Publications by authors named "Andrew Gennery"

253 Publications

STAT3 Hyper-IgE Syndrome-an Update and Unanswered Questions.

J Clin Immunol 2021 May 1. Epub 2021 May 1.

Paediatric Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital (GNCH), Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.

The hyper-IgE syndromes (HIES) are a heterogeneous group of inborn errors of immunity sharing manifestations including increased infection susceptibility, eczema, and raised serum IgE. Since the prototypical HIES description 55 years ago, areas of significant progress have included description of key disease-causing genes and differentiation into clinically distinct entities. The first two patients reported had what is now understood to be HIES from dominant-negative mutations in signal transduction and activator of transcription 3 (STAT3-HIES), conferring a broad immune defect across both innate and acquired arms, as well as defects in skeletal, connective tissue, and vascular function, causing a clinical phenotype including eczema, staphylococcal and fungal skin and pulmonary infection, scoliosis and minimal trauma fractures, and vascular tortuosity and aneurysm. Due to the constitutionally expressed nature of STAT3, initial reports at treatment with allogeneic stem cell transplantation were not positive and treatment has hinged on aggressive antimicrobial prophylaxis and treatment to prevent the development of end-organ disease such as pneumatocele. Research into the pathophysiology of STAT3-HIES has driven understanding of the interface of several signaling pathways, including the JAK-STAT pathways, interleukins 6 and 17, and the role of Th17 lymphocytes, and has been expanded by identification of phenocopies such as mutations in IL6ST and ZNF341. In this review we summarize the published literature on STAT3-HIES, present the diverse clinical manifestations of this syndrome with current management strategies, and update on the uncertain role of stem cell transplantation for this disease. We outline key unanswered questions for further study.
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http://dx.doi.org/10.1007/s10875-021-01051-1DOI Listing
May 2021

Adenosine Deaminase Deficient SCID with Myocardial Hypertrophy.

J Clin Immunol 2021 Mar 11. Epub 2021 Mar 11.

Children's Health Ireland at Crumlin, Dublin, Ireland.

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http://dx.doi.org/10.1007/s10875-021-01018-2DOI Listing
March 2021

Thymopoiesis, Alterations in Dendritic Cells and Tregs, and Reduced T Cell Activation in Successful Extracorporeal Photopheresis Treatment of GVHD.

J Clin Immunol 2021 Mar 2. Epub 2021 Mar 2.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

Acute graft-versus-host disease (aGVHD) is a significant complication of allogeneic hematopoietic stem cell transplant (HSCT) and negatively affects T cell reconstitution. Extracorporeal photopheresis (ECP) reduces aGVHD, but the mechanisms remain incompletely understood. Our objective was to examine the impact of ECP on thymopoiesis in pediatric aGVHD and the mechanisms at a cellular and transcriptional level. Sixteen pediatric HSCT patients were recruited: 6 with ECP-treated aGVHD, 5 without aGVHD, and 5 with aGVHD treated with corticosteroids only. Thymopoiesis was evaluated by measuring naive T cells, TRECs, IL-7, and T cell receptor repertoire diversity. Regulatory T cell (Treg) enumeration and function and dendritic cell (DC) enumeration and phenotype were analyzed using flow cytometry. T cell transcriptome analysis was performed on ECP patients after treatment and responders pre- and post-treatment. Four ECP responders demonstrated thymic-dependent T cell recovery, and superior median naïve T cell numbers at 8 and 12 months post-HSCT compared to the aGVHD corticosteroid group. Increased Tregs and Treg suppressive function, reduced cDC/pDC and DC co-stimulatory marker expression in ECP responders suggest upregulated peripheral tolerance; these findings were not observed in partial responders. Responder post-ECP CD3+ T cell transcriptional profile demonstrated 3333 downregulated and 364 upregulated genes, with significant downregulation of ERRα and GαS pathways, and reduced expression of pro-inflammatory and adhesion proteins.Thymic function improves with successful ECP treatment. ECP reduces T cell activation and impacts peripheral tolerance via DCs and Tregs. Differences in thymic recovery, DC, and Treg cellular patterns and the T cell transcriptome were observed between ECP responders and partial responders and require further validation and investigation in additional patients.
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http://dx.doi.org/10.1007/s10875-021-00991-yDOI Listing
March 2021

Allogeneic hematopoietic stem cell transplantation in leukocyte adhesion deficiency type I and III.

Blood Adv 2021 01;5(1):262-273

Pediatric Hematology, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara, Turkey.

