Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study

Background: Activated PI3-Kinase Delta Syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ).\ud Objective: To review the clinical, immunological, histopathological and radiological features of APDS in a large genetically-defined international cohort.\ud Methods: Clinical questionnaire, and review of medical notes, radiology histopathology and laboratory investigations of 53 APDS patients.\ud Results: Recurrent sino-pulmonary infections (96%) and non-neoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system (CNS); consistent with this PI3Kδ is broadly expressed in the developing murine CNS. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60% in cohort); the incidence of bronchiectasis was greater than in common variable immunodeficiency (CVID). Elevated IgM (78%), IgG deficiency (43%) and CD4 lymphopenia (84%) were significant immunological features. No immunological marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and five patients underwent haematopoietic stem cell transplant (HSCT). Five patients died from complications of APDS.\ud Conclusion: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of HSCT for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.