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

Abstract

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). [Display omitted] [Display omitted] NIAID whole exome sequencing (WES) revealed 2 compound heterozygous variants in CTLA-4 in trans: a novel pathogenic variant c.373G > A, p.Gly125Arg, and a non-pathogenic c.326G > A, p.Gly109Glu, shared with his mother(allele frequency of 0.000367 popmaxv.3.1.1 and Cadd score 17). Other variants that may contribute to EBV-LPD are under investigation.EBV-LPD in CTLA-4 haploinsufficiency is rare, previously reported in only 2 pediatric cases (PMID34329649). Additionally, WES revealed compound heterozygous variants in CTLA-4; however, only 1 variant was proven pathogenic. While this patient initially demonstrated excellent response to first line therapy, long-term prognosis is guarded. Abatacept was not included in this patient’s treatment because of an association with progressive LPD in patients with and without CTLA-4 haploinsufficiency. Immune reconstitution with bone marrow transplantation will likely be required for permanent disease control.