Tropical Triggers and Overactive Immunity

Purpose: In tropical regions like South India, unique environmental triggers lead to a high prevalence of infection-associated hemophagocytic lymphohistiocytosis (iHLH), a life-threatening hyperinflammatory state. This study aims to delineate the clinical profile and identify specific predictors of mortality in a pediatric cohort to optimize early intervention in these resource-distinct settings. Methods: This is a retrospective single-centre study on children (1 mo to 18 y age) with iHLH between January 2022 and June 2024 meeting HLH-2004 criteria. Treatment included dexamethasone or methyl prednisolone +/- immunoglobulin +/- etoposide. Results: The cohort comprised 109 children with a median age of 60 months, 57% males. Dengue was the primary trigger (79.8%), followed by bacterial sepsis (8.2%) and rickettsia (5.6%). All children presented with fever, hepatomegaly, while 24% splenomegaly and 51.4% pancytopenia. The median (IQR) Pediatric Risk Mortality (PRISM III) score was 8.5 (5;12). Key laboratory findings were [median (IQR)]- Hb nadir 8.6 (7;10) g/dL, platelet nadir 29,000 (17,000; 50,000)/mm 3 , peak AST 744 (246;3 042) U/L, baseline ferritin 9541(4560; 28,392) ng/mL. Complications included acute liver failure (91.7%), ARDS (81.7%), and shock (63.3%). Overall mortality was 23%. Children received steroids (80%), IVIG (24%), both (24%), and etoposide (1%). Nonsurvivors were significantly older ( P = 0.017), had higher PRISM III scores ( P < 0.001), and higher baseline ferritin ( P = 0.001). They also required longer durations of mechanical ventilation ( P = 0.035) and inotropic support ( P = 0.01). Multivariate analysis identified PRISM III score (OR: 1.15; 95% CI: 1.0-1.3; P = 0.03) and requirement for hemodialysis (OR: 5.4; 95% CI: 1.3-21; P = 0.01) as independent mortality predictors. A baseline ferritin ≥16,500 ng/ml predicted mortality with 83% sensitivity and 95% specificity (AUC: 0.71). Conclusions: Pediatric iHLH in South India is characterized by rapid multi-organ dysfunction and high mortality. Our findings suggest that in tropical contexts, a PRISM III score and the requirement for organ support (respiratory or renal) are decisive indicators of poor outcomes. Most notably, a baseline ferritin level ≥16500 ng/mL serves as a critical prognostic “red flag,” allowing clinicians to identify high-risk tropical infections before they escalate into irreversible overactive immunity.