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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 Publisher



Maccari ME1, 2 ; Abolhassani H3, 4 ; Aghamohammadi A4 ; Aiuti A5 ; Aleinikova O6 ; Bangs C7 ; Baris S8 ; Barzaghi F5 ; Baxendale H9 ; Buckland M10 ; Burns SO10 ; Cancrini C11, 12 ; Cant A13 ; Cathebras P14 Show All Authors
Authors
  1. Maccari ME1, 2
  2. Abolhassani H3, 4
  3. Aghamohammadi A4
  4. Aiuti A5
  5. Aleinikova O6
  6. Bangs C7
  7. Baris S8
  8. Barzaghi F5
  9. Baxendale H9
  10. Buckland M10
  11. Burns SO10
  12. Cancrini C11, 12
  13. Cant A13
  14. Cathebras P14
  15. Cavazzana M15, 16, 17
  16. Chandra A18, 19
  17. Conti F11, 12
  18. Coulter T20
  19. Devlin LA20
  20. Edgar JDM20
  21. Faust S21
  22. Fischer A17, 22, 23
  23. Prat MG24
  24. Hammarstrom L3
  25. Heeg M1, 2
  26. Jolles S25
  27. Karakocaydiner E8
  28. Kindle G1
  29. Kiykim A8
  30. Kumararatne D17
  31. Grimbacher B1
  32. Longhurst H10
  33. Mahlaoui N22, 26
  34. Milota T27
  35. Moreira F10
  36. Moshous D17, 22, 23
  37. Mukhina A28
  38. Neth O29
  39. Neven B17, 22, 30
  40. Nieters A1
  41. Olbrich P29
  42. Ozen A8
  43. Schmid JP31
  44. Picard C32, 33
  45. Prader S31
  46. Rae W21
  47. Reichenbach J31
  48. Rusch S1
  49. Savic S32
  50. Scarselli A11, 12
  51. Scheible R1
  52. Sediva A27
  53. Sharapova SO6
  54. Shcherbina A28
  55. Slatter M12
  56. Solerpalacin P24
  57. Stanislas A15
  58. Suarez F23
  59. Tucci F5
  60. Uhlmann A1
  61. Montfrans J34
  62. Warnatz K1
  63. Williams AP21
  64. Wood P35
  65. Kracker S16, 17
  66. Condliffe AM36
  67. Ehl S1, 2
Show Affiliations
Authors Affiliations
  1. 1. Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Freiburg, Germany
  2. 2. Department of Pediatrics and Adolescent Medicine, Medical Center-University of Freiburg, Freiburg, Germany
  3. 3. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
  4. 4. Research Center for Immunodeficiencies, Pediatric Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
  6. 6. Research Department, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus
  7. 7. Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom
  8. 8. Division of Pediatric Allergy/Immunology, Marmara University, Istanbul, Turkey
  9. 9. Cambridge Centre for Lung Defense, Papworth Hospital, Cambridge, United Kingdom
  10. 10. Institute of Immunity and Transplantation, Royal Free Hospital, London, United Kingdom
  11. 11. University Department of Pediatrics, Bambino Gesu Children's Hospital IRCCS, Rome, Italy
  12. 12. Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
  13. 13. Department of Paediatric Immunology, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
  14. 14. Internal Medicine, University Hospital of Saint-Etienne, Saint-Etienne, France
  15. 15. Biotherapy Department, Assistance Publique-Hopitaux de Paris (AP-HP), Necker Children's Hospital, Paris, France
  16. 16. Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Imagine Institute, Paris, France
  17. 17. Paris Descartes-Sorbonne Paris Cite University, Paris, France
  18. 18. Department of Clinical Immunology, Addenbrookes Hospital, Cambridge, United Kingdom
  19. 19. Department of Medicine, University of Cambridge, Cambridge, United Kingdom
  20. 20. Regional Immunology Service, The Royal Hospitals and Queen's University, Belfast, United Kingdom
  21. 21. NIHR Clinical Research Facility, University Hospital Southampton NHSFT, Southampton, United Kingdom
  22. 22. Department of Pediatric Immunology, Hematology and Rheumatology, Assistance Publique-Hopitaux de Paris (AP-HP), Necker Children's Hospital, Paris, France
  23. 23. INSERM UMR 1163, Imagine Institute, Paris, France
  24. 24. Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
  25. 25. Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, United Kingdom
  26. 26. French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hopitaux de Paris, Paris, France
  27. 27. Department of Immunology, 2nd Faculty of Medicine Charles University and Motol University Hospital, Prague, Czech Republic
  28. 28. Department of Immunology, Research and Clinical Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
  29. 29. Seccion de Infectologia, Rheumatologia and Inmunodeficiencias, Unidad de Pediatria, Hospital Virgen del Rocio, Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain
  30. 30. Laboratory of Immunogenetics of Pediatric Autoimmunity, INSERM UMR 1163, Imagine Institute, Paris, France
  31. 31. Division of Immunology, University Children's Hospital Zurich and Children's Research Centre, University Zurich, Zurich, Switzerland
  32. 32. Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique-Hopitaux de Paris (AP-HP), Necker Medical School, Paris, France
  33. 33. Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Imagine Institute, Paris, France
  34. 34. Wilhelmina Children's Hospital, Utrecht, Netherlands
  35. 35. Department of Clinical Immunology and Allergy, St James's University Hospital, Leeds, United Kingdom
  36. 36. Department of Infection, Immunity and Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom

Source: Frontiers in Immunology Published:2018


Abstract

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. © 2018 Maccari, et al.
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