BACKGROUND: Activated phosphoinositide 3-kinase δ 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). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic 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; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic 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 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. 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 hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.

Barts Health NHS Trust London United Kingdom

Center for Chronic Immunodeficiency University Hospital Freiburg Freiburg Germany

Center for Chronic Immunodeficiency University Hospital Freiburg Freiburg Germany; Department of Pediatrics and Adolescent Medicine University Medical Center Freiburg Germany

Départment de Biothérapie Centre d'Investigation Clinique intégré en Biothérapies Necker Children's Hospital Assistance Publique Hôpitaux de Paris Paris France; Université Paris Descartes Sorbonne Paris Cité Institut Imagine Paris France; INSERM UMR1163 Paris France

Department of Allergology Rheumatology and Clinical Immunology University Children's Hospital University Medical Center Ljubljana Slovenia

Department of Clinical Biochemistry and Immunology Addenbrooke's Hospital Cambridge United Kingdom

Department of Clinical Biochemistry and Immunology Addenbrooke's Hospital Cambridge United Kingdom; Lymphocyte Signalling and Development Babraham Institute Cambridge United Kingdom; Department of Medicine University of Cambridge Cambridge United Kingdom

Department of Clinical Biochemistry and Immunology Addenbrooke's Hospital Cambridge United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre Cambridge United Kingdom

Department of Clinical Immunology and Allergy St James's University Hospital Leeds United Kingdom

Department of Community Pediatrics Perinatal and Maternal Medicine Tokyo Medical and Dental University Tokyo Japan

Department of Immunology Epsom and St Helier University Hospitals NHS Trust Surrey United Kingdom

Department of Immunology Great Ormond Street Hospital NHS Foundation Trust London United Kingdom

Department of Immunology School of Medicine Trinity College Dublin and St James's Hospital Dublin Ireland

Department of Immunology School of Medicine Trinity College Dublin and St James's Hospital Dublin Ireland; Department of Paediatric Immunology and Infectious Diseases Our Lady's Children's Hospital Crumlin Dublin Ireland

Department of Infectious Disease and Immunology University Hospitals Bristol NHS Foundation Trust Bristol Royal Hospital for Children Bristol United Kingdom

Department of Medicine University of Cambridge Cambridge United Kingdom

Department of Medicine University of Cambridge Cambridge United Kingdom; Department of Infection Immunity and Cardiovascular Disease University of Sheffield Sheffield United Kingdom

Department of Paediatric Immunology and Infectious Diseases Our Lady's Children's Hospital Crumlin Dublin Ireland

Department of Paediatric Immunology Newcastle upon Tyne hospitals NHS Foundation Trust Newcastle upon Tyne United Kingdom; Institute of Cellular Medicine Newcastle University Newcastle upon Tyne Hospitals NHS Trust Newcastle upon Tyne United Kingdom

Department of Pathology Queen Elizabeth University Hospital Glasgow United Kingdom

Department of Pathology Western General Hospital Edinburgh United Kingdom

Department of Pediatrics Ospedale Pediatrico Bambino Gesù and University of Rome Tor Vergata Rome Italy

Department of Radiology Cambridge University Hospitals NHS Foundation Trust Cambridge United Kingdom

Department of Radiology Papworth Hospital NHS Foundation Trust Papworth Everard Hospital Cambridge United Kingdom

Department of Royal Hospital for Children Glasgow United Kingdom

Division of Bone Marrow Transplantation and Immune Deficiency Cincinnati Children's Hospital Medical Center Cincinnati Ohio

Faculty of Medicine and Institute of Life Sciences University of Southampton Southampton United Kingdom

Faculty of Medicine and Institute of Life Sciences University of Southampton Southampton United Kingdom; NIHR Wellcome Trust Clinical Research Facility University Hospital Southampton NHS Foundation Trust Southampton United Kingdom

Institute of Immunology University Hospital Motol Prague Czech Republic

King's College London King's Health Partners King's College Hospital NHS Foundation Trust School of Medicine Division of Asthma Allergy and Lung Biology Department of Immunological Medicine London United Kingdom

Lymphocyte Signalling and Development Babraham Institute Cambridge United Kingdom

Northern Institute for Cancer Research Newcastle University Newcastle upon Tyne United Kingdom; Northern England Haemato Oncology Diagnostic Service Newcastle upon Tyne NHS Foundation Trust Newcastle upon Tyne United Kingdom

Papworth Hospital NHS trust Papworth Everard Cambridge United Kingdom

Raigmore Hospital Inverness United Kingdom

Regional Immunology Service The Royal Hospitals Belfast United Kingdom

Royal Aberdeen Childrens' Hospital Aberdeen United Kingdom

UCL Cancer Institute University College London London United Kingdom

Unité d'Onco hémato immunologie Pédiatrique CHU Angers Angers France; Centre de Référence Déficits Immunitaires Héréditaires AP HP Paris France; Inserm UMR 892 Angers France; CNRS UMR 6299 Angers France

Université Paris Descartes Sorbonne Paris Cité Institut Imagine Paris France; Department of Pediatric Immunology Hematology and Rheumatology AP HP Necker Children's Hospital Paris France

Université Paris Descartes Sorbonne Paris Cité Institut Imagine Paris France; Department of Pediatric Immunology Hematology and Rheumatology AP HP Necker Children's Hospital Paris France; Laboratory of Human Genetics of Infectious Diseases Necker Branch INSERM UMR1163 Imagine Institute Necker Children's Hospital Paris France; St Giles Laboratory of Human Genetics of Infectious Diseases Rockefeller Branch Rockefeller University New York NY; Howard Hughes Medical Institute Chevy Chase Md

Université Paris Descartes Sorbonne Paris Cité Institut Imagine Paris France; INSERM UMR1163 Paris France

Université Paris Descartes Sorbonne Paris Cité Institut Imagine Paris France; INSERM UMR1163 Paris France; Department of Pediatric Immunology Hematology and Rheumatology AP HP Necker Children's Hospital Paris France; Centre de Référence Déficits Immunitaires Héréditaires AP HP Paris France; Laboratory of Human Genetics of Infectious Diseases Necker Branch INSERM UMR1163 Imagine Institute Necker Children's Hospital Paris France; St Giles Laboratory of Human Genetics of Infectious Diseases Rockefeller Branch Rockefeller University New York NY

Université Paris Descartes Sorbonne Paris Cité Institut Imagine Paris France; INSERM UMR1163 Paris France; Department of Pediatric Immunology Hematology and Rheumatology AP HP Necker Children's Hospital Paris France; Collège de France Paris France

University College London Institute of Immunity and Transplantation London United Kingdom

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A randomised, placebo-controlled, phase III trial of leniolisib in activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS): Adolescent and adult subgroup analysis

Long-term treatment with selective PI3Kδ inhibitor leniolisib in adults with activated PI3Kδ syndrome

Interim analysis: Open-label extension study of leniolisib for patients with APDS

A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome

Natural Course of Activated Phosphoinositide 3-Kinase Delta Syndrome in Childhood and Adolescence

The EuroFlow PID Orientation Tube for Flow Cytometric Diagnostic Screening of Primary Immunodeficiencies of the Lymphoid System

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CVID-Associated Tumors: Czech Nationwide Study Focused on Epidemiology, Immunology, and Genetic Background in a Cohort of Patients With CVID

Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisib