Chronic Granulomatous Disease: The European Experience

Abstract

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 (∼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 (gp91phox 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 γ-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.

Functional and genetic characterization of two extremely rare cases of Williams–Beuren Syndrome associated with chronic granulomatous disease

“…3 Carriers of AR 47 0 CGD have an estimated prevalence of 1/500, because AR 47 0 CGD patients make up about 25% of all CGD patients, and CGD in total occurs in about 1/250 000 newborns. 7,8 Therefore, the combination of WBS and AR 47 0 CGD may be expected in about 1/15 000 Â 1/500 Â 1/2 ¼ 1/15 000 000 newborns. The absence of oxidase activity was confirmed by the absence of immunodetection of p47 phox expression in both patients, whereas the other oxidase components were present.…”

“…The clinical consequence of this mutation is severe, with life-threatening, recurrent infections in childhood. 8 However, p47 phox is also expressed in non-phagocytic cells and may be involved in many other diseases, such as cardiovascular disorders. 9 Depending on the LCR in which the recombination event leading to the WBS deletion occurs, the NCF1 gene may or may not be deleted in WBS individuals.…”

Chronic Granulomatous Disease

“…There are no autosomal dominant cases of CGD. A large voluntary retrospective study in the United States ad Europe suggested rates of CGD of around 1:200,000-1:250,000 live births (14,15). Rates in other countries vary depending on the ethnic practices and degrees of intermarriage: Sweden 1/450,000; Japan 1/300,000; Israeli Jews 1/218,000; Israeli Arabs 1/111,000 (16).…”

“…However, the relative rates of X-linked compared to recessive CGD are very distinct. In many countries with high rates of consanguineous marriage recessive CGD rates exceed X-linked rates (15,16). Clinically, Xlinked gp91 phox deficient CGD is more severe with earlier presentation and diagnosis, and more severe infections and earlier death than the p47 phox deficient form (14,15).…”

Monocyte/macrophage-Specific NADPH Oxidase Contributes to Antimicrobial Host Defense in X-CGD

“…Invasive fungal infections, principally aspergillosis, increase with age and account for one-third to half of all deaths [2,[16][17][18][19]. CGD patients also frequently experience a variety of inflammatory complications such as granulomatous enteritis resembling Crohn's disease, and some have autoimmune disorders [20][21][22][23].…”