Distinct immune trajectories after severe trauma identify a Th17-biased immunophenotype in chronic critical illness.

Severe trauma triggers a dynamic disturbance of immune function that can progress from early hyperinflammation to prolonged dysregulation, increasing patient vulnerability to infection and chronic critical illness (CCI). To identify immune features linked to different postinjury clinical trajectories, we prospectively evaluated severely injured trauma patients and categorized them as rapid recovery, intermediate, or CCI based on clinical outcome by day 14 of intensive care unit admission. CCI patients developed infections earlier and more frequently than rapid recovery or intermediate patients, with nearly one-third experiencing their first infection (primarily pneumonia) within 4 d of intensive care unit admission and >80% did so within 8 d. Immune profiling showed trauma-associated alterations across all groups, including neutrophilia and early T cell lymphopenia. However, CCI patients exhibited a distinct immunophenotype characterized by elevated neutrophil counts, recovery of total CD3+ T cells by day 7, preserved inducible interferon γ (IFNγ) production, and a selective expansion of CD4+ T helper 17 (Th17) cells. Functional assays revealed sustained or amplified T cell cytokine responses in CCI patients, including persistent IFNγ and interleukin (IL)-17A production. Plasma cytokine analysis further demonstrated prolonged elevation of IL-17A, IL-17C, IFNγ, and IL-10, indicating a mixed but enduring pro- and anti-inflammatory state. These findings suggest that CCI after trauma is not driven by classic immunosuppression, but rather is driven by an IL-17-skewed immune program coupled with ineffective pathogen control. The persistent Th17/neutrophil axis may contribute to heightened infection risk and progression to CCI, highlighting dysregulated IL-17-mediated innate and adaptive circuits as a potential mechanism of ongoing immune dysfunction following severe trauma.