Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2-3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.

Biotherapy Department Assistance Publique Hôpitaux de Paris Necker Children's Hospital Paris France

Cambridge Centre for Lung Defense Papworth Hospital Cambridge United Kingdom

Center for Chronic Immunodeficiency Medical Center University of Freiburg Freiburg Germany

Central Manchester University Hospitals NHS Foundation Trust Manchester United Kingdom

Department of Clinical Immunology Addenbrookes Hospital Cambridge United Kingdom

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

Department of Immunology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czechia

Department of Immunology Research and Clinical Center for Pediatric Hematology Oncology and Immunology Moscow Russia

Department of Infection Immunity and Cardiovascular Science University of Sheffield Sheffield United Kingdom

Department of Medicine University of Cambridge Cambridge United Kingdom

Department of Paediatric Immunology Newcastle upon Tyne Hospital NHS Foundation Trust Newcastle upon Tyne United Kingdom

Department of Pediatric Immunology Hematology and Rheumatology Assistance Publique Hôpitaux de Paris Necker Children's Hospital Paris France

Department of Pediatrics and Adolescent Medicine Medical Center University of Freiburg Freiburg Germany

Department of Systems Medicine University of Rome Tor Vergata Rome Italy

Division of Clinical Immunology Department of Laboratory Medicine Karolinska Institute at Karolinska University Hospital Huddinge Stockholm Sweden

Division of Immunology University Children's Hospital Zurich and Children's Research Centre University Zurich Zurich Switzerland

Division of Pediatric Allergy Immunology Marmara University Istanbul Turkey

French National Reference Center for Primary Immune Deficiencies Necker Enfants Malades University Hospital Assistance Publique Hôpitaux de Paris Paris France

Immunodeficiency Centre for Wales University Hospital of Wales Cardiff United Kingdom

INSERM UMR 1163 Imagine Institute Paris France

Institute of Immunity and Transplantation Royal Free Hospital London United Kingdom

Internal Medicine University Hospital of Saint Etienne Saint Etienne France

Laboratory of Human Lymphohematopoiesis INSERM UMR 1163 Imagine Institute Paris France

Laboratory of Immunogenetics of Pediatric Autoimmunity INSERM UMR 1163 Imagine Institute Paris France

Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection INSERM UMR 1163 Imagine Institute Paris France

NIHR Clinical Research Facility University Hospital Southampton NHSFT Southampton United Kingdom

Paris Descartes Sorbonne Paris Cité University Paris France

Pediatric Infectious Diseases and Immunodeficiencies Unit Hospital Universitari Vall d'Hebron Vall d'Hebron Research Institute Barcelona Spain

Regional Immunology Service The Royal Hospitals and Queen's University Belfast United Kingdom

Research Center for Immunodeficiencies Pediatric Center of Excellence Children's Medical Center Tehran University of Medical Sciences Tehran Iran

Research Department Belarusian Research Center for Pediatric Oncology Hematology and Immunology Minsk Belarus

San Raffaele Telethon Institute for Gene Therapy Pediatric Immunohematology and Bone Marrow Transplantation Unit IRCCS San Raffaele Scientific Institute Milan Italy

Sección de Infectologıa Rheumatología and Inmunodeficiencias Unidad de Pediatria Hospital Virgen del Rocıo Instituto de Biomedicina de Sevilla Sevilla Spain

Study Center for Primary Immunodeficiencies Necker Enfants Malades Hospital Assistance Publique Hôpitaux de Paris Necker Medical School Paris France

University Department of Pediatrics Bambino Gesù Children's Hospital IRCCS Rome Italy

Wilhelmina Children's Hospital Utrecht Netherlands

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