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1.
Pediatr Allergy Immunol ; 30(3): 378-386, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30716179

RESUMO

BACKGROUND: Chronic granulomatous disease (CGD) is a rare disease in China, and very little large-scale studies have been conducted to date. We aimed to investigate the clinical and genetic features of CGD in Chinese pediatric patients. METHODS: Pediatric patients with CGD from Beijing Children's Hospital, Capital Medical University, China, were enrolled from January 2006 to December 2016. RESULTS: A total of 159 pediatric patients with CGD were enrolled. The median age of clinical onset was 1.4 months, and 73% (116/159) had clinical onset symptoms before the 1 year of age. The most common site of invasion was the lungs. The lymph nodes, liver, and skin were more frequently invaded in X-linked (XL) CGD patients than in autosomal recessive (AR) CGD patients (P < 0.05). Approximately 64% (92/144) of the pediatric patients suffered from abnormal response to BCG vaccination. The most frequent pathogens were Aspergillus and Mycobacterium tuberculosis. Gene analysis indicated that 132 cases (89%, 132/147) harbored CYBB pathogenic variants, 7 (5%, 7/147) carried CYBA pathogenic variants, 4 (3%, 4/147) had NCF1 pathogenic variants, and 4 (3%, 4/147) had NCF2 pathogenic variants. The overall mortality rate in this study was 43%, particularly the patients were males, with CYBB mutant and did not receive HSCT treatment. CONCLUSIONS: Chronic granulomatous disease is a rare disease affecting Chinese children; however, it is often diagnosed at a later age, and thus, the mortality rate is relatively high. The prevalence and the severity of disease in XL-CGD are higher than AR-CGD.


Assuntos
Doença Granulomatosa Crônica/diagnóstico , NADPH Oxidases/genética , Adolescente , Anti-Infecciosos/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Criança , Pré-Escolar , China , Feminino , Testes Genéticos/métodos , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/mortalidade , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Estudos Retrospectivos
2.
J Clin Pathol ; 71(5): 425-435, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28970295

RESUMO

BACKGROUND: Primary immunodeficiency disorders (PID) include a wide spectrum of inherited disorders characterised by functional abnormalities of one or more components of the immune system. Recent updates from the genomic data have contributed significantly to its better understanding with identification of new entities. Diagnosis is always challenging due to their variable clinical presentation. With the evolution of molecular diagnosis, many of these children are being diagnosed early and offered appropriate therapy. However, in developing countries, early diagnosis is still not being made: as a result these patients succumb to their disease. Autopsy data on PID is notably lacking in the literature with histopathological evaluation of PID being limited to rare case reports. OBJECTIVE: To analyse the clinical, immunologic (including mutational) and morphologic features at autopsy in 10 proven and suspected cases of primary immunodeficiency disorders diagnosed at our Institute over the past decade. METHODS: Study includes a detailed clinico-pathological analysis of 10 proven and suspected cases of primary immunodeficiency disorders. RESULTS: A varied spectrum of infectious and non-infectious complications were identified in these cases of which fungal infections were found to be more frequent compared with viral or bacterial infections. Rare and novel morphological findings, like granulomatous involvement of the heart in a patient with chronic granulomatous disease, systemic amyloidosis in a teenage girl with X-linked agammaglobulinemia, are highlighted which is distinctly lacking in the literature. CONCLUSIONS: The present study is perhaps the first autopsy series on PID. Even in the molecular era, such analysis is still important, as correlation of pathological features with clinical symptoms provides clues for a timely diagnosis and appropriate therapeutic intervention.


Assuntos
Amiloidose/patologia , Doença Granulomatosa Crônica/patologia , Hospedeiro Imunocomprometido , Síndromes de Imunodeficiência/patologia , Infecções Oportunistas/patologia , Amiloidose/genética , Amiloidose/imunologia , Amiloidose/mortalidade , Autopsia , Biópsia , Causas de Morte , Criança , Pré-Escolar , Análise Mutacional de DNA , Países em Desenvolvimento , Diagnóstico Precoce , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/imunologia , Doença Granulomatosa Crônica/mortalidade , Humanos , Imuno-Histoquímica , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/mortalidade , Índia , Lactente , Recém-Nascido , Masculino , Mutação , Infecções Oportunistas/genética , Infecções Oportunistas/imunologia , Infecções Oportunistas/mortalidade , Fenótipo , Valor Preditivo dos Testes , Prognóstico
3.
J Clin Immunol ; 37(6): 548-558, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28752258

