title: Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study.
abstract: 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).
  
  
  
  We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort.
  
  
  
  We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Tanya I
authors.initials: TI
authors.lastname: Coulter
authors.affiliation: Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, United Kingdom; Lymphocyte Signalling & Development, Babraham Institute, Cambridge, United Kingdom; Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Anita
authors.initials: A
authors.lastname: Chandra
authors.affiliation: 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.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Bacon
authors.affiliation: Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
authors.forename: Judith
authors.initials: J
authors.lastname: Babar
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Curtis
authors.affiliation: Department of Radiology, Papworth Hospital NHS Foundation Trust, Papworth Everard Hospital, Cambridge, United Kingdom.
authors.forename: Nick
authors.initials: N
authors.lastname: Screaton
authors.affiliation: Department of Pathology, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: John R
authors.initials: JR
authors.lastname: Goodlad
authors.affiliation: Raigmore Hospital, Inverness, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Farmer
authors.affiliation: Regional Immunology Service, The Royal Hospitals, Belfast, United Kingdom.
authors.forename: Cathal Laurence
authors.initials: CL
authors.lastname: Steele
authors.affiliation: Department of Paediatric Immunology and Infectious Diseases, Our Lady's Children's Hospital Crumlin, Dublin, Ireland.
authors.forename: Timothy Ronan
authors.initials: TR
authors.lastname: Leahy
authors.affiliation: Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, United Kingdom; National Institute for Health Research, Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
authors.forename: Rainer
authors.initials: R
authors.lastname: Doffinger
authors.affiliation: Papworth Hospital NHS trust, Papworth Everard, Cambridge, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Baxendale
authors.affiliation: Department of Infectious Disease and Immunology, University Hospitals Bristol NHS Foundation Trust, Bristol Royal Hospital for Children, Bristol, United Kingdom.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Bernatoniene
authors.affiliation: Regional Immunology Service, The Royal Hospitals, Belfast, United Kingdom.
authors.forename: J David M
authors.initials: JD
authors.lastname: Edgar
authors.affiliation: Barts Health NHS Trust, London, United Kingdom.
authors.forename: Hilary J
authors.initials: HJ
authors.lastname: Longhurst
authors.affiliation: Center for Chronic Immunodeficiency, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
authors.affiliation: Center for Chronic Immunodeficiency, University Hospital Freiburg, Freiburg, Germany; Department of Pediatrics and Adolescent Medicine, University Medical Center, Freiburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Speckmann
authors.affiliation: Center for Chronic Immunodeficiency, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.affiliation: Institute of Immunology, University Hospital Motol, Prague, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Sediva
authors.affiliation: Institute of Immunology, University Hospital Motol, Prague, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Milota
authors.affiliation: 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.
authors.forename: Saul N
authors.initials: SN
authors.lastname: Faust
authors.affiliation: Faculty of Medicine and Institute of Life Sciences, University of Southampton, Southampton, United Kingdom.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Williams
authors.affiliation: Department of Immunology, Epsom & St Helier University Hospitals NHS Trust, Surrey, United Kingdom.
authors.forename: Grant
authors.initials: G
authors.lastname: Hayman
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Zeynep Yesim
authors.initials: ZY
authors.lastname: Kucuk
authors.affiliation: Department of Royal Hospital for Children, Glasgow, United Kingdom.
authors.forename: Rosie
authors.initials: R
authors.lastname: Hague
authors.affiliation: Department of Pathology, Queen Elizabeth University Hospital, Glasgow, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: French
authors.affiliation: Royal Aberdeen Childrens' Hospital, Aberdeen, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Brooker
authors.affiliation: Raigmore Hospital, Inverness, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Forsyth
authors.affiliation: Royal Aberdeen Childrens' Hospital, Aberdeen, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Herriot
authors.affiliation: Department of Pediatrics, Ospedale Pediatrico Bambino Gesù and University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Cancrini
authors.affiliation: Department of Pediatrics, Ospedale Pediatrico Bambino Gesù and University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Palma
authors.affiliation: Department of Pediatrics, Ospedale Pediatrico Bambino Gesù and University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ariganello
authors.affiliation: Department of Immunology, School of Medicine, Trinity College, Dublin, and St James's Hospital, Dublin, Ireland.
authors.forename: Niall
authors.initials: N
authors.lastname: Conlon
authors.affiliation: Department of Immunology, School of Medicine, Trinity College, Dublin, and St James's Hospital, Dublin, Ireland.
authors.forename: Conleth
authors.initials: C
authors.lastname: Feighery
authors.affiliation: Department of Paediatric Immunology and Infectious Diseases, Our Lady's Children's Hospital Crumlin, Dublin, Ireland.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Gavin
authors.affiliation: Department of Immunology, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Jones
authors.affiliation: Department of Community Pediatrics, Perinatal and Maternal Medicine Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Imai
authors.affiliation: King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, United Kingdom.
authors.forename: Mohammad A A
authors.initials: MA
authors.lastname: Ibrahim
authors.affiliation: Department of Allergology, Rheumatology and Clinical Immunology, University Children's Hospital, University Medical Center, Ljubljana, Slovenia.
authors.forename: Gašper
authors.initials: G
authors.lastname: Markelj
authors.affiliation: 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.
authors.forename: Mario
authors.initials: M
authors.lastname: Abinun
authors.affiliation: Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; INSERM UMR1163, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rieux-Laucat
authors.affiliation: Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; INSERM UMR1163, Paris, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Latour
authors.affiliation: 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.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pellier
authors.affiliation: 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.
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Départment de Biothérapie, Centre d'Investigation Clinique intégré en Biothérapies, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; INSERM UMR1163, Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Touzot
authors.affiliation: 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.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; INSERM UMR1163, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.affiliation: University College London Institute of Immunity and Transplantation, London, United Kingdom.
authors.forename: Siobhan O
authors.initials: SO
authors.lastname: Burns
authors.affiliation: Department of Clinical Immunology and Allergy, St James's University Hospital, Leeds, United Kingdom.
authors.forename: Sinisa
authors.initials: S
authors.lastname: Savic
authors.affiliation: Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: D S
authors.initials: DS
authors.lastname: Kumararatne
authors.affiliation: 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.
authors.forename: Despina
authors.initials: D
authors.lastname: Moshous
authors.affiliation: Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; INSERM UMR1163, Paris, France.
authors.forename: Sven
authors.initials: S
authors.lastname: Kracker
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.affiliation: Lymphocyte Signalling & Development, Babraham Institute, Cambridge, United Kingdom.
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.affiliation: 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.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Sergey
authors.initials: S
authors.lastname: Nejentsev
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom. Electronic address: a.m.condliffe@sheffield.ac.uk.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Condliffe
authors.affiliation: 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.
authors.forename: Andrew James
authors.initials: AJ
authors.lastname: Cant
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D019072:Antibiotic Prophylaxis; D002648:Child; D002675:Child, Preschool; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D015331:Cohort Studies; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006566:Herpesviridae Infections / Q000235:genetics / Q000401:mortality / Q000628:therapy; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D007223:Infant; D007391:International Cooperation; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D012008:Recurrence; D012141:Respiratory Tract Infections / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D011795:Surveys and Questionnaires; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D016756:Immunoglobulins, Intravenous; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human
keywords: Activated phosphoinositide 3-kinase δ syndrome; PIK3CD gene; bronchiectasis; hematopoietic stem cell transplantation; immunodeficiency; p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency; phosphoinositide 3-kinase inhibitor; phosphoinositide 3-kinase δ