Navigating the Gray Zone: Differentiating Sepsis and Secondary HLH in Adults Using T Cell Activation Markers.

UNLABELLED: Life-threatening organ dysfunction due to a dysregulated host response to infection defines sepsis, and uncontrolled T-cell activation results in Hemophagocytic lymphohistiocytosis (HLH). Sepsis and HLH share numerous overlapping clinical and laboratory features. To differentiate between sepsis and HLH, we conducted a cross-sectional study on the steroid-naïve adult population (> 16 years) using peripheral blood flow cytometric immunophenotyping. We compared T-cell surface activation markers, viz. HLA-DR and CD38, on CD4 and CD8 T cells among patients with sepsis, HLH and healthy controls. The percentage of CD8⁺CD38⁺ and CD8⁺CD38⁺HLA-DR⁺ T-cell subsets differ significantly between sepsis and HLH. A cut-off of > 46.8% for CD8⁺CD38⁺ and > 14.7% for CD8⁺CD38⁺HLA-DR⁺ achieves a sensitivity of 100%, with specificities of 96.7% and 93.3%, respectively. T-cell surface activation markers show promise in differentiating sepsis from HLH in adults. Larger, multicentric, longitudinal studies are required to validate these results and define their prognostic significance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s12288-025-02206-5.