RESUMO

PURPOSE: The purpose of this study was to evaluate engraftment and adverse events with a conditioning and prophylactic regimen intended to achieve high rates of engraftment with minimal graft-versus-host disease (GVHD) in allogeneic transplantation for chronic granulomatous disease in a single center. METHODS: Forty patients, 37 male, with chronic granulomatous disease were transplanted. Transplant products were matched sibling peripheral blood stem cells (PBSCs) in four and matched unrelated donor (MUD) bone marrow in three, and one patient received mismatched unrelated PBSCs. Thirty-two patients received MUD PBSCs. All patients received a conditioning regimen of busulfan/alemtuzumab (with low-dose total body irradiation for MUD recipients) with sirolimus graft-versus-host disease prophylaxis. RESULTS: Engraftment occured in 38/40 recipients (95%). Acute or chronic GVHD occurred in 18 (45%) and 5 (12.5%), respectively, with 6 episodes of grades III-IV and/or steroid refractory GVHD. Overall survival was 33/40 (82.5%) and event-free survival was 30/40 (80%). Successful engraftment was associated with myeloid and NK cell, but not CD3+ chimerism. Myeloid engraftment was greater than 70% in 30/32 recipients at mean follow-up of 3.4 years. Evidence of persistent immunodeficiency was not seen in successful transplants. Attempts to rescue failed or poorly functioning grafts were associated with unacceptable morbidity and mortality. CONCLUSIONS: A reduced-intensity allogeneic transplant protocol based on alemtuzumab and busulfan with sirolimus GVHD prophylaxis produced high rates of successful engraftment and minimal regimen-related toxicity. Prolonged clinical follow-up has confirmed its efficacy in ameliorating CGD-related disease. Outcomes were not acceptable with donor cell infusion rescue of cause with poor graft function.


Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas , Imunoglobulinas Intravenosas/uso terapêutico , Quimerismo , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/mortalidade , Histocompatibilidade , Humanos , Imunossupressores/uso terapêutico , Masculino , Estudos Prospectivos , Irmãos , Doadores de Tecidos , Condicionamento Pré-Transplante , Transplante Homólogo
4.
Clin Infect Dis ; 64(6): 767-775, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28362954

RESUMO

Background: Although prognosis of Chronic Granulomatous Disease (CGD) has greatly improved, few studies have focused on its long-term outcome. We studied the clinical course and sequelae of CGD patients diagnosed before age 16, at various adult time points. Method: Cross-sectional French nationwide retrospective study of patients screened through the National Reference Center for Primary Immunodeficiencies (CEREDIH) registry. Results: Eighty CGD patients (71 males [88.7%], 59 X-linked [73.7%], median age 23.9 years [minimum, 16.6; maximum, 59.9]) were included, Median ages at diagnosis and last follow-up were 2.52 and 23.9 years, respectively. Seven patients underwent hematopoietic stem cell transplantation. A total of 553 infections requiring hospitalization occurred in 2017 patient-years. The most common site of infection was pulmonary (31%). Aspergillus spp. (17%) and Staphylococcus aureus (10.7%) were the commonest pathogens. A total of 224 inflammatory episodes occurred in 71 patients, mainly digestive (50%). Their characteristics as well as their annual frequency did not vary before and after age 16. Main sequelae were a small adult height and weight and mild chronic restrictive respiratory failure. At age 16, only 53% of patients were in high school. After age 30 years, 9/13 patients were working. Ten patients died during adulthood. Conclusions: Adult CGD patients displayed similar characteristics and rates of severe infections and inflammatory episodes that those of childhood. The high rate of handicap has become a matter of medical and social consideration. Careful follow-up in centers of expertise is strongly recommended and an extended indication of curative treatment by HSCT should be considered.


Assuntos
Doença Granulomatosa Crônica/epidemiologia , Adolescente , Fatores Etários , Antibioticoprofilaxia , Autoimunidade , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/etiologia , Infecções Bacterianas/prevenção & controle , Criança , Pré-Escolar , Efeitos Psicossociais da Doença , Estudos Transversais , Feminino , França/epidemiologia , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/mortalidade , Humanos , Lactente , Recém-Nascido , Masculino , Micoses/tratamento farmacológico , Micoses/epidemiologia , Micoses/etiologia , Micoses/prevenção & controle , Fenótipo , Vigilância da População , Sistema de Registros , Estudos Retrospectivos , Análise de Sobrevida , Avaliação de Sintomas
5.
J Clin Immunol ; 36(7): 677-83, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27497975

RESUMO

INTRODUCTION: Chronic granulomatous disease (CGD) is a genetic disorder in which phagocyte dysfunction leads to recurrent infection. Persistent pulmonary infections sometimes require thoracic surgical intervention. We reviewed our 25-year experience to identify outcomes and prognostic factors associated with thoracic surgery in these patients. METHODS: A retrospective single-institution review of all patients with CGD from 1990 through 2015 was performed. Univariate analysis identified prognostic variables to include in a Cox model. Overall survival was estimated by the Kaplan-Meier method. RESULTS: We identified 258 patients who had 2221 admissions (both scheduled and emergent). During the period examined, 51 thoracic operations were performed in 13.6 % (35/258) of patients and 2.3 % (35/2221) of overall admissions. Patients undergoing surgery did not have statistically significant differences in disease genotype compared to those that did not require surgery. Pathogens were identified from 67 % (34/51) of specimens. Complications occurred in 27 % (14/51), including 10 % (5/51) with wound and 12 % (6/51) with pulmonary infections. Mortality at 30 and 90 days was 0 and 6 % (3/51), respectively. Overall survival probabilities were 75 and 62 % at 5- and 10-year follow-up (median potential follow-up: 16.5 years), respectively. Undergoing thoracic surgery was associated with an increased hazard ratio for death of 3.71 (p < 0.0001). Both chest wall resection and EBL > 500 mL were negative prognostic factors (p < 0.05). CONCLUSIONS: A minority of CGD patients required thoracic surgery for infections refractory to antibiotic or antifungal therapy. Patients who had these operations had significant morbidity and relatively poor long-term survival, particularly in the cases of chest wall resection or significant blood loss.


