Primary EBV Lymphoproliferative Disease Responsive to Therapy in a Patient with CTLA4-Haploinsufficiency

Epstein-Barr virus lymphoproliferative disease (EBV-LPD) occurs most often in patients with acquired immunosuppression. However, several inborn errors of immunity have been associated with primary EBV-LPD, including pathogenic variants in SH2D1A, ITK, MAGT1, CORO1A, CD27, CTPS1, RASGRP1, and ZAP70 (PMID29942301,34239742). Here, we present a patient with primary EBV-LPD in the setting of CTLA-4 haploinsufficiency. JC is a 25yo male with Evans syndrome, hypogammaglobulinemia, and central nervous system vasculitis who presented to the NIH for evaluation of EBV-LPD. After a complicated course of legionella pneumonia at age 23, he developed recurrent fevers, respiratory distress, hypoxia, and night sweats responsive to dexamethasone. Chest CT revealed innumerable bilateral pulmonary nodules and masses with mediastinal hilar lymphadenopathy and scattered ground glass opacities. Transbronchial biopsy demonstrated EBV-positive B-cell LPD with extensive necrosis and clonal gene rearrangements. He responded well to 1 cycle of rituximab. Two years later, he again had fever, dyspnea on exertion, and hypoxia requiring glucocorticoids. Chest CT revealed ground glass opacities of the lungs, lung nodules/masses, and consolidation. Lung biopsy showed T and B-cell infiltrates, EBV+ B-cells by immunohistochemistry, and a clonal B-cell population (Figure 1). His course was also complicated by concurrent Pneumocystis Jirovecii (PJP) infection. He received 1 cycle of rituximab, trimethoprim-sulfamethoxazole, and sirolimus for treatment of his EBV-LPD, PJP, and underlying CTLA-4 haploinsufficiency respectively with symptomatic and radiologic response (Figure 2).Figure 1Histological features of needle core biopsy from the lung – (A) 10x and (B) 20× magnification H&E stain shows dense lympho-histiocytic infiltrate. (C) Lympho-histiocytic infiltrate is predominantly CD3+ T-cells. (D) Scattered CD79+ B-cells are also identified in the infiltrate. (E) 10x magnification (F) 20X magnification shows numerous EBV-encoded RNA (EBER) positive cells, mostly small in size. (D&F) EBER+ cells are in a similar distribution to CD79+ B cells.Figure 2EBV viral load and absolute B-cell count over the course of therapy with rituximab and sirolimus. Dates of medication initiation (sirolimus) or infusion (rituximab) are listed about the graph. B) Radiologic improvement on therapy. May 9,2022 shows lung nodules, lung masses, and ground glass opacities prior to starting therapy. July 19, 2022 shows some improvement in lung nodules and masses after 1 dose of rituximab and initiation of sirolimus. September 27, 2022 shows marked improvement in lung nodules and masses and near resolution of ground glass opacities on continuous sirolimus therapy and 1 month after completion of rituximab.