Chronic granulomatous diseaseD71.-

CGD is a heterogeneous group of diseases characterized by impaired generation of the "respiratory burst" in human phagocytes (neutrophils, mononuclear cells, macrophages, and eosinophils). The resulting defect leads to the inability to generate superoxide and thus the inability to contain certain infectious pathogens. The disease manifests as repeated, severe bacterial and mycotic infections leading to the formation of inflammatory granulomas. The first report of this disease was in 1954 by Janeway and colleagues [Janeway CA et al 1954) . Landing and Shirkey (Landing BH et al 1957) later described a patient with recurrent infections and associated histiocyte infiltration. Disruption of phagocyte function in the disease was later recognized. In 1986, Baehner reported the localization of the gene for X-linked CGD to xp21 (Baehner RL et al 1968; Curnutte JT et al 1974). Subsequently, defects in several components of the NADPH oxidase complex have been described by various investigators, including gp91phox, p22 phox, p67phox, and p47phox (Curnutte JT et al. 1987)

Chronic granulomatous disease" (CGD)is the most common immunodeficiency involving phagocytes. The term refers to a genetically distinct group of diseases with largely analogous phenotypes. Recurrent infections with bacterial and mycotic pathogens and the formation of granulomas in various organs characterize its clinical spectrum. The cause of the disease is a disturbance of the NADPH oxidase system, which leads to the inability of the phagocyte to generate superoxide, resulting in inadequate killing of pathogenic organisms.

The biological consequence is recurrent infections with Staphylococcus aureus, Pseudomonas species, Nocardia species, and fungi (such as Aspergillus species and Candida albicans). Involvement of vital or major organs may contribute to morbidity and/or mortality in affected patients.

Pathogen spectrum

• Sepsis: B Cepacia Pseudomonas Serratia Staphylococcus Salmonella
• Pneumonia: Aspergillus Nocardia Serratia Pseudomonas Staphylococcus Klebsiella Candida
• Skin: Abscesses: Staphylococcus Klebsiella Aspergillus/Candida Serratia
• Lymph nodes (adenitis adenopathy):Candida/Nocardia Aspergillus Serratia/Klebsiella
• Liver (abscesses): Staphylococcus Streptococcus Aspergillus/Nocardia Serratia
• Bone (osteomyelitis):Serratia, Aspergillus Staphylococcus Pseudomonas/Nocardia
• GI tract (perirectal abscesses, fistulas): Enterobacteriaceae Staphylococcus
• Urinary tract (pyelonephritis): Enterobacteriaceae

X-linked CGD (XL-CGD = CYBB gene) results from mutations in the gp91phox gene and is responsible for 65-70% of clinical cases. This gene is referred to as CYBB and spans a 30 kb region in the Xp21.1 region.

Autosomal recessive CGDs (AR-CGD) occur in 35% of cases. Mutations of the other components of NADH oxidase (with the exception of p40phox and Rac, which have not previously been associated with a CGD phenotype) (Curnutte JT et al 1993) these include the genes: p22phox , p67phox and p47phox . Of these, the p22phox gene is the dominant mutation, occurring in nearly 25% of cases. These phenotypes can be referred to as X-CGD and as A22/A47/A67-CGD. Concomitant immunodeficiencies such as IgA deficiency or mannose-binding lectin (MBL) mutations are partly responsible for the heterogeneity of these clinical pictures.

NADPH oxidase: The cytochrome b558 heterodimer is located in the membrane and consists of the units gp91phox and p22phox, while there are three cytosolic components, p67phox , p47phox and p40phox (see Fig.). After cellular activation, the soluble cytosolic components p67phox, p47phox and a p40phox migrate to the membrane and bind to components of the cytochrome b558 heterodimer. This is also accompanied by binding of the GTPase protein Rac, which leads to activation of the flavocytochrome. This catalyzes the transfer of electrons from NADPH to oxygen, leading to the formation of superoxide in the extracellular component. Subsequent reactions via superoxide dismutase (SOD), catalase, or myeloperoxidase (MPO) that occur in the phagolysome can lead to the formation of H2O2, H2O, and HOCl-, respectively.