Assuntos
Doença Granulomatosa Crônica/cirurgia , Procedimentos Cirúrgicos Torácicos , Biomarcadores , Criança , Pré-Escolar , Comorbidade , Gerenciamento Clínico , Feminino , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/mortalidade , Humanos , Lactente , Masculino , Mutação , NADPH Oxidase 2/genética , Estudos Retrospectivos , Procedimentos Cirúrgicos Torácicos/métodos , Resultado do Tratamento
6.
Blood ; 128(3): 440-8, 2016 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-27216217

RESUMO

Chronic granulomatous disease (CGD) can be cured by allogeneic hemopoietic stem cell transplantation (HSCT). Complications include graft failure, graft-versus-host disease (GVHD), infection, and transplant-related mortality; therefore, reduced-intensity conditioning regimens are being used to improve outcomes. In this retrospective study, the aim was to determine the outcome of treosulfan-based conditioning in HSCT for pediatric patients with CGD. The following data were collected: risk features pre-HSCT, additional conditioning agents, donor type and stem cell source, toxicity, engraftment, GVHD, chimerism, viral reactivation, post-HSCT complications, length of follow-up, and outcome. Seventy patients (median age, 107 months; interquartile range [IQR], 46-232 months) from 16 centers worldwide were transplanted between 2006 and 2015. Ninety-one percent had high-risk features. Fifty-seven HLA-matched donors, 12 HLA-mismatched donors, and 1 CD3(+)TCR αß/CD19 depleted parental haploidentical transplants were performed. No major toxicity was reported. Median times to neutrophil and platelet engraftment were 17 (IQR, 15-35) and 16 (IQR, 13-50) days. At a median follow-up of 34 months (IQR, 13-102 months), the overall survival was 91.4%, and event-free survival was 81.4%. The cumulative incidence of acute grade III-IV GVHD was 12%. Nine patients developed chronic GVHD. When split cell chimerism was available, 95% or more myeloid donor chimerism was documented in 80% of surviving patients. Secondary graft failure occurred in 12% of patients. Treosulfan-containing conditioning regimens can be used safely in HSCT for children with CGD and high-risk clinical features, achieving excellent survival with high myeloid chimerism. Further studies are needed to compare with other regimens and evaluate the long-term outcome, particularly on fertility.


Assuntos
Bussulfano/análogos & derivados , Doença Granulomatosa Crônica , Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante/métodos , Doença Aguda , Adolescente , Adulto , Aloenxertos , Plaquetas/metabolismo , Bussulfano/administração & dosagem , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Sobrevivência de Enxerto/efeitos dos fármacos , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/mortalidade , Doença Granulomatosa Crônica/sangue , Doença Granulomatosa Crônica/mortalidade , Doença Granulomatosa Crônica/terapia , Humanos , Lactente , Masculino , Neutrófilos/metabolismo , Taxa de Sobrevida
7.
J Allergy Clin Immunol ; 138(1): 241-248.e3, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26936803

RESUMO

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients. OBJECTIVE: Our objective was to assess the effect of mycobacterial disease in patients with CGD. METHODS: We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria. RESULTS: Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients. CONCLUSION: Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.


Assuntos
Doença Granulomatosa Crônica/complicações , Infecções por Mycobacterium/diagnóstico , Infecções por Mycobacterium/etiologia , Vacina BCG/administração & dosagem , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/etiologia , Infecções Bacterianas/mortalidade , Criança , Pré-Escolar , Feminino , Doença Granulomatosa Crônica/epidemiologia , Doença Granulomatosa Crônica/mortalidade , Doença Granulomatosa Crônica/terapia , Humanos , Lactente , Masculino , Infecções por Mycobacterium/epidemiologia , Infecções por Mycobacterium/mortalidade , Micoses/diagnóstico , Micoses/epidemiologia , Micoses/etiologia , Micoses/mortalidade , Avaliação de Resultados da Assistência ao Paciente , Estudos Retrospectivos , Tuberculose/diagnóstico , Tuberculose/etiologia
8.
Pediatr Infect Dis J ; 34(10): 1110-4, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26181896

