Chronic active Epstein-Barr virus (EBV) disease (CAEBV) is a lethal syndrome because of persistent EBV infection. When diagnosed as CAEBV, EBV infection was observed in multiple hematopoietic lineages, but the etiology of CAEBV is still elusive. Bone marrow and peripheral cells derived from 5 patients with CAEBV, 1 patient with EBV-associated hemophagocytic lymphohistiocytosis, and 2 healthy controls were analyzed. Multiple assays were applied to identify and characterize EBV-infected cells, including quantitative polymerase chain reaction, PrimeFlow, and single-cell RNA-sequencing (scRNA-seq). Based on scRNA-seq data, alterations in gene expression of particular cell types were analyzed between patients with CAEBV and controls, and between infected and uninfected cells. One patient with CAEBV was treated with allogeneic hematopoietic stem cell transplantation (HSCT), and the samples derived from this patient were analyzed again 6 months after HSCT. EBV infected the full spectrum of the hematopoietic system including both lymphoid and myeloid lineages, as well as the hematopoietic stem cells (HSCs) of the patients with CAEBV. EBV-infected HSCs exhibited a higher differentiation rate toward downstream lineages, and the EBV infection had an impact on both the innate and adaptive immunity, resulting in inflammatory symptoms. EBV-infected cells were thoroughly removed from the hematopoietic system after HSCT. Taken together, multiple lines of evidence presented in this study suggest that CAEBV disease originates from the infected HSCs, which might potentially lead to innovative therapy strategies for CAEBV.

Background: Currently, most research on hemophagocytic lymphohistiocytosis (HLH) have focused on etiology and therapy, leaving few epidemiological reports. The published studies of China are mainly regional investigations. We aimed to present the overall epidemiological status of HLH in China, and provide Chinese data for the international HLH epidemiological investigation. Methods: The data of HLH cases in China in 2019 were collected and statistically analyzed. Findings: Epstein-Barr virus accounted for 44.01% of the 1445 cases in 31 regions and was the most common cause. Lymphoma-associated HLH patients were more often male (P < 0.05) while rheumatic and immune-associated HLH were more often female (P < 0.001). Primary HLH and Epstein-Barr Virus-associated HLH were predominant in children (P < 0.001) while tumor-associated HLH was predominant in adults. Lymphoma-associated HLH was positively correlated with the age of onset (P < 0.01). The diagnosis rate of 29 areas had a significant correlation with per capita Gross domestic product (P < 0.05). Conclusion: The different distribution of HLH etiology by age and gender contributes to the diagnosis of HLH by clinicians; The suboptimal diagnosis rate in regions with a high incidence of HLH in China is a result of the effect of the local economic level indicating the importance of improving the regional medical level.

Summary: Haemophagocytic lymphohistiocytosis (HLH) is a severe, even fatal, inflammatory condition. Epstein–Barr virus (EBV) infection‐associated HLH (EBV‐HLH) is one of the most common types of secondary HLH. Etoposide is a key drug in HLH‐94/04 regimen. We sought to identify the importance of etoposide in the initial treatment of EBV‐HLH. Ninety‐three patients with EBV‐HLH of all ages admitted to our centre in 2017 were divided into two groups according to whether the initial treatment contained etoposide or not. The survival of the group whose initial therapy included etoposide (Group 1, 52 patients; 6‐month survival rate 0·769) was significantly better than that of the group whose initial therapy did not include etoposide (Group 2, 41 patients; 6‐month survival rate 0·269) (P < 0·001). In patients aged <18 years old, the survival of Group 1 patients was not significantly better than that of Group 2 patients (P = 0·447), in contrast to patients aged ≥18 years, where the survival of Group1 patients was significantly better than that of Group 2 patients (P < 0·001). We concluded that including etoposide in the initial treatment of EBV‐HLH patients can improve their prognosis, especially adult patients. This may be because that adult patients are recognized as “higher risk” patients.