Clinical features, course, and risk factors of infection-associated secondary hemophagocytic lymphohistiocytosis.

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is an orphan disease characterized by excessive inflammation and poor outcome. We sought to further characterize clinical features, courses, and risk factors of secondary HLH (sHLH) triggered by infection (iHLH). 28 (43.1%) of 65 adult sHLH cases treated at our hospital from 2012-2024 were infection-associated. iHLH patients were mostly male (71.4%). Infectious agents most frequently detected were EBV (57.1%) and leishmania (14.3%). The median time to diagnosis was 13 [6.0;24.8] days. iHLH patients had a mortality rate of 39.3% (median follow-up time: 735 [336;1140] days), worse survival than patients with autoimmune-triggered (hazard ratio: 3.33 (1.01-11.10), p = 0.049), and better survival than patients with paraneoplastic HLH (hazard ratio: 0.19 (0.10-0.84), p = 0.002). Elevated levels of soluble interleukin-2 receptor (sIL2R; > 6,000 I/U), low thrombocyte counts (< 40 G/l), and a history of malignant disease were associated with adverse outcomes. Protracted time to diagnosis was associated with severe disease courses and with leishmaniosis. Further, sIL2R levels correlated positively with prolonged aPTT and thrombocytopenia, and hypertriglyceridemia with elevated INRs. Patients with an elevated sIL2R:ferritin ratio were more likely to have a history of malignant comorbidities. Taken together, sIL2R, thrombocytopenia, and a history of malignant disease are important prognostic factors of iHLH. Patients with high sIL2R levels or hypertriglyceridemia may be at higher risk of bleeding, and patients with elevated sIL2R:ferritin ratios should be assessed for possible malignant comorbidities. Lastly, increased awareness of the disease and newly emerging pathogens (i.e. leishmania) may shorten the time to diagnosis, and thus reduce severe courses of iHLH.