RESUMO

BACKGROUND: Chronic granulomatous disease (CGD) is an uncommon primary immunodeficiency that can be inherited in an X-linked (XL) or an autosomal recessive (AR) manner. We reviewed our large, single-center US experience with CGD. METHODS: We reviewed 27 patients at Ann & Robert H. Lurie Children's Hospital of Chicago from March 1985 to November 2013. Fisher exact test was used to compare differences in categorical variables, and Student t test was used to compare means for continuous variables. Serious infections were defined as those requiring intravenous antibiotics or hospitalization. RESULTS: There were 23 males and 4 females; 19 were XL and 8 were AR. The average age at diagnosis was 3.0 years; 2.1 years for XL and 5.3 years for AR inheritance (P = 0.02). There were 128 serious infections. The most frequent infectious agents were Staphylococcus aureus (n = 13), Serratia (n = 11), Klebsiella (n = 7), Aspergillus (n = 6) and Burkholderia (n = 4). The most common serious infections were pneumonia (n = 38), abscess (n = 32) and lymphadenitis (n = 29). Thirteen patients had granulomatous complications. Five patients were below the 5th percentile for height and 4 were below the 5th percentile for weight. Average length of follow-up after diagnosis was 10.1 years. Twenty-four patients were compliant and maintained on interferon-γ, trimethoprim-sulfamethoxazole and an azole. The serious infection rate was 0.62 per patient-year. Twenty-three patients are alive (1 was lost to follow-up). CONCLUSIONS: We present a large, single-center US experience with CGD. Twenty-three of 27 patients are alive after 3276 patient-months of follow-up (1 has been lost to follow-up), and our serious infection rate was 0.62 per patient-year.


Assuntos
Doença Granulomatosa Crônica , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/mortalidade , Doença Granulomatosa Crônica/terapia , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Estudos Retrospectivos , Adulto Jovem
9.
Curr Opin Hematol ; 22(1): 41-5, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25394312

RESUMO

PURPOSE OF REVIEW: We update and summarize the recent findings in conventional treatment and hematopoietic stem cell transplantation in chronic granulomatous disease (CGD). We also summarize the contemporary view on when hematopoietic stem cell transplantation should be the preferred treatment of choice in CGD. RECENT FINDINGS: Azole antifungal treatment in CGD has improved survival. With prolonged survival, inflammatory complications are an emerging problem in CGD. Several studies now present excellent results with stem cell transplantation in severe CGD, also with reduced intensity conditioning. SUMMARY: Several lines of evidence now suggest that stem cell transplantation should be the preferred treatment of choice in severe CGD, if there is an available donor. This should be performed as soon as possible to avoid severe sequelae from infection and inflammation.


Assuntos
Antifúngicos/uso terapêutico , Azóis/uso terapêutico , Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas , Aloenxertos , Doença Granulomatosa Crônica/mortalidade , Doença Granulomatosa Crônica/patologia , Humanos
10.
Transfusion ; 55(2): 265-74, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25143186

RESUMO

BACKGROUND: Granulocyte-colony-stimulating factor (G-CSF)-mobilized autologous hematopoietic progenitor cells (HPCs) may be collected by apheresis of patients with chronic granulomatous disease (CGD) and severe combined immunodeficiency (SCID) for use in gene therapy trials. CD34+ cell mobilization has not been well characterized in such patients. STUDY DESIGN AND METHODS: We retrospectively evaluated CD34+ cell mobilization and collection in 73 consecutive CGD and SCID patients and in 99 age-, weight-, and G-CSF dose-matched healthy allogeneic controls. RESULTS: In subjects aged not more than 20 years, Day 5 preapheresis circulating CD34+ counts were significantly lower in CGD and SCID patients than in controls; mean peak CD34+ cell counts were 58 × 10(6) , 64 × 10(6) , and 87 × 10(6) /L, respectively (p = 0.01). The SCIDs had lower CD34+ collection efficiency than CGDs and controls; mean efficiencies were 40, 63, and 57%, respectively (p = 0.003). In subjects aged more than 20 years, the CGDs had significantly lower CD34+ cell mobilization than controls; mean peak CD34+ cell counts were 41 × 10(6) and 113 × 10(6) /L, respectively (p < 0.0001). In a multivariate analysis, lower erythrocyte sedimentation rate (ESR) at mobilization was significantly correlated with better CD34+ cell mobilization (p = 0.007). In SCIDs, CD34 collection efficiency was positively correlated with higher red blood cell (RBC) indices (mean RBC volume, R(2) = 0.77; mean corpuscular hemoglobin [Hb], R(2) = 0.94; mean corpuscular Hb concentration, R(2) = 0.7; p < 0.007) but not Hb. CONCLUSIONS: CGD and SCID populations are characterized by significantly less robust CD34+ HPC mobilization than healthy controls. The presence of active inflammation or infection as suggested by an elevated ESR may negatively impact mobilization. Among SCIDs, markedly reduced CD34 collection efficiencies were related to iron deficiency, wherein decreased RBC size and density may impair apheresis cell separation mechanics.