Type I and III leukocyte adhesion deficiencies (LADs) are primary immunodeficiency disorders resulting in early death due to infections and additional bleeding tendency in LAD-III. The curative treatment of LAD-I and LAD-III is allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this retrospective multicenter study, data were collected using the European Society for Blood and Marrow Transplantation registry; we analyzed data from 84 LAD patients from 33 centers, all receiving an allo-HSCT from 2007 to 2017. The 3-year overall survival estimate (95% confidence interval [CI]) was 83% (74-92) for the entire cohort: 84% (75-94) and 75% (50-100) for LAD-I and LAD-III, respectively. We observed cumulative incidences (95% CI) of graft failure (GF) at 3 years of 17% (9%-26%) and grade II to IV acute graft-versus-host disease (aGVHD) at 100 days of 24% (15%-34%). The estimate (95% CI) at 3 years for GF- and GVHD-II to IV-free survival as event-free survival (EFS) was 56% (46-69) for the entire cohort; 58% (46-72) and 56% (23-88) for LAD-I and LAD-III, respectively. Grade II to IV acute GVHD was a relevant risk factor for death (hazard ratio 3.6; 95% CI 1.4-9.1; P = .006). Patients' age at transplant ≥13 months, transplantation from a nonsibling donor, and any serological cytomegalovirus mismatch in donor-recipient pairs were significantly associated with severe acute GVHD and inferior EFS. The choice of busulfan- or treosulfan-based conditioning, type of GVHD prophylaxis, and serotherapy did not impact overall survival, EFS, or aGVHD. An intrinsic inflammatory component of LAD may contribute to inflammatory complications during allo-HSCT, thus providing the rationale for considering anti-inflammatory therapy pretreatment.
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http://dx.doi.org/10.1182/bloodadvances.2020002185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805328PMC
January 2021

Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome.

J Clin Immunol 2021 Feb 1. Epub 2021 Feb 1.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

Autosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor T17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.
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http://dx.doi.org/10.1007/s10875-021-00971-2DOI Listing
February 2021

BCG lymphadenitis: a potential complication of immune reconstitution following haematopoietic stem cell transplant.

Arch Dis Child Educ Pract Ed 2020 Dec 18. Epub 2020 Dec 18.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK.

Case reportAn MHC class II deficient 2-year-old boy presented with fever and an enlarging left neck mass 100 days post allogeneic haematopoietic stem cell transplant (HSCT). Fever persisted despite treatment with broad-spectrum β-lactam antibiotics. His BCG vaccination site at presentation was quiescent. Ultrasound showed enlarged cervical lymph nodes. An incisional biopsy of the large nodal mass yielded acid-fast bacilli, identified as by genome sequencing. Treatment with rifampicin, isoniazid and pyridoxine was started. The mass suppurated (figure 1), before healing concurrently with T-lymphocyte reconstitution at approximately day 130 post-HSCT.edpract;archdischild-2020-320883v1/F1F1F1Figure 1Suppurative BCG lymphadenitis following spontaneous rupture.BCG infection can complicate vaccination in patients with severe combined immunodeficiencies (SCID), including MHC II deficiency1 causing a spectrum ranging from simple adenitis to disseminated disease. BCG immune reconstitution inflammatory syndrome, typically presenting as localised adenitis ipsilateral to vaccination site, is well-described after commencing antiretroviral therapy for HIV and is recognised in patients post-HSCT.2 3 In this case, T-lymphocyte reconstitution restoring the T-lymphocyte mediated response in a previously BCG-vaccinated child is likely to have precipitated both this presentation and its resolution.Early identification of SCID though newborn screening might prevent vaccine administration to patients at risk of complications. QUESTIONS: How is MHC class II deficiency inherited?Autosomal dominantAutosomal recessiveX-linked recessiveMitochondrialWhat role do MHC class II molecules have in the immune response?Costimulation of naïve CD4+ T-helper lymphocytes to prevent anergyInitiation of immunoglobulin class-switch recombination in B-lymphocytesPresentation of antigen to naïve CD4+ T-lymphocytesPresentation of antigen to naïve CD8+ T-lymphocytesWhich method has been proposed for newborn screening for SCID in the UK?Absolute lymphocyte countDetection of T-lymphocyte receptor excision circles (TRECs)Tandem mass spectrometry to detect toxic metabolitesImmunoassay for CD3 and CD45Which is the most appropriate treatment for localised BCG disease in immunocompromised children?Rifampicin and isoniazidSurgical resectionSurgical resection and instillation of isoniazidRifampicin, isoniazid, ethambutol and pyrazinamideWhat common side-effect should patients receiving isoniazid be counselled for?Peripheral neuropathyIncreased seizure frequencyAcute kidney injuryChange in colour of urine
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http://dx.doi.org/10.1136/archdischild-2020-320883DOI Listing
December 2020

Transplantation for congenital heart disease is associated with an increased risk of Epstein-Barr virus-related post-transplant lymphoproliferative disorder in children.

J Heart Lung Transplant 2021 Jan 26;40(1):24-32. Epub 2020 Oct 26.

Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom; Department of Paediatric Haematology and Oncology, The Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust. Electronic address:

Background: Children undergoing heart transplant are at higher risk of developing post-transplant lymphoproliferative disorder (PTLD) than other solid organ recipients. The factors driving that risk are unclear. This study investigated risk factors for PTLD in children transplanted at 1 of 2 United Kingdom pediatric cardiac transplantation centers.

