Adult hemophagocytic lymphohistiocytosis: A multicenter retrospective analysis of etiology and impact on survival in China

Abstract Background Hemophagocytic lymphohistiocytosis (HLH) is a rare yet life-threatening hyperinflammatory syndrome characterized by persistent fever, hepatosplenomegaly, cytopenias, hypertriglyceridemia/hypofibrinogenemia, and demonstrable hemophagocytic activity in the bone marrow, spleen, or lymph nodes. While international understanding of HLH pathogenesis has advanced, large-scale systematic studies focusing specifically on adult HLH patients in China remain scarce. Purpose This multicenter, retrospective cohort study aimed to delineate the etiological spectrum of adult HLH in China and examine the association between underlying etiologies and survival outcomes. Method Inclusion criteria: (1) Primary discharge diagnosis of HLH ranked among the top three diagnostic positions; (2) Age ≥18 years; (3) Fulfillment of ≥5 out of the 8 diagnostic criteria defined by the 2001 HLH diagnostic guidelines. Due to limited access to specialized external testing, sCD25 and NK cell activity assays were unavailable for the majority of patients; therefore, diagnosis was established by meeting ≥5 of the remaining 6 criteria points. Exclusion criterion: Absence of critical data elements. Data collection encompassed demographics, clinical manifestations, laboratory parameters, treatment regimens, therapeutic responses, and survival status extracted from electronic medical records. Categorical variables are presented as percentages; continuous variables as medians with interquartile ranges (IQR). Survival time was calculated from both hospital admission date and HLH diagnosis date until death or last follow-up. Kaplan-Meier curves and log-rank tests were utilized for survival analysis and subgroup comparisons. Results Between January 2020 and January 2024, 437 patients were enrolled (242 males, 55.4%; median age 57 years, IQR 41-68). Predominant clinical manifestations included fever (415, 95.0%), rash (59, 13.5%), and pharyngalgia (44, 10.0%). Key laboratory/clinical findings were leukopenia (<4.0×10⁹/L: 266, 60.9%; <2.0×10⁹/L: 125, 28.6%), neutropenia (<2.0×10⁹/L: 170, 38.9%; <1.0×10⁹/L: 82, 18.8%; agranulocytosis <0.5×10⁹/L: 42, 9.6%), anemia (Hb<90g/L: 206, 47.1%; severe <60g/L: 58, 13.3%), thrombocytopenia (<100×10⁹/L: 349, 79.9%; severe <50×10⁹/L: 227, 51.8%), splenomegaly (388, 88.7%), hypofibrinogenemia (<1.5g/L: 334, 76.4%), hypertriglyceridemia (>3.0mmol/L: 249, 57.0%), and bone marrow hemophagocytosis (306, 70.0%). Etiologies included EBV reactivation (30, 6.8%), lymphoma (198, 45.3%; T-cell: 72, 36.4%; NK/T-cell: 64, 32.3%; B-cell: 62, 31.1%), autoimmune diseases (21, 4.8%), other infections (91, 20.8%), and other/unknown causes (97, 22.2%). With follow-up until June 30, 2025, only 154 patients (35.2%) survived. Median OS from admission was 89 days (95%CI: 54-124), with 167 deaths (38.2%) within 30 days; etiologic subgroup median OS differed significantly (EBV: 31d [23-38], Autoimmune: not reached, Lymphoma: 128d [87-168], Infection: 40d [0-81], Other/Unknown: 52d [23-97]; P<0.001). Median OS from HLH diagnosis was 85 days (51-119), with 180 deaths (41.1%) within 30 days; subgroup OS also differed significantly (EBV: 31d [14-48], Autoimmune: not reached, Lymphoma: 129d [93-165], Infection: 36d [0-100], Other/Unknown: 37d [20-54]; P<0.001). Conclusion The entire cohort exhibited a median overall survival (OS) of only 85 days from the time of HLH diagnosis, with an overall mortality rate reaching 64.8%. Critically, 41.1% of patients died within 30 days of diagnosis. Etiology was a critical prognostic factor: EBV-associated HLH demonstrated the poorest prognosis (median OS merely 31 days), while HLH associated with autoimmune diseases showed the most favorable survival outcome (median OS not reached). Keyword Adult Hemophagocytic Lymphohistiocytosis (HLH),China,Etiology,Survival,Prognosis,Mortality