slow resolvers had increased adjusted odds for mortality (primary cohort odds ratio, 1.91 [P = 0.03]; validation cohort odds ratio, 2.19 [P < 0.001]) and bloodstream infection (primary odds ratio, 1.54 [P = 0.04]; validation cohort odds ratio, 2.15 [P < 0.001]). Conclusions: Temperature trajectory subphenotypes were independently associated with important outcomes among hospitalized patients with neutropenia in two independent cohorts.

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