A40-07 Adult-Onset Coatomer Protein Complex Subunit Alpha Syndrome With Cystic Lung Disease

Introduction Coatomer Protein Complex Subunit Alpha (COPA) syndrome was first reported in 2015 after pathogenic variants in the COPA gene were identified in multiple kindreds with childhood-onset interstitial lung disease (ILD), positive autoantibodies, and inflammatory arthritis. Herein, we report a unique case of adult-onset case of COPA syndrome. Case Presentation A 59-year-old male with end-stage renal disease (ESRD) presented with chronic cough. Chest computed tomography (CT) showed numerous bilateral, lower-lobe-predominant cysts (Image 1) with scattered faint ground-glass opacities (GGOs). Serologies demonstrated high-titer antinuclear antibodies (ANA) and perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) with elevated anti-myeloperoxidase (anti-MPO). Serum vascular endothelial growth factor-D (VEGF-D) was normal and folliculin (FLCN) testing was negative. Surgical lung biopsies revealed extensive alveolar hemosiderosis consistent with prior diffuse alveolar hemorrhage (DAH) without active vasculitis, follicular bronchiolitis, and cystic changes. Genetic testing identified a pathogenic COPA variant, confirming COPA syndrome. Discussion COPA syndrome is an autosomal-dominant immune-dysregulation disorder presenting with interstitial lung disease (ILD) and inflammatory arthritis with multi-autoantibody positivity; most patients present in childhood; adult-onset disease is uncommon. Pathophysiology reflects a defect in retrograde transport of proteins from Golgi apparatus to endoplasmic reticulum, leading to constitutive type I interferon activation and downstream autoimmunity with lung injury. Pulmonary involvement is near-universal; diffuse alveolar hemorrhage (DAH)—often occult—may be an early clue. Chest CT typically demonstrates cystic changes, bronchiolitis, and fibrosis. Pulmonary function tests commonly show mixed obstruction-restriction with reduced diffusing capacity. Extra-pulmonary features include inflammatory arthritis (≈100%) and renal involvement (∼50%). Serologies are frequently positive for ANA, p-ANCA (often MPO), and rheumatoid factor.Lung biopsy is essential for definitive diagnosis, characteristically showing cystic remodeling, alveolar hemosiderosis, and follicular bronchiolitis. Cystic lung mimics should be excluded systematically—VEGF-D testing for lymphangioleiomyomatosis (LAM) and FLCN sequencing for Birt-Hogg-Dubé (BHD). Among autoimmune/inflammatory comparators—ANCA-associated vasculitis (AAV), rheumatoid arthritis-associated ILD, and systemic lupus erythematosus with DAH—cystic lung disease is not a reported hallmark, whereas characteristic lung cysts are a defining imaging feature of COPA. Distinct cystic entities (LAM, BHD, pulmonary Langerhans cell histiocytosis) are non-vasculitis and must be ruled out. Final confirmation of COPA syndrome requires COPA gene sequencing. Conclusion In adults with cystic lung disease, arthralgia, ANCA positivity, and elevated ANA, with lung biopsy showing cystic changes, alveolar hemosiderosis, and follicular bronchiolitis without vasculitis, COPA syndrome should be strongly considered and confirmed by genetic testing to avoid misclassification as primary AAV and to guide therapy.