Clinical and prognostic significance of whole blood Epstein-Barr virus DNA in patients with primary hemophagocytic lymphohistiocytosis: a retrospective observational study from China

Abstract

Hemophagocytic lymphohistiocytosis (HLH) has been described as a threshold disease depending on triggering factors and the residual cytotoxic capacity of NK cells. This study aimed to investigate the clinical characteristics of Epstein-Barr virus (EBV)-triggered primary HLH and the prognostic value of EBV-DNA load in EBV-triggered primary HLH cases. We retrospectively analyzed the clinical data of 95 patients with primary HLH treated between January 2013 and January 2024. Based on the peripheral blood EBV status at initial diagnosis, 57 patients were categorized into the EBV-triggered primary HLH group and 38 patients into the non-EBV-triggered primary HLH group. Clinical and functional characteristics, response to treatment, and prognosis were compared between the two groups. Among patients with EBV-triggered primary HLH, the proportion of patients with familial HLH type 2 (FHL2) was significantly lower (P = 0.011), whereas the proportion of patients with X-linked lymphoproliferative disorder (XLP) was higher (P = 0.037). Functional assays showed that in primary HLH patients with gene defects in cytotoxic degranulation, the proportion of EBV-triggered primary HLH patients with reduced NK cell activity and degranulation function was significantly higher (P = 0.026 and P = 0.030). Importantly, multivariate Cox regression analysis identified EBV-DNA > 10,000 copies/mL as an independent risk factor affecting the prognosis of patients with EBV-triggered primary HLH, particularly in non-FHL cases (P = 0.045). EBV-triggered primary HLH is more prevalent in patients with XLP but less frequent in FHL2 patients. High EBV-DNA load is an adverse prognostic factor in EBV-triggered primary HLH patients.

Keywords: Epstein-Barr virus; Overall survival; Primary hemophagocytic lymphohistiocytosis; Prognosis; Trigger.

Fig. 1

Distribution of the genetic diagnoses in the 95 patients

Fig. 2

Kaplan-Meier curves of overall survival (OS). A Comparison of OS in patients with EBV-triggered and non-EBV-triggered primary HLH. B Comparison of the effects of different EBV-DNA loads on OS in patients with EBV-triggered primary HLH. C Comparison of the effects of different EBV-DNA loads on OS in patients with EBV-triggered FHL. D Comparison of the effects of different EBV-DNA loads on OS in patients with EBV-triggered non-FHL. E Comparison of the effect of EBV predominantly infected lymphocyte subsets on OS in patients with EBV-triggered primary HLH. F Comparison of the effect of post-treatment EBV-DNA load on OS in patients with EBV-triggered primary HLH