Carsten Speckmann1, Sam Doerken2, Alessandro Aiuti3, Michael H Albert4, Waleed Al-Herz5, Luis M Allende6, Alessia Scarselli7, Tadej Avcin8, Ruy Perez-Becker9, Caterina Cancrini7, Andrew Cant10, Silvia Di Cesare7, Andrea Finocchi7, Alain Fischer11, H Bobby Gaspar12, Sujal Ghosh13, Andrew Gennery10, Kimberly Gilmour12, Luis I González-Granado14, Monica Martinez-Gallo15, Sophie Hambleton10, Fabian Hauck16, Manfred Hoenig17, Despina Moshous18, Benedicte Neven11, Tim Niehues9, Luigi Notarangelo19, Capucine Picard18, Nikolaus Rieber20, Ansgar Schulz17, Klaus Schwarz21, Markus G Seidel22, Pere Soler-Palacin15, Polina Stepensky23, Brigitte Strahm24, Thomas Vraetz24, Klaus Warnatz25, Christine Winterhalter26, Austen Worth12, Sebastian Fuchs25, Annette Uhlmann26, Stephan Ehl27. 1. Department of Pediatric Hematology and Oncology, Center for Pediatrics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 2. Institute for Medical Biometry and Statistics, Center for Medical Biometry and Medical Informatics, Medical Center - University of Freiburg, Freiburg, Germany. 3. Pediatric Immunohematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute, Milan, Italy; Department of Pediatrics, Ospedale Pediatrico Bambino Gesù and University of Rome "Tor Vergata," Rome, Italy. 4. Dr von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany. 5. Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait. 6. Servicio de Inmunología, Hospital Universitario 12 de Octubre and Instituto de Investigación i+12, Madrid, Spain. 7. Department of Pediatrics, Ospedale Pediatrico Bambino Gesù and University of Rome "Tor Vergata," Rome, Italy. 8. Department of Allergology, Rheumatology and Clinical Immunology, University Children's Hospital, University Medical Center, Ljubljana, Slovenia. 9. Center for Pediatrics and Adolescent Medicine, Helios Hospital Krefeld, Krefeld, Germany. 10. Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom. 11. AP-HP, Hôpital Necker-Enfants Malades, Immunologie et Hématologie Pédiatriques, Paris, France. 12. Department of Immunology, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom. 13. Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany. 14. Servicio de Inmunología, Hospital Universitario 12 de Octubre and Instituto de Investigación i+12, Madrid, Spain; Immunodeficiencies Unit, Hematology & Oncology Unit, Pediatrics, Hospital 12 Octubre, Madrid, Spain. 15. Immunology Division, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain. 16. Immunodeficiency Unit and Immunological Diagnostics Laboratory, Dr von Hauner Children's Hospital Ludwig-Maximilians-University, Munich, Germany. 17. Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany. 18. AP-HP, Hôpital Necker-Enfants Malades, Immunologie et Hématologie Pédiatriques, Paris, France; INSERM UMR1163, Genome Dynamics in the Immune System, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, Paris, France. 19. Division of Immunology, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Mass. 20. Department of Pediatrics I, University of Tübingen, Tübingen, Germany; Department of Pediatrics, StKM GmbH and Technical University Muenchen, Munich, Germany. 21. Institute for Transfusion Medicine, University of Ulm, and the Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service, Baden-Württemberg-Hessen, Ulm, Germany. 22. Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology-Oncology, Medical University Graz, Graz, Austria. 23. Pediatric Hematology-Oncology and Bone Marrow Transplantation, Hadassah Hebrew University Hospital, Jerusalem, Israel. 24. Department of Pediatric Hematology and Oncology, Center for Pediatrics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 25. Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 26. Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Clinical Trials Unit, Medical Center - University of Freiburg, Freiburg, Germany. 27. Department of Pediatric Hematology and Oncology, Center for Pediatrics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address: stephan.ehl@uniklinik-freiburg.de.
Abstract
BACKGROUND: Absent T-cell immunity resulting in life-threatening infections provides a clear rationale for hematopoetic stem cell transplantation (HSCT) in patients with severe combined immunodeficiency (SCID). Combined immunodeficiencies (CIDs) and "atypical" SCID show reduced, not absent T-cell immunity. If associated with infections or autoimmunity, they represent profound combined immunodeficiency (P-CID), for which outcome data are insufficient for unambiguous early transplant decisions. OBJECTIVES: We sought to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome. METHODS: In this prospective and retrospective observational study, we recruited nontransplanted patients with P-CID aged 1 to 16 years to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome. RESULTS: A total of 51 patients were recruited (median age, 9.6 years). Thirteen of 51 had a genetic diagnosis of "atypical" SCID and 14 of 51 of CID. About half of the patients had less than 10% naive T cells, reduced/absent T-cell proliferation, and at least 1 significant clinical event/year, demonstrating their profound immunodeficiency. Nineteen patients (37%) underwent transplantation within 1 year of enrolment, and 5 of 51 patients died. Analysis of the HSCT decisions revealed the anticipated heterogeneity, favoring an ongoing prospective matched-pair analysis of patients with similar disease severity with or without transplantation. Importantly, so far neither the genetic diagnosis nor basic measurements of T-cell immunity were good predictors of disease evolution. CONCLUSIONS: The P-CID study for the first time characterizes a group of patients with nontypical SCID T-cell deficiencies from a therapeutic perspective. Because genetic and basic T-cell parameters provide limited guidance, prospective data from this study will be a helpful resource for guiding the difficult HSCT decisions in patients with P-CID.
BACKGROUND: Absent T-cell immunity resulting in life-threatening infections provides a clear rationale for hematopoetic stem cell transplantation (HSCT) in patients with severe combined immunodeficiency (SCID). Combined immunodeficiencies (CIDs) and "atypical" SCID show reduced, not absent T-cell immunity. If associated with infections or autoimmunity, they represent profound combined immunodeficiency (P-CID), for which outcome data are insufficient for unambiguous early transplant decisions. OBJECTIVES: We sought to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome. METHODS: In this prospective and retrospective observational study, we recruited nontransplanted patients with P-CID aged 1 to 16 years to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome. RESULTS: A total of 51 patients were recruited (median age, 9.6 years). Thirteen of 51 had a genetic diagnosis of "atypical" SCID and 14 of 51 of CID. About half of the patients had less than 10% naive T cells, reduced/absent T-cell proliferation, and at least 1 significant clinical event/year, demonstrating their profound immunodeficiency. Nineteen patients (37%) underwent transplantation within 1 year of enrolment, and 5 of 51 patients died. Analysis of the HSCT decisions revealed the anticipated heterogeneity, favoring an ongoing prospective matched-pair analysis of patients with similar disease severity with or without transplantation. Importantly, so far neither the genetic diagnosis nor basic measurements of T-cell immunity were good predictors of disease evolution. CONCLUSIONS: The P-CID study for the first time characterizes a group of patients with nontypical SCID T-cell deficiencies from a therapeutic perspective. Because genetic and basic T-cell parameters provide limited guidance, prospective data from this study will be a helpful resource for guiding the difficult HSCT decisions in patients with P-CID.
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