Methods: All children (<18 years, n = 200) transplanted at our institution over a 16-year period were analyzed. Freedom from PTLD was assessed using the Kaplan-Meier method and Cox proportional regression.

Results: PTLD occurred in 17 of 71 children transplanted for congenital heart disease (CHD) and 18 of 129 transplanted for acquired cardiomyopathy (ACM). The cumulative incidence of all PTLD was 21.1% at 5 years after transplant. Median time from transplant to PTLD was 2.9 years (interquartile range: 0.9-4.6). Negative Epstein-Barr virus (EBV) serostatus pre-transplant (adjusted hazard ratio [HR]: 2.7, 95% CI: 1.3-5.6, p = 0.01) and underlying CHD (adjusted HR: 3.2, 95% CI: 1.4-7.4, p = 0.007) were independently associated with higher risk of PTLD. Age at thymectomy was significantly different between children with CHD and ACM (0.4 vs 5.5 years, p < 0.01). Median CD4 and CD8 T lymphocyte counts at 2 years after transplant were significantly lower in children transplanted for CHD vs ACM (CD4: 391/µl vs 644/µl, p = 0.01; CD8: 382/µl vs 500/µl, p = 0.01). At 5 years after transplant, those differences persisted among patients who developed PTLD (CD4, 430/µl vs 963/µl, p < 0.01 and CD8, 367/µl vs 765/µl, p < 0.01).

Conclusion: Underlying CHD is an independent risk factor for PTLD and is associated with a younger age at thymectomy. A persistent association with altered T lymphocyte subsets may contribute to the impaired response to primary EBV infection and increase the risk of PTLD.
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http://dx.doi.org/10.1016/j.healun.2020.10.006DOI Listing
January 2021

HSCT is effective in patients with PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome.

J Allergy Clin Immunol 2020 Dec 15. Epub 2020 Dec 15.

Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

Background: Proline-serine-threonine phosphatase-interacting protein 1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a novel genetic disorder, causing hypercalprotectinemia and hyperzincemia with inflammatory complications accompanied by cytopenia. Immunosuppressive and/or anticytokine therapy is of limited effect.

Objectives: Because of cytokine production in nonhematopoietic tissues, the potential therapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) in autoinflammatory disorders, including PAMI syndrome, has remained uncertain.

Methods: Five patients with PAMI syndrome underwent allogeneic HSCT with myeloablative (4) or reduced-intensity (1) conditioning regimens. Lack of PAMI disease control served as indication for the HSCT in 4 patients and myelodysplastic syndrome development in 1.

Results: All 5 patients engrafted; however, 1 patient at day +13 developed hemophagocytic syndrome, followed by graft rejection at day +17. After 5.5 months, a second HSCT was performed from an alternative donor. A further patient at day +116 developed an intense inflammatory syndrome with significant serositis and severe mitral and aortic valve regurgitation, controlled with adalimumab, tacrolimus, and prednisone. No other noninfectious inflammatory episodes, or acute or chronic graft-versus-host disease, occurred in any patient. At the last follow-up (median, 2.2 years), all 5 patients have predominantly or complete donor chimerism and adequate immune recovery and are free of any PAMI symptoms.

Conclusions: Allogeneic HSCT seems to be an effective option to cure cytopenia and severe autoinflammation in PAMI syndrome and may be a curative option for other proline-serine-threonine phosphatase-interacting protein 1-associated inflammatory disorders with poor therapeutic control.
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http://dx.doi.org/10.1016/j.jaci.2020.11.043DOI Listing
December 2020

Managing Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency Disorders: e-GLILDnet International Clinicians Survey.

Front Immunol 2020 26;11:606333. Epub 2020 Nov 26.

UCL Respiratory, University College London, London, United Kingdom.

Background: Granulomatous-lymphocytic interstitial lung disease (GLILD) is a rare, potentially severe pulmonary complication of common variable immunodeficiency disorders (CVID). Informative clinical trials and consensus on management are lacking.

Aims: The European GLILD network (e-GLILDnet) aims to describe how GLILD is currently managed in clinical practice and to determine the main uncertainties and unmet needs regarding diagnosis, treatment and follow-up.

Methods: The e-GLILDnet collaborators developed and conducted an online survey facilitated by the European Society for Immunodeficiencies (ESID) and the European Respiratory Society (ERS) between February-April 2020. Results were analyzed using SPSS.

Results: One hundred and sixty-one responses from adult and pediatric pulmonologists and immunologists from 47 countries were analyzed. Respondents treated a median of 27 (interquartile range, IQR 82-maximum 500) CVID patients, of which a median of 5 (IQR 8-max 200) had GLILD. Most respondents experienced difficulties in establishing the diagnosis of GLILD and only 31 (19%) had access to a standardized protocol. There was little uniformity in diagnostic or therapeutic interventions. Fewer than 40% of respondents saw a definite need for biopsy in all cases or performed bronchoalveolar lavage for diagnostics. Sixty-six percent used glucocorticosteroids for remission-induction and 47% for maintenance therapy; azathioprine, rituximab and mycophenolate mofetil were the most frequently prescribed steroid-sparing agents. Pulmonary function tests were the preferred modality for monitoring patients during follow-up.