Assuntos
Remoção de Componentes Sanguíneos/métodos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Doença Granulomatosa Crônica/terapia , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa/terapia , Adolescente , Adulto , Autoenxertos , Criança , Feminino , Doença Granulomatosa Crônica/mortalidade , Humanos , Masculino , Estudos Retrospectivos , Imunodeficiência Combinada Severa/mortalidade
11.
J Allergy Clin Immunol ; 132(5): 1156-1163.e5, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23910690

RESUMO

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder of phagocytes resulting in impaired killing of bacteria and fungi. A mutation in one of the 4 genes encoding the components p22(phox), p47(phox), p67(phox), and p40(phox) of the leukocyte nicotinamide dinucleotide phosphate reduced (NADPH) oxidase leads to autosomal recessive (AR) CGD. A mutation in the CYBB gene encoding gp91(phox) leads to X-linked recessive CGD. OBJECTIVE: The aim of this study is to show the correlation between clinical, functional, and genetic data of patients with CGD from Turkey. METHODS: We report here the results of 89 patients with CGD from 73 Turkish families in a multicenter study. RESULTS: Most of the families (55%) have an AR genotype, and 38% have an X-linked genotype; patients from 5 families with a suspected AR genotype (7%) were not fully characterized. We compared patients with CGD according to the severity of NADPH oxidase deficiency of neutrophils. Patients with A22(0), A67(0) or X91(0) phenotypes with a stimulation index of 1.5 or less have early clinical presentation and younger age at diagnosis (mean, 3.2 years). However, in p47(phox)-deficient cases and in 5 other AR cases with high residual oxidase activity (stimulation index ≥ 3), later and less severe clinical presentation and older age at diagnosis (mean, 7.1 years) were found. Pulmonary involvement was the most common clinical feature, followed by lymphadenitis and abscesses. CONCLUSION: Later and less severe clinical presentation and older age at diagnosis are related to the residual NADPH oxidase activity of neutrophils and not to the mode of inheritance. CGD caused by A22(0) and A67(0) subtypes manifests as severe as the X91(0) subtype.


Assuntos
Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/genética , Causas de Morte , Pré-Escolar , Ativação Enzimática , Feminino , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/mortalidade , Humanos , Incidência , Infecção/etiologia , Masculino , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Neutrófilos/metabolismo , Análise de Sequência de DNA
12.
Acta Paediatr ; 102(11): 1087-94, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23937637

RESUMO

AIM: Chronic granulomatous disease (CGD) is a rare X-linked or autosomal recessive primary immune deficiency characterized by recurrent, life-threatening bacterial and fungal infections. Mortality rates are high with conventional treatment. However, haematopoietic stem cell transplantation (HSCT) offers cure. Here, we compare the outcome of HSCT in 14 Swedish patients with CGD to that in 27 patients with CGD who were given conventional treatment. METHODS: Forty-one patients in Sweden were diagnosed with CGD between 1990 and 2012. From 1997 to 2012, 14 patients with CGD, aged 1-35 years, underwent HSCT and received grafts either from an HLA-matched sibling donor or a matched unrelated donor. RESULTS: Thirteen of the 14 transplanted patients are alive and well. Mean age at transplantation was 10.4 years, and the mean survival time was 7.7 years. In contrast, seven of 13 Swedish men or boys with X-linked CGD who were treated conventionally died from complications of CGD at a mean age of 19 years, while the remaining patients suffered life-threatening infections. CONCLUSION: The outcome of the patients who underwent HSCT supports HSCT as being the preferable treatment for severe CGD. Our results advocate early HSCT for all patients with X-linked CGD, using grafts from either a matched sibling donor or a matched unrelated donor.


Assuntos
Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Doença Granulomatosa Crônica/mortalidade , Humanos , Lactente , Masculino , Estudos Retrospectivos , Suécia/epidemiologia , Resultado do Tratamento , Adulto Jovem
13.
Biol Blood Marrow Transplant ; 19(3): 338-43, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23228588

RESUMO

We performed a retrospective analysis on the outcomes of 135 hematopoietic stem cell transplantations (HSCTs) for primary immunodeficiency disorders in Australian and New Zealand Children's Haematology Oncology Group transplantation centers between 1992 and 2008. The most common indications for HSCT were severe combined immunodeficiency, Wiskott-Aldrich syndrome, and chronic granulomatous disease. Five-year overall survival (OS) was 72% for the entire cohort. Disease-specific 5-year OS was 70% for severe combined immunodeficiency, 81% for Wiskott-Aldrich syndrome, and 69% for chronic granulomatous disease. Transplantation-related mortality (TRM) was 10% at day +100. TRM and OS were equivalent in recipients of related and unrelated donor transplants. Source of stem cells had no impact on TRM or OS with outcomes following unrelated umbilical cord blood similar to unrelated bone marrow. The presence of interstitial pneumonitis, active cytomegalovirus infection, or veno-occlusive disease were all independent variables that significantly decreased OS. This large series supports the use of HSCT as curative therapy for a range of primary immunodeficiency disorders, demonstrating excellent survival after both related and unrelated donor transplantation.


