19-year-old previously healthy female with infectious mononucleosis complicated by recurrent fevers and persistent EBV viremia. Approximately three months later, she presented with quotidian fevers, hepatosplenomegaly (HSM), pancytopenia, and rising EBV viremia. Laboratory studies revealed elevated ferritin, lactate dehydrogenase (LDH), transaminases, triglycerides, and hypercytokinemia (sIL-2R, CXCL9, IL-18, IL-10, IL-8, ADA2, and serum amyloid A [SAA]). Initial bone marrow (BM) biopsy showed atypical lymphocytosis consistent with acute EBV infection, histiocytes with marked increase in hemophagocytosis, and significant EBV-encoded small RNA (EBER) staining of T and natural killer (NK) cells. B cells were absent in BM. Cerebrospinal fluid (CSF) did not show evidence of inflammation. Treatment was initiated for chronic active EBV-T cell lymphoproliferative disease (CAEBV-TLPD) with improvement in symptoms and viremia. One month later, there was rebound EBV viremia, worsening fevers, hepatosplenomegaly (HSM), and patchy pulmonary infiltrates progressing to respiratory failure requiring intubation, hepatic, and renal failure with coagulopathy. Quantitative EBV analysis in different cell subsets showed florid increase in EBV within the B cell compartment suggestive of EBV-driven B cell lymphoproliferation/malignancy. EBV was positive in T and NK cell subsets but less significantly. Treatment was transitioned to focus on the B cell lymphoproliferative process (Fig. 1). Quantitative EBV DNA methylation was performed at 25 EBV loci and found to have intermediate EBV methylation (47%). Methylation pattern was consistent with lymphoproliferative disease/lymphoma. Immunophenotyping in blood revealed increased activated CD4+ and CD8+ T cells (HLA-DR+CD38+++). There were also increased CD5+CD38++ T cells. There was also increased exhausted (LAG3+) and senescent (KLRG1, CD57+) T cells in the CD4+ T cell subset. PD1 expression was not increased on CD4+ or CD8+ T cells due to prior treatment with nivolumab. An atypical B cell subset (CD19+CD20-) was identified prior to EBV infection in B cells. Additional phenotyping revealed numerous B cell marker anomalies consistent with aberrant differentiation, prior to rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (RTXx2). There was rebound of CD19+CD20+ and CD19+CD20- B cells within 2+ weeks of treatment. At this time, there was evidence of central nervous system (CNS) involvement with expressive aphasia and volume loss. CSF analysis demonstrated CD19+CD20- B cells as well as T cells along with elevated cytokines. She developed warm autoantibodies against RBCs without hemolysis. She also had anti-smooth muscle antibodies suggestive of active endogenous production, rather than passive administration via immunoglobulin replacement. Rapid genome sequencing was performed and negative, despite evaluation for EBV predisposing genes. A single maternally inherited variant in MEFV was present, which could have contributed to the overall clinical phenotype, albeit indirectly. Despite numerous therapies, there was continued decompensation, resulting in fulminant liver failure and severe metabolic acidosis, resulting in irreversible organ failure and death.
With no prior history of immune dysregulation, this patient developed rapid and fulminant course of EBV-LPD (lymphoproliferative disease), which was refractory. While the aggressive course of disease is not fully understood, the atypical CD19+CD20- B cells could have contributed to disease pathogenesis, along with EBV strain and replicative potential, and possible uncharacterized host genetic contributions. Most cases of biclonal (B and T cell) EBV-LPD are associated with significant immune compromise, often in the setting of solid organ transplantation. This case illustrates CAEBV evolving to B cell-EBV-LPD with the inability to pursue hematopoietic cell transplant (HCT) due to clinical instability and exemplifies the need to understand the molecular and immunological underpinnings of EBV-LPD.