Conclusions: These data demonstrate an urgent need for clinical studies to provide more evidence for an international consensus regarding management of GLILD. These studies will need to address optimal procedures for definite diagnosis and a better understanding of the pathogenesis of GLILD in order to provide individualized treatment options. Non-availability of well-established standardized protocols risks endangering patients.
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http://dx.doi.org/10.3389/fimmu.2020.606333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726128PMC
November 2020

CD27-CD70 defects: a wolf in wolf's clothing?

Authors:
Andrew R Gennery

Blood 2020 12;136(23):2600-2602

Newcastle University.

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http://dx.doi.org/10.1182/blood.2020007763DOI Listing
December 2020

Improved survival and graft function in ex vivo T-cell depleted haploidentical hematopoietic cell transplantation for primary immunodeficiency.

Bone Marrow Transplant 2021 May 24;56(5):1200-1204. Epub 2020 Nov 24.

Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle upon Tyne, UK.

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http://dx.doi.org/10.1038/s41409-020-01152-2DOI Listing
May 2021

Outcome of Non-hematological Autoimmunity After Hematopoietic Cell Transplantation in Children with Primary Immunodeficiency.

J Clin Immunol 2021 Jan 3;41(1):171-184. Epub 2020 Nov 3.

Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital NHS Foundation Trust, Clinical Resource Building, Floor 4, Block 2, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.

Purpose: Knowledge of post-hematopoietic cell transplantation (HCT) non-hematological autoimmune disease (AD) is far from satisfactory.

Method: This multicenter retrospective study focuses on incidence, risk factors, and outcomes of post-HCT AD in 596 children with primary immunodeficiency (PID) who were transplanted from 2009 to 2018.

Results: The indications of HCT were severe combined immunodeficiency (SCID, n = 158, 27%) and non-SCID PID (n = 438, 73%). The median age at HCT was 2.3 years (range, 0.04 to 18.3 years). The 5-year overall survival for the entire cohort was 79% (95% cumulative incidence (CIN), 74-83%). The median follow-up of surviving patients was 4.3 years (0.08 to 14.7 years). The CIN of post-HCT AD was 3% (2-5%) at 1 year post-HCT, 7% (5-11%) at 5 years post-HCT, and 11% (7-17%) at 8 years post-HCT. The median onset of post-HCT AD was 2.2 years (0.12 to 9.6 years). Autoimmune thyroid disorder (n = 19, 62%) was the most common post-HCT AD, followed by neuromuscular disorders (n = 7, 22%) and rheumatological manifestations (n = 5, 16%). All patients but one required treatment for post-HCT AD. After multivariate analysis, age at transplant (p = 0.01) and T cell-depleted graft (p < 0.001) were significant predictors of post-HCT AD. None of the T cell-depleted graft recipients developed post-HCT AD. Patients with a lower CD3+ count at 6 months post-HCT had a significant higher incidence of post-HCT AD compared to disease controls. Graft-versus-host disease, viral infection, and donor chimerism had no association with post-HCT AD.

Conclusion: Post-HCT AD occurred in 11% at 8 years post-HCT and its occurrence was associated with older age at HCT and unmanipulated graft.
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http://dx.doi.org/10.1007/s10875-020-00895-3DOI Listing
January 2021

Diagnosis and management of severe combined immunodeficiency in Australia and New Zealand.

J Paediatr Child Health 2020 10;56(10):1508-1513

Department of Allergy and Immunology, The Royal Children's Hospital, Melbourne, Victoria, Australia.

This consensus document outlines the recommendations from the Australasian Society of Clinical Immunology and Allergy Transplantation and Primary Immunodeficiency group for the diagnosis and management of patients with severe combined immunodeficiency. It also provides a proposed framework for the early investigation, management and supportive care prior to haematopoietic stem cell transplantation.
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http://dx.doi.org/10.1111/jpc.15158DOI Listing
October 2020

Hematopoietic Stem Cell Transplantation Positively Affects the Natural History of Cancer in Nijmegen Breakage Syndrome.

Clin Cancer Res 2021 Jan 20;27(2):575-584. Epub 2020 Oct 20.

Research Unit Pediatric Hematology and Immunology, Division of Pediatric Hematology-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University Graz, Graz, Austria.

Purpose: Nijmegen breakage syndrome (NBS) is a DNA repair disorder with a high predisposition to hematologic malignancies.

Experimental Design: We describe the natural history of NBS, including cancer incidence, risk of death, and the potential effectiveness of hematopoietic stem cell transplantation (HSCT) in preventing both pathologies: malignancy and immunodeficiency.

