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Shi L, Dou L, Wang J, Wang Z. Epstein-Barr virus infection plays a crucial role in triggering hemophagocytic lymphohistiocytosis in patients with X-linked inhibitor of apoptosis protein deficiency. Hematology 2025; 30:2503745. [PMID: 40360445 DOI: 10.1080/16078454.2025.2503745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Accepted: 04/24/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND X-linked inhibitor of apoptosis protein (XIAP) deficiency is a congenital immunodeficiency disorder characterized by increased susceptibility to Epstein-Barr virus (EBV) infection and is frequently associated with hemophagocytic lymphohistiocytosis (HLH). OBJECTIVE To investigate the correlation between EBV and XIAP deficiency-related HLH, including EBV infection status, XIAP genetic mutation sites, and the efficacy of different treatment regimens in patients with EBV-positive XIAP deficiency-related HLH, and to analyse the prognosis of these patients. METHODS We retrospectively analysed patients diagnosed with EBV-positive XIAP deficiency-related HLH. RESULTS Data were collected from August 2017 to August 2024, and 10 patients were included in this study. All patients exhibited an elevated EBV-DNA load. EBV-DNA was detected in both plasma (2/10) and peripheral blood mononuclear cells (10/10), specifically B cells (9/9) and T cells (4/9). Treatment regimens containing rituximab, HLH-2004, and dexamethasone with or without ruxolitinib achieved complete remission. However, only the regimen containing rituximab successfully eradicated EBV from plasma and peripheral blood mononuclear cells in all patients. None of the patients underwent allogeneic haematopoietic stem cell transplantation. No cases of HLH recurrence or EBV reactivation were observed during a median follow-up of 28 months. CONCLUSIONS EBV infection plays a crucial role in triggering HLH in patients with XIAP deficiency. XIAP deficiency-related HLH is frequently associated with EBV infection, which predominantly affects B cells. Treatment regimens containing rituximab can effectively control HLH and eliminate EBV infection. Allogeneic haematopoietic stem cell transplantation may be avoidable in paediatric patients achieving EBV eradication through rituximab-containing regimens.
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Affiliation(s)
- Lin Shi
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Liurui Dou
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Jingshi Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Zhao Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
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Mahendran M, Upton JEM, Ramasubramanian R, Memmott HL, Germain G, Büsch K, Laliberté F, Harrington A. Overall survival among patients with activated phosphoinositide 3-kinase delta syndrome (APDS). Orphanet J Rare Dis 2025; 20:212. [PMID: 40319290 PMCID: PMC12049806 DOI: 10.1186/s13023-025-03734-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 04/15/2025] [Indexed: 05/07/2025] Open
Abstract
BACKGROUND This study aimed to describe overall survival (OS) of patients with APDS relative to the global population as well as among subsets of patients with concurrent lymphoma or hematopoietic stem cell transplant (HSCT) relative to the overall APDS population. METHODS Patient-level data were extracted from a recent systematic literature review of 351 unique patients with APDS. OS was evaluated using the Kaplan-Meier method up to age 65 years. OS rate and corresponding 95% CI were reported at each decade of age. Global mortality estimates were obtained from World Health Organization life tables for 2019. RESULTS Of the 351 patients with APDS (APDS1, 267 [76.1%]; APDS2, 83 [23.6%]; unspecified, 1 [0.3%]), 41 (11.7%) died. The OS rate was 25.0% (95% CI, 1.6-62.7%) by the last death event at 64 years of age. Starting at 12 years of age, the OS rate was numerically lower in patients with APDS relative to the global population (median OS, 64 vs. 75 years, respectively). Relative to the overall APDS population, OS rates were numerically similar in those who underwent HSCT (median OS, 64 years for both; p = 0.569), whereas OS rates were numerically lower in patients with concurrent lymphoma (median OS, 41 vs. 64 years, respectively; p = 0.109). Publication bias in source data was a possible limitation. CONCLUSION Reduced survival in patients with APDS suggests a high disease burden, particularly in those with concurrent lymphoma. These results highlight the unmet need for disease-modifying treatments for APDS.
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Affiliation(s)
| | - Julia E M Upton
- Clinical Immunology and Allergy, Department of Pediatrics, The Hospital For Sick Children, Toronto, ON, Canada
- Department of Pediatrics, University of Toronto, Toronto, ON, Canada
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Büsch K, Memmott HL, McLaughlin HM, Upton JEM, Harrington A. Genetic Etiologies and Outcomes in Malignancy and Mortality in Activated Phosphoinositide 3-Kinase Delta Syndrome: A Systematic Review. Adv Ther 2025; 42:752-771. [PMID: 39636570 PMCID: PMC11787279 DOI: 10.1007/s12325-024-03066-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 11/05/2024] [Indexed: 12/07/2024]
Abstract
INTRODUCTION This analysis evaluated literature on patients with activated phosphoinositide 3-kinase delta syndrome (APDS) to better understand the genetic etiologies and occurrence of mortality in this population. METHODS A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses approach, including all articles published in English prior to March 13, 2023, in PubMed and Embase. Patients included in the study had reported either (1) APDS diagnosis or (2) ≥ 1 clinical sign consistent with APDS and a first-degree relative with genetically confirmed APDS. Reported age at last observation was also a required outcome. Publications not meeting these criteria were excluded. Data were summarized using descriptive statistics. RESULTS The search identified 108 publications describing 351 unique patients with 39 distinct disease-causing variants. Among these, 41 (12%) deaths were reported, with a mean age at last follow-up of 19.6 (range, 1-64) years. A cause of death was reported for 80% (33/41) of deaths; lymphoma (24%, 10/41) and infections (22%, 9/41) were the most common causes. Types of infections causing death were severe uncontrollable infections (n = 3), sepsis (n = 2), viral infection (varicella zoster pneumonitis [n = 1], cytomegalovirus and adenovirus [n = 1], and Epstein-Barr virus [n = 1]), and infection (n = 1). Mean age at death for lymphoma was 24.9 (range, 1-41) years, and all nine patients who died from infections died before the age of 15 years. The mean age at first APDS symptom was 2.0 (range, < 1-22) years, and mean age at APDS diagnosis was 13.4 (range, 0-56) years; the mean time between symptoms and diagnosis was 10.6 (range, 0-44) years. Limitations of the study were primarily related to the data source. CONCLUSION Patients with APDS suffer early mortality, largely from lymphoma and infection, with large time gaps between symptoms and diagnosis. These findings highlight the need for improved diagnostics, earlier genetic testing for APDS, increased awareness of familial testing, and targeted therapies.
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Affiliation(s)
- Katharina Büsch
- KJM Büsch Consulting GmbH, Industriestrasse 24, 6300, Zug, Switzerland
| | - Heidi L Memmott
- Pharming Healthcare, Inc., 10 Independence Blvd, Warren, NJ, 07059, USA
| | | | - Julia E M Upton
- Division of Immunology and Allergy, Department of Paediatrics, The Hospital For Sick Children, 175 Elizabeth St, Room 13-14-027, Toronto, ON, M5G 2G3, Canada
- Department of Paediatrics, Temerty School of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Amanda Harrington
- Pharming Healthcare, Inc., 10 Independence Blvd, Warren, NJ, 07059, USA.
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Fox TA, Massey V, Lever C, Pearce R, Laurence A, Grace S, Oliviero F, Workman S, Symes A, Lowe DM, Fiaccadori V, Hough R, Tadros S, Burns SO, Seidel MG, Carpenter B, Morris EC. Pre-Transplant Immune Dysregulation Predicts for Poor Outcome Following Allogeneic Haematopoietic Stem Cell Transplantation in Adolescents and Adults with Inborn Errors of Immunity (IEI). J Clin Immunol 2025; 45:64. [PMID: 39760904 PMCID: PMC11703937 DOI: 10.1007/s10875-024-01854-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 12/17/2024] [Indexed: 01/07/2025]
Abstract
Allogeneic haematopoietic stem cell transplantation (alloHSCT) is safe and effective for adolescents and adults with inborn errors of immunity (IEI) with severe disease manifestations of their disease. The haematopoietic cell transplantation comorbidity index (HCT-CI) score predicts transplant survival in non-malignant diseases, including IEIs. We hypothesised that immune dysregulation pre-transplant may also influence transplant outcomes. We calculated the pre-transplant immune dysregulation and disease activity score (IDDA v2.1) for 82 adolescent and adult IEI patients (aged ≥ 13 years). Three-year overall survival (OS) for the whole cohort was 90% (n = 82) with a median follow up of 44.7 months (range 8.4 to 225.8). Events were defined as acute graft-versus-host disease (GvHD) grades II or above, chronic GvHD of any grade, graft failure, or death from any cause. Three-year event free survival (EFS) for the whole cohort was 72%. In multivariable analysis the IDDA v2.1 score pre-transplant and HCT-CI score significantly impacted OS (hazard ratio 1.08, p = 0.028) and EFS (hazard ratio 1.04, p = 0.0005). Importantly, 35% of this cohort had a high IDDA v2.1 score (≥ 15) and low HCT-CI score (< 3) suggesting that the risks of alloHSCT may be underestimated in a proportion of patients with IEI if the HCT-CI score is used alone. These findings support the potential for improved outcomes following successful modulation of immune dysregulation pre-transplant. The IDDA v2.1 score has utility as an objective measurement of pre-transplant immune dysregulation providing additional information reagrding the risks and potential complications of alloHSCT in an individual IEI patient.
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Affiliation(s)
- Thomas A Fox
- UCL Institute of Immunity and Transplantation, UCL, London, UK
- Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Valerie Massey
- Department of Immunology, Royal Free London Hospitals NHS Foundation Trust, London, UK
| | - Charley Lever
- Department of Immunology, Royal Free London Hospitals NHS Foundation Trust, London, UK
| | | | - Arian Laurence
- Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK
- Department of Immunology, Royal Free London Hospitals NHS Foundation Trust, London, UK
| | - Sarah Grace
- Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Filippo Oliviero
- Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Sarita Workman
- Department of Immunology, Royal Free London Hospitals NHS Foundation Trust, London, UK
| | - Andrew Symes
- Department of Immunology, Royal Free London Hospitals NHS Foundation Trust, London, UK
| | - David M Lowe
- UCL Institute of Immunity and Transplantation, UCL, London, UK
- Department of Immunology, Royal Free London Hospitals NHS Foundation Trust, London, UK
| | - Valeria Fiaccadori
- Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Rachael Hough
- Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Susan Tadros
- Department of Immunology, Royal Free London Hospitals NHS Foundation Trust, London, UK
| | - Siobhan O Burns
- UCL Institute of Immunity and Transplantation, UCL, London, UK
- Department of Immunology, Royal Free London Hospitals NHS Foundation Trust, London, UK
| | - Markus G Seidel
- Division of Pediatric Hematology-Oncology, Department of Pediatrics and Adolescent Medicine, Styrian Children's Cancer Research Unit for Cancer and Inborn Errors of the Blood and Immunity in Children, Medical University of Graz, Graz, Austria
| | - Ben Carpenter
- Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Emma C Morris
- UCL Institute of Immunity and Transplantation, UCL, London, UK.
- Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK.
- Department of Immunology, Royal Free London Hospitals NHS Foundation Trust, London, UK.
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5
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Ali SB, Gurnari C. Allogenic haematopoietic stem cell transplantation in VEXAS: A review of 33 patients. Clin Rheumatol 2024; 43:3565-3575. [PMID: 39347920 PMCID: PMC11489273 DOI: 10.1007/s10067-024-07160-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 09/21/2024] [Accepted: 09/23/2024] [Indexed: 10/01/2024]
Abstract
Vacuolation, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a multisystem disease due to a genetic mutation in the ubiquitin-activating enzyme (UBA1). Allogeneic haematopoietic stem cell transplantation (allo-HSCT) offers both therapeutic and cure but also carries significant risks. A review of VEXAS and HSCT cases was undertaken. Thirty-three patients were identified; majority males (n = 32, 97.0%), median time from symptoms to HSCT: 3 years (IQR 2.0-4.8) and median age of 59 years (IQR 52.5-65.5). UBA1 mutation Met41Thr was most common (11/32, 34.4%). The median variant allele frequency was 56.5% (IQR 43.0-73.5) with no correlation with increasing age. Prior to HSCT, 4.5 (IQR 2.8-6) treatments were trialled. Peripheral blood HSCT (30/31, 96.8%) and HLA-matched, unrelated donor (18/32, 56.3%) were most common. Conditioning regimens varied, with reduced intensity treatment with fludarabine as a co-agent most frequently administered (12/31, 38.7%). Both acute and/or chronic GVHD (18/32, 56.3%) and infections were common (12/32, 37.5%). Overall, 27 individuals (81.8%) were alive, and those undergoing HSCT prospectively had median follow up of 9 months (IQR 3.8-14.4). Of the six deceased, infection was implicated in four. In 11 cases with post-HSCT molecular data, a complete eradication of UBA1 mutation was reported. In summary, while consensus treatment strategy regarding VEXAS is lacking, this review highlights HSCT may remain not only a therapeutic option but also enable cure. However, considerations regarding comorbidities, concurrent haematological disorders as well as overall risks of GVHD and infections need to be made. Key points • Very few reported prospective cases of VEXAS and allogeneic haematopoietic stem cell transplantation (allo-HSCT) have been reported. • While risks of graft versus host disease and infection remain barriers, this treatment modality remains an option for selected patients. • Allo-HSCT is the only treatment strategy which can remove the UBA1 mutation.
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Affiliation(s)
- Syed B Ali
- Department of Clinical Immunology and Allergy, Flinders Medical Centre, Bedford Park, South Australia, Australia.
- School of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia.
- Department of Clinical Immunology and Allergy, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
- School of Medicine and Biomedical Sciences, University of Adelaide, Adelaide, South Australia, Australia.
| | - Carmelo Gurnari
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
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Lum SH, Albert MH, Gilbert P, Sirait T, Algeri M, Muratori R, Fournier B, Laberko A, Karakukcu M, Unal E, Ayas M, Yadav SP, Fisgin T, Elfeky R, Fernandes J, Faraci M, Cole T, Schulz A, Meisel R, Zecca M, Ifversen M, Biffi A, Diana JS, Vallée T, Giardino S, Ersoy GZ, Moshous D, Gennery AR, Balashov D, Bonfim C, Locatelli F, Lankester A, Neven B, Slatter M. Outcomes of HLA-mismatched HSCT with TCRαβ/CD19 depletion or post-HSCT cyclophosphamide for inborn errors of immunity. Blood 2024; 144:565-580. [PMID: 38669631 DOI: 10.1182/blood.2024024038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 03/27/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
ABSTRACT HLA-mismatched transplants with either in vitro depletion of CD3+ T-cell receptor (TCR)αβ/CD19 (TCRαβ) cells or in vivo T-cell depletion using posttransplant cyclophosphamide (PTCY) have been increasingly used for patients with inborn errors of immunity (IEIs). We performed a retrospective multicenter study via the EBMT registry on 306 children with IEIs undergoing their first transplant between 2010 and 2019 from an HLA-mismatched donor using TCRαβ (n = 167) or PTCY (n = 139). The median age for hematopoietic stem cell transplantation (HSCT) was 1.2 years (range, 0.03-19.6 years). The 3-year overall survival (OS) was 78% (95% confidence interval (CI), 71-84) after TCRαβ and 66% (57-74) after PTCY (P = .013). Pre-HSCT morbidity score (hazard ratio [HR], 2.27; 1.07-4.80, P = .032) and non-busulfan/treosulfan conditioning (HR, 3.12; 1.98-4.92, P < .001) were the only independent predictors of unfavorable OS. The 3-year event-free survival (EFS) was 58% (50%-66%) after TCRαβ and 57% (48%-66%) after PTCY (P = .804). The cumulative incidence of severe acute graft-versus-host disease (GvHD) was higher after PTCY (15%, 9%-21%) than TCRαβ (6%, 2%-9%, P = .007), with no difference in chronic GvHD (PTCY, 11%, 6%-17%; TCRαβ, 7%, 3%-11%, P = .173). The 3-year GvHD-free EFS was 53% (44%-61%) after TCRαβ and 41% (32%-50%) after PTCY (P = .080). PTCY had significantly higher rates of veno-occlusive disease (14.4% vs TCRαβ 4.9%, P = .009), acute kidney injury (12.7% vs 4.6%, P = .032), and pulmonary complications (38.2% vs 24.1%, P = .017). Adenoviremia (18.3% vs PTCY 8.0%, P = .015), primary graft failure (10% vs 5%, P = .048), and second HSCT (17.4% vs 7.9%, P = .023) were significantly higher in TCRαβ. In conclusion, this study demonstrates that both approaches are suitable options in patients with IEIs, although they are characterized by different advantages and outcomes.
