Abstract Background Activated PI3Kδ syndrome (APDS) is a rare primary immunodeficiency caused by gain-of-function mutations in PIK3CD or PIK3R1, resulting in hyperactivation of the PI3K-AKT-mTOR signaling pathway. This leads to profound immune dysregulation characterized by recurrent sinopulmonary infections, lymphoproliferation, autoimmunity, and increased lymphoma risk. Although early diagnosis is crucial for preventing irreversible lung damage, APDS often remains underrecognized due to heterogeneous clinical presentation. Objective To determine the frequency and characterize the clinical, immunologic, radiographic, and genetic features of patients with molecularly confirmed Activated PI3Kδ Syndrome identified through a bronchiectasis and Primary Ciliary Dyskinesia (PCD) program, and to outline key diagnostic and management challenges. Methods We evaluated 65 patients with previously undiagnosed chronic pulmonary disease seen at a specialized bronchiectasis and PCD clinic. All underwent targeted genetic testing panels for primary immunodeficiency, PCD, and cystic fibrosis. Clinical, demographic, and laboratory data were systematically collected, including infection history, pulmonary function, imaging findings, immunophenotyping, and sequencing results. Results Of 65 patients evaluated for undiagnosed rare lung diseases by genetic testing, six (9%) were diagnosed with Activated PI3Kδ Syndrome. Four carried PIK3CD and two carried PIK3R1 variants, the latter also showing overlapping features with PCD. All six presented in childhood with recurrent respiratory infections, persistent productive cough, eczema, rhinitis, and chronic otitis media. Gastrointestinal involvement, including chronic diarrhea and malabsorption, was observed in five cases. Chest computed tomography demonstrated bilateral cylindrical and varicose bronchiectasis in five patients, with additional findings of peribronchial thickening and mucus plugging, the main reasons for referral to the bronchiectasis clinic. Immunophenotyping showed reduced class-switched memory B cells, impaired vaccine responses, and increased double-negative T cells, consistent with immune dysregulation. One patient received immunoglobulin replacement therapy with clinical improvement, underscoring the importance of early molecular diagnosis and targeted management. Conclusions This research underscores the importance of comprehensive genetic testing within bronchiectasis and rare lung disease programs, including those focused on Primary Ciliary Dyskinesia. The clinical overlap between PCD phenotypes and Activated PI3Kδ Syndrome highlights the need for early recognition and molecular confirmation in patients with recurrent infections, bronchiectasis, and immune dysregulation. The multisystem involvement affecting pulmonary, cutaneous, and gastrointestinal systems should raise suspicion for APDS and support consideration of targeted therapies such as PI3Kδ inhibitors. Increased awareness of this rare immunogenetic disorder is critical to enable timely diagnosis, prevent irreversible organ damage, and improve long-term outcomes. This abstract is funded by: none
Ceballos et al. (Fri,) studied this question.