Chronic granulomatous disease: review of a cohort of egyptian patients

BACKGROUND: Chronic granulomatous disease (CGD) is an inherited disease that results from a defect in the phagocytic cells of the immune system. It is caused by defects in one of the major subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. The clinical presentations of CGD patients are heterogeneous. OBJECTIVES: This is the first report from Egypt discussing clinical and laboratory data of twenty-nine patients (from 26 families) with CGD from a single tertiary referral centre. RESULTS: There were twenty male and nine female patients. The consanguinity rate was 76% (19/25). Their age of diagnosis ranged from 2 to 168 months with a mean of 52.8 months ± 49.6 SD. The most common manifestations were abscesses in 79.3% (deep organ abscesses in 37.9% of patients), followed by pneumonia in 75.8% and gastrointestinal symptoms in 27.5%. Rare but fatal complications were also reported among patients as one patient developed haemophagocytic lymphohistiocytosis (HLH) syndrome. Although X linked-CGD universally constitutes the most common pattern of inheritance; only 6 of our patients 6/25 (24%) belonged to this group with a Stimulation Index (SI) of 1-5, and confirmed by carrier pattern of their mothers. Mothers were not available for testing in four male children. Nineteen patients (76%) had autosomal recessive patterns; ten males and nine females patients based on having abnormal SI, positive history of consanguinity and their mothers showing normal SI. CONCLUSION: Increasing the awareness of physicians about symptoms of CGD may lead to earlier diagnosis of the disease, thus enhancing proper management and better quality of life

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Hyperinflammation of chronic granulomatous disease is abolished by NOX2 reconstitution in macrophages and dendritic cells.

Chronic granulomatous disease (CGD), caused by a lack of reactive oxygen species (ROS) generation by the phagocyte NADPH oxidase NOX2, leads to massively increased inflammatory responses. In order to identify the type of phagocyte which requires NOX2 activity to limit inflammation, we investigated mice with a loss of function mutation in the Ncf1 gene coding for the p$47^{\rm{phox}}$ subunit of NOX2 and mice with transgenic rescue of Ncf1 under control of the CD68 promoter. To induce CGD hyperinflammation, different mouse genotypes were injected intradermally with ß-glucan. Ncf1 mutant mice showed massive and prolonged hyperinflammation. Hyperinflammatory lesions were characterized by persistent neutrophilic infiltration, along with ulceration and necrosis. In contrast, in CD68 promoter rescue mice inflammation resolved within days, as seen in wild-type animals. Measurements of ROS in rescue mice demonstrated functional NOX2 in mononuclear phagocytes (macrophages and dendritic cells) but not in neutrophils. This absence of NOX2 function was also confirmed in inflammatory tissue neutrophils. Lack of functional NOX2 in mononuclear phagocytes increased the secretion of IL-1ß at early time points and of IL-6 and TNFα at later time points. Thus, CGD hyperinflammation is a redox dysregulation in mononuclear phagocytes, demonstrating a cell type-specific anti-inflammatory function of NOX2.

Exogenous pentraxin 3 restores antifungal resistance and restrains inflammation in murine chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening bacterial and fungal infections and hyperinflammation. The susceptibility to aspergillosis in experimental CGD (p47(phox-/-) mice) is associated with the failure to control the inherent inflammatory response to the fungus and to restrict the activation of inflammatory Th17 cells. We assessed whether pentraxin (PTX)3, a member of a family of multimeric pattern-recognition proteins with potent anti-Aspergillus activity, could limit pathogenic inflammation in p47(phox-/-) mice by curbing the IL-23/Th17 inflammatory axis in response to the fungus. We found that the production of PTX3 was delayed in CGD mice in infection but exogenous administration of PTX3 early in infection restored antifungal resistance and restrained the inflammatory response to the fungus. This occurred through down-regulation of IL-23 production by dendritic cells and epithelial cells which resulted in limited expansion of IL-23R+ gammadelta+ T cells producing IL-17A and the emergence of Th1/Treg responses with minimum pathology. Thus, PTX3 could be therapeutically used for the exploitation of NADPH-independent mechanism(s) of antifungal immune protection with limited immunopathology in CGD.