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Affiliation(s)
- Su Han Lum
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Paediatric Stem Cell Transplantation Unit, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom
| | - Michael H Albert
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
| | | | | | - Mattia Algeri
- Department of Paediatric Hematology/Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
- Magna Graecia University, Catanzaro, Italy
| | - Rafaella Muratori
- Pediatric Hematology and Transplantation Unit, Hospital de Clínicas da Universidade Federal do Paraná, Curitiba, Brazil
| | - Benjamin Fournier
- Pediatric Immunology, Hematology and Rheumatology Department, Necker-Enfants Malades University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Alexandra Laberko
- Hematopoietic Stem Cell Transplantation, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Musa Karakukcu
- Erciyes University, KANKA Pediatric Hematology/Oncology and BMT Hospital, Kayseri, Turkey
| | - Elrem Unal
- Hasan KALYONCU University and Medicalpoint Hospital, Gaziantep, Turkey
| | - Mouhab Ayas
- King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | | | - Tunc Fisgin
- Pediatric Hematology/Oncology and BMT Unit, Altinbas University Faculty of Medicine Medical Park Bahcelievler Hospital, Istanbul, Turkey
| | - Reem Elfeky
- Department of Paediatric Immunology, Great Ormand Street Children's Hospital, London, United Kingdom
| | - Juliana Fernandes
- Stem Cell Transplantation Unit, ITACI-Instituto da Criança-Hospital das Clínicas, University of São Paulo, São Paulo, Brazil
- Hematology and Stem Cell Transplantation Unit, Hospital Israelita Albert Einstein, São Paulo, Brazil
- Hematology and Stem Cell Transplantation Unit, Hospital 9 de Julho, São Paulo, Brazil
| | | | - Theresa Cole
- Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, Australia
- Murdoch Children's Research Institute, Melbourne, Australia
| | - Ansgar Schulz
- Department of Pediatrics, University Medical Center Ulm, Ulm, Germany
| | - Roland Meisel
- Division of Pediatric Stem Cell Therapy, Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany
| | - Marco Zecca
- Paediatric Haematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Marianne Ifversen
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Alessandra Biffi
- Division of Pediatric Hematology, Oncology and Stem Cell Transplant, Women and Child Health Department, University of Padua and Padua University Hospital, Padua, Italy
| | - Jean-Sebastien Diana
- Pediatric Immunology, Hematology and Rheumatology Department, Necker-Enfants Malades University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Tanja Vallée
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
| | | | - Gizem Zengin Ersoy
- Pediatric Hematology/Oncology and BMT Unit, Altinbas University Faculty of Medicine Medical Park Bahcelievler Hospital, Istanbul, Turkey
| | - Despina Moshous
- Pediatric Immunology, Hematology and Rheumatology Department, Necker-Enfants Malades University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Andrew R Gennery
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Paediatric Stem Cell Transplantation Unit, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom
| | - Dmitry Balashov
- Hematopoietic Stem Cell Transplantation, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Carmem Bonfim
- Instituto de Pesquisa Pele Pequeno Príncipe/Faculdades Pequeno Príncipe, Pediatric Blood and Marrow Transplantation Service Hospital Pequeno Príncipe, Curitiba, Brazil
| | - Franco Locatelli
- Department of Paediatric Hematology/Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
- Catholic University of the Sacred Heart, Rome, Italy
| | - Arjan Lankester
- Willem-Alexander Children's Hospital, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
| | - Bénédicte Neven
- Pediatric Immunology, Hematology and Rheumatology Department, Necker-Enfants Malades University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Mary Slatter
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Paediatric Stem Cell Transplantation Unit, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom
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7
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Hurabielle C, LaFlam TN, Gearing M, Ye CJ. Functional genomics in inborn errors of immunity. Immunol Rev 2024; 322:53-70. [PMID: 38329267 PMCID: PMC10950534 DOI: 10.1111/imr.13309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Inborn errors of immunity (IEI) comprise a diverse spectrum of 485 disorders as recognized by the International Union of Immunological Societies Committee on Inborn Error of Immunity in 2022. While IEI are monogenic by definition, they illuminate various pathways involved in the pathogenesis of polygenic immune dysregulation as in autoimmune or autoinflammatory syndromes, or in more common infectious diseases that may not have a significant genetic basis. Rapid improvement in genomic technologies has been the main driver of the accelerated rate of discovery of IEI and has led to the development of innovative treatment strategies. In this review, we will explore various facets of IEI, delving into the distinctions between PIDD and PIRD. We will examine how Mendelian inheritance patterns contribute to these disorders and discuss advancements in functional genomics that aid in characterizing new IEI. Additionally, we will explore how emerging genomic tools help to characterize new IEI as well as how they are paving the way for innovative treatment approaches for managing and potentially curing these complex immune conditions.
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Affiliation(s)
- Charlotte Hurabielle
- Division of Rheumatology, Department of Medicine, UCSF, San Francisco, California, USA
| | - Taylor N LaFlam
- Division of Pediatric Rheumatology, Department of Pediatrics, UCSF, San Francisco, California, USA
| | - Melissa Gearing
- Division of Rheumatology, Department of Medicine, UCSF, San Francisco, California, USA
| | - Chun Jimmie Ye
- Institute for Human Genetics, UCSF, San Francisco, California, USA
- Institute of Computational Health Sciences, UCSF, San Francisco, California, USA
- Gladstone Genomic Immunology Institute, San Francisco, California, USA
- Parker Institute for Cancer Immunotherapy, UCSF, San Francisco, California, USA
- Department of Epidemiology and Biostatistics, UCSF, San Francisco, California, USA
- Department of Microbiology and Immunology, UCSF, San Francisco, California, USA
- Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, California, USA
- Arc Institute, Palo Alto, California, USA
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8
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Tadros S, Prévot J, Meyts I, Sánchez-Ramón S, Erwa NH, Fischer A, Lefevre G, Hotchko M, Jaworski PM, Leavis H, Boersma C, Drabwell J, van Hagen M, Van Coillie S, Pergent M, Burns SO, Mahlaoui N. The PID Odyssey 2030: outlooks, unmet needs, hurdles, and opportunities - proceedings from the IPOPI global multi-stakeholders' summit (June 2022). Front Immunol 2023; 14:1245718. [PMID: 37654496 PMCID: PMC10465327 DOI: 10.3389/fimmu.2023.1245718] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 07/24/2023] [Indexed: 09/02/2023] Open
Abstract
IPOPI held its first Global Multi-Stakeholders' Summit on 23-24 June 2022 in Cascais, Portugal. This IPOPI initiative was designed to set the stage for a stimulating forward-thinking meeting and brainstorming discussion among stakeholders on the future priorities of the PID community. All participants were actively engaged in the entire Summit, bringing provocative questions to ensure a high level of discussion and engagement, and partnered in identifying the outlooks, unmet needs, hurdles and opportunities of PIDs for 2030. The topics that were covered include diagnosis (e.g., newborn screening [NBS], genomic sequencing- including ethical aspects on the application of genomics on NBS, the role of more accurate and timely diagnostics in impacting personalized management), treatment (e.g., the therapeutic evolution of immunoglobulins in a global environment, new therapies such as targeted therapies, new approaches in curative therapies), the interactions of Primary ID with Secondary ID, Autoinflammatory Diseases and other diseases as the field experiences an incessant evolution, and also the avenues for research in the field of humanities and human sciences such as Patient-Reported Outcome Measures (PROMs), Patient-Reported Experience Measures (PREMs), and Health-Related Quality Of Life (HRQoL). During this meeting, all participants contributed to the drafting of recommendations based on our common understanding of the future opportunities, challenges, and scenarios. As a collection of materials, perspectives and summaries, they are succinct and impactful and may help determine some of the next key steps for the PID community.
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Affiliation(s)
- Susan Tadros
- Department of Immunology, Royal Free London NHS Foundation Trust, London, United Kingdom
| | | | - Isabelle Meyts
- Department of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Silvia Sánchez-Ramón
- Department of Immunology, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), IML and IdISSC, Madrid, Spain
| | - Nahla H. Erwa
- Faculty of Medicine, University of Khartoum, Khartoum, Sudan
| | - Alain Fischer
- Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
- French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker-Enfants malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
- Collège de France, Paris, France
- Imagine Institute, UMR Inserm 1163, Paris, France
| | - Guillaume Lefevre
- Univ. Lille, Inserm, CHU Lille, U1286 – INFINITE Institut de recherche translationnelle sur l'inflammation, Lille, France
- Institut d'Immunologie, CHU Lille, Lille, France
| | | | - Peter M. Jaworski
- Strategy, Ethics, Economics, and Public Policy, McDonough School of Business, Georgetown University, Washington, DC, United States
| | - Helen Leavis
- Department of Rheumatology & Clinical Immunology, University Medical Center (UMC), Utrecht University, Utrecht, Netherlands
| | - Cornelis Boersma
- Health-Ecore B.V., Zeist, Netherlands
- Unit of Global Health, Department of Health Sciences, University Medical Center Groningen (UMCG), University of Groningen, Groningen, Netherlands
- Department of Management Sciences, Open University, Heerlen, Netherlands
| | | | - Martin van Hagen
- Department of Internal Medicine, Division of Allergy & Clinical Immunology, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
- Department of Immunology, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | | | | | - Siobhan O. Burns
- Department of Immunology, Royal Free London NHS Foundation Trust, London, United Kingdom
| | - Nizar Mahlaoui
- IPOPI, Brussels, Belgium
- Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
- French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker-Enfants malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
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9
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Daza-Cajigal V, Segura-Guerrero M, López-Cueto M, Robles-Marhuenda Á, Camara C, Gerra-Galán T, Gómez-de-la-Torre R, Avendaño-Monje CL, Sánchez-Ramón S, Bosque-Lopez MJ, Quintero-Duarte A, Bonet-Vidal ML, Pons J. Clinical manifestations and approach to the management of patients with common variable immunodeficiency and liver disease. Front Immunol 2023; 14:1197361. [PMID: 37342345 PMCID: PMC10277479 DOI: 10.3389/fimmu.2023.1197361] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 05/22/2023] [Indexed: 06/22/2023] Open
Abstract
Purpose The clinical spectrum of common variable immunodeficiency (CVID) includes predisposition to infections, autoimmune/inflammatory complications and malignancy. Liver disease is developed by a proportion of patients with CVID, but limited evidence is available about its prevalence, pathogenesis and prognostic outcome. This lack of evidence leads to the absence of guidelines in clinical practice. In this study, we aimed at defining the characteristics, course and management of this CVID complication in Spain. Methods Spanish reference centers were invited to complete a cross-sectional survey. Thirty-eight patients with CVID-related liver disease from different hospitals were evaluated by a retrospective clinical course review. Results In this cohort, abnormal liver function and thrombocytopenia were found in most of the patients (95% and 79% respectively), in keeping with the higher incidence of abnormal liver imaging and splenomegaly. The most common histological findings included nodular regenerative hyperplasia (NRH) and lymphocytic infiltration, which have been associated with portal hypertension (PHTN) leading to a poorer prognosis. Autoimmune/inflammatory complications occurred in 82% of the CVID patients that developed liver disease and 52% of the patients treated with immunomodulators showed a reduction in the liver function tests' abnormalities during treatment. Among the experts that conducted the survey, there was 80% or more consensus that the workup of CVID-related liver disease requires liver profile, abdominal ultrasound and transient elastography. The majority agreed that liver biopsy should be essential for diagnosis. There was 94% consensus that endoscopic studies should be performed in the presence of PHTN. However, there was 89% consensus that there is insufficient evidence on the management of these patients. Conclusion Liver disease varies in severity and may contribute substantially to morbidity and mortality in patients with CVID. Hence the importance of close follow-up and screening of this CVID complication to prompt early targeted intervention. Further research is needed to evaluate the pathophysiology of liver disease in patients with CVID to identify personalized treatment options. This study emphasizes the urgent need to develop international guidelines for the diagnosis and management of this CVID complication.
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Affiliation(s)
- Vanessa Daza-Cajigal
- Department of Immunology, Hospital Universitario Son Espases, Palma, Spain
- Research Unit, Balearic Islands Health Research Institute (IdISBa), Palma, Spain
| | - Marina Segura-Guerrero
- Department of Immunology, Hospital Universitario Son Espases, Palma, Spain
- Research Unit, Balearic Islands Health Research Institute (IdISBa), Palma, Spain
| | - María López-Cueto
- Department of Immunology, Hospital Universitario Son Espases, Palma, Spain
- Research Unit, Balearic Islands Health Research Institute (IdISBa), Palma, Spain
| | | | - Carmen Camara
- Department of Immunology, Hospital Universitario La Paz, Madrid, Spain
| | - Teresa Gerra-Galán
- Department of Clinical Immunology, Instituto de Medicina del Laboratorio (IML), Hospital Clínico San Carlos, Madrid, Spain
| | | | | | - Silvia Sánchez-Ramón
- Department of Clinical Immunology, Instituto de Medicina del Laboratorio (IML), Hospital Clínico San Carlos, Madrid, Spain
| | | | | | - María L. Bonet-Vidal
- Department of Gastroenterology, Hospital Universitario Son Espases, Palma, Spain
| | - Jaime Pons
- Department of Immunology, Hospital Universitario Son Espases, Palma, Spain
- Research Unit, Balearic Islands Health Research Institute (IdISBa), Palma, Spain
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10
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Allogeneic stem cell transplantation compared to conservative management in adults with inborn errors of immunity. Blood 2023; 141:60-71. [PMID: 36167031 DOI: 10.1182/blood.2022015482] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 06/30/2022] [Accepted: 07/11/2022] [Indexed: 01/10/2023] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (alloSCT) is curative for severe inborn errors of immunity (IEIs), with recent data suggesting alloSCT in adulthood is safe and effective in selected patients. However, questions remain regarding the indications for and optimal timing of transplant. We retrospectively compared outcomes of transplanted vs matched nontransplanted adults with severe IEIs. Seventy-nine patients (aged ≥ 15 years) underwent alloSCT between 2008 and 2018 for IEIs such as chronic granulomatous disease (n = 20) and various combined immune deficiencies (n = 59). A cohort of nontransplanted patients from the French Centre de Référence Déficits Immunitaires Héréditaires registry was identified blindly for case-control analysis, with ≤3 matched controls per index patient, without replacement. The nontransplanted patients were matched for birth decade, age at last review greater than index patient age at alloSCT, chronic granulomatous disease or combined immune deficiencies, and autoimmune/lymphoproliferative complications. A total of 281 patients were included (79 transplanted, 202 nontransplanted). Median age at transplant was 21 years. Transplant indications were mainly lymphoproliferative disease (n = 23) or colitis (n = 15). Median follow-up was 4.8 years (interquartile range, 2.5-7.2). One-year transplant-related mortality rate was 13%. Estimated disease-free survival at 5 years was higher in transplanted patients (58% vs 33%; P = .007). Nontransplanted patients had an ongoing risk of severe events, with an increased mean cumulative number of recurrent events compared with transplanted patients. Sensitivity analyses removing patients with common variable immune deficiency and their matched transplanted patients confirm these results. AlloSCT prevents progressive morbidity associated with IEIs in adults, which may outweigh the negative impact of transplant-related mortality.
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11
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Fox TA, Houghton BC, Petersone L, Waters E, Edner NM, McKenna A, Preham O, Hinze C, Williams C, de Albuquerque AS, Kennedy A, Pesenacker AM, Genovese P, Walker LSK, Burns SO, Sansom DM, Booth C, Morris EC. Therapeutic gene editing of T cells to correct CTLA-4 insufficiency. Sci Transl Med 2022; 14:eabn5811. [PMID: 36288278 DOI: 10.1126/scitranslmed.abn5811] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/29/2024]
Abstract
Heterozygous mutations in CTLA-4 result in an inborn error of immunity with an autoimmune and frequently severe clinical phenotype. Autologous T cell gene therapy may offer a cure without the immunological complications of allogeneic hematopoietic stem cell transplantation. Here, we designed a homology-directed repair (HDR) gene editing strategy that inserts the CTLA-4 cDNA into the first intron of the CTLA-4 genomic locus in primary human T cells. This resulted in regulated expression of CTLA-4 in CD4+ T cells, and functional studies demonstrated CD80 and CD86 transendocytosis. Gene editing of T cells isolated from three patients with CTLA-4 insufficiency also restored CTLA-4 protein expression and rescued transendocytosis of CD80 and CD86 in vitro. Last, gene-corrected T cells from CTLA-4-/- mice engrafted and prevented lymphoproliferation in an in vivo murine model of CTLA-4 insufficiency. These results demonstrate the feasibility of a therapeutic approach using T cell gene therapy for CTLA-4 insufficiency.
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Affiliation(s)
- Thomas Andrew Fox
- UCL Institute of Immunity and Transplantation, University College London, London, NW3 2PP, UK
- Department of Haematology, University College London NHS Foundation Trust, London, NW1 2BU UK
- UCL Great Ormond Street Institute of Child Health, UCL, London WC1N 1EH, UK
| | | | - Lina Petersone
- UCL Institute of Immunity and Transplantation, University College London, London, NW3 2PP, UK
| | - Erin Waters
- UCL Institute of Immunity and Transplantation, University College London, London, NW3 2PP, UK
| | - Natalie Mona Edner
- UCL Institute of Immunity and Transplantation, University College London, London, NW3 2PP, UK
| | - Alex McKenna
- UCL Institute of Immunity and Transplantation, University College London, London, NW3 2PP, UK
| | - Olivier Preham
- UCL Institute of Immunity and Transplantation, University College London, London, NW3 2PP, UK
| | - Claudia Hinze
- UCL Institute of Immunity and Transplantation, University College London, London, NW3 2PP, UK
| | - Cayman Williams
- UCL Institute of Immunity and Transplantation, University College London, London, NW3 2PP, UK
| | - Adriana Silva de Albuquerque
- UCL Institute of Immunity and Transplantation, University College London, London, NW3 2PP, UK
- University College London Hospital, National Institute for Health and Care Research Biomedical Research Centre, London W1T 7DN, UK
| | - Alan Kennedy
- UCL Institute of Immunity and Transplantation, University College London, London, NW3 2PP, UK
| | - Anne Maria Pesenacker
- UCL Institute of Immunity and Transplantation, University College London, London, NW3 2PP, UK
| | - Pietro Genovese
- Dana-Farber/Boston Children's Cancer and Blood Disorder Center, Boston, MA 02115, USA
| | - Lucy Sarah Kate Walker
- UCL Institute of Immunity and Transplantation, University College London, London, NW3 2PP, UK
| | - Siobhan Oisin Burns
- UCL Institute of Immunity and Transplantation, University College London, London, NW3 2PP, UK
- Department of Immunology, Royal Free London Hospitals NHS Foundation Trust, London, NW3 2QG, UK
| | - David Michael Sansom
- UCL Institute of Immunity and Transplantation, University College London, London, NW3 2PP, UK
| | - Claire Booth
- UCL Great Ormond Street Institute of Child Health, UCL, London WC1N 1EH, UK
- Department of Paediatric Immunology, Great Ormond Street Hospital, London WC1N 3JH, UK
| | - Emma Catherine Morris
- UCL Institute of Immunity and Transplantation, University College London, London, NW3 2PP, UK
- Department of Haematology, University College London NHS Foundation Trust, London, NW1 2BU UK
- University College London Hospital, National Institute for Health and Care Research Biomedical Research Centre, London W1T 7DN, UK
- Department of Immunology, Royal Free London Hospitals NHS Foundation Trust, London, NW3 2QG, UK
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12
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13
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Albert MH, Sirait T, Eikema DJ, Bakunina K, Wehr C, Suarez F, Fox ML, Mahlaoui N, Gennery AR, Lankester AC, Beier R, Bernardo ME, Bigley V, Lindemans CA, Burns SO, Carpenter B, Dybko J, Güngör T, Hauck F, Lum SH, Balashov D, Meisel R, Moshous D, Schulz A, Speckmann C, Slatter MA, Strahm B, Uckan-Cetinkaya D, Meyts I, Vallée TC, Wynn R, Neven B, Morris EC, Aiuti A, Maschan A, Aljurf M, Gedde-Dahl T, Gurman G, Bordon V, Kriván G, Locatelli F, Porta F, Valcárcel D, Beguin Y, Faraci M, Kröger N, Kulagin A, Shaw PJ, Veelken JH, Diaz de Heredia C, Fagioli F, Felber M, Gruhn B, Holter W, Rössig C, Sedlacek P, Apperley J, Ayas M, Bodova I, Choi G, Cornelissen JJ, Sirvent A, Khan A, Kupesiz A, Lenhoff S, Ozdogu H, von der Weid N, Rovira M, Schots R, Vinh DC. Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study. Blood 2022; 140:1635-1649. [PMID: 35344580 DOI: 10.1182/blood.2022015506] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/17/2022] [Indexed: 11/20/2022] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT.
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Affiliation(s)
- Michael H Albert
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität, Munich, Germany
| | - Tiarlan Sirait
- Statistical Unit and Data Office, European Society for Blood and Marrow Transplantation (EBMT), Leiden, The Netherlands
| | - Dirk-Jan Eikema
- Statistical Unit and Data Office, European Society for Blood and Marrow Transplantation (EBMT), Leiden, The Netherlands
| | - Katerina Bakunina
- Statistical Unit and Data Office, European Society for Blood and Marrow Transplantation (EBMT), Leiden, The Netherlands
| | - Claudia Wehr
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Felipe Suarez
- Department of Adult Hematology, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Maria Laura Fox
- Department of Hematology, Hospital Universitari Vall d'Hebron, Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Nizar Mahlaoui
- Pediatric Immuno-Hematology and Rheumatology Unit, Necker-Enfants University Hospital and French National Reference Center for Primary Immunodeficiencies (CEREDIH), AP-HP, Paris, France
| | - Andrew R Gennery
- Department of Pediatric Immunology & Haematopoietic Stem Cell Transplantation (HSCT), Great North Children's Hospital, Newcastle upon Tyne, United Kingdom
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Arjan C Lankester
- Department of Pediatrics, Pediatric Stem Cell Transplantation Program, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands
| | - Rita Beier
- Department of Pediatric Hematology and Oncology, Medizinische Hochschule Hannover (MHH), Hannover, Germany
| | - Maria Ester Bernardo
- Department of Pediatric Immunohematology, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy
| | - Venetia Bigley
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Northern Center for Cancer Care, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Caroline A Lindemans
- Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Pediatric Blood and Bone Marrow Transplantation, Princess Maxima Center, Utrecht, The Netherlands
| | - Siobhan O Burns
- Department of Immunology, Royal Free London Hospitals NHS Foundation Trust, London, United Kingdom
- Institute of Immunity and Transplantation, University College London (UCL), London, United Kingdom
| | - Ben Carpenter
- Department of Clinical Hematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
| | - Jaroslaw Dybko
- Department of Hematology and Cellular Transplantation, Lower Silesian Center of Oncology, Wroclaw, Poland
| | - Tayfun Güngör
- Department of Hematology/Oncology/Immunology, Gene-Therapy, and Stem Cell Transplantation, University Children's Hospital Zurich - Eleonore Foundation & Children's Research Center (CRC), Zürich, Switzerland
| | - Fabian Hauck
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität, Munich, Germany
| | - Su Han Lum
- Department of Pediatric Immunology & Haematopoietic Stem Cell Transplantation (HSCT), Great North Children's Hospital, Newcastle upon Tyne, United Kingdom
| | - Dmitry Balashov
- Department of Hematopoietic Stem Cell Transplantation, Dmitriy Rogachev National Center for Pediatric Hematology, Oncology, and Immunology, Moscow, Russian Federation
| | - Roland Meisel
- Division of Pediatric Stem Cell Therapy, Department of Paediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Despina Moshous
- Department of Pediatric Immunology, Hematology, and Rheumatology, Necker-Enfants Malades University Hospital, AP-HP, Paris, France
| | - Ansgar Schulz
- Department of Pediatrics, University Medical Center Ulm, Ulm, Germany
| | - Carsten Speckmann
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Pediatric Hematology and Oncology, Center for Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Mary A Slatter
- Department of Pediatric Immunology & Haematopoietic Stem Cell Transplantation (HSCT), Great North Children's Hospital, Newcastle upon Tyne, United Kingdom
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Brigitte Strahm
- Department of Pediatric Hematology and Oncology, Center for Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Duygu Uckan-Cetinkaya
- Department of Pediatrics, Bone Marrow Transplantation (BMT) Unit, Hacettepe University, Faculty of Medicine, Ankara, Turkey
| | - Isabelle Meyts
- Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
- Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Tanja C Vallée
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität, Munich, Germany
| | - Robert Wynn
- Blood and Marrow Transplant Program, Royal Manchester Children's Hospital, Manchester, United Kingdom
| | - Bénédicte Neven
- Department of Pediatric Immunology, Hematology, and Rheumatology, Necker-Enfants Malades University Hospital, AP-HP, Paris, France
| | - Emma C Morris
- Department of Immunology, Royal Free London Hospitals NHS Foundation Trust, London, United Kingdom
- Institute of Immunity and Transplantation, University College London (UCL), London, United Kingdom
- Department of Clinical Hematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
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14
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van Leeuwen-Kerkhoff N, de Witte MA, Heijstek MW, Leavis HL. Case report: Up-front allogeneic stem cell transplantation in a patient with the VEXAS syndrome. Br J Haematol 2022; 199:e12-e15. [PMID: 36039520 DOI: 10.1111/bjh.18424] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/05/2022] [Accepted: 08/11/2022] [Indexed: 11/28/2022]
Affiliation(s)
- Nathalie van Leeuwen-Kerkhoff
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Moniek A de Witte
- Department of Hematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Marloes W Heijstek
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Helen L Leavis
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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15
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Marçais A, Mahlaoui N, Neven B, Lanternier F, Catherinot É, Salvator H, Cheminant M, Jeljeli M, Asnafi V, van Endert P, Couderc LJ, Lortholary O, Picard C, Moshous D, Hermine O, Fischer A, Suarez F. Curative allogeneic hematopoietic stem cell transplantation following reduced toxicity conditioning in adults with primary immunodeficiency. Bone Marrow Transplant 2022; 57:1520-1530. [PMID: 35794259 PMCID: PMC9258769 DOI: 10.1038/s41409-022-01739-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 05/17/2022] [Accepted: 06/08/2022] [Indexed: 11/09/2022]
Abstract
Primary immunodeficiencies (PID) are heterogeneous inborn errors of the immune system. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative and safe at the pediatric age but remains underperformed in adults. We report our experience on 32 consecutive adult patients with various PID including 17 (53%) with a combined immune deficiency, six (19%) with a disease of immune dysregulation and nine (28%) with a chronic granulomatous disease (CGD) who underwent an allo-HSCT between 2011 and 2020. The median age at transplant was 27 years (17-41). All assessable patients engrafted. The majority of patients received a fludarabine-Busulfan (FB) based regimen (FB2-3 in 16, FB4 in 12). Overall survival (OS) was 80.4% (100% for CGD and 74% for other PID patients) at 9 months and beyond (median follow-up 51.6 months). Six patients died, all in the first-year post-transplant. Cumulative incidences of grade II-IV acute GVHD/chronic GVHD were 18%/22%. Stem cell source, GVHD prophylaxis and conditioning intensity had no impact on OS. All surviving patients had over 90% donor chimerism, immune reconstitution, no sign of active PID related complications and were clinically improved. Allo-HSCT is effective in young adults PID patients with an acceptable toxicity and should be discussed in case of life-threatening PID.
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Affiliation(s)
- Ambroise Marçais
- Service d'Hématologie Adultes, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Université Paris Cité, Paris, France. .,Laboratoire d'onco-hématologie, Institut Necker-Enfants Malades, INSERM U1151, Université Paris Cité, Paris, France.
| | - Nizar Mahlaoui
- Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Institut Imagine, Paris, France
| | - Bénédicte Neven
- Service d'immuno-hématologie pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Université Paris Cité, Paris, France
| | - Fanny Lanternier
- Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker-Pasteur, Assistance Publique-Hôpitaux de Paris, IHU Imagine, Hôpital Necker Enfants Malades, Université Paris Cité, Paris, France
| | | | | | - Morgane Cheminant
- Service d'Hématologie Adultes, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Université Paris Cité, Paris, France
| | - Maxime Jeljeli
- Laboratoire d'immunologie, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Université Paris Cité, Paris, France
| | - Vahid Asnafi
- Laboratoire d'onco-hématologie, Institut Necker-Enfants Malades, INSERM U1151, Université Paris Cité, Paris, France
| | - Peter van Endert
- Laboratoire immunologie, INSERM, U1151, 75015, Université Paris Cité, Paris, France
| | | | - Olivier Lortholary
- Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker-Pasteur, Assistance Publique-Hôpitaux de Paris, IHU Imagine, Hôpital Necker Enfants Malades, Université Paris Cité, Paris, France
| | - Capucine Picard
- Centre d'études des Déficits Immunitaires, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Université Paris Cité, Institut Imagine, Paris, France
| | - Despina Moshous
- Service d'immuno-hématologie pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Université Paris Cité, Paris, France
| | - Olivier Hermine
- Service d'Hématologie Adultes, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Université Paris Cité, Paris, France
| | - Alain Fischer
- Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Institut Imagine, Paris, France.,Service d'immuno-hématologie pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Université Paris Cité, Paris, France
| | - Felipe Suarez
- Service d'Hématologie Adultes, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Université Paris Cité, Paris, France.
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Fox TA, Houghton BC, Booth C. Gene Edited T Cell Therapies for Inborn Errors of Immunity. Front Genome Ed 2022; 4:899294. [PMID: 35783679 PMCID: PMC9244397 DOI: 10.3389/fgeed.2022.899294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 05/31/2022] [Indexed: 11/30/2022] Open
Abstract
Inborn errors of immunity (IEIs) are a heterogeneous group of inherited disorders of the immune system. Many IEIs have a severe clinical phenotype that results in progressive morbidity and premature mortality. Over 450 IEIs have been described and the incidence of all IEIs is 1/1,000–10,000 people. Current treatment options are unsatisfactory for many IEIs. Allogeneic haematopoietic stem cell transplantation (alloHSCT) is curative but requires the availability of a suitable donor and carries a risk of graft failure, graft rejection and graft-versus-host disease (GvHD). Autologous gene therapy (GT) offers a cure whilst abrogating the immunological complications of alloHSCT. Gene editing (GE) technologies allow the precise modification of an organisms’ DNA at a base-pair level. In the context of genetic disease, this enables correction of genetic defects whilst preserving the endogenous gene control machinery. Gene editing technologies have the potential to transform the treatment landscape of IEIs. In contrast to gene addition techniques, gene editing using the CRISPR system repairs or replaces the mutation in the DNA. Many IEIs are limited to the lymphoid compartment and may be amenable to T cell correction alone (rather than haematopoietic stem cells). T cell Gene editing has the advantages of higher editing efficiencies, reduced risk of deleterious off-target edits in terminally differentiated cells and less toxic conditioning required for engraftment of lymphocytes. Although most T cells lack the self-renewing property of HSCs, a population of T cells, the T stem cell memory compartment has long-term multipotent and self-renewal capacity. Gene edited T cell therapies for IEIs are currently in development and may offer a less-toxic curative therapy to patients affected by certain IEIs. In this review, we discuss the history of T cell gene therapy, developments in T cell gene editing cellular therapies before detailing exciting pre-clinical studies that demonstrate gene editing T cell therapies as a proof-of-concept for several IEIs.
