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dc.contributor.authorCoulter, Tanya Ien
dc.contributor.authorChandra, Anitaen
dc.contributor.authorBacon, Chris Men
dc.contributor.authorBabar, Judithen
dc.contributor.authorCurtis, Jamesen
dc.contributor.authorScreaton, Nicken
dc.contributor.authorGoodlad, John Ren
dc.contributor.authorFarmer, Georgeen
dc.contributor.authorSteele, Cathal Laurenceen
dc.contributor.authorLeahy, Timothy Ronanen
dc.contributor.authorDoffinger, Raineren
dc.contributor.authorBaxendale, Helenen
dc.contributor.authorBernatoniene, Jolantaen
dc.contributor.authorEdgar, JDMen
dc.contributor.authorLonghurst, Hilary Jen
dc.contributor.authorEhl, Stephanen
dc.contributor.authorSpeckmann, Carstenen
dc.contributor.authorGrimbacher, Bodoen
dc.contributor.authorSediva, Annaen
dc.contributor.authorMilota, Tomasen
dc.contributor.authorFaust, Saul Nen
dc.contributor.authorWilliams, Anthony Pen
dc.contributor.authorHayman, Granten
dc.contributor.authorKucuk, Zeynep Yesimen
dc.contributor.authorHague, Rosieen
dc.contributor.authorFrench, Paulen
dc.contributor.authorBrooker, Richarden
dc.contributor.authorForsyth, Peteren
dc.contributor.authorHerriot, Richarden
dc.contributor.authorCancrini, Caterinaen
dc.contributor.authorPalma, Paoloen
dc.contributor.authorAriganello, Paolaen
dc.contributor.authorConlon, Niallen
dc.contributor.authorFeighery, Conlethen
dc.contributor.authorGavin, Patrick Jen
dc.contributor.authorJones, Alisonen
dc.contributor.authorImai, Kohsukeen
dc.contributor.authorIbrahim, Mohammad AAen
dc.contributor.authorMarkelj, Gašperen
dc.contributor.authorAbinun, Marioen
dc.contributor.authorRieux-Laucat, Frédéricen
dc.contributor.authorLatour, Sylvainen
dc.contributor.authorPellier, Isabelleen
dc.contributor.authorFischer, Alainen
dc.contributor.authorTouzot, Fabienen
dc.contributor.authorCasanova, Jean-Laurenten
dc.contributor.authorDurandy, Anneen
dc.contributor.authorBurns, Siobhan Oen
dc.contributor.authorSavic, Sinisaen
dc.contributor.authorKumararatne, DSen
dc.contributor.authorMoshous, Despinaen
dc.contributor.authorKracker, Svenen
dc.contributor.authorVanhaesebroeck, Barten
dc.contributor.authorOkkenhaug, Klausen
dc.contributor.authorPicard, Capucineen
dc.contributor.authorNezhentsev, Sergeyen
dc.contributor.authorCondliffe, Alison Men
dc.contributor.authorCant, Andrew Jamesen
dc.description.abstract$\textbf{Background:}$ Activated phosphoinositide 3-kinase $\delta$ syndrome (APDS)is a recently described combined immunodeficiency resulting from gain-of-function mutations in $\textit{PIK3CD}$, the gene encoding the catalytic subunit of phosphoinositide 3-kinase $\delta$ (PI3K$\delta$). $\textbf{Objective:}$ We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. $\textbf{Methods:}$ We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. $\textbf{Results:}$ 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 PI3K$\delta$ in the central nervous system; consistent with this, PI3K$\delta$ 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. $\textbf{Conclusion:}$ 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 PI3K$\delta$ inhibitors offer new prospects for APDS treatment.
dc.description.sponsorshipT.C. is supported by National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland. A.C. has a Wellcome Trust Postdoctoral Training Fellowship for Clinicians (103413/Z/13/Z). K.O. is supported by funding from BBSRC, MRC, Wellcome Trust and GSK. R.D. and D.S.K are funded by National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK. C.S. and S.E. are supported by the German Federal Ministry of Education and Research (BMBF 01 EO 0803 grant to the Center of Chronic immunodeficiency and BMBF 01GM1111B grant to the PID-NET initiative). S.N.F is supported in part by the Southampton UK National Institute for Health Research (NIHR) Wellcome Trust Clinical Research Facility and NIHR Respiratory Biomedical Research Unit. M.A.A.I. is funded by NHS Innovation London and King’s College Hospital Charitable Trust. A.F., S.L., A.D., F.R-L and S.K. are supported by the European Union’s 7th RTD Framework Programme (ERC advanced grant PID-IMMUNE contract 249816) and a government grant managed by the French Agence Nationale de la Recherche as part of the "Investments for the Future" program (ANR-10-IAHU-01). S.L. is supported by the Agence Nationale de la Recherche (ANR) (ANR-14-CE14-0028-01), the Foundation ARC pour la Recherche sur le Cancer (France), the Rare Diseases Foundation (France) and François Aupetit Association (France). S.L. is a senior scientist and S.K is a researcher at the Centre National de la Recherche Scientifique-CNRS (France). A.D. and S.K. are supported by the “Institut National de la Santé et de la Recherche Médicale". S.K. also supported by the Fondation pour la Recherche Médicale (grant number: ING20130526624), la Ligue Contre le Cancer (Comité de Paris) and the Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH). S.O.B is supported by the Higher Education Funding Council for England. B.V. is supported by the UK Biotechnology and Biological Sciences Research Council [BB/I007806/1], Cancer Research UK [C23338/A15965) and the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre. B.V. is consultant to Karus Therapeutics (Oxford, UK). S.N. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science (095198/Z/10/Z). S.N. is also supported by the European Research Council Starting grant 260477, the EU FP7 collaborative grant 261441 (PEVNET project) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, UK. A.M.C. is funded by the Medical Research Council, British Lung Foundation, University of Sheffield and Cambridge NIHR-BRC. Research in A.M.C. laboratory has received non-commercial grant support from GSK, Novartis, and MedImmune.
dc.rightsAttribution 4.0 International*
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.subjectActivated phosphoinositide 3-kinase $\delta$ syndromeen
dc.subjectp110$\delta$-activating mutation causing senescent T cellsen
dc.subjectphosphoinositide 3-kinase δ (PI3Kδ)en
dc.subjectPIK3CD geneen
dc.subjecthematopoietic stem cell transplantationen
dc.subjectphosphoinositide 3-kinase inhibitoren
dc.titleClinical spectrum and features of activated phosphoinositide 3-kinase $\delta$ syndrome: A large patient cohort studyen
dc.description.versionThis is the author accepted manuscript. The final version is available from Elsevier via
prism.publicationNameThe Journal of Allergy and Clinical Immunologyen
dc.contributor.orcidChandra, Anita [0000-0002-9061-879X]
dc.contributor.orcidOkkenhaug, Klaus [0000-0002-9432-4051]
dc.contributor.orcidNezhentsev, Sergey [0000-0002-7528-4461]
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMedical Research Council (MR/M012328/1)
pubs.funder-project-idWellcome Trust (095198/Z/10/Z)
pubs.funder-project-idWellcome Trust (103413/Z/13/Z)
cam.orpheus.successThu Jan 30 12:57:33 GMT 2020 - The item has an open VoR version.*

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