Assuntos
Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas , Sistema de Registros , Imunodeficiência Combinada Severa/terapia , Síndrome de Wiskott-Aldrich/terapia , Adolescente , Austrália , Transplante de Medula Óssea , Criança , Pré-Escolar , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/mortalidade , Humanos , Lactente , Nova Zelândia , Estudos Retrospectivos , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/mortalidade , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Síndrome de Wiskott-Aldrich/diagnóstico , Síndrome de Wiskott-Aldrich/mortalidade
14.
J Mycol Med ; 22(1): 52-7, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23177814

RESUMO

OBJECTIVE: Fungal infection presents a serious risk to individuals with compromised immune systems. Chronic granulomatous disease is a primary immunodeficiency with X-linked or autosomal recessive inheritance. Patients with CGD are predisposed to bacterial and fungal infections. The aim of this study was to determine the incidence of fungal infections, identify the most common fungal pathogens, and determine the risk factors associated with fungal infections and mortality in patients with chronic granulomatous disease (CGD). MATERIAL AND METHODS: We reviewed retrospectively 12 patients with CGD in the period of 1995-2008. All of the patients were suspected to fungal infections. The data was gathered from the medical records of all patients as having CGD. Twelve patients had adequate medical records to enter the study. The diagnostic of fungal infections were confirmed by histopathology and direct preparation, culture techniques, histopathology of surgical biopsies, and radiological examination of the affected site. RESULTS: We evaluated 12 cases of chronic granulomatosis. Patients that are susceptible to recurrent, sever infections. Patients consisted of seven males and five females. The median age of patients at the time of the study was 11.66 years (3 to18). Neutrophil oxidative burst were absent (NBT=0) in all patients. Fungal infections were confirmed in five patients (41/7%) by histology and mycological methods. The most common isolated fungi in this study were Aspergillus spp. Out of five cases of fungal infections identified, tree were Aspergillus spp, and two Fusarium spp. The most common manifestations of CGD due to fungal infections (in descending order) were osteomyelitis (42.8%), pulmonary infections (28.6%), lymphadenopathy (14.3%) and skin involvement (14.3%) during their illness. CONCLUSION: Invasive fungal infections are a frequent and life-threatening complication in CGD patients. The lungs and skeletal, were the most commonly affected organ; however, lymphatic, and skin involvement have also been described. Our present study showed that fusariosis also is a threat to CGD patients.


Assuntos
Doença Granulomatosa Crônica/mortalidade , Micoses/mortalidade , Adolescente , Criança , Pré-Escolar , Feminino , Doença Granulomatosa Crônica/complicações , Humanos , Irã (Geográfico)/epidemiologia , Pneumopatias/complicações , Pneumopatias/mortalidade , Doenças Linfáticas/complicações , Doenças Linfáticas/mortalidade , Masculino , Micoses/complicações , Osteomielite/complicações , Osteomielite/mortalidade , Estudos Retrospectivos
15.
Biol Blood Marrow Transplant ; 18(9): 1368-77, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22326631

RESUMO

The curative potential of hematopoietic stem cell transplantation in patients with chronic granulomatous disease depends on availability of a suitable donor, successful donor engraftment, and maintenance of long-term donor chimerism. Twelve consecutive children (median age, 59.5 months; range, 8-140 months) with severe chronic granulomatous disease (serious bacterial/fungal infections pretransplantation; median, 3; range, 2-9) received myeloablative hematopoietic stem cell transplantation using sibling bone marrow ([SibBM]; n = 5), unrelated cord blood (UCB; n = 6), and sibling cord blood (n = 1) at our center between 1997 and 2010. SibBM and sibling cord blood were HLA matched at 6/6, whereas UCB were 5/6 (n = 5) or 6/6 (n = 1). Recipients of SibBM were conditioned with busulfan and cyclophosphamide ± anti-thymocyte globulin (ATG), whereas 6 of 7 cord blood recipients received fludarabine/busulfan/cyclophosphamide/ATG. Seven patients received granulocyte-colony stimulating factor-mobilized granulocyte transfusions from directed donors. The first 2 UCB recipients had primary graft failure but successfully underwent retransplantation with UCB. Highest acute graft-versus-host disease was grade III (n = 1). Extensive chronic graft-vs-host disease developed in 3 patients. All patients are alive with median follow-up of 70.5 months (range, 12-167 months) with high donor chimerism (>98%, n = 10; 94%, n = 1; and 92%, n = 1). Myeloablative hematopoietic stem cell transplantation led to correction of neutrophil dysfunction, durable donor chimerism, excellent survival, good quality of life, and low incidence of graft-vs-host disease regardless of graft source.