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Affiliation(s)
- T. A. Fox
- UCL Institute of Immunity and Transplantation, University College London, London, United Kingdom
- Department of Clinical Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
| | - B. C. Houghton
- Molecular and Cellular Immunology Section, UCL GOS Institute of Child Health, London, United Kingdom
| | - C. Booth
- Molecular and Cellular Immunology Section, UCL GOS Institute of Child Health, London, United Kingdom
- Department of Paediatric Immunology, Great Ormond Street Hospital for Sick Children NHS Foundation Trust, London, United Kingdom
- *Correspondence: C. Booth,
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17
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Meesters-Ensing J, Admiraal R, Ebskamp L, Lacna A, Boelens JJ, Lindemans CA, Nierkens S. Therapeutic Drug Monitoring of Anti-Thymocyte Globulin in Allogeneic Stem Cell Transplantation: Proof of Concept. Front Pharmacol 2022; 13:828094. [PMID: 35370695 PMCID: PMC8974913 DOI: 10.3389/fphar.2022.828094] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/25/2022] [Indexed: 01/08/2023] Open
Abstract
Anti-thymocyte globulin (ATG), a polyclonal antibody, is used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-vs.-host-disease (GvHD) and graft failure (GF). Overexposure to ATG leads to poor early T-cell recovery, which is associated with viral infections and poor survival. Patients with severe inflammation are at high risk for GF and GvHD, and may have active infections warranting swift T-cell recovery. As ATG exposure may be critical in these patients, individualized dosing combined with therapeutic drug monitoring (TDM) may improve outcomes. We describe the individualized dosing approach, an optimal sampling scheme, the assay to measure the active fraction of ATG, and the workflow to perform TDM. Using a previously published population pharmacokinetic (PK) model, we determine the dose to reach optimal exposures associated with low GvHD and rejection, and at the same time promote T-cell recovery. Based on an optimal sampling scheme, peak and trough samples are taken during the first 3 days of once-daily dosing. The fraction of ATG able to bind to T-cells (active ATG) is analyzed using a bio-assay in which Jurkat cells are co-cultured with patient's plasma and the binding is quantified using flow cytometry. TDM is performed based on these ATG concentrations on the third day of dosing; subsequent doses can be adjusted based on the expected area under the curve. We show that individualized ATG dosing with TDM is feasible. This approach is unique in the setting of antibody treatment and may result in better immune reconstitution post-HCT and subsequently better survival chances.
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Affiliation(s)
| | - R. Admiraal
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
- Department of Pediatrics, University Medical Center Utrecht, Utrecht, Netherlands
| | - L. Ebskamp
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
| | - A. Lacna
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
| | - J. J. Boelens
- Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - C. A. Lindemans
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
- Department of Pediatrics, University Medical Center Utrecht, Utrecht, Netherlands
| | - S. Nierkens
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
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18
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Ravendran S, Hernández SS, König S, Bak RO. CRISPR/Cas-Based Gene Editing Strategies for DOCK8 Immunodeficiency Syndrome. Front Genome Ed 2022; 4:793010. [PMID: 35373187 PMCID: PMC8969908 DOI: 10.3389/fgeed.2022.793010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 02/14/2022] [Indexed: 12/17/2022] Open
Abstract
Defects in the DOCK8 gene causes combined immunodeficiency termed DOCK8 immunodeficiency syndrome (DIDS). DIDS previously belonged to the disease category of autosomal recessive hyper IgE syndrome (AR-HIES) but is now classified as a combined immunodeficiency (CID). This genetic disorder induces early onset of susceptibility to severe recurrent viral and bacterial infections, atopic diseases and malignancy resulting in high morbidity and mortality. This pathological state arises from impairment of actin polymerization and cytoskeletal rearrangement, which induces improper immune cell migration-, survival-, and effector functions. Owing to the severity of the disease, early allogenic hematopoietic stem cell transplantation is recommended even though it is associated with risk of unintended adverse effects, the need for compatible donors, and high expenses. So far, no alternative therapies have been developed, but the monogenic recessive nature of the disease suggests that gene therapy may be applied. The advent of the CRISPR/Cas gene editing system heralds a new era of possibilities in precision gene therapy, and positive results from clinical trials have already suggested that the tool may provide definitive cures for several genetic disorders. Here, we discuss the potential application of different CRISPR/Cas-mediated genetic therapies to correct the DOCK8 gene. Our findings encourage the pursuit of CRISPR/Cas-based gene editing approaches, which may constitute more precise, affordable, and low-risk definitive treatment options for DOCK8 deficiency.
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Affiliation(s)
| | | | | | - Rasmus O. Bak
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
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19
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Tucci F, Galimberti S, Naldini L, Valsecchi MG, Aiuti A. A systematic review and meta-analysis of gene therapy with hematopoietic stem and progenitor cells for monogenic disorders. Nat Commun 2022; 13:1315. [PMID: 35288539 PMCID: PMC8921234 DOI: 10.1038/s41467-022-28762-2] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 02/08/2022] [Indexed: 12/12/2022] Open
Abstract
Ex-vivo gene therapy (GT) with hematopoietic stem and progenitor cells (HSPCs) engineered with integrating vectors is a promising treatment for monogenic diseases, but lack of centralized databases is hampering an overall outcomes assessment. Here we aim to provide a comprehensive assessment of the short and long term safety of HSPC-GT from trials using different vector platforms. We review systematically the literature on HSPC-GT to describe survival, genotoxicity and engraftment of gene corrected cells. From 1995 to 2020, 55 trials for 14 diseases met inclusion criteria and 406 patients with primary immunodeficiencies (55.2%), metabolic diseases (17.0%), haemoglobinopathies (24.4%) and bone marrow failures (3.4%) were treated with gammaretroviral vector (γRV) (29.1%), self-inactivating γRV (2.2%) or lentiviral vectors (LV) (68.7%). The pooled overall incidence rate of death is 0.9 per 100 person-years of observation (PYO) (95% CI = 0.37-2.17). There are 21 genotoxic events out of 1504.02 PYO, which occurred in γRV trials (0.99 events per 100 PYO, 95% CI = 0.18-5.43) for primary immunodeficiencies. Pooled rate of engraftment is 86.7% (95% CI = 67.1-95.5%) for γRV and 98.7% (95% CI = 94.5-99.7%) for LV HSPC-GT (p = 0.005). Our analyses show stable reconstitution of haematopoiesis in most recipients with superior engraftment and safer profile in patients receiving LV-transduced HSPCs.
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Affiliation(s)
- Francesca Tucci
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Stefania Galimberti
- Bicocca Bioinformatics Biostatistics and Bioimaging B4 Center, School of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy
| | - Luigi Naldini
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Maria Grazia Valsecchi
- Bicocca Bioinformatics Biostatistics and Bioimaging B4 Center, School of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy
| | - Alessandro Aiuti
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.
- Vita-Salute San Raffaele University, Milan, Italy.
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20
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Gonzalez C. Pediatric immune deficiencies: current treatment approaches. Curr Opin Pediatr 2022; 34:61-70. [PMID: 34907131 DOI: 10.1097/mop.0000000000001092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
PURPOSE OF REVIEW To summarize the currently available definitive therapies for patients with inborn errors of immunity (IEIs) with a strong focus on recent advances in allogeneic hematopoietic cell transplantation (HCT) and gene therapy, including the use of alternative donors, graft manipulation techniques, less toxic approaches for pretransplant conditioning and gene transfer using autologous hematopoietic stem cells. RECENT FINDINGS In the absence of a matched sibling or a matched related donor, therapeutic alternatives for patients with IEIs include alternative donor transplantation or autologous gene therapy, which is only available for selected IEIs. In recent years, several groups have published their experience with haploidentical hematopoietic cell transplantation (HHCT) using different T-cell depletion strategies. Overall survival and event free survival results, although variable among centers, are encouraging. Preliminary results from autologous gene therapy trials with safer vectors and low-dose busulfan conditioning have shown reproducible and successful results. Both strategies have become valid therapeutic options for patients with IEIs. A new promising and less toxic conditioning regimen strategy is also discussed. SUMMARY Definitive therapies for IEIs with HCT and gene therapy are in stage of evolution, not only to refine their efficacy and safety but also their reach to a larger number of patients.
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Affiliation(s)
- Corina Gonzalez
- Immune Deficiency Cellular Therapy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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21
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Alligon M, Mahlaoui N, Courteille V, Costes L, Afonso V, Randrianomenjanahary P, de Vergnes N, Ranohavimparany A, Vo D, Hafsa I, Bach P, Benoit V, Garcelon N, Fischer A. An appraisal of the frequency and severity of non-infectious manifestations in primary immunodeficiencies. A study of a national retrospective cohort of 1375 patients over 10 years. J Allergy Clin Immunol 2022; 149:2116-2125. [PMID: 35031273 DOI: 10.1016/j.jaci.2021.12.790] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 12/16/2021] [Accepted: 12/23/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND Non-infectious manifestations, i.e. allergy, autoimmunity/inflammation, lymphoproliferation and malignancies are known to be observed in many primary immunodeficiency diseases (PID) and to participate to their prognosis. OBJECTIVE In order to have a global view on their occurrence, we retrieved data from a retrospective cohort of 1375 patients included in the French national registry of PID (CEREDIH) for whom we had a 10-year follow-up since inclusion in the registry. METHODS These patients were followed for 10 years (2009-2018) by specialized centers in University Hospitals. This study shows that 20.1% of patients without prior curative therapy (n=1163) developed at least one manifestation (event) encompassing 277 events. RESULTS Autoimmune/inflammatory events (n=138) and malignancies (n=85) affected all age classes and virtually all PID diagnostic groups. They were associated with a risk of death that occurred in 14.2% of them (n=195), being found as causal in 43% of cases. Malignancies (OR: 5.62 [3.66 - 8.62]) and autoimmunity (OR: 1.9 [1.27 - 2.84]) were clearly identified as risk factors for lethality. Patients who underwent curative therapy (i.e. mostly allogeneic hematopoietic stem cell transplantation, a few cases of gene therapy or thymic transplantation) prior to the 10-year study period (n=212) had comparatively reduced but still detectable clinical manifestations (n=16) leading to death in 9.4% of them. CONCLUSION This study points to the frequency and severity of non-infectious manifestations in various PID groups across all age groups. These results warrant further prospective analysis to better assess their consequences and to adapt therapy, notably indication of curative therapy.
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Affiliation(s)
- Mickaël Alligon
- French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Nizar Mahlaoui
- French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Pediatric Immuno-Hematology and Rheumatology Unit, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Virginie Courteille
- French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Laurence Costes
- French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Veronica Afonso
- French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Philippe Randrianomenjanahary
- French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Nathalie de Vergnes
- French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Anja Ranohavimparany
- French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Duy Vo
- French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Inès Hafsa
- French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Perrine Bach
- French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Vincent Benoit
- Université de Paris, Imagine Institute, Data Science Platform, INSERM UMR 1163, F-75015, Paris, France
| | - Nicolas Garcelon
- Université de Paris, Imagine Institute, Data Science Platform, INSERM UMR 1163, F-75015, Paris, France
| | - Alain Fischer
- French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Pediatric Immuno-Hematology and Rheumatology Unit, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France; Collège de France, Paris, France.
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22
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Yang L, Booth C, Speckmann C, Seidel MG, Worth AJ, Kindle G, Lankester AC, B G, Gennery AR, Seppanen MR, Morris EC, Burns SO. Phenotype, genotype, treatment, and survival outcomes in patients with X-linked inhibitor of apoptosis deficiency. J Allergy Clin Immunol 2021; 150:456-466. [PMID: 34920033 DOI: 10.1016/j.jaci.2021.10.037] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/06/2021] [Accepted: 10/13/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND X-linked inhibitor of apoptosis (XIAP) deficiency is a rare, primary immunodeficiency disease caused by XIAP gene mutations. A broad range of phenotype, severity, and age of onset present challenges for patient management. OBJECTIVE To characterize the phenotype, treatment, and survival outcomes of XIAP deficiency and assess parameters influencing prognosis. METHODS Data published from 2006-2020 were retrospectively analyzed. RESULTS 167 patients from 117 families with XIAP deficiency were reported with 90 different mutations. A wide spectrum of clinical features were seen, of which hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD) were the most common. Patients frequently developed multiple features with no clear genotype-phenotype correlation. 117 patients were managed conservatively and 50 underwent hematopoietic stem cell transplantation (HSCT), with respective overall survival probabilities of 90% and 53% at age 16 years. The predominant indication for HSCT was early-onset HLH. Active HLH and myeloablative conditioning regimens increased HSCT-related mortality, although HSCT outcome was much better after 2015 than before. For conservatively managed patients reaching adulthood, survival probabilities were 86% at age 30 years and 37% by age 52 years, with worse outcomes for patients developing the disease before the age of 5 years or with new disease features in adulthood. 9 asymptomatic mutation carriers were identified with a median age of 13.5 years. CONCLUSIONS Our study demonstrates the variable nature of XIAP deficiency which evolves over life for individual patients. Better therapeutic strategies and prospective studies are required to reduce morbidity and mortality and improve decision-making and long-term outcomes for patients with XIAP deficiency.
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Affiliation(s)
- Linlin Yang
- Department of Clinical Immunology, Royal Free London NHS Foundation Trust, London NW3 2PF, United Kingdom; Institute for Immunity and Transplantation, University College London, London NW3 2PF, United Kingdom; Department of Hematology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Claire Booth
- Department of Immunology and Gene Therapy, Great Ormond Street Hospital for Children NHS Trust, London WC1N 1JH; Molecular and Cellular Immunology, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Carsten Speckmann
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, Medical Center - University of Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, Department of Pediatric Hematology and Oncology, Faculty of Medicine, Medical Center - University of Freiburg, Germany
| | - Markus G Seidel
- Research Unit for Pediatric Hematology and Immunology, Division of Pediatric Hematology-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Austen Jj Worth
- Department of Immunology and Gene Therapy, Great Ormond Street Hospital for Children NHS Trust, London WC1N 1JH
| | - Gerhard Kindle
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, Medical Center - University of Freiburg, Germany
| | - Arjan C Lankester
- Willem-Alexander Children's Hospital, Department of Pediatrics, Stem Cell Transplantation program, Leiden University Medical Center, Leiden, The Netherlands
| | - Grimbacher B
- Institute for Immunity and Transplantation, University College London, London NW3 2PF, United Kingdom; Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, Medical Center - University of Freiburg, Germany; DZIF - German Center for Infection Research, Satellite Center Freiburg, Germany; CIBSS - Centre for Integrative Biological Signalling Studies, Albert-Ludwigs University, Freiburg, Germany; RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Germany
| | | | - Andrew R Gennery
- Translational and Clinical Research Institute, Newcastle University and Pediatric Immunology + HSCT, Great North Children's Hospital, Newcastle upon Tyne, UK
| | - Mikko Rj Seppanen
- HUS Rare Disease Center, Children and Adolescents, University of Helsinki and Helsinki University Hospital, Finland
| | - Emma C Morris
- Department of Clinical Immunology, Royal Free London NHS Foundation Trust, London NW3 2PF, United Kingdom; Institute for Immunity and Transplantation, University College London, London NW3 2PF, United Kingdom
| | - Siobhan O Burns
- Department of Clinical Immunology, Royal Free London NHS Foundation Trust, London NW3 2PF, United Kingdom; Institute for Immunity and Transplantation, University College London, London NW3 2PF, United Kingdom.
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23
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How I Treat: Allogeneic HSCT for adults with Inborn Errors of Immunity. Blood 2021; 138:1666-1676. [PMID: 34077952 DOI: 10.1182/blood.2020008187] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 05/10/2021] [Indexed: 11/20/2022] Open
Abstract
Inborn Errors of Immunity (IEI) are rare inherited disorders arising from monogenic germline mutations in genes that regulate the immune system. The majority of IEI are Primary Immunodeficiencies characterised by severe infection often associated with autoimmunity, autoinflammation and/or malignancy. Allogeneic hematopoietic stem cell transplant (HSCT) has been the corrective treatment of choice for many IEI presenting with severe disease in early childhood and experience has made this a successful and comparatively safe treatment in affected children. Early HSCT outcomes in adults were poor, resulting in extremely limited use worldwide. This is changing due to a combination of improved IEI diagnosis to inform patient selection, better understanding of the natural history of specific IEI and improvements in transplant practice. Recently published HSCT outcomes for adults with IEI have been comparable with pediatric data, making HSCT an important option for correction of clinically severe IEI in adulthood. Here we discuss our practice for patient selection, timing of HSCT, donor selection and conditioning, peri- and post HSCT management and our approach to long term follow up. We stress the importance of multidisciplinary involvement in the complex decision-making process that we believe is required for successful outcomes in this rapidly emerging area.