According to retrospective data, the AR variant is diagnosed later, and the median survival time was significantly longer in these patients (49.6 years) than in XL disease (37.8 years). Pulmonary (66% of patients), dermatologic (53%), lymphatic (50%), alimentary (48%), and hepatobiliary (32%) complications were observed most frequently [van den Berg JM et al.(2009) Staphylococcus aureus, Aspergillus spp. and Salmonella spp. were the most commonly cultured pathogens, in that order, while Pseudomonas spp. and Burkholderia cepacia were rarely observed.

The disease is usually diagnosed in childhood and sometimes in early adulthood.

CGD most commonly presents as infectious disease, although some patients may also develop failure to thrive, granulomatous complications, or inflammatory disease. More than 90% of patients have severe respiratory defects. These patients usually develop severe or life-threatening bacterial or fungal infections early in life (usually in infancy). On the other hand, some patients may also not develop recurrent and unusual infections until late childhood or early adulthood, at which time they are diagnosed. Typical infections include purulent bacterial infections (e.g., pneumonia, sinusitis, or liver abscesses) or necrotizing fungal infections of skin, deep tissue, or bone.

Frequencies of disease signs:

>50%

• Lymphadenopathy
• Hepatosplenomegaly
• Anemia
• Hyperglobulinemia
• Weight disorders

≤50%

• Diarrhea
• Gingivitis
• Hydronephrosis
• Granulomatous IIeocolitis
• Stomatitis
• Granulomatous cystitis
• Pulmonary fibrosis
• Esophagitis
• Glomerulonephritis
• Chorioretinitis
• Discoid lupus erythematosus
• Subcutaneous abscesses

Patient survival has increased decisively since the introduction of lifelong continuous prophylaxis with the cell- and tissue-targeting cotrimoxazole. CGD granulocytes achieve limited bactericidal activity in the presence of cotrimoxazole, especially against staphylococci. Treatment consists of uniform prophylactic antibiotic doses, especially trimethoprim-sulfamethoxazole 160/800 mg p.o. 2 times/day. In cotrimoxazole allergy or G-6 PDH deficiency, trimethoprim in combination with rifampicin or ciprofloxacin can be tried.

• In severe infections, granulocyte transfusions.
• Hematopoietic stem cell transplantation.

Oral antifungals are given as primary prophylaxis or added if fungal infections occur even once; most useful are

• Itraconazole p.o. every 12 h (100 mg for patients <13 years of age, 200 mg for those ≥ 13 years of age or weighing > 50 kg)
• Voriconazole p.o. every 12 h (100 mg for those weighing <40 kg; 200 mg for those weighing ≥ 40 kg)
• Posaconazole (400 mg twice daily).

Interferon-gamma may reduce the severity and frequency of infections and is usually added to treatment. The usual dose is 50 μg/m2 subcutaneously 3 times/week.

In severe infections, granulocyte transfusions may be life-saving.

If transplantation is preceded by chemotherapy, human leukocyte antigen-identical hemotopoietic stem cell transplantation from siblings is usually successful.

Gene therapy is being investigated in current trials.

Mortality: 18%. Bacterial pneumonia and/or lung abscess, systemic sepsis and brain abscess are the most frequent causes of death .

1. Janeway CA et al.(1954) Hypergammaglobulinemia associated with severe, recurrent and chronic non-specific infection. Am J Dis Child 88:388-392.
2. Bridges RA et al.(1959) A fatal granulomatous disease of childhood; the clinical, pathological, and laboratory features of a new syndrome. AMA J Dis Child 97:387-408.
3. Baehner RL et al (1974) Deficiency of reduced nicotinamide-adenine dinucleotide oxidase in chronic granulomatous disease. Science 162:1277-1279.
4. Curnutte JT et al (1974) Defective superoxide production by granulocytes from patients with chronic granulomatous disease. N Engl J Med 290:593-597.
5. Curnutte JT et al (1987) Activation of neutrophil NADPH oxidase in a cell-free system. Partial purification of components and characterization of the activation process. J Biol Chem 262:5563-5569.
6. Curnutte JT (1993) Chronic granulomatous disease: the solving of a clinical riddle at the molecular level. Clin Immunol Immunopathol 67: 2-15.
7. Holmes B et al (1966) Fatal granulomatous disease of childhood. An inborn abnormality of phagocytic function.Lancet 1:1225-1228.
8. Landing BH et al (1957) A syndrome of recurrent infection and infiltration of viscera by pigmented lipid histiocytes.Pediatrics 20:431-438.
9. van den Berg JM et al (2009) Chronic granulomatous disease: the European experience. PLoS One 4:e5234.