Assuntos
Transplante de Medula Óssea , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Granulomatosa Crônica/terapia , Agonistas Mieloablativos/administração & dosagem , Condicionamento Pré-Transplante/métodos , Criança , Pré-Escolar , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Doença Enxerto-Hospedeiro/imunologia , Granulócitos/transplante , Doença Granulomatosa Crônica/imunologia , Doença Granulomatosa Crônica/mortalidade , Teste de Histocompatibilidade , Humanos , Lactente , Masculino , Qualidade de Vida , Irmãos , Quimeras de Transplante/imunologia , Transplante Homólogo , Doadores não Relacionados
16.
J Allergy Clin Immunol ; 129(1): 176-83, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22078471

RESUMO

BACKGROUND: Matched related donor (MRD) hematopoietic stem cell transplantation (HSCT) is a successful treatment for chronic granulomatous disease (CGD), but the safety and efficacy of HSCT from unrelated donors is less certain. OBJECTIVE: We evaluated the outcomes and overall survival in patients with CGD after HSCT. METHODS: We report the outcomes for 11 children undergoing HSCT from an MRD (n = 4) or an HLA-matched unrelated donor (MUD) (n = 7); 9 children were boys, and the median age was 3.8 years (range, 1-13 years). We treated both X-linked (n = 9) and autosomal recessive (n = 2) disease. Nine children had serious clinical infections before transplantation. The conditioning regimens contained busulfan, cyclophosphamide, cytarabine, or fludarabine according to the donor used. All patients received alemtuzumab (anti-CD52 antibody). Additional graft-versus-host disease (GvHD) prophylaxis included cyclosporine and methotrexate for MUD recipients and cyclosporine and prednisone for MRD recipients. RESULTS: Neutrophil recovery took a median of 16 days (range, 12-40 days) and 18 days (range, 13-24 days) for MRD and MUD recipients, respectively. Full donor neutrophil engraftment occurred in 9 patients, and 2 had stable mixed chimerism; all patients had sustained correction of neutrophil oxidative burst defect. Four patients had grade I skin acute GVHD responding to topical treatment. No patient had grade II to IV acute GvHD or chronic GvHD. All patients are alive between 1 and 8 years after HSCT. CONCLUSION: For CGD, equivalent outcomes can be obtained with MRD or MUD stem cells, and HSCT should be considered an early treatment option.


Assuntos
Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Doadores de Tecidos , Doadores não Relacionados , Atividades Cotidianas , Adolescente , Criança , Pré-Escolar , Escolaridade , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Granulomatosa Crônica/imunologia , Doença Granulomatosa Crônica/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Recém-Nascido , Masculino , Qualidade de Vida , Relações entre Irmãos , Transplante Homólogo , Resultado do Tratamento
17.
J Clin Immunol ; 31(3): 332-7, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21384251

RESUMO

Chronic granulomatous disease (CGD) is phagocytic cell metabolic disorder resulting in recurrent infections and granuloma formation. This paper reports the favourable outcome of allogeneic transplantation in six high-risk CGD patients. The following donors were used: HLA-matched, related (two) and unrelated (three), and HLA-mismatched, unrelated (one). One patient was transplanted twice using the same sibling donor because of graft rejection at 6 months after reduced-intensity conditioning transplant (fludarabine and melphalan). Myeloablative conditioning regimen consisted of busulphan and cyclophosphamide. Stem cell source was unmanipulated bone marrow containing: 5.2 (2.6-6.5) × 10(8) nucleated cells, 3.8 (2.0-8.0) × 10(6) CD34+ cells and 45 (27-64) × 10(6) CD3+ cells per kilogramme. Graft-versus-host disease prophylaxis consisted of cyclosporine A and, for unrelated donors, short course of methotrexate and anti-T-lymphocyte globulin. Mean neutrophile and platelet engraftments were observed at day 22 (20-23) and day 20 (16-29), respectively. Pre-existing infections and inflammatory granulomas resolved. With the follow-up of 4-35 months (mean, 20 months), all patients are alive and well with full donor chimerism and normalized superoxide production.


Assuntos
Bussulfano/administração & dosagem , Ciclofosfamida/administração & dosagem , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas , Agonistas Mieloablativos/administração & dosagem , Condicionamento Pré-Transplante , Adolescente , Antígenos CD , Criança , Pré-Escolar , Ciclosporina/administração & dosagem , Intervalo Livre de Doença , Feminino , Sobrevivência de Enxerto , Doença Granulomatosa Crônica/imunologia , Doença Granulomatosa Crônica/mortalidade , Doença Granulomatosa Crônica/patologia , Antígenos HLA/imunologia , Humanos , Lactente , Masculino , Fatores de Risco , Quimeras de Transplante/imunologia , Transplante Homólogo
18.
Biol Blood Marrow Transplant ; 17(1 Suppl): S123-31, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21195301