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24
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Dimitrova D, Nademi Z, Maccari ME, Ehl S, Uzel G, Tomoda T, Okano T, Imai K, Carpenter B, Ip W, Rao K, Worth AJJ, Laberko A, Mukhina A, Néven B, Moshous D, Speckmann C, Warnatz K, Wehr C, Abolhassani H, Aghamohammadi A, Bleesing JJ, Dara J, Dvorak CC, Ghosh S, Kang HJ, Markelj G, Modi A, Bayer DK, Notarangelo LD, Schulz A, Garcia-Prat M, Soler-Palacín P, Karakükcü M, Yilmaz E, Gambineri E, Menconi M, Masmas TN, Holm M, Bonfim C, Prando C, Hughes S, Jolles S, Morris EC, Kapoor N, Koltan S, Paneesha S, Steward C, Wynn R, Duffner U, Gennery AR, Lankester AC, Slatter M, Kanakry JA. International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome. J Allergy Clin Immunol 2021; 149:410-421.e7. [PMID: 34033842 PMCID: PMC8611111 DOI: 10.1016/j.jaci.2021.04.036] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 04/10/2021] [Accepted: 04/30/2021] [Indexed: 12/01/2022]
Abstract
Background: Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT). Objectives: This study sought to characterize HCT outcomes in APDS. Methods: Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2–66 years) who underwent HCT. Results: Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure–free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential nonimmunologic roles of phosphoinositide 3-kinase not correctable through HCT. Conclusions: Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer-term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time.
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Affiliation(s)
- Dimana Dimitrova
- Experimental Transplantation and Immunotherapy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md.
| | - Zohreh Nademi
- Children's Bone Marrow Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom; The Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Maria Elena Maccari
- 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
| | - Stephan Ehl
- 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
| | - Gulbu Uzel
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Takahiro Tomoda
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tsubasa Okano
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kohsuke Imai
- Department of Community Pediatrics, Perinatal, and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Benjamin Carpenter
- Department of Haematology, University College Hospital National Health Service Trust, London, United Kingdom
| | - Winnie Ip
- Department of Immunology, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, United Kingdom; University College London Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Kanchan Rao
- Department of Bone Marrow Transplantation, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, United Kingdom
| | - Austen J J Worth
- Department of Immunology, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, United Kingdom; University College London Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Alexandra Laberko
- Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Anna Mukhina
- Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - Bénédicte Néven
- Unité d'Immuno-hématologie Pédiatrique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France; Université de Paris, Paris, France; Institut Imagine, Paris, France
| | - Despina Moshous
- Unité d'Immuno-hématologie Pédiatrique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France; Université de Paris, Paris, France; Institut Imagine, Paris, France
| | - Carsten Speckmann
- 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
| | - Klaus Warnatz
- Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Claudia Wehr
- Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Hassan Abolhassani
- Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Asghar Aghamohammadi
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Jacob J Bleesing
- Division of Bone Marrow Transplantation and Immunodeficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jasmeen Dara
- Department of Pediatrics, Division of Allergy, Immunology, Blood and Marrow Transplantation, Benioff Children's Hospital, University of California San Francisco, San Francisco, Calif
| | - Christopher C Dvorak
- Department of Pediatrics, Division of Allergy, Immunology, Blood and Marrow Transplantation, Benioff Children's Hospital, University of California San Francisco, San Francisco, Calif
| | - Sujal Ghosh
- Department of Pediatric Oncology, Hematology and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Hyoung Jin Kang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Wide River Institute of Immunology, Seoul, Korea
| | - Gašper Markelj
- Department of Allergology, Rheumatology and Clinical Immunology, University Children's Hospital, University Medical Center, Ljubljana, Slovenia
| | - Arunkumar Modi
- University of Arkansas for Medical Sciences Department of Pediatrics, Little Rock, Ark
| | - Diana K Bayer
- Stead Family Department of Pediatrics, University of Iowa, Iowa City, Iowa
| | - Luigi D Notarangelo
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Ansgar Schulz
- Department of Pediatrics, University Medical Center Ulm, Ulm, Germany
| | - Marina Garcia-Prat
- Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Pere Soler-Palacín
- Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Musa Karakükcü
- Department of Pediatric Hematology and Oncology, Erciyes University, Kayseri, Turkey
| | - Ebru Yilmaz
- Department of Pediatric Hematology and Oncology, Erciyes University, Kayseri, Turkey
| | - Eleonora Gambineri
- Department of "NEUROFARBA": Section of Child's Health, University of Florence, Florence, Italy; Department of Haematology-Oncology: BMT Unit, "Anna Meyer" Children's Hospital, Florence, Italy
| | - Mariacristina Menconi
- Unità Operativa Oncoematologia Pediatrica, Azienda Ospedaliero Universitaria Pisana Santa Chiara, Pisa, Italy
| | - Tania N Masmas
- Pediatric Hematopoietic Stem Cell Transplantation and Immunodeficiency, The Child and Adolescent Clinic, Copenhagen University Hospital, Copenhagen, Denmark
| | - Mette Holm
- Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Carmem Bonfim
- Department of Immunology, Hospital Pequeno Principe, Curitiba, Brazil
| | - Carolina Prando
- Faculdades Pequeno Príncipe, Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brazil
| | - Stephen Hughes
- Department of Paediatric Immunology, Royal Manchester Children's Hospital, Manchester, United Kingdom
| | - Stephen Jolles
- Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, United Kingdom
| | - Emma C Morris
- Institute of Immunity and Transplantation, University College London, London, United Kingdom
| | - Neena Kapoor
- Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Sylwia Koltan
- Department of Pediatric Hematology and Oncology, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Shankara Paneesha
- Department of Haematology and Stem Cell Transplantation, Birmingham Heartlands Hospital, Birmingham, United Kingdom
| | - Colin Steward
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
| | - Robert Wynn
- Department of Paediatric Immunology, Royal Manchester Children's Hospital, Manchester, United Kingdom
| | - Ulrich Duffner
- Blood and Bone Marrow Transplantation, Helen DeVos Children's Hospital, Grand Rapids, Mich; Department of Pediatrics and Human Development, Spectrum Health and Michigan State University, Grand Rapids, Mich
| | - Andrew R Gennery
- Children's Bone Marrow Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom; The Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Arjan C Lankester
- Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands
| | - Mary Slatter
- Children's Bone Marrow Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom; The Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Jennifer A Kanakry
- Experimental Transplantation and Immunotherapy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md.
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Altered Spectrum of Lymphoid Neoplasms in a Single-Center Cohort of Common Variable Immunodeficiency with Immune Dysregulation. J Clin Immunol 2021; 41:1250-1265. [PMID: 33876323 PMCID: PMC8310845 DOI: 10.1007/s10875-021-01016-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 03/02/2021] [Indexed: 12/14/2022]
Abstract
Purpose Common variable immune deficiency (CVID) confers an increased risk of lymphoid neoplasms, but reports describing the precise WHO specification of the lymphoma subtypes and their immunological environment are lacking. We therefore classified lymphomas—occurring in a cohort of 21 adult CVID patients during a 17-year period at our center—according to the 2016 WHO classification and characterized the local and systemic immunological context Results The median time between the onset of CVID and lymphoma was 14 years. Patients showed a high prevalence of preceding immune dysregulation: lymphadenopathy (n = 13, 62%), splenomegaly (n = 18, 86%), autoimmune cytopenia (n = 14, 67%), and gastrointestinal involvement (n = 15, 71%). The entities comprised extranodal marginal zone lymphoma (n = 6), diffuse large B cell lymphoma (n = 7), plasmablastic lymphoma (n = 1), classic Hodgkin lymphoma (n = 4, including three cases with germline CTLA4 mutations), T cell large granular lymphocytic leukemia (n = 2), and peripheral T cell lymphoma, not otherwise specified (n = 1), but no follicular lymphoma. An Epstein-Barr virus association was documented in eight of 16 investigated lymphomas. High expression of PDL1 by tumor cells in five and of PDL1 and PD1 by tumor-infiltrating macrophages and T cells in 12 of 12 investigated lymphomas suggested a tolerogenic immunological tumor environment. Conclusion In summary, a diverse combination of specific factors like genetic background, chronic immune activation, viral trigger, and impaired immune surveillance contributes to the observed spectrum of lymphomas in CVID. In the future, targeted therapies, e.g., PD1/PDL1 inhibitors in CVID associated lymphomas with a tolerogenic environment may improve therapy outcome. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-021-01016-4.
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Edwards ESJ, Bosco JJ, Ojaimi S, O'Hehir RE, van Zelm MC. Beyond monogenetic rare variants: tackling the low rate of genetic diagnoses in predominantly antibody deficiency. Cell Mol Immunol 2021; 18:588-603. [PMID: 32801365 PMCID: PMC8027216 DOI: 10.1038/s41423-020-00520-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 07/26/2020] [Indexed: 02/07/2023] Open
Abstract
Predominantly antibody deficiency (PAD) is the most prevalent form of primary immunodeficiency, and is characterized by broad clinical, immunological and genetic heterogeneity. Utilizing the current gold standard of whole exome sequencing for diagnosis, pathogenic gene variants are only identified in less than 20% of patients. While elucidation of the causal genes underlying PAD has provided many insights into the cellular and molecular mechanisms underpinning disease pathogenesis, many other genes may remain as yet undefined to enable definitive diagnosis, prognostic monitoring and targeted therapy of patients. Considering that many patients display a relatively late onset of disease presentation in their 2nd or 3rd decade of life, it is questionable whether a single genetic lesion underlies disease in all patients. Potentially, combined effects of other gene variants and/or non-genetic factors, including specific infections can drive disease presentation. In this review, we define (1) the clinical and immunological variability of PAD, (2) consider how genetic defects identified in PAD have given insight into B-cell immunobiology, (3) address recent technological advances in genomics and the challenges associated with identifying causal variants, and (4) discuss how functional validation of variants of unknown significance could potentially be translated into increased diagnostic rates, improved prognostic monitoring and personalized medicine for PAD patients. A multidisciplinary approach will be the key to curtailing the early mortality and high morbidity rates in this immune disorder.
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Affiliation(s)
- Emily S J Edwards
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
- The Jeffrey Modell Diagnostic and Research Centre for Primary Immunodeficiencies, Melbourne, VIC, Australia
| | - Julian J Bosco
- The Jeffrey Modell Diagnostic and Research Centre for Primary Immunodeficiencies, Melbourne, VIC, Australia
- Department of Allergy, Immunology and Respiratory Medicine, Central Clinical School, Monash University and Allergy, Asthma and Clinical Immunology Service, Alfred Hospital, Melbourne, VIC, Australia
| | - Samar Ojaimi
- The Jeffrey Modell Diagnostic and Research Centre for Primary Immunodeficiencies, Melbourne, VIC, Australia
- Department of Infectious Diseases, Monash Health, Clayton, VIC, Australia
- Centre for Inflammatory Diseases, Monash Health, Clayton, VIC, Australia
- Department of Allergy and Immunology, Monash Health, Clayton, VIC, Australia
| | - Robyn E O'Hehir
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
- The Jeffrey Modell Diagnostic and Research Centre for Primary Immunodeficiencies, Melbourne, VIC, Australia
- Department of Allergy, Immunology and Respiratory Medicine, Central Clinical School, Monash University and Allergy, Asthma and Clinical Immunology Service, Alfred Hospital, Melbourne, VIC, Australia
| | - Menno C van Zelm
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia.
- The Jeffrey Modell Diagnostic and Research Centre for Primary Immunodeficiencies, Melbourne, VIC, Australia.
- Department of Allergy, Immunology and Respiratory Medicine, Central Clinical School, Monash University and Allergy, Asthma and Clinical Immunology Service, Alfred Hospital, Melbourne, VIC, Australia.
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27
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King JR, Notarangelo LD, Hammarström L. An appraisal of the Wilson & Jungner criteria in the context of genomic-based newborn screening for inborn errors of immunity. J Allergy Clin Immunol 2021; 147:428-438. [PMID: 33551024 PMCID: PMC8344044 DOI: 10.1016/j.jaci.2020.12.633] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/18/2020] [Accepted: 12/18/2020] [Indexed: 11/25/2022]
Abstract
Wilson and Jungner's recommendations for population-based screening have been used to guide decisions regarding candidate disease inclusion in newborn screening programs for the past 50 years. The advent of genomic-based technologies, including next-generation sequencing and its potential application to newborn screening, along with a changing landscape in terms of modern clinical practice and ethical, social, and legal considerations has led to a call for review of these criteria. Inborn errors of immunity (IEI) are a heterogeneous group of more than 450 genetically determined disorders of immunity, which are associated with significant morbidity and mortality, particularly where diagnosis and treatment are delayed. We argue that in addition to screening for severe combined immunodeficiency disease, which has already been initiated in several countries, other clinically significant IEI should be screened for at birth. Because of disease heterogeneity and identifiable genetic targets, a next-generation sequencing-based screening approach would be most suitable. A combination of worldwide experience and technological advances has improved our ability to diagnose and effectively treat patients with IEI. Considering IEI in the context of updated recommendations for population-based screening supports their potential inclusion as disease targets in newborn screening programs.
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Affiliation(s)
- Jovanka R King
- Department of Clinical Immunology, Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Immunopathology, SA Pathology, Women's and Children's Hospital Campus, Adelaide, Australia; Robinson Research Institute and Discipline of Paediatrics, School of Medicine, University of Adelaide, Adelaide, Australia
| | - Luigi D Notarangelo
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Lennart Hammarström
- Department of Clinical Immunology, Karolinska University Hospital Huddinge, Stockholm, Sweden.
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EBMT/ESID inborn errors working party guidelines for hematopoietic stem cell transplantation for inborn errors of immunity. Bone Marrow Transplant 2021; 56:2052-2062. [PMID: 34226669 PMCID: PMC8410590 DOI: 10.1038/s41409-021-01378-8] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 05/26/2021] [Accepted: 06/09/2021] [Indexed: 02/05/2023]
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Chen X, Liu F, Yuan L, Zhang M, Chen K, Wu Y. Novel mutations in hyper-IgM syndrome type 2 and X-linked agammaglobulinemia detected in three patients with primary immunodeficiency disease. Mol Genet Genomic Med 2020; 9:e1552. [PMID: 33377626 PMCID: PMC7963428 DOI: 10.1002/mgg3.1552] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 09/01/2020] [Accepted: 10/29/2020] [Indexed: 01/04/2023] Open
Abstract
Background Ambiguous or atypical phenotypes can make a definite diagnosis of primary immunodeficiency diseases based on biochemical indices alone challenging. Further, mortality in early life because of infections in patients with these conditions supports the use of genetic tests to facilitate rapid and accurate diagnoses. Methods Genetic and clinical analyses of three unrelated Chinese children with clinical manifestations of recurrent infections, who were considered to have primary immunodeficiency diseases, were conducted. Patient clinical features and serum immunological indices were recorded. Next‐generation sequencing was used to screen for suspected pathogenic variants. Family co‐segregation and in silico analysis were conducted to evaluate the pathogenicity of identified variants, following the American College of Medical Genetics and Genomics guidance. Results All three patients were found to have predominant antibody defects. Sequencing analysis revealed that one had two compound heterozygous variants, c.255C>A and c.295C>T, in the autosomal gene, activation‐induced cytidine deaminase (AICDA). The other two patients were each hemizygous for the variants c.1185G>A and c.82C>T in the Bruton's tyrosine kinase (BTK) gene on the X chromosome. In silico analysis revealed that identified substituted amino acids were highly conserved and predicted to cause structural and functional damage to the proteins. Conclusion Four pathogenic variants in AICDA and BTK were confirmed to cause different forms of hyper‐IgM syndrome type 2 (HIGM2) and X‐linked agammaglobulinemia (XLA); two were novel mutations that have never been reported previously. This is the first report of HIGM2 caused by AICDA deficiency in a patient from the Chinese mainland.
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Affiliation(s)
- Xihui Chen
- Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, China
| | - Fangfang Liu
- Institute of Neurosciences, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Lijuan Yuan
- Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, China.,Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Meng Zhang
- Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, China
| | - Kun Chen
- Department of Anatomy, Histology and Embryology and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an, China
| | - Yuanming Wu
- Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, China
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Abstract
Primary immunodeficiencies (PIDs) are a group of rare inherited disorders of the immune system. Many PIDs are devastating and require a definitive therapy to prevent progressive morbidity and premature mortality. Allogeneic haematopoietic stem cell transplantation (alloHSCT) is curative for many PIDs, and while advances have resulted in improved outcomes, the procedure still carries a risk of mortality and morbidity from graft failure or graft-versus-host disease (GvHD). Autologous haematopoietic stem cell gene therapy (HSC GT) has the potential to correct genetic defects across haematopoietic lineages without the complications of an allogeneic approach. HSC GT for PID has been in development for the last two decades and the first licensed HSC-GT product for adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) is now available. New gene editing technologies have the potential to circumvent some of the problems associated with viral gene-addition. HSC GT for PID shows great promise, but requires a unique approach for each disease and carries risks, notably insertional mutagenesis from gamma-retroviral gene addition approaches and possible off-target toxicities from gene-editing techniques. In this review, we discuss the development of HSC GT for PID and outline the current state of clinical development before discussing future developments in the field.
