The Clinical Significance and Prognostic Role of Whole-Blood Epstein-Barr Virus DNA in Lymphoma-Associated Hemophagocytic Lymphohistiocytosis

Purpose: To evaluate the role of circulating Epstein-Barr virus (EBV) DNA in lymphoma-associated hemophagocytic lymphohistiocytosis (HLH). Methods: We conducted a retrospective cohort study to explore the clinical and prognostic significance of EBV DNA in lymphoma-associated HLH. We included adult patients with combined diagnoses of lymphoma and HLH from January 2010 and November 2022 by retrieving the medical record system. Results: A total of 281 patients with lymphoma-associated HLH were identified. Elevated whole-blood EBV DNA was observed in 54.4% (153/281) of patients, and the median copy number was significantly higher in the T/NK-cell malignancies (199,500, interquartile range, 30,000–1,390,000) than that in the B-cell non-Hodgkin lymphoma (5520, interquartile range, 1240–28,400, P < 0.001). The optimum cutoff for predicting survival was 16,100 copies/mL. Compared to the patients with EBV DNA ≤ 16,100 copies/mL, those with EBV DNA > 16,100 copies/mL were younger and had more T/NK-cell malignancies, lower levels of neutrophils and fibrinogen, and higher levels of hemoglobin, alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase, and β-microglobulin. A higher load of EBV DNA (> 16,100 copies/mL), thrombocytopenia (< 100 × 10/L), neutropenia (< 1 × 10/L), hypofibrinogenemia (≤ 1.5 g/L), and elevated levels of creatinine (> 133 μmol/L) were independent adverse predictors of 60-day overall survival and overall survival. A prognostic index based on EBV DNA and the other four factors was established to categorize the patients into four groups with significantly different outcomes. Conclusion: Our study identified high EBV load as a risk factor for lymphoma-associated HLH and established a prognostic index to predict outcomes.