Long-term outcomes of chronic active Epstein-Barr virus infection in childhood after dominantly infected lymphocyte subpopulation management.

Abstract

Chronic active Epstein-Barr virus (EBV) disease (CAEBV) is an uncommon lethal infection involving EBV-infected T and/or NK-cells, often complicated by hemophagocytic lymphohistiocytosis (HLH). Patients need curative hematopoietic cell transplantation (HCT), but the indication and timing remain unclear. This study aimed to assess the prognostic value of EBV-infected lymphocyte subsets. We analyzed 52 pediatric/young-adult patients diagnosed with persistently EBV infection from 2003 to 2025 at a single tertiary center in Japan, excluding acute infectious mononucleosis and secondary immunodeficiencies. Dominant EBV-infected cell types (CD4+, CD8+, γδT-cells, CD19+B-cells, and CD56+NK-cells) were determined at diagnosis of CAEBV (n = 21), EBV-HLH (n = 19), or inborn errors of immunity (IEI, n = 12). The long-term outcomes were analyzed by major infected cell types and treatment. CAEBV included 12 T-cell (6 CD4+, 4 CD8+, and 2 γδ) and 9 NK-cell dominant infections. EBV-HLH and IEI exclusively involved CD8+T-cell and B-cell infections, respectively. Thirteen CAEBV patients (62%) underwent HCT to control progression including 5 patients who presented with HLH. The 3-year overall survival (OS) was 88%, although CD4+T-cell disease (all CAEBV) showed a significantly lower survival rate. Posttransplant deaths occurred in 3 of 13 CAEBV and none of EBV-HLH patients. Among 9 CAEBV patients with median 11-year progression-free survival without HCT, each one of CD4+T-cell or NK-cell case transformed to lymphoma or leukemia after being untreated for >10 years. EBV-infected lymphocyte profiling guided prolonged HCT-free control of CAEBV. CD4+T-cell CAEBV requires a prompt rather than elective HCT to prevent progression and transformation.