Posted on Authorea 26 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160372861.18168312/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. Pulmonary Manifestations of Immune Dysregulation in CTLA-4 Haploinsufficiency and LRBA Deficiency Katie Krone 1 , Abbey Winant 2 , Sara Vargas 3 , Craig Platt 4 , Lisa Bartnikas 4 , Erin Janssen 4 , Craig Lillehei 2 , Edward Lee 2 , Martha Fishman 5 , and Alicia Casey 5 1 Boston Children s Hospital 2 Boston Children’s Hospital 3 Boston Children’s Hospital Department of Pathology 4 Boston Children’s Hospital Division of Immunology 5 Boston Children’s Hospital Division of Pulmonary and Respiratory Diseases October 26, 2020 Abstract Objective: The primary immunodeficiency syndromes of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) haploinsuffi- ciency and lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency present with multisystem immune dysregulation. The aim of this study was to characterize and compare the pulmonary manifestations of these two diseases. Methods: We retrospectively analyzed the pulmonary clinical, radiologic, and histopathologic characteristics of 6 patients with CTLA-4 haploinsufficiency and 4 patients with LRBA deficiency with pulmonary involvement followed at a large tertiary care center. Results: Chronic respiratory symptoms were more frequent in patients with LRBA deficiency versus CTLA-4 hap- loinsufficiency (4/4 versus 1/6). Cough was the most common respiratory symptom. Abnormalities in pulmonary exam and pulmonary function testing were more frequent in LRBA deficiency (4/4, 2/4) compared to CTLA-4 haploinsufficiency (1/6, 2/6). Chest CT findings included mediastinal lymphadenopathy (4/4 in LRBA deficiency versus 1/4 in CTLA-4 haploinsuf- ficiency), pulmonary nodules (4/4, 3/4), ground-glass opacification (4/4, 3/4), and bronchiectasis (3/4, 1/4). Lymphocytic inflammation, concentrated bronchovasculocentrically and paraseptally, was observed in all patients who had lung biopsies (N=3 with LRBA deficiency; N=3 with CTLA-4 haploinsufficiency). Granulomas were seen in all patients with CTLA-4 haploinsufficiency and in no patients with LRBA deficiency. Conclusion: Despite phenotypic overlap amongst these diseases, LRBA deficiency demonstrated greater severity of pulmonary disease, indicated by respiratory symptoms, pulmonary exam, and intrathoracic radiologic findings. Lymphocytic inflammation is a key histologic feature of both of these disorders. Pedi- atric pulmonologists should suspect these disorders in the appropriate clinical, radiological, and pathological context to better diagnose and treat these patients. Introduction Primary immune deficiency syndromes predispose to chronic lung disease as a consequence of immune dys- regulation, encompassing immune deficiency and autoimmunity 1 . With our evolving understanding of their genetic underpinnings, new monogenic disorders of immune dysregulation affecting regulatory T cell func- tion are being identified. Previously classified as common variable immunodeficiency (CVID), cytotoxic T lymphocyte-associated protein 4 (CTLA-4) haploinsufficiency and lipopolysaccharide-responsive and beige- like anchor protein (LRBA) deficiency were first described in 2012 and 2014, respectively 2; 3 . The features of immune dysregulation that characterize both disorders are strikingly similar, and include hypogamma- globulinemia, autoimmune cytopenias, recurrent infections, enteropathy, lymphoproliferative infiltration of organs, and lung disease 4-7 . 1