RESUMO

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency with X-linked or autosomal recessive inheritance involving defects in genes encoding phox proteins, which are the subunits of the phagocyte NADPH oxidase. This results in failure to produce superoxide anion and downstream antimicrobial oxidant metabolites and to activate antimicrobial proteases. Affected patients are susceptible to severe, life-threatening bacterial and fungal infections and excessive inflammation characterized by granulomatous enteritis resembling Crohn's disease and genitourinary obstruction. Early diagnosis of CGD and rapid treatment of infections are critical. Prophylaxis with antibacterial and mold-active antifungal agents and the administration of interferon-γ has significantly improved the natural history of CGD. Currently, the only cure is allogeneic hematopoietic cell transplant (HCT), although there remains controversy as to which patients with CGD should get a transplant. Allele-based HLA typing of alternative donors, improved supportive care measures, and use of reduced toxicity conditioning have resulted in event-free survival (EFS) of at least 80% even with an unrelated donor and even better when the patient has no active infections/inflammation. Gene correction of CGD would eliminate the risks of graft-versus-host disease (GVHD) and the immunoablative chemotherapy required for allogeneic HCT. Based on gene therapy trials in patients with SCID-X1, ADA-SCID, and the early experience with CGD, it is clear that at least some degree of myeloablation will be necessary for CGD as there is no inherent selective growth advantage for gene-corrected cells. Current efforts for gene therapy focus on use of lentivector constructs, which are thought to be safer from the standpoint of insertional mutagenesis and more efficient in transducing hematopoietic stem cells (HSCs).


Assuntos
Doença Granulomatosa Crônica/terapia , Terapia Genética/métodos , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/mortalidade , Transplante de Células-Tronco Hematopoéticas , Humanos , NADPH Oxidases/imunologia , Resultado do Tratamento
19.
N Engl J Med ; 363(27): 2600-10, 2010 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-21190454

RESUMO

BACKGROUND: Failure to generate phagocyte-derived superoxide and related reactive oxygen intermediates (ROIs) is the major defect in chronic granulomatous disease, causing recurrent infections and granulomatous complications. Chronic granulomatous disease is caused by missense, nonsense, frameshift, splice, or deletion mutations in the genes for p22(phox), p40(phox), p47(phox), p67(phox) (autosomal chronic granulomatous disease), or gp91(phox) (X-linked chronic granulomatous disease), which result in variable production of neutrophil-derived ROIs. We hypothesized that residual ROI production might be linked to survival in patients with chronic granulomatous disease. METHODS: We assessed the risks of illness and death among 287 patients with chronic granulomatous disease from 244 kindreds. Residual ROI production was measured with the use of superoxide-dependent ferricytochrome c reduction and flow cytometry with dihydrorhodamine oxidation assays. Expression of NADPH oxidase component protein was detected by means of immunoblotting, and the affected genes were sequenced to identify causal mutations. RESULTS: Survival of patients with chronic granulomatous disease was strongly associated with residual ROI production as a continuous variable, independently of the specific gene affected. Patients with mutations in p47(phox) and most missense mutations in gp91(phox) (with the exception of missense mutations in the nucleotide-binding and heme-binding domains) had more residual ROI production than patients with nonsense, frameshift, splice, or deletion mutations in gp91(phox). After adolescence, mortality curves diverged according to the extent of residual ROI production. CONCLUSIONS: Patients with chronic granulomatous disease and modest residual production of ROI have significantly less severe illness and a greater likelihood of long-term survival than patients with little residual ROI production. The production of residual ROI is predicted by the specific NADPH oxidase mutation, regardless of the specific gene affected, and it is a predictor of survival in patients with chronic granulomatous disease. (Funded by the National Institutes of Health.).


Assuntos
Doença Granulomatosa Crônica/enzimologia , NADPH Oxidases/sangue , Espécies Reativas de Oxigênio/metabolismo , Análise de Variância , Feminino , Genótipo , Doença Granulomatosa Crônica/sangue , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/mortalidade , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Mutação , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Neutrófilos/metabolismo , Fenótipo , Modelos de Riscos Proporcionais , Fatores de Risco , Análise de Sequência de DNA , Índice de Gravidade de Doença , Análise de Sobrevida
20.
Clin Infect Dis ; 51(12): 1429-34, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21058909

RESUMO

BACKGROUND: Chronic granulomatous disease (CGD) is a genetic disorder of the phagocyte NADPH oxidase, which predisposes patients to infections and inflammatory complications, including severe colitis. Management of CGD colitis is a challenge because standard immunosuppressive therapy increases the risk of infection in already immunocompromised hosts. METHODS: We report the use of infliximab in 5 patients with CGD. RESULTS: Infliximab administration predisposed patients to severe infections with typical CGD pathogens but not mycobacteria, as reported with infliximab in other conditions. In addition to infections, infliximab administration led to successful closure of fistulae, sometimes with other untoward consequences. Infliximab-associated complications were associated with 2 deaths. CONCLUSIONS: Infliximab use in the treatment of CGD inflammatory bowel disease requires aggressive antimicrobial prophylaxis, assiduous surveillance for infection, and vigilance for untoward gastrointestinal complications. This experience suggests that infliximab therapy is effective but has untoward consequences in patients with CGD.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Colite/tratamento farmacológico , Doença Granulomatosa Crônica/tratamento farmacológico , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adolescente , Adulto , Infecções Bacterianas/induzido quimicamente , Infecções Bacterianas/mortalidade , Colite/imunologia , Colite/mortalidade , Colite/patologia , Feminino , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/imunologia , Doença Granulomatosa Crônica/mortalidade , Doença Granulomatosa Crônica/patologia , Humanos , Infliximab , Masculino , Adulto Jovem
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