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Affiliation(s)
- Thomas A Fox
- University College London (UCL) Institute of Immunity and Transplantation, UCL, London, UK.,Department of Clinical Haematology, UCL Hospitals NHS Foundation Trust, London, UK.,Molecular and Cellular Immunology Section, UCL Great Ormond Street (GOS) Institute of Child Health, London, UK
| | - Claire Booth
- Molecular and Cellular Immunology Section, UCL Great Ormond Street (GOS) Institute of Child Health, London, UK.,Department of Paediatric Immunology, GOS Hospital for Sick Children NHS Foundation Trust, London, UK
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31
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Morris EC. Allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2020; 2020:649-660. [PMID: 33275750 PMCID: PMC7727582 DOI: 10.1182/hematology.2020000152] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
With recent advances in genetic sequencing and its widespread adoption for clinical diagnostics, the identification of a primary immunodeficiency (PID) as the underlying cause of diseases presenting to hematologists including refractory autoimmunity, cytopenias, immune dysregulation, and hematologic malignancy, is increasing, particularly in the adult population. Where the pathogenic genetic variants are restricted to the hematopoietic system, selected patients may benefit from allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although it is generally accepted that early allo-HSCT (ie, in infancy or childhood) for PID is preferable, this is not always possible. The clinical phenotype of non-severe combined immune deficiency forms of PID can be very heterogeneous, in part because of the high number of genetic and functional defects affecting T, B, and natural killer cells, neutrophils, and/or antigen presentation. As a result, some patients have less severe disease manifestations in childhood and/or a later de novo presentation. For others, a delayed diagnosis, lack of a genetic diagnosis, or a previous lack of a suitable donor has precluded prior allo-HSCT. Specific issues which make transplantation for adult PID patients particularly challenging are discussed, including understanding the natural history of rare diseases and predicting outcome with conservative management alone; indications for and optimal timing of transplant; donor selection; conditioning regimens; and PID-specific transplant management. The role of gene therapy approaches as an alternative to allo-HSCT in high-risk monogenic PID is also discussed.
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Affiliation(s)
- Emma C Morris
- Institute of Immunity and Transplantation, University College London, London, United Kingdom
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32
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Ghosh S, Köstel Bal S, Edwards ESJ, Pillay B, Jiménez Heredia R, Erol Cipe F, Rao G, Salzer E, Zoghi S, Abolhassani H, Momen T, Gostick E, Price DA, Zhang Y, Oler AJ, Gonzaga-Jauregui C, Erman B, Metin A, Ilhan I, Haskologlu S, Islamoglu C, Baskin K, Ceylaner S, Yilmaz E, Unal E, Karakukcu M, Berghuis D, Cole T, Gupta AK, Hauck F, Kogler H, Hoepelman AIM, Baris S, Karakoc-Aydiner E, Ozen A, Kager L, Holzinger D, Paulussen M, Krüger R, Meisel R, Oommen PT, Morris E, Neven B, Worth A, van Montfrans J, Fraaij PLA, Choo S, Dogu F, Davies EG, Burns S, Dückers G, Becker RP, von Bernuth H, Latour S, Faraci M, Gattorno M, Su HC, Pan-Hammarström Q, Hammarström L, Lenardo MJ, Ma CS, Niehues T, Aghamohammadi A, Rezaei N, Ikinciogullari A, Tangye SG, Lankester AC, Boztug K. Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency. Blood 2020; 136:2638-2655. [PMID: 32603431 PMCID: PMC7735164 DOI: 10.1182/blood.2020006738] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 06/10/2020] [Indexed: 12/31/2022] Open
Abstract
Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV+ at diagnosis, but only ∼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.
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Affiliation(s)
- Sujal Ghosh
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany
| | - Sevgi Köstel Bal
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Emily S J Edwards
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St. Vincent's Clinical School, UNSW Sydney, Randwick, NSW, Australia
| | - Bethany Pillay
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St. Vincent's Clinical School, UNSW Sydney, Randwick, NSW, Australia
| | - Raúl Jiménez Heredia
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Funda Erol Cipe
- Department of Pediatric Allergy and Immunology, Istinye University, Istanbul, Turkey
| | - Geetha Rao
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Elisabeth Salzer
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- St. Anna Children's Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
| | - Samaneh Zoghi
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hassan Abolhassani
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Tooba Momen
- Department of Allergy and Clinical Immunology, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Emma Gostick
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - David A Price
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
- Vaccine Research Center
| | - Yu Zhang
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research
- Clinical Genomics Program, and
| | - Andrew J Oler
- Clinical Genomics Program, and
- Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD
| | | | - Baran Erman
- Institute of Child Health, Hacettepe University, Ankara, Turkey
- Can Sucak Research Laboratory for Translational Immunology, Center for Genomics and Rare Diseases, Hacettepe University, Ankara, Turkey
| | - Ayse Metin
- Division of Pediatric Allergy and Immunology, University of Health Sciences/Ankara City Hospital/Children's Hospital, Ankara, Turkey
| | - Inci Ilhan
- Division of Pediatric Oncology, University of Health Sciences/Ankara City Hospital/Children's Hospital, Ankara, Turkey
| | - Sule Haskologlu
- Department of Pediatric Allergy and Immunology, School of Medicine, Ankara University, Ankara, Turkey
| | - Candan Islamoglu
- Department of Pediatric Allergy and Immunology, School of Medicine, Ankara University, Ankara, Turkey
| | - Kubra Baskin
- Department of Pediatric Allergy and Immunology, School of Medicine, Ankara University, Ankara, Turkey
| | - Serdar Ceylaner
- Intergen Genetic Diagnosis and Research Center, Ankara, Turkey
| | - Ebru Yilmaz
- Department of Pediatrics, Division of Pediatric Hematology & Oncology & Molecular Biology and Genetic Department, Erciyes University, Kayseri, Turkey
- Gevher Nesibe Genom and Stem Cell Institution, GENKOK Genome and Stem Cell Center, Erciyes University, Kayseri, Turkey
| | - Ekrem Unal
- Department of Pediatrics, Division of Pediatric Hematology & Oncology & Molecular Biology and Genetic Department, Erciyes University, Kayseri, Turkey
- Gevher Nesibe Genom and Stem Cell Institution, GENKOK Genome and Stem Cell Center, Erciyes University, Kayseri, Turkey
| | - Musa Karakukcu
- Department of Pediatrics, Division of Pediatric Hematology & Oncology & Molecular Biology and Genetic Department, Erciyes University, Kayseri, Turkey
- Gevher Nesibe Genom and Stem Cell Institution, GENKOK Genome and Stem Cell Center, Erciyes University, Kayseri, Turkey
| | - Dagmar Berghuis
- Willem-Alexander Children's Hospital, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
| | - Theresa Cole
- Department of Allergy and Immunology, The Royal Children's Hospital, Melbourne, VIC, Australia
| | - Aditya K Gupta
- Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Fabian Hauck
- Dr von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
| | - Hubert Kogler
- St. Anna Children's Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
| | - Andy I M Hoepelman
- Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Safa Baris
- Division of Allergy and Immunology, Marmara University, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
| | - Elif Karakoc-Aydiner
- Division of Allergy and Immunology, Marmara University, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
| | - Ahmet Ozen
- Division of Allergy and Immunology, Marmara University, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
| | - Leo Kager
- St. Anna Children's Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
| | - Dirk Holzinger
- Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany
| | - Michael Paulussen
- Vestische Kinder-und Jugendklinik, Witten/Herdecke University, Datteln, Germany
| | - Renate Krüger
- Department of Pediatric Pulmonology, Immunology, and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Roland Meisel
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany
| | - Prasad T Oommen
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany
| | - Emma Morris
- Institute of Immunity & Transplantation, University College London, Royal Free Hospital, London, United Kingdom
| | - Benedicte Neven
- Unité d'Immuno-Hematologie et Rhumatologie, Département de Pédiatrie Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
- INSERM U1163, Imagine Institute, Université de Paris, Paris, France
| | - Austen Worth
- UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Joris van Montfrans
- Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital, UMC Utrecht, Utrecht, The Netherlands
| | - Pieter L A Fraaij
- Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands
- Department of Pediatrics, Subdivision Infectious Diseases and Immunology, Erasmus MC-Sophia, Rotterdam, The Netherlands
| | - Sharon Choo
- Department of Allergy and Immunology, The Royal Children's Hospital, Melbourne, VIC, Australia
| | - Figen Dogu
- Department of Pediatric Allergy and Immunology, School of Medicine, Ankara University, Ankara, Turkey
| | - E Graham Davies
- UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Siobhan Burns
- Institute of Immunity & Transplantation, University College London, Royal Free Hospital, London, United Kingdom
- Department of Immunology, Royal Free London National Health Service (NHS) Foundation Trust, London, United Kingdom
| | - Gregor Dückers
- Department of Pediatrics, Helios Children's Hospital, Krefeld, Germany
| | - Ruy Perez Becker
- Department of Pediatrics, Helios Children's Hospital, Krefeld, Germany
| | - Horst von Bernuth
- Department of Pediatric Pulmonology, Immunology, and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Department of Immunology, Labor Berlin GmbH, Berlin, Germany
- Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany
| | - Sylvain Latour
- Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM U1163, Imagine Institute, Université de Paris, Paris, France
| | - Maura Faraci
- Hematopoietic Stem Cell Transplantation Unit and Istituto di Ricovero e Cura Pediatrico a Carattere Scientifico (IRCSS) Istituto Giannina Gaslini Research Institute Genova, Italy
| | - Marco Gattorno
- Center for Autoinflammatory Diseases and Immunodeficiency, Istituto di Ricovero e Cura Pediatrico a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genova, Italy
| | - Helen C Su
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research
- Clinical Genomics Program, and
| | - Qiang Pan-Hammarström
- Department of Biosciences and Nutrition (NEO), Karolinska Institutet, Karolinska, Sweden
| | - Lennart Hammarström
- Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden
- Beijing Genomics Institute (BGI) Shenzhen, Shenzhen, China
| | - Michael J Lenardo
- Clinical Genomics Program, and
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, NIAID, National Institutes of Health, Bethesda, MD
| | - Cindy S Ma
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St. Vincent's Clinical School, UNSW Sydney, Randwick, NSW, Australia
| | - Tim Niehues
- Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands
| | - Asghar Aghamohammadi
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran; and
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran; and
| | - Aydan Ikinciogullari
- Department of Pediatric Allergy and Immunology, School of Medicine, Ankara University, Ankara, Turkey
| | - Stuart G Tangye
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St. Vincent's Clinical School, UNSW Sydney, Randwick, NSW, Australia
| | - Arjan C Lankester
- Willem-Alexander Children's Hospital, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
| | - Kaan Boztug
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- St. Anna Children's Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
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Abstract
INTRODUCTION Primary immunodeficiencies (PIDs) are monogenic disorders of the immune system associated with increased susceptibility to life-threatening infection. Curative treatment has been limited to hematopoietic stem cell transplant (HSCT), however toxic immunosuppression, graft failure, and graft versus host disease greatly reduce overall survival rates. Gene therapy is a targeted curative therapy that reduces these risks by utilizing autologous hematopoietic stem cells. The treatment has found significant success and is anticipated to become the standard of care in a number of PIDs. AREAS COVERED This review is a summary of the developments in gene therapy, gene editing, and current gene therapy approaches in specific PIDs. EXPERT OPINION The field of gene therapy has rapidly developed over the last three decades, with the first licensed pharmaceutical gene therapy product now available. After initial clinical trials discovered serious adverse events in the form of insertional oncogenesis, significant improvements in vector design have made the treatment a viable curative therapy. Cryopreservation has expanded the scope of gene therapy by increasing accessibility of the product to wider geographic locations. Targeted gene editing using engineered nucleases, while still in early stages of development, will further add to the repertoire of potential treatments available for PIDs.
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Affiliation(s)
- Kritika Chetty
- Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.,Department of Immunology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Claire Booth
- Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.,Department of Immunology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
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Kleymann J, Schütz C, Körholz J, Taube F, Vogler M, Halank M, Kolditz M, Langner S, Geberzahn L, Holotiuk O, Roesler J, Koschel D. Septische Granulomatose als seltene Differenzialdiagnose rezidivierender pulmonaler Infektionen bei Erwachsenen. Pneumologie 2020; 74:678-683. [DOI: 10.1055/a-1175-4122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
ZusammenfassungDie septische Granulomatose (engl.: chronic granulomatous disease, CGD) ist bei Kindern und Jugendlichen mit häufigen Infektionen durch bestimmte Erreger differenzialdiagnostisch zu berücksichtigen.In vorliegender Kasuistik berichten wir über eine 64-jährige Patientin mit über Jahre zunehmenden bronchopulmonalen Infektionen, teilweise durch seltene Erreger, Autoimmunphänomenen, Malignomen und im weiteren Verlauf rezidivierenden organisierenden Pneumonien (OP) mit Nachweis von Granulomen. Ursächlich wurde bei der Patientin eine septische Granulomatose, Unterform p47phox-Defizienz diagnostiziert. Ein Überleben von Patienten mit einem primären Immundefekt (PID) bis ins hohe Erwachsenenalter wird trotz wiederholter Komplikationen in Einzelfällen beobachtet, insbesondere wenn die defekte Zellstruktur eine Restaktivität aufweist. Bei rezidivierenden bronchopulmonalen Infektionen insbesondere durch bestimmte seltene Erreger und in Kombination mit organisierend-granulomatösen Lungenreaktionen sowie Autoimmunphänomenen ist auch bei älteren Erwachsenen an eine CGD zu denken. Durch eine Diagnoseverzögerung kommt es oft zu einem erheblichen Anstieg der Morbidität und Mortalität.
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Affiliation(s)
- J. Kleymann
- Medizinische Klinik 1, Bereich Pneumologie, Universitätsklinikum Carl Gustav Carus, Dresden
| | - C. Schütz
- Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Dresden
| | - J. Körholz
- Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Dresden
| | - F. Taube
- Medizinische Klinik 1, Bereich Hämatologie, Universitätsklinikum Carl Gustav Carus, Dresden
| | - M. Vogler
- Fachkrankenhaus Coswig, Abteilung Innere Medizin und Pneumologie, Coswig
| | - M. Halank
- Medizinische Klinik 1, Bereich Pneumologie, Universitätsklinikum Carl Gustav Carus, Dresden
| | - M. Kolditz
- Medizinische Klinik 1, Bereich Pneumologie, Universitätsklinikum Carl Gustav Carus, Dresden
| | - S. Langner
- Medizinische Klinik 1, Bereich Pneumologie, Universitätsklinikum Carl Gustav Carus, Dresden
| | - L. Geberzahn
- Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Dresden
| | - O. Holotiuk
- Pathologische Gemeinschaftspraxis Dr. Holotiuk, Dresden
| | - J. Roesler
- Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Dresden
| | - D. Koschel
- Medizinische Klinik 1, Bereich Pneumologie, Universitätsklinikum Carl Gustav Carus, Dresden
- Fachkrankenhaus Coswig, Abteilung Innere Medizin und Pneumologie, Coswig
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35
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36
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Sacco KA, Stack M, Notarangelo LD. Targeted pharmacologic immunomodulation for inborn errors of immunity. Br J Clin Pharmacol 2020; 88:2500-2508. [PMID: 32738057 DOI: 10.1111/bcp.14509] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 07/21/2020] [Accepted: 07/24/2020] [Indexed: 12/16/2022] Open
Abstract
Inborn errors of immunity consist of over 400 known single gene disorders that may manifest with infection susceptibility, autoimmunity, autoinflammation, hypersensitivity and cancer predisposition. Most patients are treated symptomatically with immunoglobulin replacement, prophylactic antimicrobials or broad immunosuppression pertaining to their disease phenotype. Other than haematopoietic stem cell transplantation, the aforementioned treatments do little to alter disease morbidity or mortality. Further, many patients may not be transplant candidates. In this review, we describe monogenic disorders affecting leucocyte migration, disorders of immune synapse formation and dysregulation of immune cell signal transduction. We highlight the use of off-label small molecules and biologics mechanistically targeted to altered disease pathophysiology of such diseases.