Results: Among 241 patients with NBS enrolled in the study from 11 countries, 151 (63.0%) patients were diagnosed with cancer. Incidence rates for primary and secondary cancer, tumor characteristics, and risk factors affecting overall survival (OS) were estimated. The cumulative cancer incidence was 40.21% ± 3.5% and 77.78% ± 3.4% at 10 years and 20 years of follow-up, respectively. Most of the tumors = 95 (62.9%) were non-Hodgkin lymphomas. Overall, 20 (13.2%) secondary malignancies occurred at a median age of 18 (interquartile range, 13.7-21.5) years. The probability of 20-year overall survival (OS) for the whole cohort was 44.6% ± 4.5%. Patients who developed cancer had a shorter 20-year OS than those without malignancy (29.6% vs. 86.2%; < 10). A total of 49 patients with NBS underwent HSCT, including 14 patients transplanted before malignancy. Patients with NBS with diagnosed cancer who received HSCT had higher 20-year OS than those who did not (42.7% vs. 30.3%; = 0.038, respectively). In the group of patients who underwent preemptive transplantation, only 1 patient developed cancer, which is 6.7 times lower as compared with nontransplanted patients [incidence rate ratio 0.149 (95% confidence interval, 0.138-0.162); < 0.0001].

Conclusions: There is a beneficial effect of HSCT on the long-term survival of patients with NBS transplanted in their first complete remission of cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2574DOI Listing
January 2021

Hematopoietic Stem Cell Transplantation and Vasculopathy Associated With STAT3-Dominant-Negative Hyper-IgE Syndrome.

Front Pediatr 2020 10;8:575. Epub 2020 Sep 10.

Immunodeficiency Centre for Wales, University Hospital for Wales, Cardiff, United Kingdom.

Dominant negative mutations in the transcription-factor underlie the rare primary immunodeficiency Job's syndrome. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) has shown promise in correction of the underlying immunological defect, with one report suggesting HSCT can prevent development of wider connective tissue complications. Here, we report the case of a 26 year old male who developed an acute ST-elevation myocardial infarction due to coronary artery ectasia and thrombosis, occurring despite pediatric allogeneic HSCT for STAT3-HIES and a predicted 10-year conventional cardiovascular risk of 0.1%. Vasculopathy associated with STAT3-HIES may persist or arise following HSCT and can precipitate life-threatening complications. This has implications for counseling and vascular surveillance, and highlights the need for further studies to determine the risk, pathogenesis, and optimal management of the vasculopathy associated with STAT3-HIES.
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http://dx.doi.org/10.3389/fped.2020.00575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511721PMC
September 2020

Systematic Review of Primary Immunodeficiency Diseases in Malaysia: 1979-2020.

Front Immunol 2020 26;11:1923. Epub 2020 Aug 26.

Primary Immunodeficiency Diseases Group, Regenerative Medicine Cluster, Institut Perubatan and Pergigian Termaju, Universiti Sains Malaysia, Kepala Batas, Malaysia.

Primary immunodeficiency diseases (PIDs) are under-reported in Malaysia. The actual disease frequency of PID in this country is unknown due to the absence of a national patient registry for PID. This systematic review aimed to determine the prevalence rates of PID cases diagnosed and published in Malaysia from 1st of January 1979 until 1st of March 2020. It also aimed to describe the various types of PIDs reported in Malaysia. Following the development of a comprehensive search strategy, all published literature of PID cases from Malaysia was identified and collated. All cases that fulfilled the International Union of Immunological Societies (IUIS) classification diagnosis were included in the systematic review. Data were retrieved and collated into a proforma. A total of 4,838 articles were identified and screened, with 34 publications and 119 patients fulfilling the criteria and being included in the systematic review. The prevalence rate was 0.37 per 100,000 population. In accordance with the IUIS, the distribution of diagnostic classifications was immunodeficiencies affecting cellular and humoral immunities (36 patients, 30.3%), combined immunodeficiencies with associated or syndromic features (21 patients, 17.6%), predominant antibody deficiencies (24 patients, 20.2%), diseases of immune dysregulation (13 patients, 10.9%), congenital defects in phagocyte number or function (20 patients, 16.8%), defects in intrinsic and innate immunity (4 patients, 3.4%), and autoinflammatory disorders (1 patient, 0.8%). Parental consanguinity was 2.5%. Thirteen different gene mutations were available in 21.8% of the cases. PIDs are underdiagnosed and under-reported in Malaysia. Developing PID healthcare and a national patient registry is much needed to enhance the outcome of PID patient care.
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http://dx.doi.org/10.3389/fimmu.2020.01923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479198PMC
April 2021

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study.

J Allergy Clin Immunol 2021 Feb 24;147(2):520-531. Epub 2020 Sep 24.

Istituto Molecolare "A Nocivelli," Department of Experimental and Clinical Sciences, University of Brescia & Asst Spedali civili, Brescia, Italy.

Background: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense.

Objective: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2.

Methods: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI.

Results: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died.

Conclusions: This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.
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http://dx.doi.org/10.1016/j.jaci.2020.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832563PMC
February 2021

Long-term outcomes for adults with chronic granulomatous disease in the United Kingdom.

