Lymphopenia and mortality in adult sepsis: A systematic review and focused meta-analysis of prognostic evidence.

BACKGROUND: Lymphopenia is common in sepsis, but published studies use heterogeneous exposure definitions and time points. We evaluated its prognostic association with mortality using a focused meta-analysis of comparable lymphopenia phenotypes and used additional evidence to contextualize biologic and infectious-source interpretation. METHODS: PubMed and Embase were searched from inception to April 1, 2026. Studies directly estimating lymphopenia-related mortality associations were assessed for quantitative synthesis. Pooling was restricted to comparable threshold-based, persistent, or baseline definitions using a random-effects generic inverse-variance model; trajectory-based and continuous-exposure studies were displayed separately. Additional mechanistic, biomarker, modeling, therapeutic, and pathogen-context studies were synthesized qualitatively. RESULTS: Of 29 included studies, seven provided direct prognostic evidence and four were eligible for quantitative pooling. Adverse lymphopenia-related phenotypes were associated with mortality (pooled relative effect 1.94, 95% CI 1.39-2.70; I2 = 62.4%). Leave-one-out analyses retained the direction of association, although heterogeneity was sensitive to individual studies. Two trajectory-based studies and one continuous-exposure study were not pooled. Pathogen-related observations were insufficient for pathogen-specific quantitative inference. CONCLUSIONS: Lymphopenia-related phenotypes are associated with mortality in adult sepsis, but the small quantitative evidence base and moderate-to-substantial heterogeneity limit the precision and generalizability of the pooled effect. Pathogen-context interpretations should be considered hypothesis-generating. Standardized definitions, repeated measurements, and prospective validation are needed before routine use for risk stratification or treatment selection. PROTOCOL REGISTRATION: PROSPERO CRD420261413974.