Chronic granulomatous disease in pediatric patients: 25 years of experience / Enfermedad granulomatosa crónica en pediatría: 25 años de experiencia

Introduction: Chronic granulomatous disease (CGD) is an uncommon primary immune deficiency (affecting 1/200,000 newborn infants) caused by a defect in phagocyte production of oxygen metabolites, and resulting in bacterial infections produced by catalase-positive microorganisms and fungal diseases that occasionally may prove fatal. Methods: A review is made of the clinical records of 13 pediatric patients diagnosed with CGD between 1980 and 2005. Results: All patients were males. The mean age at diagnosis was 36 months. The clinical manifestations at the time of diagnosis comprised the following: Abscesses or abscessified adenopathies 4/13 (Staphylococcus aureus (2), Serratia liquefaciens, S. marcescens and Klebsiella sp.), pneumonia 3/13 (Rhodococcus equi, Salmonella typhimurium plus Pneumocystis jiroveci), osteomyelitis 1/13 (Aspergillus sp.), sepsis 1/13 (S. aureus), urinary infection 1/13 (Klebsiella sp.), severe gastroenteritis 1/13, oral aphthae 1/13 and Crohn-like inflammatory bowel disease 1/13. The diagnosis was initially established by the nitroblue tetrazolium test, and confirmed by flow cytometry 10/13 and genetic techniques (gp91) 9/13. In the course of these disease processes there were 88 infections: abscesses (n = 26), lymphadenitis (n = 12), pneumoniae (n = 10), gastroenteritis (n = 7), sepsis (n = 6), osteomyelitis (n = 3) and others (n = 24). As to the germs isolated, the frequency distribution was as follows (n = 49): Aspergillus sp. (n = 10), Staphylococcus sp. (n = 7), Salmonella sp. (n = 6), Serratia sp. (n = 5), Pseudomonas aeruginosa (n = 4), Klebsiella sp. (n = 4), Proteus sp. (n = 3), Leishmania sp. (n = 2) and others (n = 8). IFN-ã was administered in 7/13 cases, and itraconazole in 9/13; all received cotrimoxazole. There were four deaths, with one case each of sepsis due to gramnegative bacterial infection; disseminated aspergillosis; visceral leishmaniasis and hemophagocytosis; and post-kidney transplant complications. Conclusions: Clinical suspicion and flow cytometry are the keys for diagnosis of CGD and detection of carrier relatives. Specific prophylactic measures and medical controls are required to prevent serious infections. IFN-gamma has been used intermittently, though its effectiveness is controversial

Introducción: La enfermedad granulomatosa crónica (EGC) es una inmunodeficiencia primaria infrecuente (1/200.000 recién nacidos vivos) por defecto de la producción de metabolitos del oxígeno por los fagocitos, causando infecciones bacterianas por microorganismos catalasa positivos y fúngicas, en ocasiones letales. Métodos: Revisión de historias clínicas de 13 pacientes diagnosticados de EGC en edad pediátrica de 1980 a 2005. Resultados: 100% varones. Edad mediana al diagnóstico: 36 meses. Clínica al diagnóstico: abscesos o adenopatías abscesificadas 4/13 (Staphylococcus aureus (2), Serratia liquefaciens, S. marcescens y Klebsiella sp.), neumonía 3/13 (Rhodococcus equi, Salmonella typhimurium más Pneumocystis jiroveci), osteomielitis 1/13 (Aspergillus sp.), sepsis 1/13 (S. aureus), infección urinaria 1/13 (Klebsiella sp.), gastroenteritis grave 1/13, aftas orales 1/13 y enfermedad inflamatoria intestinal Crohn-like 1/13. Diagnosticados inicialmente por Nitroblue Tetrazolium Test, confirmados por citometría de flujo 10/13 y genéticamente (gp91) 9/13. En su evolución presentaron 88 infecciones: abscesos (26), adenopatías (12), neumonías (10), gastroenteritis (7), sepsis (6), osteomielitis (3) y otras (24). Gérmenes aislados (49): Aspergillus sp. (10), Staphylococcus sp. (7), Salmonella sp. (6), Serratia sp. (5), Pseudomonas aeruginosa (4), Klebsiella sp. (4), Proteus sp. (3), Leishmania sp. (2) y otros (8). Han recibido Interferón Gamma 7/13; itraconazol 9/13 y todos cotrimoxazol. Cuatro fallecidos (1 sepsis por un bacilo gram negativo, 1 aspergilosis diseminada, 1 leishmaniasis visceral y hemofagocitosis, 1 complicaciones post-trasplante renal). Conclusiones: La sospecha clínica y la citometría de flujo son los pilares del diagnóstico en la EGC para el paciente y para la detección de familiares portadores. Debemos establecer una profilaxis específica y controles médicos para prevenir infecciones graves. Se ha usado intermitentemente IFN-gamma, aunque su efectividad es discutida

Current treatment options for chronic granulomatous disease.