J Allergy Clin Immunol 2021 Mar 21;147(3):1104-1107. Epub 2020 Sep 21.

Department of Immunology, Royal Free London NHS Foundation Trust, London, United Kingdom; University College London Institute of Immunity and Transplantation, London, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.08.034DOI Listing
March 2021

UK national audit of extracorporeal photopheresis (ECP) in chronic graft versus host disease.

Leuk Lymphoma 2020 12 2;61(14):3511-3514. Epub 2020 Sep 2.

UK Photopheresis Society, Birmingham, Rotherham, Newcastle, Leeds, Sheffield, UK.

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http://dx.doi.org/10.1080/10428194.2020.1815015DOI Listing
December 2020

Guidelines on the use of irradiated blood components.

Br J Haematol 2020 12 18;191(5):704-724. Epub 2020 Aug 18.

Department of Clinical Nephrology and Transplantation, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

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http://dx.doi.org/10.1111/bjh.17015DOI Listing
December 2020

Update on DNA-Double Strand Break Repair Defects in Combined Primary Immunodeficiency.

Curr Allergy Asthma Rep 2020 07 9;20(10):57. Epub 2020 Jul 9.

Paediatric Immunology and Haematopoietic Stem Cell Transplantation, Great North Children's Hospital, Clinical Resource Building, Floor 4, Block 2, Newcastle upon Tyne, UK.

Purpose Of Review: The most serious DNA damage, DNA double strand breaks (DNA-dsb), leads to mutagenesis, carcinogenesis or apoptosis if left unrepaired. Non-homologous end joining (NHEJ) is the principle repair pathway employed by mammalian cells to repair DNA-dsb. Several proteins are involved in this pathway, defects in which can lead to human disease. This review updates on the most recent information available for the specific diseases associated with the pathway.

Recent Findings: A new member of the NHEJ pathway, PAXX, has been identified, although no human disease has been associated with it. The clinical phenotypes of Artemis, DNA ligase 4, Cernunnos-XLF and DNA-PKcs deficiency have been extended. The role of haematopoietic stem cell transplantation, following reduced intensity conditioning chemotherapy, for many of these diseases is being advanced. In the era of newborn screening, urgent genetic diagnosis is necessary to correctly target appropriate treatment for patients with DNA-dsb repair disorders.
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http://dx.doi.org/10.1007/s11882-020-00955-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347510PMC
July 2020

Progress in treating chronic granulomatous disease.

Authors:
Andrew R Gennery

Br J Haematol 2021 01 8;192(2):251-264. Epub 2020 Jul 8.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

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, gp91 , 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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http://dx.doi.org/10.1111/bjh.16939DOI Listing
January 2021

Hematopoietic cell transplantation in chronic granulomatous disease: a study of 712 children and adults.

Blood 2020 09;136(10):1201-1211

División of Pediatric Hematology and Oncology, Department of Pediatrics, Erciyes University, Kayseri, Turkey.

Chronic granulomatous disease (CGD) is a primary immunodeficiency resulting in life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (allo-HCT) can cure the disease, but the indication to transplant remains controversial. We performed a retrospective multicenter study of 712 patients with CGD who underwent allo-HCT transplantation from March 1993 through December 2018. We studied 635 children (aged <18 years) and 77 adults. Median follow-up was 45 months. Median age at transplantation was 7 years (range, 0.1-48.6). Kaplan-Meier estimates of overall survival (OS) and event-free survival (EFS) at 3 years were 85.7% and 75.8%, respectively. In multivariate analysis, older age was associated with reduced survival and increased chronic graft-versus-host disease. Nevertheless, OS and EFS at 3 years for patients ≥18 years were 76% and 69%, respectively. Use of 1-antigen-mismatched donors was associated with reduced OS and EFS . No significant difference was found in OS, but a significantly reduced EFS was noted in the small group of patients who received a transplant from a donor with a >1 antigen mismatch. Choice of conditioning regimen did not influence OS or EFS. In summary, we report an excellent outcome after allo-HCT in CGD, with low incidence of graft failure and mortality in all ages. Older patients and recipients of 1-antigen-mismatched grafts had a less favorable outcome. Transplantation should be strongly considered at a younger age and particularly in the presence of a well-matched donor.
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http://dx.doi.org/10.1182/blood.2020005590DOI Listing
September 2020

New insights into risk factors for transplant-associated thrombotic microangiopathy in pediatric HSCT.

Blood Adv 2020 06;4(11):2418-2429

Department of Blood and Marrow Transplantation, Great Ormond Street (GOS) Hospital for Children NHS Foundation Trust, University College London GOS Institute of Child Health, and NIHR GOSH BRC, London, United Kingdom.

