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.

Keywords: Hemophagocytic lymphohistiocytosis; Infection-associated HLH; Prognostic factors of HLH; Risk factors of HLH; Secondary HLH.

Fig. 1

sHLH cases by triggers. sHLH cases treated at LMU university hospital from Jan 1st, 2012, to October 28th, 2024, are depicted based on their respective triggers. Unknown = lack of documentation; unclear = various likely triggers

Fig. 2

Survival of sHLH patients depending on underlying triggers. Survival data of sHLH patients treated at LMU university hospital from Jan 1st, 2012, to October 28th, 2024, are plotted as Kaplan–Meier survival curves. n.s. = not significant (p-value > 0.05); * = p-value ≤ 0.05; ** = p-value ≤ 0.01

Fig. 3

Survival of iHLH patients with and without a history of malignant disease. Kaplan–Meier survival curves of iHLH patients with a history of malignant comorbidities/diagnoses in remission and/or with no indication for oncologic treatment (n = 6) compared to iHLH patients without a history of malignant comorbidities (n = 22). Only patients with infectious HLH triggers were included. ** = p-value ≤ 0.01

Fig. 4

Correlation matrix of iHLH patients’ clinical and laboratory parameters. The parameters assessed include iHLH patients’ demographic, outcome, clinical and laboratory data. The matrix depicts Pearson’s correlation coefficients (r). Positive correlations between the variables are depicted in blue, negative correlations in red, with color intensity reflecting correlation strength (range: r = −1 to + 1). Asterisks indicate statistical significance (* = p ≤ 0.05; ** = p ≤ 0.01; *** = p ≤ 0.001). Only the most relevant findings/parameters from the exploratory correlation analysis are plotted. The full correlation analysis is shown in Supplementary Fig. 1

Fig. 5

Survival of iHLH patients depending on thrombocyte counts and sIL2R levels. Kaplan–Meier survival curves of iHLH patients with thrombocyte counts (A) or sIL2R levels (B) below or above the respective cutoff values