Sepsis Endotypes Defined by Lymphocyte Thresholds and Inflammation Inform Precision Immunomodulation

Area of Science:

• Immunology
• Critical Care Medicine
• Genomics

Background:

• Sepsis treatment efficacy varies due to patient heterogeneity not captured by current methods.
• Lymphopenia is a known mortality predictor, but its functional role alongside inflammation is unclear.

Purpose of the Study:

• To determine if integrating lymphocyte status with systemic inflammation defines sepsis endotypes with distinct treatment responses.
• To identify critical lymphocyte count thresholds associated with sepsis mortality.

Main Methods:

• Retrospective analysis of 714 sepsis patients within 24 hours, profiling lymphocyte subsets and inflammatory biomarkers.
• Used restricted cubic spline analysis to assess nonlinear associations between lymphocyte counts and mortality.
• Applied principal component analysis for endotype classification and integrated transcriptomic data to identify a T-cell dysfunction signature.

Main Results:

• Nonlinear associations between lymphocyte counts and mortality were observed, with critical thresholds identified for total T cells, CD4+, and CD8+ cells.
• Four discrete sepsis endotypes were classified, showing significantly divergent 28-day survival rates (55%-58% vs. 82-87%).
• Patients with immunosuppressed/hypo-inflammatory endotypes receiving corticosteroids had improved survival, unlike hyperinflammatory endotypes. A 15-gene T-cell dysfunction signature showed strong external validation (AUC 0.76-0.85).

Conclusions:

• Immune-inflammatory co-profiling effectively identifies biologically distinct sepsis subgroups.
• These endotypes exhibit differential associations with treatment responses, particularly corticosteroids in hypo-inflammatory states.
• Findings support endotype-guided trials for personalized sepsis management and generate hypotheses for future validation.