This study aimed to identify a risk profile for development of transplant-associated thrombotic microangiopathy (TA-TMA) in children undergoing hematopoietic stem cell transplantation (HSCT). Between 2013 and 2016, 439 children underwent 474 HSCTs at 2 supraregional United Kingdom centers. At a median of 153 days post-HSCT, TA-TMA occurred among 25 of 441 evaluable cases (5.6%) with no evidence of center variation. Sex, underlying disease, intensity of the conditioning, total body irradiation-based conditioning, the use of calcineurin inhibitors, venoocclusive disease, and viral reactivation did not influence the development of TA-TMA. Donor type: matched sibling donor/matched family donor vs matched unrelated donor vs mismatched unrelated donor/haplo-HSCT, showed a trend toward the development of TA-TMA in 1.8% vs 6.1% vs 8.3%, respectively. Presence of active comorbidity was associated with an increased risk for TA-TMA; 13% vs 3.7% in the absence of comorbidity. The risk of TA-TMA was threefold higher among patients who received >1 transplant. TA-TMA rates were significantly higher among patients with acute graft-versus-host disease (aGVHD) grades III to IV vs aGVHD grade 0 to II. On multivariate analysis, the presence of active comorbidity, >1 transplant, aGVHD grade III to IV were risk factors for TA-TMA (odds ratio [OR]: 5.1, 5.2, and 26.9; respectively), whereas the use of cyclosporine A/tacrolimus-based GVHD prophylaxis was not a risk factor for TA-TMA (OR: 0.3). Active comorbidity, subsequent transplant, and aGVHD grades III to IV were significant risk factors for TA-TMA. TA-TMA might represent a form of a vascular GVHD, and therefore, continuing control of aGVHD is important to prevent worsening of TA-TMA associated with GVHD.
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http://dx.doi.org/10.1182/bloodadvances.2019001315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284098PMC
June 2020

Outcome of autoimmune cytopenia after hematopoietic cell transplantation in primary immunodeficiency.

J Allergy Clin Immunol 2020 08 19;146(2):406-416. Epub 2020 May 19.

Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom; Translational and Clinical Research Institute, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom.

Background: Post hematopoietic cell transplantation (HCT) autoimmune cytopenia (AIC) is a potentially life-threatening complication, but studies focusing on large cohorts of patients transplanted for primary immunodeficiency are lacking.

Objectives: This study sought to determine the incidence, risk factors, and outcomes of post-HCT AIC and B-lymphocyte function following rituximab.

Methods: We retrospectively studied 502 children with primary immunodeficiency who were transplanted at our center between 1987 and 2018.

Results: Thirty-six patients (9%) developed post-HCT AIC, with a median onset of 6.5 months post-HCT. On univariate analysis, pre-HCT AIC, mismatched donor, alemtuzumab, anti-thymocyte antiglobulin, and acute and chronic graft versus host disease were significantly associated with post-HCT AIC. After multivariate analysis, alemtuzumab (subdistribution hazard ratio, 9.0; 95% CI, 1.50-54.0; P = .02) was independently associated with post-HCT AIC. Corticosteroid and high-dose intravenous immunoglobulin achieved remission in 50% (n = 18), additional rituximab led to remission in 25% (n = 9), and the remaining 25% were treated with a combination of various modalities including sirolimus (n = 5), bortezomib (n = 3), mycophenolate mofetil (n = 2), splenectomy (n = 2), and second HCT (n = 3). The mortality of post-HCT AIC reduced from 25% (4 of 16) prior to 2011 to 5% (1 of 20) after 2011. The median follow-up of 5.8 years (range, 0.4 to 29.1 years) showed that 26 of 30 survivors (87%) were in complete remission, and 4 were in remission with ongoing sirolimus and low-dose steroids. Of the 17 who received rituximab, 7 had B-lymphocyte recovery, 5 had persistent low B-lymphocyte count and remained on intravenous immunoglobulin replacement, 2 had second HCT, and 3 died.

Conclusions: The frequency of post HCT AIC in our cohort was 9%, and the most significant risk factors for its occurrence were the presence of graft versus host disease and the use of alemtuzumab.
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http://dx.doi.org/10.1016/j.jaci.2020.04.053DOI Listing
August 2020

Targeted busulfan-based reduced-intensity conditioning and HLA-matched HSCT cure hemophagocytic lymphohistiocytosis.

Blood Adv 2020 05;4(9):1998-2010

Department of Immunology. Hematology, Oncology and SCT, University Children's Hospital, Zurich, Switzerland.

