Failure of early lymphocyte recovery identifies sepsis patients with initial lymphopenia at highest risk for late mortality

BACKGROUND: Sepsis-induced lymphopenia is associated with adverse outcomes, yet static assessments at a single time point fail to capture the clinical significance of its dynamic evolution, and the effects of the trajectories of lymphopenia on prognosis are to be elucidated in sepsis. METHODS: This retrospective cohort study extracted data from the MIMIC-IV (v3.1) database. Adult septic patients with initial lymphopenia (<1.0 × 10⁹/L) were included. Group-Based Trajectory Modeling (GBTM) identified lymphocyte count trajectories. Kaplan-Meier analysis with log-rank test was used to visualize survival differences. Multivariable Cox and logistic regression assessed associations between trajectories and 7-day, 28-day, ICU, and in-hospital mortality. Subgroup analyses validated result consistency. RESULTS: A total of 1,640 patients were included. GBTM identified 4 distinct lymphocyte count trajectories. Kaplan-Meier analysis revealed that patients in Trajectory 4 (Persistent Low Level, N = 544, 33.2%), characterized by persistent lymphopenia, had the lowest cumulative 7-day and 28-day survival rates. After multivariable adjustment, Trajectory 4 was independently associated with an increased risk of 28-day mortality [adjusted HR = 1.76, 95% CI: 1.266-2.446, P = 0.001], ICU mortality (adjusted OR = 1.831, 95% CI: 1.196-2.832, P = 0.006), and in-hospital mortality (adjusted OR = 1.881, 95% CI: 1.298-2.767, P = 0.001) compared to Trajectory 1 (Sustained Recovery), and these associations remained robust across all predefined subgroups. In contrast, no significant association was observed between Trajectory 4 and 7-day mortality after full adjustment for confounders. CONCLUSION: Lymphocyte count Trajectory 4 (Persistent Low Level) in initially lymphopenic sepsis patients is independently associated with late (28-day) but not early (7-day) mortality, as well as worse ICU and hospital outcomes. Failure of lymphopenia to recover by days 3-4 may signal a transition to the highest-risk state, suggesting a potential window for immunomodulatory strategies.