RESUMEN
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by a defect of phagocyte NADPH-oxidase and characterized by severe, recurrent bacterial and fungal infections. Invasive aspergillosis (IA) is the leading cause of mortality in patients with CGD. We report the case of a 3-year-old boy with CGD, who developed IA despite antifungal prophylaxis. His treatment consisted of a 10-month-long multi-drug antifungal therapy, together with surgery, but these did not cause any substantial clinical improvement. BMT in high-risk patients with CGD remains a challenge due to both, higher risk of graft rejection and inflammatory flare in the course of immune recovery. Our patient rejected the first matched unrelated donor (MUD) allograft after RIC regimen recommended by the EBMT Inborn Errors Working Party for high-risk patients. After treosulfan-based conditioning and second MUD peripheral blood stem cell transplantation both, full reconstitution of the granulocytic series and complete recovery from IA, were achieved.
Asunto(s)
Aspergilosis/terapia , Busulfano/análogos & derivados , Enfermedad Granulomatosa Crónica/terapia , Trasplante de Células Madre de Sangre Periférica/métodos , Reoperación/métodos , Acondicionamiento Pretrasplante/métodos , Antineoplásicos Alquilantes/uso terapéutico , Busulfano/uso terapéutico , Preescolar , Supervivencia de Injerto , Enfermedad Granulomatosa Crónica/complicaciones , Humanos , MasculinoRESUMEN
CGD is an immunodeficiency caused by deletions or mutations in genes that encode subunits of the leukocyte NADPH oxidase complex. Normally, assembly of the NADPH oxidase complex in phagosomes of certain phagocytic cells leads to a "respiratory burst", essential for the clearance of phagocytosed micro-organisms. CGD patients lack this mechanism, which leads to life-threatening infections and granuloma formation. However, a clear picture of the clinical course of CGD is hampered by its low prevalence (approximately 1:250,000). Therefore, extensive clinical data from 429 European patients were collected and analyzed. Of these patients 351 were males and 78 were females. X-linked (XL) CGD (gp91(phox) deficient) accounted for 67% of the cases, autosomal recessive (AR) inheritance for 33%. AR-CGD was diagnosed later in life, and the mean survival time was significantly better in AR patients (49.6 years) than in XL CGD (37.8 years), suggesting a milder disease course in AR patients. The disease manifested itself most frequently in the lungs (66% of patients), skin (53%), lymph nodes (50%), gastrointestinal tract (48%) and liver (32%). The most frequently cultured micro-organisms per episode were Staphylococcus aureus (30%), Aspergillus spp. (26%), and Salmonella spp. (16%). Surprisingly, Pseudomonas spp. (2%) and Burkholderia cepacia (<1%) were found only sporadically. Lesions induced by inoculation with BCG occurred in 8% of the patients. Only 71% of the patients received antibiotic maintenance therapy, and 53% antifungal prophylaxis. 33% were treated with gamma-interferon. 24 patients (6%) had received a stem cell transplantation. The most prominent reason of death was pneumonia and pulmonary abscess (18/84 cases), septicemia (16/84) and brain abscess (4/84). These data provide further insight in the clinical course of CGD in Europe and hopefully can help to increase awareness and optimize the treatment of these patients.
Asunto(s)
Enfermedad Granulomatosa Crónica/patología , Europa (Continente)/epidemiología , Femenino , Enfermedad Granulomatosa Crónica/epidemiología , Enfermedad Granulomatosa Crónica/genética , Humanos , MasculinoRESUMEN
Primary immunodeficiencies (PIDs) are group of more than 200 different genetic disorders. Reccurrent, severe infections are major clinical manifestation of these disorders. Ethiology and course of infections in PIDs are different, depending on type of immunodeficiency. We present short characteristics of infections in PIDs, as well as difficulties in diagnostics and treatment of infectious complications.