Chronic granulomatous disease is a rare inherited disorder of phagocytic cells which results in a susceptibility to infections of catalase-positive bacteria and fungi (especially Aspergillus species), as well as granuloma formation. The mainstay of therapy is antibacterial and antifungal prophylaxis. Trimethoprim sulfamethoxazole is the drug of choice for the prevention of bacterial infection, while itraconazole is most widely used for the prevention of fungal infection. Immunomodulatory agents, such as IFN-phi, have a role in the prevention and treatment of intractable infection. New antifungal agents provide the promise of improved cure rates for invasive Aspergillus, while bone marrow transplants and gene therapy may offer the promise of complete cure.

Chronic granulomatous disease: a different pattern in Hong Kong?

From July 1988 to December 1989, six boys with chronic granulomatous disease were diagnosed in our institutions. Their clinical features were reviewed in order to delineate the pattern of infections which seems to have both similarities and differences when compared with published reports of Caucasian patients. The most striking differences was the lack of skin sepsis and chronic lymphadenitis in our six patients. Gram-negative organisms were the commonest pathogens while Staphylococci sp. were not isolated. Clinical features which should alert one to the diagnosis were also highlighted. Prophylactic co-trimoxazole was effective in reducing the frequency of bacterial infections. Early diagnosis is not only essential for optimal patient management but also for genetic counselling for the extended family.

Suppression of streptococcal cell wall-induced arthritis by a potent protease inhibitor, bis(5-amidino-2-benzimidazolyl)methane.

Bis(5-amidino-2-benzimidazolyl)methane, a powerful synthetic trypsin inhibitor, proved to be highly effective in suppressing the arthritis induced by streptococcal cell wall fragments in Lewis rats. It reduced not only the degree of synovitis, osteitis, and hematopoietic hyperplasia in the distal extremities, but also the degree of associated granulomatous inflammation in the liver. The results suggest that trypsin-like proteases play an important role in this arthritis model and that inhibitors may be useful in the treatment of similar arthritic conditions in humans.

Antibacterial prophylaxis in chronic granulomatous disease. A case report.

The value of long-term prophylactic treatment of chronic granulomatous disease (CGD) in childhood cannot be established with certainty, as controlled studies are not available. We describe a boy, presently 15 years old, who suffered from CGD since early infancy. By the clinical, laboratory and genetic features, this case appeared to be a new variant of CGD, combining elements of the "childhood" type with others that characterize the "adult" type of the syndrome. For years, the patient had been almost continuously ill and needed frequent and prolonged hospitalizations because of severe bacterial infections. At age 13 years, long-term prophylactic treatment with trimethoprim-sulfamethoxazole (TMP-SMX) was instituted. With this regimen, the patient was maintained practically infection-free, relapsing only in those instances when he neglected to comply with the prophylactic regimen for 1 to 2 weeks. Thus, the patient served as his own control in demonstrating the efficacy of antimicrobial prophylaxis in CGD. The rationale for employing TMP-SMX for the prophylactic regimen is discussed.

Chronic granulomatous disease of childhood: a changing pattern?

We have followed nine male patients with Chronic Granulomatous Disease at The Hospital for Sick Children, Toronto, since 1972. The diagnosis was established in each case by the failure of neutrophils to reduce nitroblue tetrazolium dye and to kill Staphylococcus aureus normally in vitro. Bacterial infections began between 6 months and 14 years of age. In five of the nine patients, infections began after 4 years of age. The first significant infection in five patients was a liver abscess(es), and one patient each had lymphadenitis, pulmonary aspergillosis, a parapharyngeal abscess, and a draining inguinal incision following surgery. Following diagnosis, all patients were started on Trimethoprim-Sulfamethoxazole at a dose of 2 mg/kg/day of Trimethoprim. The patients have been followed for 50 patient-years. Five of nine patients have been free of infection during 16 years of observation. For the remaining four patients, there have been six infections during 34 years of observation. A possible infection-related death occurred in one patient. The patients reported here appear to differ from those in previous reports. They present later in life, often with a liver abscess. They have a low incidence of subsequent bacterial infections which may, in part, be due to Trimethoprim-Sulfamethoxazole prophylaxis. The patients with chronic granulomatous disease reported here appear to have a better prognosis than previously thought.