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1.
Blood ; 123(6): 809-21, 2014 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-24227816

RESUMO

Haploinsufficiency of the hematopoietic transcription factor GATA2 underlies monocytopenia and mycobacterial infections; dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency; familial myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML); and Emberger syndrome (primary lymphedema with MDS). A comprehensive examination of the clinical features of GATA2 deficiency is currently lacking. We reviewed the medical records of 57 patients with GATA2 deficiency evaluated at the National Institutes of Health from January 1, 1992, to March 1, 2013, and categorized mutations as missense, null, or regulatory to identify genotype-phenotype associations. We identified a broad spectrum of disease: hematologic (MDS 84%, AML 14%, chronic myelomonocytic leukemia 8%), infectious (severe viral 70%, disseminated mycobacterial 53%, and invasive fungal infections 16%), pulmonary (diffusion 79% and ventilatory defects 63%, pulmonary alveolar proteinosis 18%, pulmonary arterial hypertension 9%), dermatologic (warts 53%, panniculitis 30%), neoplastic (human papillomavirus+ tumors 35%, Epstein-Barr virus+ tumors 4%), vascular/lymphatic (venous thrombosis 25%, lymphedema 11%), sensorineural hearing loss 76%, miscarriage 33%, and hypothyroidism 14%. Viral infections and lymphedema were more common in individuals with null mutations (P = .038 and P = .006, respectively). Monocytopenia, B, NK, and CD4 lymphocytopenia correlated with the presence of disease (P < .001). GATA2 deficiency unites susceptibility to MDS/AML, immunodeficiency, pulmonary disease, and vascular/lymphatic dysfunction. Early genetic diagnosis is critical to direct clinical management, preventive care, and family screening.


Assuntos
Fator de Transcrição GATA2/genética , Síndromes de Imunodeficiência/mortalidade , Leucemia Mieloide Aguda/mortalidade , Síndromes Mielodisplásicas/mortalidade , Adolescente , Adulto , Idoso , Criança , Feminino , Fator de Transcrição GATA2/deficiência , Estudos de Associação Genética , Haploinsuficiência , Hematopoese , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Lactente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Sistema Linfático , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Adulto Jovem
2.
N Engl J Med ; 367(8): 725-34, 2012 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-22913682

RESUMO

BACKGROUND: Autoantibodies against interferon-γ are associated with severe disseminated opportunistic infection, but their importance and prevalence are unknown. METHODS: We enrolled 203 persons from sites in Thailand and Taiwan in five groups: 52 patients with disseminated, rapidly or slowly growing, nontuberculous mycobacterial infection (group 1); 45 patients with another opportunistic infection, with or without nontuberculous mycobacterial infection (group 2); 9 patients with disseminated tuberculosis (group 3); 49 patients with pulmonary tuberculosis (group 4); and 48 healthy controls (group 5). Clinical histories were recorded, and blood specimens were obtained. RESULTS: Patients in groups 1 and 2 had CD4+ T-lymphocyte counts that were similar to those in patients in groups 4 and 5, and they were not infected with the human immunodeficiency virus (HIV). Washed cells obtained from patients in groups 1 and 2 had intact cytokine production and a response to cytokine stimulation. In contrast, plasma obtained from these patients inhibited the activity of interferon-γ in normal cells. High-titer anti-interferon-γ autoantibodies were detected in 81% of patients in group 1, 96% of patients in group 2, 11% of patients in group 3, 2% of patients in group 4, and 2% of controls (group 5). Forty other anticytokine autoantibodies were assayed. One patient with cryptococcal meningitis had autoantibodies only against granulocyte-macrophage colony-stimulating factor. No other anticytokine autoantibodies or genetic defects correlated with infections. There was no familial clustering. CONCLUSIONS: Neutralizing anti-interferon-γ autoantibodies were detected in 88% of Asian adults with multiple opportunistic infections and were associated with an adult-onset immunodeficiency akin to that of advanced HIV infection. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research; ClinicalTrials.gov number, NCT00814827.).


Assuntos
Anticorpos Neutralizantes/sangue , Autoanticorpos/sangue , Doenças Autoimunes/imunologia , Interferon gama/imunologia , Infecções por Mycobacterium/imunologia , Infecções Oportunistas/imunologia , Adolescente , Adulto , Idade de Início , Idoso , Contagem de Linfócito CD4 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Micoses/imunologia , Taiwan , Tailândia , Tuberculose Pulmonar/imunologia , Adulto Jovem
4.
Am J Respir Crit Care Med ; 178(10): 1066-74, 2008 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-18703788

