This condition was first described in 1957 as "a fatal granulomatosus of childhood". The underlying cellular mechanism that causes chronic granulomatous disease was discovered in 1967, and research since that time has further elucidated the molecular mechanisms underlying the disease.
Phagocytes (i.e., neutrophils, monocytes, and macrophages) require an enzyme to produce reactive oxygen species to destroy bacteria after they ingest the bacteria in a process called phagocytosis. This enzyme is termed "phagocyte NADPH oxidase" (PHOX). The initial step in this process involves the one-electron reduction of molecular oxygen to produce superoxide free radical. Superoxide then undergoes a further series of reactions to produce products such as peroxide, hydroxyl radical and hypochlorite. The reactive oxygen species this enzyme produces are toxic to bacteria and help the phagocyte kill them once they are ingested. Defects in one of the four essential subunits of this enzyme can all cause CGD of varying severity, dependent on the defect. There are over 410 known possible defects in the PHOX enzyme complex that can lead to chronic granulomatous disease.
A low level of NADPH, the cofactor required for superoxide synthesis, can lead to CGD. This has been reported in women who are homozygous for the genetic defect causing glucose-6-phosphate dehydrogenase deficiency (G6PD), which is characterised by reduced NADPH levels.
People with CGD are sometimes infected with unique organisms that usually do not cause disease in people with normal immune systems. Some of the organisms that cause disease in CGD patients are Staphylococcus aureus, Escheria coli, Klebsiella species, Aspergillus species, and Candida species.
Aspergillus has a unique propensity to cause infection in people with CGD. Of the Aspergillus species, Aspergillus fumigatus seems to be the one that most commonly causes disease.
Most people with CGD are diagnosed in childhood, usually before age 5. Early diagnosis is important since these people can be placed on antibiotics to ward off infections before they occur.
Physicians often prescribe the antibiotic trimethoprim-sulfamethoxazole to prevent bacterial infections. This drug also has the benefit of sparing the normal bacteria of the digestive tract. Fungal infection is commonly prevented with itraconazole, although a newer drug of the same type called voriconazole may be more effective. The use of this drug for this purpose is still under scientific investigation.
Interferon, in the form of interferon gamma-1b (Actimmune) is approved by the Food and Drug Administration for the prevention of infection in CGD. It has been shown to prevent infections in CGD patients by 70% and to reduce their severity. Although its exact mechanism is still not entirely understood, it has the ability to give CGD patients more immune function and therefore, greater ability to fight off infections. This therapy has been standard treatment for CGD for several years.
Gene therapy is currently being studied as a possible treatment for chronic granulomatous disease. CGD is well-suited for gene therapy since it is caused by a mutation in single gene which only affects one body system (the hematopoietic system). Viruses have been used to deliver a normal gp91 gene to rats with a mutation in this gene, and subsequently the phagocytes in these rats were able to produce oxygen radicals.
In 2006, two human patients with X-linked chronic granulomatous disease underwent gene therapy and blood cell precursor stem cell transplantation to their bone marrow. Both patients recovered from their CGD, clearing pre-existing infections and demonstrating increased oxidase activity in their neutrophils. However, long-term complications of this therapy are unknown.