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Front Immunol. 2018 Mar 16;9:543. doi: 10.3389/fimmu.2018.00543. eCollection 2018.

Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry.

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Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Freiburg, Germany.
Department of Pediatrics and Adolescent Medicine, Medical Center - University of Freiburg, Freiburg, Germany.
Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden.
Research Center for Immunodeficiencies, Pediatric Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Research Department, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus.
Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
Division of Pediatric Allergy/Immunology, Marmara University, Istanbul, Turkey.
Cambridge Centre for Lung Defense, Papworth Hospital, Cambridge, United Kingdom.
Institute of Immunity and Transplantation, Royal Free Hospital, London, United Kingdom.
University Department of Pediatrics, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Department of Paediatric Immunology, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
Internal Medicine, University Hospital of Saint-Etienne, Saint-Etienne, France.
Biotherapy Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Children's Hospital, Paris, France.
Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Imagine Institute, Paris, France.
Paris Descartes-Sorbonne Paris Cité University, Paris, France.
Department of Clinical Immunology, Addenbrookes Hospital, Cambridge, United Kingdom.
Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
Regional Immunology Service, The Royal Hospitals & Queen's University, Belfast, United Kingdom.
NIHR Clinical Research Facility, University Hospital Southampton NHSFT, Southampton, United Kingdom.
Department of Pediatric Immunology, Hematology and Rheumatology, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Children's Hospital, Paris, France.
INSERM UMR 1163, Imagine Institute, Paris, France.
Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain.
Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, United Kingdom.
French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
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.
Sección de Infectologıa, Rheumatología and Inmunodeficiencias, Unidad de Pediatria, Hospital Virgen del Rocıo, Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain.
Laboratory of Immunogenetics of Pediatric Autoimmunity, INSERM UMR 1163, Imagine Institute, Paris, France.
Division of Immunology, University Children's Hospital Zurich and Children's Research Centre, University Zurich, Zurich, Switzerland.
Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Medical School, Paris, France.
Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Imagine Institute, Paris, France.
Wilhelmina Children's Hospital, Utrecht, Netherlands.
Department of Clinical Immunology and Allergy, St James's University Hospital, Leeds, United Kingdom.
Department of Infection, Immunity and Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom.


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.


PIK3CD; PIK3R1; activated phosphoinositide 3-kinase δ syndrome; natural history; rapamycin; registry

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