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1.
J Allergy Clin Immunol ; 144(1): 280-293, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30731121

RESUMO

BACKGROUND: Mismatched stem cell transplantation is associated with a high risk of graft loss, graft-versus-host disease (GvHD), and transplant-related mortality. Alternative graft manipulation strategies have been used over the last 11 years to reduce these risks. OBJECTIVE: We investigated the outcome of using different graft manipulation strategies among children with primary immunodeficiencies. METHODS: Between 2006 and 2017, 147 patients with primary immunodeficiencies received 155 mismatched grafts: 30 T-cell receptor (TCR) αß/CD19-depleted grafts, 43 cord blood (CB) grafts (72% with no serotherapy), 17 CD34+ selection with T-cell add-back grafts, and 65 unmanipulated grafts. RESULTS: The estimated 8-year survival of the entire cohort was 79%, transplant-related mortality was 21.7%, and the graft failure rate was 6.7%. Posttransplantation viral reactivation, grade II to IV acute graft-versus-host disease (aGvHD), and chronic graft-versus-host disease (cGvHD) complicated 49.6%, 35%, and 15% of transplantations, respectively. Use of TCRαß/CD19 depletion was associated with a significantly lower incidence of grade II to IV aGvHD (11.5%) and cGvHD (0%), although with a greater incidence of viral reactivation (70%) in comparison with other grafts. T-cell immune reconstitution was robust among CB transplants, although with a high incidence (56.7%) of grade II to IV aGvHD. Stable full donor engraftment was significantly greater at 80% among TCRαß+/CD19+-depleted and CB transplants versus 40% to 60% among the other groups. CONCLUSIONS: Rapidly accessible CB and haploidentical grafts are suitable alternatives for patients with no HLA-matched donor. Cord transplantation without serotherapy and TCRαß+/CD19+-depleted grafts produced comparable survival rates of around 80%, although with a high rate of aGvHD with the former and a high risk of viral reactivation with the latter that need to be addressed.

3.
J Clin Immunol ; 36(5): 472-9, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27091141

RESUMO

INTRODUCTION: Patients with congenital agammaglobulinemia, characterized by a defect in B lymphocyte differentiation causing B alymphocytosis, require life-long IgG replacement. There is scant literature regarding the effectiveness of IgG treatment at preventing mucosal (particularly sinopulmonary tract) infection and whether current management adequately restores "normal" health and quality of life (QoL). We aimed to document infective episodes pre- and post-commencing IgG replacement, determine any change in lung function and structure and assess respiratory status and QoL in a cohort of patients treated in Newcastle. METHODS: Clinical data were extracted from medical records of 15 patients identified from the immunology database, focusing on infective episodes, serial chest CT and spirometry results. Thirteen patients completed a selection of standardized and validated questionnaires assessing physical health, respiratory health and QoL. RESULTS: Pediatric patients on IgG therapy suffered fewer infections per patient year (0.74) than adults (2.13). 6/14 patients showed deteriorating respiratory status despite adequate therapy. Health questionnaires revealed a significant burden of respiratory disease on a patient's life. CONCLUSION: Clinical data showed patients with congenital agammaglobulinemia receiving immunoglobulin therapy retained a higher than average infection rate, most of which affected mucosal barriers. Most patients self-reported worse respiratory symptoms, a lower respiratory-related QoL and a lower general health QoL relative to a healthy population. Most participants had progressive structural lung damage and decreased lung function. These results suggest that current management is not entirely effective at preventing deterioration of respiratory health or restoring QoL.


Assuntos
Agamaglobulinemia/epidemiologia , Linfócitos B/fisiologia , Doenças Genéticas Ligadas ao Cromossomo X/epidemiologia , Qualidade de Vida , Testes de Função Respiratória , Infecções Respiratórias/prevenção & controle , Adolescente , Adulto , Agamaglobulinemia/complicações , Agamaglobulinemia/terapia , Diferenciação Celular , Criança , Pré-Escolar , Estudos de Coortes , Gerenciamento Clínico , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Respiração , Infecções Respiratórias/etiologia , Inquéritos e Questionários , Reino Unido , Adulto Jovem
4.
Pediatr Blood Cancer ; 61(6): 1041-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24482108

RESUMO

OBJECTIVES: To describe the clinical profile and the prevalence of severe congenital neutropenia (SCN) and HAX1 mutations, so-called Kostmann syndrome, in France. STUDY DESIGN: Two pedigrees were identified from the French registry. RESULTS: The study included five subjects (three males), which represent 0.7% of the 759 SCN cases registered in France. The age at diagnosis was 0.3 years (range: 0.1-1.2 years) and the median age at the last follow-up was 7.3 years (range: 1.2-17.8 years). A novel large homozygous deletion of the HAX1 gene (exons 2-5) was found in one pedigree; while, a homozygous frameshift mutation was identified in exon 3 (c.430dupG, p.Val144fs) in the second pedigree. Severe bacterial infections were observed in four patients, including two cases of sepsis, one case of pancolitis, a lung abscess, and recurrent cellulitis and stomatitis. During routine follow-up, the median neutrophil value was 0.16 × 10(9)/L, associated with monocytosis (2 × 10(9)/L). Bone marrow (BM) smears revealed a decrease of the granulocytic lineage with no mature myeloid cells above the myelocytes. One patient died at age 2 from neurological complications, while two other patients, including one who underwent a hematopoietic stem cell transplantation (HSCT) at age 5, are living with very severe neurological retardation. CONCLUSIONS: SCN with HAX1 mutations, is a rare sub type of congenital neutropenia, mostly observed in population from Sweden and Asia minor, associating frequently neurological retardation, when the mutations involved the B isoform of the protein.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neutropenia/congênito , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Atrofia , Infecções Bacterianas/etiologia , Encéfalo/patologia , Criança , Pré-Escolar , Consanguinidade , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Grupos Étnicos/genética , Éxons/genética , Feminino , França , Genes Recessivos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Hospedeiro Imunocomprometido , Lactente , Deficiência Intelectual/genética , Masculino , Mutação de Sentido Incorreto , Mielopoese/genética , Mielopoese/fisiologia , Neutropenia/sangue , Neutropenia/genética , Neutropenia/patologia , Neutropenia/cirurgia , Paquistão/etnologia , Linhagem , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Deleção de Sequência
5.
Biol Blood Marrow Transplant ; 20(2): 243-9, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24225641