Reduced-intensity/reduced-toxicity conditioning and allogeneic T-cell replete hematopoietic stem cell transplantation are curative in patients with hemophagocytic lymphohistiocytosis (HLH). Unstable donor chimerism (DC) and relapses are clinical challenges . We examined the effect of a reduced-intensity conditioning regimen based on targeted busulfan to enhance myeloid DC in HLH. The European Society for Bone and Marrow Transplantation-approved reduced-intensity conditioning protocol comprised targeted submyeloablative IV busulfan, IV fludarabine, and serotherapy comprising IV alemtuzumab (0.5-0.8 mg/kg) for unrelated-donor and IV rabbit anti-T-cell globulin for related-donor transplants. We assessed toxicity, engraftment, graft-versus-host disease (GHVD), DC in blood cell subtypes, and overall survival/event-free survival. Twenty-five patients from 7 centers were treated (median age, 0.68 year). The median total dose and cumulative area under the curve of busulfan was 13.1 mg/kg (6.4-26.4) and 63.1 mg/L × h (48-77), respectively. Bone marrow, peripheral blood stem cell, or cord blood transplants from HLA-matched related (n = 7) or unrelated (n = 18) donors were administered. Donor cells engrafted in all patients (median: neutrophils d+20/platelets d+28). At last follow-up (median, 36 months; range, 8-111 months), the median DC of CD15+ neutrophils, CD3+ T cells, and CD16+56+ natural killer cells was 99.5% (10-100), 97% (30-100), and 97.5% (30-100), respectively. Eight patients (32%) developed sinusoidal obstruction syndrome, resolving after defibrotide treatment. The 3-year overall survival and event-free survival rates were both 100%. None of the patients developed acute grade III to IV GHVD. Limited chronic GVHD was encountered in 4%. This regimen achieves excellent results with stable DC in patients with HLH.
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http://dx.doi.org/10.1182/bloodadvances.2020001748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218427PMC
May 2020

Cutaneous barrier leakage and gut inflammation drive skin disease in Omenn syndrome.

J Allergy Clin Immunol 2020 11 18;146(5):1165-1179.e11. Epub 2020 Apr 18.

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Md.

Background: Severe early-onset erythroderma and gut inflammation, with massive tissue infiltration of oligoclonal activated T cells are the hallmark of Omenn syndrome (OS).

Objective: The impact of altered gut homeostasis in the cutaneous manifestations of OS remains to be clarified.

Methods: We analyzed a cohort of 15 patients with OS and the 129Sv/C57BL/6 knock-in Rag2 (Rag2) mouse model. Homing phenotypes of circulating lymphocytes were analyzed by flow cytometry. Inflammatory cytokines and chemokines were examined in the sera by ELISA and in skin biopsies by immunohistochemistry and in situ RNA hybridization. Experimental colitis was induced in mice by dextran sulfate sodium salt.

Results: We show that memory/activated T cells from patients with OS and from the Rag2 mouse model of OS abundantly express the skin homing receptors cutaneous lymphocyte associated antigen and CCR4 (Ccr4), associated with high levels of chemokine C-C motif ligands 17 and 22. Serum levels of LPS are also elevated. A broad T1/T2/T17 inflammatory signature is detected in the periphery and in the skin. Increased Tlr4 expression in the skin of Rag2 mice is associated with enhanced cutaneous inflammation on local and systemic administration of LPS. Likewise, boosting colitis in Rag2 mice results in increased frequency of Ccr4 splenic T cells and worsening of skin inflammation, as indicated by epidermal thickening, enhanced epithelial cell activation, and dermal infiltration by T1 effector T cells.

Conclusions: These results support the existence of an interplay between gut and skin that can sustain skin inflammation in OS.
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http://dx.doi.org/10.1016/j.jaci.2020.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649331PMC
November 2020

Neonatal thymectomy in children-accelerating the immunologic clock?

J Allergy Clin Immunol 2020 08 10;146(2):236-243. Epub 2020 Mar 10.

Paediatric Immunology and Haematopoietic Stem Cell Transplantation, Great North Childrens' Hospital, Newcastle upon Tyne, United Kingdom; Primary Immunodeficiency Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom. Electronic address:

The thymus is critical for central tolerance and diverse T-lymphocyte repertoire development, to provide lifelong defense against pathogens while maintaining self-tolerance. Peak thymic output occurs in utero, during infancy, and in early childhood, diminishing throughout life. Infants with congenital heart disease requiring sternotomy often undergo thymectomy to clear the surgical field. The long-term effects of early thymectomy are just being appreciated. Many patients remain asymptomatic despite immunologic findings mirroring those of immunosenescence. Few develop increased infection or lymphoreticular malignancy risk. When considering the effects of infant thymectomy, patients with partial DiGeorge syndrome or hypomorphic recombination-activating gene (RAG) mutations may be instructive. These patients are lymphocytopenic, with increased early-onset infection and autoimmunity risk that is not seen in most patients who underwent thymectomy during infancy. The thymic structure of patients with partial DiGeorge syndrome or hypomorphic RAG is abnormal, with disrupted architecture inclining to perturbation of central tolerance. Similar findings may be seen in patients with myasthenia gravis, although disrupted peripheral tolerance may play a greater role in autoimmunity development. In conclusion, thymectomy during infancy may increase future risk of infection or autoimmunity, with premature immunosenescence mediated through disruption of central and peripheral tolerance mechanisms initiated by early cessation or diminution of thymic output. Ideally, some thymic tissue should be preserved at the time of surgery.
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http://dx.doi.org/10.1016/j.jaci.2020.02.028DOI Listing
August 2020