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Affiliation(s)
- Keith A Sacco
- Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, NIH, Maryland, USA
| | - Michael Stack
- Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, NIH, Maryland, USA
| | - Luigi D Notarangelo
- Laboratory of Clinical Immunology and Microbiology, National Institute for Allergy and Infectious Diseases, NIH, Maryland, USA
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37
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Yanagimachi M, Kato K, Iguchi A, Sasaki K, Kiyotani C, Koh K, Koike T, Sano H, Shigemura T, Muramatsu H, Okada K, Inoue M, Tabuchi K, Nishimura T, Mizukami T, Nunoi H, Imai K, Kobayashi M, Morio T. Hematopoietic Cell Transplantation for Chronic Granulomatous Disease in Japan. Front Immunol 2020; 11:1617. [PMID: 32849547 PMCID: PMC7403177 DOI: 10.3389/fimmu.2020.01617] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 06/17/2020] [Indexed: 12/05/2022] Open
Abstract
Hematopoietic cell transplantation (HCT) is established as a curative treatment for severe chronic granulomatous disease (CGD). However, outcomes of HCT for CGD in Japan had not been precisely reported. We evaluated the outcome of HCT for CGD in Japan by means of a nationwide survey. A total of 91 patients (86 males and 5 females) with CGD who received HCT between 1992 and 2013 was investigated. Their median age at HCT was 11 years (0–39). Sixty-four patients had X-linked CGD caused by CYBB gene mutations, 13 had autosomal recessive CGD (7 CYBA and 6 NCF2), and 14 were genetically undetermined. Seventy patients are still alive at a median follow-up of 38.9 (3.7–230) months. Three-year OS and EFS was 73.7 and 67.6%, respectively. Twenty-one patients died mainly from transplant-related mortality. The cumulative incidence of grade II to IV acute GVHD and extensive chronic GVHD was 27.2 and 17.9%, respectively. Risk factors for EFS after HCT for CGD were age >30 years (P < 0.01), non-CYBB gene mutations (P < 0.01) and CBT (P < 0.01). Regarding the reduced intensity conditioning (RIC) regimen, risk factors for EFS included anti-thymocyte globulin (P = 0.048) and not using low-dose irradiation therapy (P < 0.01), in addition to the preceding risk factors. We report outcomes of HCT for CGD in Japan. Future studies are needed to improve such outcomes, especially for patients harboring non-CYBB gene mutations and suffering from adult CGD. A RIC regimen including low-dose irradiation may be a good option to explore further.
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Affiliation(s)
- Masakatsu Yanagimachi
- Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Hematology/Oncology, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Koji Kato
- Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.,Central Japan Cord Blood Bank, Seto, Japan
| | - Akihiro Iguchi
- Department of Pediatrics, Hokkaido University Hospital, Sapporo, Japan
| | - Koji Sasaki
- Department of Pediatrics, Yokohama City University, Yokohama, Japan
| | - Chikako Kiyotani
- Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| | - Katsuyoshi Koh
- Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan
| | - Takashi Koike
- Department of Pediatrics, Tokai University School of Medicine, Isehara, Japan
| | - Hideki Sano
- Department of Pediatric Oncology, Fukushima Medical University Hospital, Fukushima, Japan
| | - Tomonari Shigemura
- Department of Pediatrics, Shinshu University School of Medicine, Nagano, Japan
| | - Hideki Muramatsu
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Keiko Okada
- Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan
| | - Masami Inoue
- Department of Pediatric Hematology/Oncology, Osaka Women's and Children's Hospital, Osaka, Japan
| | - Ken Tabuchi
- Division of Pediatrics, Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital, Tokyo, Japan
| | - Toyoki Nishimura
- Division of Pediatrics, Developmental and Urological-Reproductive Medicine Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Tomoyuki Mizukami
- Division of Pediatrics, Developmental and Urological-Reproductive Medicine Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.,Department of Pediatrics, NHO Kumamoto Medical Center, Kumamoto, Japan
| | - Hiroyuki Nunoi
- Division of Pediatrics, Developmental and Urological-Reproductive Medicine Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Kohsuke Imai
- Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masao Kobayashi
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan
| | - Tomohiro Morio
- Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan
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38
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Prince BT, Thielen BK, Williams KW, Kellner ES, Arnold DE, Cosme-Blanco W, Redmond MT, Hartog NL, Chong HJ, Holland SM. Geographic Variability and Pathogen-Specific Considerations in the Diagnosis and Management of Chronic Granulomatous Disease. Pediatric Health Med Ther 2020; 11:257-268. [PMID: 32801991 PMCID: PMC7383027 DOI: 10.2147/phmt.s254253] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 06/26/2020] [Indexed: 12/18/2022] Open
Abstract
Chronic granulomatous disease (CGD) is a rare but serious primary immunodeficiency with varying prevalence and rates of X-linked and autosomal recessive disease worldwide. Functional defects in the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex predispose patients to a relatively narrow spectrum of bacterial and fungal infections that are sometimes fastidious and often difficult to identify. When evaluating and treating patients with CGD, it is important to consider their native country of birth, climate, and living situation, which may predispose them to types of infections that are atypical to your routine practice. In addition to recurrent and often severe infections, patients with CGD and X-linked female carriers are also susceptible to developing many non-infectious complications including tissue granuloma formation and autoimmunity. The DHR-123 oxidation assay is the gold standard for making the diagnosis and it along with genetic testing can help predict the severity and prognosis in patients with CGD. Disease management focuses on prophylaxis with antibacterial, antifungal, and immunomodulatory medications, prompt identification and treatment of acute infections, and prevention of secondary granulomatous complications. While hematopoietic stem-cell transplantation is the only widely available curative treatment for patients with CGD, recent advances in gene therapy may provide a safer, more direct alternative.
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Affiliation(s)
- Benjamin T Prince
- Division of Allergy and Immunology, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Beth K Thielen
- Division of Pediatric Infectious Diseases and Immunology, University of Minnesota, Minneapolis, MN, USA
| | - Kelli W Williams
- Department of Pediatrics, Division of Pediatric Pulmonology, Allergy & Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Erinn S Kellner
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Danielle E Arnold
- Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Wilfredo Cosme-Blanco
- Department of Allergy and Immunology, Veteran Affairs Caribbean Healthcare System, San Juan, Puerto Rico
| | - Margaret T Redmond
- Division of Allergy and Immunology, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Nicholas L Hartog
- Department of Allergy and Immunology, Spectrum Health Helen DeVos Children’s Hospital, Michigan State University College of Human Medicine, Grand Rapids, MI, USA
| | - Hey J Chong
- Division of Allergy and Immunology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Steven M Holland
- National Institute of Allergy and Infectious Diseases, Bethesda, Maryland National Institutes of Health, Bethesda, MD, USA
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39
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Barkai T, Somech R, Broides A, Gavrieli R, Wolach B, Marcus N, Hagin D, Stauber T. Late diagnosis of chronic granulomatous disease. Clin Exp Immunol 2020; 201:297-305. [PMID: 32506450 DOI: 10.1111/cei.13474] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 05/16/2020] [Accepted: 06/01/2020] [Indexed: 12/26/2022] Open
Abstract
Modern era advancements in medical care, with improved treatment of infections, can result in delayed diagnosis of congenital immunodeficiencies. In this study we present a retrospective cohort of 16 patients diagnosed with Chronic Granulomatous Disease (CGD) at adulthood. Some of the patients had a milder clinical phenotype, but others had a classic phenotype with severe infectious and inflammatory complications reflecting a profoundly impaired neutrophil function. It is therefore of great importance to investigate the individual journey of each patient through different misdiagnoses and the threads which led to the correct diagnosis. Currently the recommended definitive treatment for CGD is hematopoietic stem cell transplantation (HSCT). Although survival of our patients to adulthood might argue against the need for early HSCT during infancy, we claim that the opposite is correct, as most of them grew to be severely ill and diagnosed at a stage when HSCT is debatable with potentially an unfavorable outcome. This cohort stresses the need to increase awareness of this severe congenital immunodeficiency among clinicians of different specialties who might be treating undiagnosed adult patients with CGD.
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Affiliation(s)
- T Barkai
- Pediatric Ward A, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
| | - R Somech
- Pediatric Ward A, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.,Primary Immunodeficiency Clinic, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - A Broides
- Immunology Clinic, Soroka Medical Center, Beer Sheva, Israel
| | - R Gavrieli
- The Laboratory for Leukocyte Function, Meir Medical Center, Kfar Saba, Israel
| | - B Wolach
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,The Laboratory for Leukocyte Function, Meir Medical Center, Kfar Saba, Israel.,Pediatric Hematology Clinic Meir Medical Center, Kfar Saba, Israel
| | - N Marcus
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Kipper Institute for Allergy and Immunology, Schneider children`s medical center of Israel, Petah Tikva, Israel
| | - D Hagin
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Allergy and Clinical Immunology, Department of Medicine, Sourasky Medical Center, Tel Aviv, Israel
| | - T Stauber
- Pediatric Ward A, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.,Primary Immunodeficiency Clinic, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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40
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Abstract
Chronic granulomatous disease is a primary immunodeficiency due to a defect in one of six subunits that make up the nicotinamide adenine dinucleotide phosphate oxidase complex. The most commonly defective protein, gp91phox , is inherited in an X-linked fashion; other defects have autosomal recessive inheritance. Bacterial and fungal infections are common presentations, although inflammatory complications are increasingly recognized as a significant cause of morbidity and are challenging to treat. Haematopoietic stem cell transplantation offers cure from the disease with improved quality of life; overall survival in the current era is around 85%, with most achieving long-term cure free of medication. More recently, gene therapy is emerging as an alternative approach. Results using gammaretroviral vectors were disappointing with genotoxicity and loss of efficacy, but preliminary results using lentiviral vectors are extremely encouraging.
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Affiliation(s)
- Andrew R Gennery
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.,Paediatric Immunology and Haematopoietic Stem Cell Transplantation, Great North Children's Hospital, Newcastle upon Tyne, UK
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41
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Froehlich M, Schwaneck EC, Gernert M, Gadeholt O, Strunz PP, Morbach H, Tony HP, Schmalzing M. Autologous Stem Cell Transplantation in Common Variable Immunodeficiency: A Case of Successful Treatment of Severe Refractory Autoimmune Encephalitis. Front Immunol 2020; 11:1317. [PMID: 32670291 PMCID: PMC7330058 DOI: 10.3389/fimmu.2020.01317] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 05/26/2020] [Indexed: 12/22/2022] Open
Abstract
Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults. It is associated with hypogammaglobulinemia, recurring infections and autoimmune phenomena. Treatment includes immunoglobulin substitution and immunosuppressants. Autoimmune neurological manifestations of CVID are rare and occur predominantly as granulomatous disease. We report the case of a 35-year-old woman with CVID who developed autoimmune encephalitis as demonstrated by double cerebral biopsy. Infectious or malignant causes could be excluded. Despite intensive immunosuppressive therapy with common regimens no significant improvement could be achieved. Ultimately, an autologous hematopoietic stem cell transplantation (HSCT) was performed, resulting in lasting complete remission of the encephalitis. To our knowledge, this is the first report of refractory autoimmune phenomena in CVID treated by autologous HSCT.
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Affiliation(s)
- Matthias Froehlich
- Schwerpunkt Rheumatologie/Klinische Immunologie, Medizinische Klinik und Poliklinik II, Universität Würzburg, Würzburg, Germany
| | - Eva C Schwaneck
- Schwerpunkt Rheumatologie/Klinische Immunologie, Medizinische Klinik und Poliklinik II, Universität Würzburg, Würzburg, Germany
| | - Michael Gernert
- Schwerpunkt Rheumatologie/Klinische Immunologie, Medizinische Klinik und Poliklinik II, Universität Würzburg, Würzburg, Germany
| | - Ottar Gadeholt
- Rheumatologische Schwerpunktpraxis Würzburg, Würzburg, Germany
| | - Patrick-Pascal Strunz
- Schwerpunkt Rheumatologie/Klinische Immunologie, Medizinische Klinik und Poliklinik II, Universität Würzburg, Würzburg, Germany
| | - Henner Morbach
- Kinderklinik und Poliklinik, Universität Würzburg, Würzburg, Germany
| | - Hans-Peter Tony
- Schwerpunkt Rheumatologie/Klinische Immunologie, Medizinische Klinik und Poliklinik II, Universität Würzburg, Würzburg, Germany
| | - Marc Schmalzing
- Schwerpunkt Rheumatologie/Klinische Immunologie, Medizinische Klinik und Poliklinik II, Universität Würzburg, Würzburg, Germany
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Keller MD, Bollard CM. Virus-specific T-cell therapies for patients with primary immune deficiency. Blood 2020; 135:620-628. [PMID: 31942610 PMCID: PMC7046606 DOI: 10.1182/blood.2019000924] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 09/23/2019] [Indexed: 02/07/2023] Open
Abstract
Viral infections are common and are potentially life-threatening in patients with moderate to severe primary immunodeficiency disorders. Because T-cell immunity contributes to the control of many viral pathogens, adoptive immunotherapy with virus-specific T cells (VSTs) has been a logical and effective way of combating severe viral disease in immunocompromised patients in multiple phase 1 and 2 clinical trials. Common viral targets include cytomegalovirus, Epstein-Barr virus, and adenovirus, though recent published studies have successfully targeted additional pathogens, including HHV6, BK virus, and JC virus. Though most studies have used VSTs derived from allogenic stem cell donors, the use of banked VSTs derived from partially HLA-matched donors has shown efficacy in multicenter settings. Hence, this approach could shorten the time for patients to receive VST therapy thus improving accessibility. In this review, we discuss the usage of VSTs for patients with primary immunodeficiency disorders in clinical trials, as well as future potential targets and methods to broaden the applicability of virus-directed T-cell immunotherapy for this vulnerable patient population.
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Affiliation(s)
- Michael D Keller
- Center for Cancer and Immunology Research and
- Division of Allergy and Immunology, Children's National Health System, Washington, DC
- GW Cancer Center, George Washington University, Washington, DC; and
| | - Catherine M Bollard
- Center for Cancer and Immunology Research and
- GW Cancer Center, George Washington University, Washington, DC; and
- Division of Blood and Marrow Transplantation, Children's National Health System, Washington, DC
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43
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Dimitrova D, Gea-Banacloche J, Steinberg SM, Sadler JL, Hicks SN, Carroll E, Wilder JS, Parta M, Skeffington L, Hughes TE, Blau JE, Broadney MM, Rose JJ, Hsu AP, Fletcher R, Nunes NS, Yan XY, Telford WG, Kapoor V, Cohen JI, Freeman AF, Garabedian E, Holland SM, Lisco A, Malech HL, Notarangelo LD, Sereti I, Shah NN, Uzel G, Zerbe CS, Fowler DH, Gress RE, Kanakry CG, Kanakry JA. Prospective Study of a Novel, Radiation-Free, Reduced-Intensity Bone Marrow Transplantation Platform for Primary Immunodeficiency Diseases. Biol Blood Marrow Transplant 2020; 26:94-106. [PMID: 31493539 PMCID: PMC6942248 DOI: 10.1016/j.bbmt.2019.08.018] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 08/28/2019] [Accepted: 08/28/2019] [Indexed: 12/20/2022]
Abstract
Allogeneic blood or marrow transplantation (BMT) is a potentially curative therapy for patients with primary immunodeficiency (PID). Safe and effective reduced-intensity conditioning (RIC) approaches that are associated with low toxicity, use alternative donors, and afford good immune reconstitution are needed to advance the field. Twenty PID patients, ranging in age from 4 to 58 years, were treated on a prospective clinical trial of a novel, radiation-free and serotherapy-free RIC, T-cell-replete BMT approach using pentostatin, low-dose cyclophosphamide, and busulfan for conditioning with post-transplantation cyclophosphamide-based graft-versus-host-disease (GVHD) prophylaxis. This was a high-risk cohort with a median hematopoietic cell transplantation comorbidity index of 3. With median follow-up of survivors of 1.9 years, 1-year overall survival was 90% and grade III to IV acute GVHD-free, graft-failure-free survival was 80% at day +180. Graft failure incidence was 10%. Split chimerism was frequently observed at early post-BMT timepoints, with a lower percentage of donor T cells, which gradually increased by day +60. The cumulative incidences of grade II to IV and grade III to IV acute GVHD (aGVHD) were 15% and 5%, respectively. All aGVHD was steroid responsive. No patients developed chronic GVHD. Few significant organ toxicities were observed. Evidence of phenotype reversal was observed for all engrafted patients, even those with significantly mixed chimerism (n = 2) or with unknown underlying genetic defect (n = 3). All 6 patients with pre-BMT malignancies or lymphoproliferative disorders remain in remission. Most patients have discontinued immunoglobulin replacement. All survivors are off immunosuppression for GVHD prophylaxis or treatment. This novel RIC BMT approach for patients with PID has yielded promising results, even for high-risk patients.
