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

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.

The online version contains supplementary material available at https://doi.org/10.1007/s12288-025-02206-5.