Chronic granulomatous disease
From Wikipedia, the free encyclopedia
| ICD-10 | D71. |
|---|---|
| ICD-9 | 758.0 |
| OMIM | 306400 |
| DiseasesDB | 2633 |
| MedlinePlus | 001239 |
| eMedicine | ped/1590 derm/719 |
Chronic granulomatous disease (CGD) is a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds used to kill certain ingested pathogens. This leads to the formation of granulomata in many organs<ref name=Heyworth>Heyworth P, Cross A, Curnutte J (2003). "Chronic granulomatous disease.". Curr Opin Immunol 15 (5): 578-84. PMID 14499268.</ref>. CGD affects about 1 in 200,000 people in the United States, with at least 20 new cases diagnosed each year.<ref name=Maryland>Maryland Pao, M.D. et al. (2004). "Cognitive Function in Patients With Chronic Granulomatous Disease: A Preliminary Report". Psychosomatics 45 (June 2004): 230-4. PMID 15123849.</ref>
This condition was first described in 1959 as "a fatal granulomatosis of childhood"<ref name=Bridges>Bridges RA, Berendes H, Good RA. A fatal granulomatosis of childhood: the clinical, pathological, and laboratory features of a new syndrome. AMA J Dis Child 1959;97:387-408. PMID 13636694</ref>. 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<ref name=Baehner>Baehner, RL, Nathan, DG. Leukocyte oxidase: a defective activity in chronic granulomatous disease. Science 1967; 155:835. PMID 6018195.</ref>.
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[edit] Pathophysiology
Phagocytes (i.e., neutrophils, eosinophils, monocytes, and macrophages) require a set of enzymes to produce reactive oxygen species to destroy bacteria after they ingest the bacteria in a process called phagocytosis. Together these enzymes are 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 these enzymes produce are toxic to bacteria and help the phagocyte kill them once they are ingested. Defects in one of these enzymes 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<ref name=Heyworth />.
[edit] Genetics
Most cases of chronic granulomatous disease are transmitted as a mutation on the X chromosome and are thus called an "X-linked trait"<ref name=Winkelstein>Winkelstein J, Marino M, Johnston R et al (2000). "Chronic granulomatous disease. Report on a national registry of 368 patients.". Medicine (Baltimore) 79 (3): 155-69. PMID 10844935.</ref>. The affected gene on the X chromosome codes for the gp91 protein (p is the weight of the protein in kDa; the g means glycoprotein). CGD can also be transmitted in an autosomal recessive fashion and affects other PHOX proteins. The type of mutation that causes both types of CGD are varied and may be deletions, frame-shift, nonsense, and missense<ref name=HeyworthPG>Heyworth P, Curnutte J, Rae J, Noack D, Roos D, van Koppen E, Cross A. "Hematologically important mutations: X-linked chronic granulomatous disease (second update).". Blood Cells Mol Dis 27 (1): 16-26. PMID 11162142.</ref><ref name=Cross>Cross A, Noack D, Rae J, Curnutte J, Heyworth P (2000). "Hematologically important mutations: the autosomal recessive forms of chronic granulomatous disease (first update).". Blood Cells Mol Dis 26 (5): 561-5. PMID 11112388.</ref>.
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.
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[edit] Clinical manifestations
Classically, patients with chronic granulomatous disease will suffer from recurrent bouts of infection due to the decreased capacity of their immune system to fight off disease-causing organisms. The recurrent infections they acquire are specific and are, in decreasing order of frequency:
- pneumonia
- abscesses of the skin, tissues, and organs
- suppurative arthritis
- osteomyelitis
- bacteremia/fungemia
- superficial skin infections such as cellulitis or impetigo
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 <ref name=Winkelstein>Winkelstein J, Marino M, Johnston R, Boyle J, Curnutte J, Gallin J, Malech H, Holland S, Ochs H, Quie P, Buckley R, Foster C, Chanock S, Dickler H (2000). "Chronic granulomatous disease. Report on a national registry of 368 patients.". Medicine (Baltimore) 79 (3): 155-69. PMID 10844935.</ref>. Early diagnosis is important since these people can be placed on antibiotics to ward off infections before they occur.
[edit] Laboratory findings
The nitroblue-tetrazolium (NBT) test is the original and most widely-known test for chronic granulomatous disease<ref name=Kasper>Kasper, DL, Fauci, AS, Longo, DL, Braunwald, E, Hauser, SL, and Jameson, JL. Harrison's Principles of Internal Medicine, 16th edition 2005;357. ISBN 0-07-139140-1. </ref>. This test depends upon the direct reduction of NBT by Superoxide free radical to form an insoluble formazan. This test is simple to perform and gives rapid results, but only tells whether or not there is a problem with the PHOX enzymes, not how much they are affected. An advanced test called the cytochrome C reduction assay tells physicians how much superoxide a patient's phagocytes can produce. Once the diagnosis of CGD is established, a genetic analysis may be used to determine exactly which mutation is the underlying cause.
[edit] Treatment
Management of chronic granulomatous disease revolves around two goals: 1) diagnose the disease early so that antibiotics can be given to keep an infection from occurring, and 2) educate the patient about his or her condition so that prompt treatment can be given if an infection occurs.
Physicians often prescribe the antibiotic trimethoprim-sulfamethoxazole to prevent bacterial infections<ref name=Weening>Weening R, Kabel P, Pijman P, Roos D (1983). "Continuous therapy with sulfamethoxazole-trimethoprim in patients with chronic granulomatous disease.". J Pediatr 103 (1): 127-30. PMID 6408232.</ref>. This drug also has the benefit of sparing the normal bacteria of the digestive tract. Fungal infection is commonly prevented with itraconazole<ref name=Cale>Cale C, Jones A, Goldblatt D (2000). "Follow up of patients with chronic granulomatous disease diagnosed since 1990.". Clin Exp Immunol 120 (2): 351-5. PMID 10792387.</ref>, although a newer drug of the same type called voriconazole may be more effective<ref name=Sabo>Sabo J, Abdel-Rahman S (2000). "Voriconazole: a new triazole antifungal.". Ann Pharmacother 34 (9): 1032-43. PMID 10981251.</ref>. 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<ref> (1991) "A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. The International Chronic Granulomatous Disease Cooperative Study Group.". N Engl J Med 324 (8): 509-16. PMID 1846940.</ref>.
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<ref name=Dinauer>Dinauer M, Gifford M, Pech N, Li L, Emshwiller P (2001). "Variable correction of host defense following gene transfer and bone marrow transplantation in murine X-linked chronic granulomatous disease.". Blood 97 (12): 3738-45. PMID 11389011.</ref>.
In 2006, two human patients with X-linked chronic granulomatous disease were been successfully treated with gene therapy along with 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<ref name=Ott>Ott M, Schmidt M, Schwarzwaelder K, et al. (2006). "Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1.". Nat Med 12 (4): 401-9. PMID 16582916.</ref>.
[edit] Prognosis
The prognosis of chronic granulomatous disease is guarded, with long-term outcomes closely tied to early diagnosis and early therapeutic intervention. With increasing treatment options for CGD the life-span for these patients is expected to also increase.
[edit] External links
- Patient information on chronic granulomatous disease from MedLine Plus Medical Encyclopedia
- CGD information from St. Jude's Children's Research Hospital
- The Chronic Granulomatous Disease Association
[edit] References
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