Asunto(s)
Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/terapia , Infecciones Oportunistas/diagnóstico , Infecciones Oportunistas/terapia , Infecciones Bacterianas/etiología , Enfermedades del Sistema Nervioso Central/etiología , Diagnóstico Diferencial , Humanos , Síndromes de Inmunodeficiencia/complicaciones , Infecciones del Sistema Respiratorio/etiología , Factores de RiesgoAsunto(s)
Vacuna BCG/efectos adversos , Síndromes de Inmunodeficiencia/microbiología , Infecciones por Mycobacterium/etiología , Mycobacterium bovis , Profilaxis Antibiótica , Vacuna BCG/inmunología , Femenino , Humanos , Recién Nacido , Masculino , Infecciones por Mycobacterium/inmunología , Infecciones por Mycobacterium/prevención & control , Mycobacterium bovis/inmunología , Mycobacterium bovis/patogenicidad , PoloniaRESUMEN
UNLABELLED: Chronic neutropenia (CN) is defined by an absolute neutrophil count (ANC) below 1500/ul, lasting at least 6 months. AIM: clinical course and treatment of children afflicted with CN was analysed. MATERIAL AND METHODS: we present 60 children treated in our department due to CN. The diagnosis was based on: bone marrow smears, ANC, immunologic investigation. RESULTS: we established the diagnosis of: Kostmann disease (KD), cyclic neutropenia (CyN), hyperIgM syndrome (HIGM), Shwachman-Diamond syndrome (SDS), severe chronic neutropenia (SCN) and chronic benign neutropenia (CBN) in: 4, 2, 2, 1, 21 and 20 children respectively. Due to positive results of tests: MAIGA, GIFT or GAT autoimmune neutropenia of infancy (AIN) was confirmed in 7 children. In 3 infants neutropenia was connected with HCMV- infection and Gancyclovir therapy. RHuG-CSF treatment was implemented in 14 and effective in 13 patients. A girl, suffering from KD, during rHuG-CSF therapy, developed chronic myeloblasts leucaemia and died. A boy, with the same diagnosis, underwent bone marrow transplantation from related donor but died from invasive pulmonary aspergillosis. Antibacterial prophylaxis was necessary in 29 children. We used Amoxicillin or Trimethoprim/Sulfametoxazole, obtaining decrease of frequency and severity of infections. During observation period all children suffered from upper respiratory tract infections, 19 had chronic gingivitis. Severe infections- bacterial pneumonia, sepsis, severe varicella and measles were observed in 30, 5, 2 and 1 patient respectively. A teenager, affected with SCN, died due to fulminant Clostridium perfringens infection. CONCLUSIONS: 1. RHuG-CSF therapy is essential in children with KD and SCN (when accompanied by severe infections). 2. AIN proved to be a mild condition, although ANC decreased below 500. In this entity rHuG-CSF is recommended during severe infections and before surgery. 3. Antibiotic prophylaxis is recommended for children with: KD, CyN, GSD1b, CN in 1st year of life, HIGM; in other cases it is considered individually.
Asunto(s)
Autoanticuerpos/inmunología , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/terapia , Neutropenia/diagnóstico , Neutropenia/terapia , Neutrófilos/inmunología , Adolescente , Antibacterianos/uso terapéutico , Enfermedades Autoinmunes/inmunología , Trasplante de Médula Ósea , Niño , Preescolar , Enfermedad Crónica , Femenino , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Hospitales , Humanos , Lactante , Infecciones/diagnóstico , Infecciones/inmunología , Infecciones/terapia , Leucemia/diagnóstico , Leucemia/inmunología , Leucemia/terapia , Recuento de Leucocitos , Masculino , Neutropenia/inmunología , Polonia , Proteínas Recombinantes , Estudios Retrospectivos , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
Chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by defects in any of four genes encoding components of the leukocyte nicotinamide dinucleotide phosphate, reduced (NADPH) oxidase. One of these is the autosomal neutrophil cytosolic factor 1 (NCF1) gene encoding the p47phox protein. Most (>97%) CGD patients without p47phox (A47 degrees CGD) are homozygotes for one particular mutation in NCF1, a GT deletion in exon 2. This is due to recombination events between NCF1 and its two pseudogenes (psiNCF1) that contain this GT deletion. We have previously set up a gene-scan method to establish the ratio of NCF1 genes and pseudogenes. With this method we now found, in three CGD families patients with the normal number of two intact NCF1 genes (and four psiNCF1 genes) and in six CGD families, patients with one intact NCF1 gene (and five psiNCF1 genes). All patients lacked p47phox protein expression. These results indicate that other mutations were present in their NCF1 gene than the GT deletion. To identify these mutations, we designed PCR primers to specifically amplify the cDNA or parts of the genomic DNA from NCF1 but not from the psiNCF1 genes. We found point mutations in NCF1 in eight families. In another family, we found a 2,860-bp deletion starting in intron 2 and ending in intron 5. In six families the patients were compound heterozygotes for the GT deletion and one of these other mutations; in two families the patients had a homozygous missense mutation; and in one family the patient was a compound heterozygote for a splice defect and a nonsense mutation. Family members with either the GT deletion or one of these other mutations were identified as carriers. This knowledge was used in one of the families for prenatal diagnosis.
Asunto(s)
Enfermedad Granulomatosa Crónica/genética , Mutación , NADPH Oxidasas/genética , Adolescente , Adulto , Niño , Análisis Mutacional de ADN , Familia , Femenino , Humanos , Masculino , NADPH Oxidasas/metabolismo , Linaje , Fagocitos/enzimología , Embarazo , Diagnóstico PrenatalRESUMEN
Chronic granulomatous disease is a rare defect of phagocytosis. Increased susceptibility to infections is limited to catalase positive bacteria and fungi. Aspergillus spp was reported as the increased clinical problem and the main cause of the deaths.
Asunto(s)
Aspergilosis/diagnóstico , Aspergilosis/tratamiento farmacológico , Enfermedad Granulomatosa Crónica/complicaciones , Antifúngicos/uso terapéutico , Aspergilosis/microbiología , Aspergillus fumigatus/aislamiento & purificación , Aspergillus nidulans/aislamiento & purificación , Niño , Ensayo de Inmunoadsorción Enzimática , Enfermedad Granulomatosa Crónica/microbiología , Humanos , Reacción en Cadena de la PolimerasaAsunto(s)
Anticuerpos Monoclonales/administración & dosificación , Ciclosporina/administración & dosificación , Enfermedad Granulomatosa Crónica/tratamiento farmacológico , Factores Inmunológicos/administración & dosificación , Inmunosupresores/administración & dosificación , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Adolescente , Anticuerpos Monoclonales de Origen Murino , Femenino , Enfermedad Granulomatosa Crónica/sangre , Enfermedad Granulomatosa Crónica/complicaciones , Humanos , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/complicaciones , RituximabRESUMEN
INTRODUCTION: Chronic granulomatous disease (CGD)is a rare inherited disorder in which phagocytic cells are unable to generate superoxide anions. Patients with CGD are predisposed to recurrent bacterial and fungal infections because the superoxide-generating NADPH oxidase activity is needed for efficient killing of microbes. Among the at least 5 subunits cre-ating a functional NADPH oxidase, a molecular defect located in any of the gp91phox, p22phox, p47phox, or p67phox subunits may cause CGD. MATERIAL/METHODS: In this study,8 patients were diagnosed with CGD on the basis of clinical findings and absence of nitroblue tetrazolium reduction in phagocytes. Southern blot analysis, GeneScan, and direct sequencing were performed to define particular DNA mutations. RESULTS: Among 6 X-linked CGD (X-CGD)patients, 4 different mutations were identified in the X-linked CYBB gene (encoding gp91phox)by direct sequencing. A novel missense mutation, located in the NADPH-binding region of gp91phox,was found in 2 brothers. One frameshift 1578delA, one splicing 252G->A mutation, and one partial gene deletion were also identified. The molecular defect in the NCF1 gene (encoding p47phox)was established in 2 patients. One was DeltaGT/DeltaGT homozygote, the other carried, besides this GT deletion on one allele, a unique Phe118stop mutation on the other. CONCLUSIONS: In general, the X-CGD patients within the group followed a more severe clinical course than the patients with an NCF1 defect. However, the lack of a straightforward genotype phenotype correlation indicates that the clinical severity of CGD depends also on other antimicrobial host-defense systems.