Chronic Granulomatous Disease
Chronic Granulomatous Disease (CGD) is a rare inherited disease that affects the immune system’s ability to fight off bacterial and fungal infections. Chronic Granulomatous Disease (CGD) is important as the study of the condition has helped understand the phagocyte oxidase system. Chronic Granulomatous Disease is caused by mutations in any one of the genes that code for the components of the NADPH oxidase enzyme complex, which generates reactive oxygen species (ROS) that are essential for the destruction of pathogens by phagocytic cells. The inheritance is most commonly x-linked.
Affected individuals suffer from recurrent infections, particularly with staphylococci.
CGD is a primary immunodeficiency that affects phagocytes of the immune system and leads to recurrent or persistent intracellular bacterial and fungal infections and to granuloma formation.
Chronic Granulomatous Disease (CGD) has an estimated incidence of 1 in 200,000 to 1 in 250,000 live births worldwide. It affects males and females equally and is more common in certain ethnic groups, including those of Middle Eastern, North African, and Turkish descent.
The clinical presentation of CGD can vary widely depending on the specific genetic mutation and the degree of residual NADPH oxidase activity. However, the most common clinical manifestations include recurrent bacterial and fungal infections, particularly of the skin, lungs, and lymph nodes. These infections can be severe and life-threatening, especially if they are not diagnosed and treated promptly.
CGD patients are also at increased risk of developing granulomatous inflammation, which can affect various organs such as the liver, spleen, and gastrointestinal tract. The granulomas can cause organ dysfunction and may require surgical intervention in some cases.
In approximately two-thirds of patients, the first symptoms of CGD appear during the first year of life in the form of infections, dermatitis (sometimes seen at birth), gastrointestinal complications (obstruction or intermittent bloody diarrhea due to colitis), and a failure to thrive.
The clinical picture can be quite variable, with some infants having several of these complications and others appearing to be far less ill.
Cutaneous disease occurs in 60-70% of patients.
There is a poorly explained failure to switch off the inflammatory reaction with the formation of granuloma in many sites and poor wound healing.
CGD manifestations include recurrent infections; multiple granulomatous lesions of the lungs, liver, lymph nodes, and GI and GU tract; abscesses; lymphadenitis; hypergammaglobulinemia; elevated ESR; and anemia.
The diagnosis of chronic granulomatous disease requires a combination of clinical suspicion, immunological testing, and genetic analysis. The gold standard for diagnosis is the demonstration of an inability of the neutrophils to reduce nitroblue tetrazolium dye (NBT test), and the defect can be further defined by molecular techniques.
The nitroblue tetrazolium (NBT) slide test is used for screening defects in NADPH oxidase. In this test, patient neutrophils are exposed to a stimulus, incubated with NBT, and made into a smear on a slide. Under the microscope, the number of neutrophils with dark granules of reaction product are counted. Normally, more than 95% of the granulocytes will be positive as shown above. In chronic granulomatous disease (CGD) there is an absent or reduced function of the respiratory burst, which is the intracellular process in neutrophils that is dependent upon the enzyme NADPH oxidase, which produces oxygen free radicals used to kill phagocytized organisms. The abnormal NBT test in CGD is shown below in which <5% of neutrophils stain.
The management of CGD involves a multidisciplinary approach that includes infectious disease specialists, immunologists, and hematologists. The primary goal is to prevent and treat infections promptly with appropriate antimicrobial agents.
Treatment is continuous prophylactic antibiotics, particularly trimethoprim/sulfamethoxazole (Septrin) 160/80 mg po bid. Oral antifungals are given as primary prophylaxis or are added if fungal infections occur even once; most useful are itraconazole po q 12 h (100 mg for patients < 13 yr; 200 mg for those ≥ 13 yr or weighing > 50 kg), voriconazole po q 12 h (100 mg for those weighing < 40 kg; 200 mg for those weighing ≥ 40 kg), or posaconazole (400 mg bid). Interferon-gamma may reduce the severity and frequency of infections and is usually included in the treatment regimen. The usual dose is 50 mcg/m2 sc 3 times/wk.
Granulocyte transfusions can be lifesaving when infections are severe. When preceded by pretransplantation chemotherapy, HLA-identical sibling bone marrow transplantation is usually successful.
Gene therapy is under study.
CGD is a rare genetic disorder that affects the immune system’s ability to fight off bacterial and fungal infections. Prompt diagnosis and appropriate management are crucial to prevent life-threatening complications. A multidisciplinary approach is essential to provide comprehensive care for CGD patients.
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Wiley Online Library. https://onlinelibrary.wiley.com/doi/abs/10.1111/jdv.16291
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