DIAGNOSIS AND MANAGEMENT OF CTLA-4 VARIANT IMMUNE DYSREGULATION

Abstract

<h3>Introduction</h3> Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative regulator of the immune system and when deficient, can result in immune dysregulation. Here we present a patient with progressive immune dysregulation and confirmed CTLA-4 haploinsufficiency. <h3>Case Description</h3> A 25-year-old male diagnosed with Evans syndrome and CNS vasculitis in childhood was stabilized on mycophenolate mofetil (MMF). At age 14, he developed pneumonia and had a lung biopsy consistent with lymphocytic interstitial pneumonia. Immune evaluation confirmed common variable immunodeficiency with dysregulated T and B cell subsets, and he was started on immunoglobulin replacement therapy. Genetic evaluation revealed 2 CTLA-4 variants of uncertain significance and functional assays confirmed CTLA-4 haploinsufficiency. Subsequently, he developed splenomegaly, chronic lung disease, and EBV viremia. A repeat lung biopsy was consistent with polymorphic EBV-positive lymphoproliferative disorder, prompting rituximab therapy. CTLA-4 Ig could not be utilized because of the potential of worsening chronic EBV. He was prescribed sirolimus. Acyclovir and trimethoprim-sulfamethoxazole were prescribed prophylactically for T cell lymphopenia. <h3>Discussion</h3> This patient with EBV and CTLA-4-driven lung disease is susceptible to worsening lung and lymphoproliferative diseases and recurrent infections. Management options include rituximab for EBV, sirolimus for immune dysregulation, and when possible, CTLA-4 Ig once EBV is controlled. The manifestations of CTLA-4 haploinsufficiency are unique and patients require close clinical follow up. Additional biomarkers of dysregulation may include monitoring of dysregulated T and B cell subsets. Management aims include targeted therapy to control immune dysregulation and potentially definitive hematopoietic stem cell transplantation.