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Affiliation(s)
- Dimana Dimitrova
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | | | - Seth M Steinberg
- Biostatistics and Data Management Section, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland
| | - Jennifer L Sadler
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Stephanie N Hicks
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Ellen Carroll
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Jennifer S Wilder
- Clinical Research Directorate/Clinical Monitoring Research Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Bethesda, Maryland
| | - Mark Parta
- Clinical Research Directorate/Clinical Monitoring Research Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Bethesda, Maryland
| | - Lauren Skeffington
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Thomas E Hughes
- National Institutes of Health Clinical Center, Bethesda, Maryland
| | - Jenny E Blau
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Miranda M Broadney
- Section on Growth and Obesity, Program in Endocrinology, Metabolism and Genetics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
| | - Jeremy J Rose
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Amy P Hsu
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland
| | - Rochelle Fletcher
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Natalia S Nunes
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Xiao-Yi Yan
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - William G Telford
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Veena Kapoor
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Jeffrey I Cohen
- Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Alexandra F Freeman
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland
| | - Elizabeth Garabedian
- Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
| | - Steven M Holland
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland
| | - Andrea Lisco
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Harry L Malech
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland
| | - Luigi D Notarangelo
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland
| | - Irini Sereti
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Nirali N Shah
- Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Gulbu Uzel
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland
| | - Christa S Zerbe
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland
| | - Daniel H Fowler
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Ronald E Gress
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Christopher G Kanakry
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Jennifer A Kanakry
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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44
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Güngör T, Chiesa R. Cellular Therapies in Chronic Granulomatous Disease. Front Pediatr 2020; 8:327. [PMID: 32676488 PMCID: PMC7333593 DOI: 10.3389/fped.2020.00327] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 05/19/2020] [Indexed: 01/30/2023] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) has become the main curative treatment in patients with chronic granulomatous disease (CGD). CGD is caused by inherited defects of the phagolysomal NADPH-oxidase, leading to a lifelong propensity for invasive infections and granulomatous inflammation. After successful allogeneic HSCT, chronic infections and inflammation resolve and quality-of-life improves. Favorable long-term outcome after HSCT is dependent on the prevention of primary and secondary graft failure (GF), including falling myeloid donor chimerism (DC) below 10 %, and chronic graft-vs.-host-disease (cGVHD). The risk of GF and GvHD increases with the use of HLA-incompatible donors and this may outweigh the benefits of HSCT, mainly in patients with severe co-morbidities and in asymptomatic patients with residual NADPH-oxidase function. Seventeen scientific papers have reported on a total of 386 CGD-patients treated by HSCT with HLA-matched family/sibling (MFD/MSD), 9/10-/10/10-matched-unrelated volunteer (MUD) and cord blood donors. The median OS/EFS-rate of these 17 studies was 91 and 82%, respectively. The median rates of GF, cGVHD and de-novo autoimmune diseases were 14, 10, and 12%, respectively. Results after MFD/MSD and 10/10-MUD-transplants were rather similar, but outcome in adults with significant co-morbidities and after transplants with 9/10 HLA-MUD were less successful, mainly due to increased GF and chronic GVHD. Transplantation protocols using T-cell depleted haploidentical donors with post-transplant cyclophosphamide or TCR-alpha/beta depletion have recently reported promising results. Autologous gene-therapy after lentiviral transduction of HSC achieved OS/EFS-rates of 78/67%, respectively. Careful retrospective and prospective studies are mandatory to ascertain the most effective cellular therapies in patients with CGD.
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Affiliation(s)
- Tayfun Güngör
- Department of Immunology, Hematology, Oncology and Stem Cell Transplantation, University Children's Hospital Zürich, Zurich, Switzerland
| | - Robert Chiesa
- Department of Bone Marrow Transplantation, Great Ormond Street Hospital for Sick Children, London, United Kingdom
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45
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Lum SH, Hoenig M, Gennery AR, Slatter MA. Conditioning Regimens for Hematopoietic Cell Transplantation in Primary Immunodeficiency. Curr Allergy Asthma Rep 2019; 19:52. [PMID: 31741098 PMCID: PMC6861349 DOI: 10.1007/s11882-019-0883-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
PURPOSE OF REVIEW Hematopoietic cell transplantation (HCT) is an established curative treatment for children with primary immunodeficiencies. This article reviews the latest developments in conditioning regimens for primary immunodeficiency (PID). It focuses on data regarding transplant outcomes according to newer reduced toxicity conditioning regimens used in HCT for PID. RECENT FINDINGS Conventional myeloablative conditioning regimens are associated with significant acute toxicities, transplant-related mortality, and late effects such as infertility. Reduced toxicity conditioning regimens have had significant positive impacts on HCT outcome, and there are now well-established strategies in children with PID. Treosulfan has emerged as a promising preparative agent. Use of a peripheral stem cell source has been shown to be associated with better donor chimerism in patients receiving reduced toxicity conditioning. Minimal conditioning regimens using monoclonal antibodies are in clinical trials with promising results thus far. Reduced toxicity conditioning has emerged as standard of care for PID and has resulted in improved transplant survival for patients with significant comorbidities.
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Affiliation(s)
- S H Lum
- Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle upon Tyne, UK
| | - M Hoenig
- Department of Pediatrics, University Medical Center Ulm, Ulm, Germany
| | - A R Gennery
- Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle upon Tyne, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - M A Slatter
- Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle upon Tyne, UK.
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
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46
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Wu J, Zhong W, Yin Y, Zhang H. Primary immunodeficiency disease: a retrospective study of 112 Chinese children in a single tertiary care center. BMC Pediatr 2019; 19:410. [PMID: 31684895 PMCID: PMC6829960 DOI: 10.1186/s12887-019-1729-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Accepted: 09/20/2019] [Indexed: 02/06/2023] Open
Abstract
Background Primary immunodeficiency disease (PID) is a disorder caused by an inherited flaw in the immune system that increases the susceptibility to infections. Methods In this study, 112 children with PID were diagnosed and classified based on the 2017 criteria presented by the International Union of Immunological Societies (IUIC) in a single tertiary care center from January 2013 to November 2018. We retrospectively studied the clinical features of those PID children and followed-up them as well. Results It was revealed that male/female ratio was 6:1. The most frequent diagnosed PID was severe combined immunodeficiency (SCID) (28.6%) and hyper-IgM (HIGM) syndrome (24.1%), followed by predominantly antibody deficiencies (17.8%). Combined immunodeficiencies with associated or syndromic features (12.5%) and congenital defects of phagocyte number, function, or both (10.7%) were less common in our center compared with SCID and HIGM syndrome. Besides, we found that 20 children (17.8%) had a positive family history of PID, and almost all cases (97.3%) had a history of recurrent infection. Recurrent respiratory tract infection was among the most common symptoms, followed by the bacterial infection of the skin and mucous membranes and diarrhea. Additionally, adverse event following immunization (AEFI) was found in 20.5% of the patients, and immune disorder was commonly observed in PID patients. In the present study, 47 patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), and 2-year overall survival (OS) rate for these patients was 78.7% (37/47). It is noteworthy that OS widely differed among PID patients with different phenotypes who underwent allo-HSCT. The 2-year OS rate for SCID, HIGM syndrome, and the remaining of PID patients who underwent allo-HSCT was 14.3, 83.3, and 100%, respectively. Conclusions PID typically emerges at early age. Recurrent infection and serious infection were the most common clinical manifestations. Allo-HSCT is a relatively effective therapeutic strategy for PID patients.
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Affiliation(s)
- Jinhong Wu
- Department of Pulmonary, Shanghai Children's Medical Center Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China
| | - Wenwei Zhong
- Department of Pulmonary, Shanghai Children's Medical Center Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China
| | - Yong Yin
- Department of Pulmonary, Shanghai Children's Medical Center Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China
| | - Hao Zhang
- Department of Pulmonary, Shanghai Children's Medical Center Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China.
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47
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Herber M, Mertz P, Dieudonné Y, Guffroy B, Jung S, Gies V, Korganow AS, Guffroy A. Primary immunodeficiencies and lymphoma: a systematic review of literature. Leuk Lymphoma 2019; 61:274-284. [DOI: 10.1080/10428194.2019.1672056] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Mathilde Herber
- Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France
| | - Philippe Mertz
- Department of Rheumatology, National Reference Center for Systemic Autoimmune Diseases (RESO), Strasbourg University Hospital, Strasbourg, France
| | - Yannick Dieudonné
- Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France
| | - Blandine Guffroy
- Department of Onco-Hematology, Strasbourg University Hospital, Strasbourg, France
- UFR Médecine, Université de Strasbourg, Strasbourg, France
| | - Sophie Jung
- Faculty of Dentistry, Strasbourg University - Reference Center for Oral Rare Diseases (O-Rares), Strasbourg University Hospital, Strasbourg, France
- INSERM UMR - S1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg University, Strasbourg, France
| | - Vincent Gies
- Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France
- INSERM UMR - S1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg University, Strasbourg, France
- UFR Sciences Pharmaceutiques, Université de Strasbourg, Strasbourg, France
| | - Anne-Sophie Korganow
- Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France
- UFR Médecine, Université de Strasbourg, Strasbourg, France
- INSERM UMR - S1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg University, Strasbourg, France
| | - Aurélien Guffroy
- Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France
- UFR Médecine, Université de Strasbourg, Strasbourg, France
- INSERM UMR - S1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg University, Strasbourg, France
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48
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Leavis H, Zwerina J, Manger B, Fritsch-Stork RDE. Novel Developments in Primary Immunodeficiencies (PID)-a Rheumatological Perspective. Curr Rheumatol Rep 2019; 21:55. [PMID: 31486986 DOI: 10.1007/s11926-019-0854-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW The purpose of this review is to provide an overview of the most relevant new disorders, disease entities, or disease phenotypes of primary immune deficiency disorders (PID) for the interested rheumatologist, using the new phenotypic classification by the IUIS (International Union of Immunological Societies) as practical guide. RECENT FINDINGS Newly recognized disorders of immune dysregulation with underlying mutations in genes pertaining to the function of regulatory T cells (e.g., CTLA-4, LRBA, or BACH2) are characterized by multiple autoimmune diseases-mostly autoimmune cytopenia-combined with an increased susceptibility to infections due to hypogammaglobulinemia. On the other hand, new mutations (e.g., in NF-kB1, PI3Kδ, PI3KR1, PKCδ) leading to the clinical picture of CVID (common variable immmune deficiency) have been shown to increasingly associate with autoimmune diseases. The mutual association of autoimmune diseases with PID warrants increased awareness of immunodeficiencies when diagnosing autoimmune diseases with a possible need to initiate appropriate genetic tests.
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Affiliation(s)
- Helen Leavis
- Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Jochen Zwerina
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Heinrich Collingasse 30, A-1140, Wien, Austria
| | - Bernhard Manger
- Department of Internal Medicine 3, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlange-Nürnberg, Erlangen, Germany
| | - Ruth D E Fritsch-Stork
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Heinrich Collingasse 30, A-1140, Wien, Austria. .,Sigmund Freud University, Vienna, Austria.
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49
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Gavrilova T. Considerations for hematopoietic stem cell transplantation in primary immunodeficiency disorders. World J Transplant 2019; 9:48-57. [PMID: 31392129 PMCID: PMC6682495 DOI: 10.5500/wjt.v9.i3.48] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 07/10/2019] [Accepted: 07/17/2019] [Indexed: 02/05/2023] Open
Abstract
Primary immunodeficiency disorders (PIDs) result from inborn errors in immunity. Susceptibility to infections and oftentimes severe autoimmunity pose life-threatening risks to patients with these disorders. Hematopoietic cell transplant (HCT) remains the only curative option for many. Severe combined immunodeficiency disorders (SCID) most commonly present at the time of birth and typically require emergent HCT in the first few weeks of life. HCT poses an unusual challenge for PIDs. Donor source and conditioning regimen often impact the outcome of immune reconstitution after HCT in PIDs. The use of matched or unmatched, as well as related versus unrelated donor has resulted in variable outcomes for different subsets of PIDs. Additionally, there is significant variability in the success of engraftment even for a single patient’s lymphocyte subpopulations. While certain cell lines do well without a conditioning regimen, others will not reconstitute unless conditioning is used. The decision to proceed with a conditioning regimen in an already immunocompromised host is further complicated by the fact that alkylating agents should be avoided in radiosensitive PIDs. This manuscript reviews some of the unique elements of HCT in PIDs and evidence-based approaches to transplant in patients with these rare and challenging disorders.
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Affiliation(s)
- Tatyana Gavrilova
- Division of Allergy and Immunology, Montefiore Medical Center, Bronx, NY 10461, United States
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50
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Vakkilainen S, Taskinen M, Klemetti P, Pukkala E, Mäkitie O. A 30-Year Prospective Follow-Up Study Reveals Risk Factors for Early Death in Cartilage-Hair Hypoplasia. Front Immunol 2019; 10:1581. [PMID: 31379817 PMCID: PMC6646460 DOI: 10.3389/fimmu.2019.01581] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 06/25/2019] [Indexed: 12/21/2022] Open
Abstract
Cartilage-hair hypoplasia (CHH) is a skeletal dysplasia with combined immunodeficiency, variable clinical course and increased risk of malignancy. Management of CHH is complicated by a paucity of long-term follow-up data, as well as knowledge on prognostic factors. We assessed clinical course and risk factors for mortality in a prospective cohort study of 80 patients with CHH recruited in 1985-1991 and followed up until 2016. For all patients we collected additional health information from health records and from the national Medical Databases and Cause-of-death Registry. The primary outcome was immunodeficiency-related death, including death from infections, lung disease and malignancy. Standardized mortality ratios (SMRs) were calculated using national mortality rates as reference. Half of the patients (57%, n = 46) manifested no symptoms of immunodeficiency during follow-up while 19% (n = 15) and 24% (n = 19) demonstrated symptoms of humoral or combined immunodeficiency, including six cases of adult-onset immunodeficiency. In a significant proportion of patients (17/79, 22%), clinical features of immunodeficiency progressed over time. Of the 15 patients with non-skin cancer, eight had no preceding clinical symptoms of immunodeficiency. Altogether 20 patients had deceased (SMR = 7.0, 95%CI = 4.3-11); most commonly from malignancy (n = 7, SMR = 10, 95%CI = 4.1-21) and lung disease (n = 4, SMR = 46, 95%CI = 9.5-130). Mortality associated with birth length below -4 standard deviation (compared to normal, SMR/SMR ratio = 5.4, 95%CI = 1.5-20), symptoms of combined immunodeficiency (compared to asymptomatic, SMR/SMR ratio = 3.9, 95%CI = 1.3-11), Hirschsprung disease (odds ratio (OR) 7.2, 95%CI = 1.04-55), pneumonia in the first year of life or recurrently in adulthood (OR = 7.6/19, 95%CI = 1.3-43/2.6-140) and autoimmunity in adulthood (OR = 39, 95%CI = 3.5-430). In conclusion, patients with CHH may develop adult-onset immunodeficiency or malignancy without preceding clinical symptoms of immune defect, warranting careful follow-up. Variable disease course and risk factors for mortality should be acknowledged.
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Affiliation(s)
- Svetlana Vakkilainen
- Pediatric Research Center, Children's Hospital, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland.,Folkhälsan Research Center, Institute of Genetics, Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Mervi Taskinen
- Pediatric Research Center, Children's Hospital, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland
| | - Paula Klemetti
- Pediatric Research Center, Children's Hospital, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland
| | - Eero Pukkala
- Faculty of Social Sciences, Tampere University, Tampere, Finland
| | - Outi Mäkitie
- Pediatric Research Center, Children's Hospital, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland.,Folkhälsan Research Center, Institute of Genetics, Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Molecular Medicine and Surgery, Karolinska Institutet, Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.,Department of Clinical Genetics, HUSLAB, Helsinki University Hospital, Helsinki, Finland
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