RESUMO

Cord blood transplantation (CBT) is curative for many primary immunodeficiencies (PIDs) but is associated with risks of viral infection and graft-versus-host disease (GvHD). Serotherapy reduces GvHD but potentially increases the risk of viral infection by delaying immune reconstitution. Because many PID patients have pre-existing viral infections, the optimal dose of serotherapy is unclear. We performed a retrospective analysis in 34 consecutive PID patients undergoing CBT and compared immune reconstitution, viral infection, GvHD, mortality, and long-term immune function between high-dose (n = 11) and low-dose (n = 9) serotherapy. Serotherapy dose had no effect on neutrophil engraftment. Median CD3(+) engraftment occurred at 92.5 and 97 days for high- and low-dose serotherapy, respectively. The low-dose serotherapy group had higher CD3(+), CD4(+), and early thymic emigrant counts at 4 months compared with the high-dose group. GvHD severity and number of viral infections did not differ between serotherapy doses. Survival from the transplantation process was 90.9% for high-dose and 100% for low-dose groups. In conclusion, low-dose serotherapy enhanced T cell reconstitution and thymopoiesis during the first year after CBT with no increase in GvHD.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Imunização Passiva/métodos , Transplante Homólogo/efeitos adversos , Adolescente , Adulto , Criança , Quimerismo , Feminino , Humanos , Síndromes de Imunodeficiência/etiologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
7.
Blood ; 117(16): 4367-75, 2011 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-21325599

RESUMO

Children with primary immunodeficiency diseases, particularly those less than 1 year of age, experience significant toxicity after hematopoietic stem cell transplantation, with busulfan- or melphalan-based conditioning. Treosulfan causes less veno-occlusive disease than busulfan and does not require pharmacokinetic monitoring. We report its use in 70 children. Children received 42 g/m(2) or 36 g/m(2) with cyclophosphamide 200 mg/kg (n = 30) or fludarabine 150 mg/m(2) (n = 40), with alemtuzumab in most. Median age at transplantation was 8.5 months (range, 1.2-175 months); 46 (66%) patients were 12 months of age or younger. Donors were as follows: matched sibling donor, 8; matched family donor, 13; haploidentical, 4; and unrelated, 45. Median follow-up was 19 months (range, 1-47 months). Overall survival was 81%, equivalent in those age less or greater than 1 year. Skin toxicity was common. Veno-occlusive disease occurred twice with cyclophosphamide. Eighteen patients (26%) had graft-versus-host disease, and only 7 (10%) greater than grade 2. Two patients rejected; 24 of 42 more than 1 year after transplantation had 100% donor chimerism. The remainder had stable mixed chimerism. T-cell chimerism was significantly better with fludarabine. Long-term follow-up is required, but in combination with fludarabine, treosulfan is a good choice of conditioning for hematopoietic stem cell transplantation in primary immunodeficiency disease.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Bussulfano/análogos & derivados , Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/cirurgia , Imunossupressores/uso terapêutico , Condicionamento Pré-Transplante/métodos , Adolescente , Antineoplásicos Alquilantes/efeitos adversos , Bussulfano/efeitos adversos , Bussulfano/uso terapêutico , Criança , Pré-Escolar , Quimerismo , Estudos de Coortes , Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Análise de Sobrevida , Reino Unido
9.
Pediatr Pulmonol ; 44(6): 622-4, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19431191

RESUMO

A female infant presented at birth with respiratory distress, which was subsequently shown to be secondary to lymphoid bronchiolitis, an exceptionally rare condition in childhood. Over the following 13 years there has been a slow progressive deterioration in her respiratory status with forced expiratory volume in 1 sec currently 40% predicted. Tests for connective tissue disease, infection, or immunodeficiency have all been negative and in the absence of any other explanation we postulate that this severe problem may have occurred as a consequence of an unrecognized intrauterine infection.


Assuntos
Bronquiolite/patologia , Doenças Pulmonares Intersticiais/patologia , Adolescente , Bronquiolite/congênito , Bronquiolite/diagnóstico , Criança , Pré-Escolar , Feminino , Humanos , Hiperplasia , Doenças Pulmonares Intersticiais/congênito , Doenças Pulmonares Intersticiais/diagnóstico , Tecido Linfoide/patologia , Espirometria
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