RESUMO

RATIONALE: Pulmonary nontuberculous mycobacterial (PNTM) disease is increasing, but predisposing features have been elusive. OBJECTIVES: To prospectively determine the morphotype, immunophenotype, and cystic fibrosis transmembrane conductance regulator genotype in a large cohort with PNTM. METHODS: We prospectively enrolled 63 patients with PNTM infection, each of whom had computerized tomography, echocardiogram, pulmonary function, and flow cytometry of peripheral blood. In vitro cytokine production in response to mitogen, LPS, and cytokines was performed. Anthropometric measurements were compared with National Health and Nutrition Examination Survey (NHANES) age- and ethnicity-matched female control subjects extracted from the NHANES 2001-2002 dataset. MEASUREMENTS AND MAIN RESULTS: Patients were 59.9 (+/-9.8 yr [SD]) old, and 5.4 (+/-7.9 yr) from diagnosis to enrollment. Patients were 95% female, 91% white, and 68% lifetime nonsmokers. A total of 46 were infected with Mycobacterium avium complex, M. xenopi, or M. kansasii; 17 were infected with rapidly growing mycobacteria. Female patients were significantly taller (164.7 vs. 161.0 cm; P < 0.001) and thinner (body mass index, 21.1 vs. 28.2; P < 0.001) than matched NHANES control subjects, and thinner (body mass index, 21.1 vs. 26.8; P = 0.002) than patients with disseminated nontuberculous mycobacterial infection. A total of 51% of patients had scoliosis, 11% pectus excavatum, and 9% mitral valve prolapse, all significantly more than reference populations. Stimulated cytokine production was similar to that of healthy control subjects, including the IFN-gamma/IL-12 pathway. CD4(+), CD8(+), B, and natural killer cell numbers were normal. A total of 36% of patients had mutations in the cystic fibrosis transmembrane conductance regulator gene. CONCLUSIONS: Patients with PNTM infection are taller and leaner than control subjects, with high rates of scoliosis, pectus excavatum, mitral valve prolapse, and cystic fibrosis transmembrane conductance regulator mutations, but without recognized immune defects.


Assuntos
Infecções por Mycobacterium não Tuberculosas/etiologia , Pneumonia Bacteriana/etiologia , Idoso , Estatura , Estudos de Casos e Controles , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Tórax em Funil/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Infecções por Mycobacterium não Tuberculosas/genética , Infecções por Mycobacterium não Tuberculosas/imunologia , Fenótipo , Estudos Prospectivos , Fatores de Risco , Escoliose/complicações , Fatores Sexuais , Fumar/efeitos adversos , Síndrome , Magreza/complicações
6.
Ann Am Thorac Soc ; 13(12): 2169-2173, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27607353

RESUMO

RATIONALE: Mycobacterium kansasii usually causes chronic pulmonary infections in immunocompetent patients. In contrast, disseminated M. kansasii disease is commonly associated with advanced human immunodeficiency virus infection, but is reported infrequently in other immunocompromised patients. OBJECTIVES: To identify common clinical manifestations and potential risk factors for M. kansasii infection in patients with GATA2 deficiency. METHODS: We reviewed M. kansasii disease associated with GATA2 deficiency at one institution and disease associated with primary and other immunodeficiencies reported in the literature. MEASUREMENTS AND MAIN RESULTS: Nine patients with GATA2 deficiency developed M. kansasii infections. Six patients developed disseminated disease. All patients presented with significant mediastinal lymphadenopathy or abscesses. Seven patients had pulmonary risk factors, including six smokers. The majority of patients had low numbers of neutrophils, monocytes, B cells, CD4+ T cells, and natural killer cells. Other conditions associated with disseminated M. kansasii disease were thymic disorders and IFN-γ/IL-12 defects. CONCLUSIONS: Disseminated M. kansasii disease involving mediastinal lymph nodes is surprisingly common in GATA2 deficiency, but also occurs in defects of IFN-γ synthesis and response. Disseminated M. kansasii should be considered a marker indicating a need to evaluate for immunodeficiency syndromes.


Assuntos
Fator de Transcrição GATA2/deficiência , Linfadenopatia/microbiologia , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Adulto , Antituberculosos/uso terapêutico , Feminino , Fator de Transcrição GATA2/genética , Humanos , Hospedeiro Imunocomprometido , Interleucina-12/deficiência , Pulmão/microbiologia , Linfonodos/microbiologia , Masculino , Mediastino/microbiologia , Pessoa de Meia-Idade , Mutação , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/genética , Mycobacterium kansasii/isolamento & purificação , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
7.
Chest ; 137(3): 629-34, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19858235

RESUMO

BACKGROUND: Nontuberculous mycobacteria (NTM) are environmental organisms associated with pulmonary disease without person-to-person transmission. Although genetic causes of disseminated NTM infection are well characterized, genetic causes for most human susceptibility to pulmonary NTM infection have not been determined. METHODS: Family histories for relevant disease characteristics were obtained as part of an ongoing natural history study. Six families were identified in which at least two blood relatives had pulmonary NTM. A systematic review of medical records extracted data relevant to pulmonary infection and baseline demographics. Data were reconfirmed by telephone interviews. RESULTS: Familial clustering of pulmonary NTM was proven in six families. Four of the families were white, and the majority of affected individuals were women. The average age at diagnosis was 56.4 +/- 10.7 years, the average height was 167.5 +/- 8.7 cm, and the mean BMI was 22.0 +/- 2.98 kg/m(2). Scoliosis was present in 31%. Five of 12 patients had cystic fibrosis transmembrane conductance regulator gene variations, but none had classic cystic fibrosis. Infections were caused by both slow and rapid growing mycobacteria, including Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium abscessus, and Mycobacterium massiliense. Family members were typically infected with different species of NTM. CONCLUSION: We identified six familial clusters of pulmonary NTM infection, suggesting that there are genetic factors contributing to host susceptibility to pulmonary infection with NTM among some individuals with nodular bronchiectatic disease.


