An improved index as a screening and early warning tool for adult patients with infection-associated hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory condition frequently triggered by infections, yet the applicability of current diagnostic criteria (HLH-2004 and HScore) in this context remains uncertain. This uncertainty stems from HLH-2004's reliance on non-routine tests (e.g., natural killer cell activity and sCD25) during initial infection workups and unoptimized diagnostic cutoffs for infection-HLH, combined with HScore's derivation from cohorts containing insufficient infected patients. The study involved 266 adult patients with infection (2017–2023), stratified by HLH status, across two medical centers. Classification and regression tree (CART) modeling and receiver operating characteristic curve analyses were used to create an index predicting infection-associated HLH. Survival analysis explored the index's correlation with 60-day survival, assessing prognosis. Patients with infection-HLH were younger (median age 53 vs 59 years, P = 0.001) and exhibited higher mortality (hazard ratio, 2.77; 95% confidence interval, 1.6–4.8) than infected patients without HLH. Conventional HLH diagnostic markers demonstrated low data completeness in routine clinical cohorts, with sCD25 at 7% and natural killer cell activity at 12.8%. To address this limitation, an Improved Infection-HLH (IIH) index was developed using CART analysis, with three routinely measurable parameters selected as optimal predictors: temperature (> 38.3 ℃), platelets (< 85.5 × 10 9 /L) and fibrinogen (< 5.5 g/L). Compared with the HLH-2004 criteria and thresholds derived from the maximal Youden’s index, the IIH index demonstrated optimal discriminatory performance, achieving a sensitivity of 71% and a specificity of 100% for identifying infected patients at high risk of HLH. Moreover, more patients with higher 60-day mortality risk unrecognized by the HLH-2004 criteria were flagged by the IIH index ( N = 56). A positive IIH index may serve as a practical triage tool for infected patients with suspected HLH risk, and may help separate patients with unfavorable survival outcomes.