Development and validation of an early risk-stratification model for hemophagocytic lymphohistiocytosis in severe fever with thrombocytopenia syndrome

Objective: To develop and validate a model for early risk stratification of secondary hemophagocytic lymphohistiocytosis (HLH) in patients with severe fever with thrombocytopenia syndrome (SFTS). Methods: This retrospective cohort included adults with laboratory-confirmed SFTS admitted to The First Affiliated Hospital with Nanjing Medical University between January 2019 and July 2024. Predictor variables were derived from clinical and laboratory data obtained within 3 days after virologic confirmation, corresponding to the predefined early-evaluation window of the study. HLH status (binary outcome) was defined using the entire-course HScore (≥170), calculated from the worst available values over the clinical course; HLH-2004 criteria and early-window HScore distributions were summarized descriptively to provide transparent outcome accounting. Twenty-eight candidate predictors entered LASSO with Boruta refinement, and retained variables were used to construct a multivariable logistic model and nomogram. Model performance was evaluated by discrimination, calibration, and decision-curve analysis in the derivation cohort, an internal validation set, and an external cohort of 60 patients from The First Affiliated Hospital with Anhui Medical University. Results: Among 249 patients (152 non-HLH, 97 HLH), HLH was associated with higher peak temperature, longer fever, more lymphadenopathy/splenomegaly and neurological symptoms, and more severe thrombocytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, higher viral load, elevated muscle/liver enzymes and LDH, and coagulopathy (all p