Assuntos
Família , Transmissão Vertical de Doenças Infecciosas , Pneumopatias/genética , Infecções por Mycobacterium não Tuberculosas/genética , Micobactérias não Tuberculosas/isolamento & purificação , Idoso , Idoso de 80 Anos ou mais , Broncoscopia , Análise por Conglomerados , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Pneumopatias/microbiologia , Masculino , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/metabolismo , Infecções por Mycobacterium não Tuberculosas/transmissão , Linhagem , Tomografia Computadorizada por Raios X
8.
Respir Med ; 103(10): 1448-55, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19467851

RESUMO

Recent studies suggest an increasing prevalence of pulmonary nontuberculous mycobacteria (NTM) disease. In the absence of prevalence and cost data, the public health burden of pulmonary NTM disease is difficult to assess. The goal of this study was to assess costs associated with NTM disease treatment and to identify risk factors associated with increased costs. Records from subjects with pulmonary NTM disease enrolled in a natural history protocol were abstracted for presenting symptoms, comorbidities, microbiology, and treatment histories. Antibiotic frequency, duration, adverse reaction, and costs were noted, the total antibiotic burden and cost were calculated, and risk factors associated with high costs were analyzed. From Jan 2004 to Dec 2005, 33 subjects were enrolled; 27 met disease criteria and had sufficient data to assess antibiotic use. Mycobacterium avium complex was present in 89% and Mycobacterium abscessus was present in 21% of subjects. Subjects received a median of 5 (1-10) antibiotics. Adverse effects were common seen in up to 50% with common antibiotics and up to 100% with uncommonly used antibiotics. Median burden of treatment was 2638 (84-7689) drug-days and the median total cost per patient was $19,876 ($398-70,917). Subjects with high treatment costs had an adjusted 9.5 fold (95% CI 1.5-97.2) likelihood of having M. abscessus and a 4.2 fold (95% CI 0.6-59.3) increased likelihood of having more extensive disease. Pulmonary NTM represent an underappreciated disease burden in the US population, with an associated treatment cost comparable to that for other chronic diseases of infectious origin such as HIV/AIDS.


Assuntos
Antibacterianos/uso terapêutico , Custos de Cuidados de Saúde , Pneumopatias/tratamento farmacológico , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/economia , Doença Crônica/tratamento farmacológico , Doença Crônica/economia , Feminino , Humanos , Pneumopatias/economia , Pneumopatias/microbiologia , Masculino , Pessoa de Meia-Idade , Infecção por Mycobacterium avium-intracellulare/economia , Infecção por Mycobacterium avium-intracellulare/microbiologia , Guias de Prática Clínica como Assunto , Fatores de Risco
9.
Pediatr Pulmonol ; 44(11): 1051-6, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19824053

RESUMO

BACKGROUND: Nontuberculous mycobacterial (NTM) infection is typically associated with lymphadenitis in immune competent children, and disseminated disease in children with immune deficiencies. Isolated pulmonary NTM disease is seen in cystic fibrosis, and is increasingly recognized in immunocompetent elderly women, where it is associated with an increased incidence of cystic fibrosis transmembrane regulator (CFTR) mutations. Thoracic NTM infection has been reported rarely in otherwise healthy children. We aimed to determine whether otherwise healthy children with pulmonary NTM disease had immunologic abnormalities or CFTR mutations. Clinical presentations of five otherwise healthy children with pulmonary NTM were reviewed. Immunologic studies were performed including a complete blood cell count (CBC), flow cytometric lymphocyte phenotyping and IFN-gamma receptor expression, in vitro cytokine stimulation, and serum immunoglobulin levels. Mutational analysis was performed for CFTR. The children ranged in age from 12 months to 2.5 years at diagnosis. Four presented with new onset wheezing or stridor failing bronchodilator therapy. One child was asymptomatic. Endobronchial lesions and/or hilar lymph nodes causing bronchial obstruction were identified in all patients. Mycobacterium avium complex was cultured from four patients, and Mycobacterium abscessus from one patient. All patients were successfully treated with anti-mycobacterial therapy with or without surgery. No definitive immunologic abnormalities were identified. No clinically significant mutations were found in CFTR. Pulmonary NTM infection should be considered in otherwise healthy young children presenting with refractory stridor or wheezing with endobronchial lesions or hilar lymphadenopathy. It does not appear to be associated with recognized underlying immune deficiency or CFTR mutations.


Assuntos
Doenças Linfáticas/diagnóstico por imagem , Infecções por Mycobacterium não Tuberculosas/diagnóstico por imagem , Antituberculosos/uso terapêutico , Broncoscopia , Pré-Escolar , Humanos , Imunocompetência , Lactente , Masculino , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/imunologia , Tomografia Computadorizada por Raios X
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