NationMaster - Encyclopedia: Chronic granulomatous disease

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 (most importantly, the superoxide radical) used to kill certain ingested pathogens. This leads to the formation of granulomata in many organs^[1]. CGD affects about 1 in 200,000 people in the United States, with at least 20 new cases diagnosed each year.^[2] The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) is a coding of diseases and signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or diseases, as classified by the World Health Organization (WHO). ... // C00-D48 - Neoplasms (C00-C14) Malignant neoplasms, lip, oral cavity and pharynx (C00) Malignant neoplasm of lip (C01) Malignant neoplasm of base of tongue (C02) Malignant neoplasm of other and unspecified parts of tongue (C03) Malignant neoplasm of gum (C04) Malignant neoplasm of floor of mouth (C05) Malignant neoplasm of... The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The Disease Bold textDatabase is a free website that provides information about the relationships between medical conditions, symptoms, and medications. ... MedlinePlus (medlineplus. ... eMedicine is an online clinical medical knowledge base that was founded in 1996. ... Medical Subject Headings (MeSH) is a huge controlled vocabulary (or metadata system) for the purpose of indexing journal articles and books in the life sciences. ... A genetic disorder is a disease caused by abnormalities in genes or chromosomes. ... A scanning electron microscope image of a single neutrophil (yellow), engulfing anthrax bacteria (orange). ... General Name, Symbol, Number oxygen, O, 8 Chemical series nonmetals, chalcogens Group, Period, Block 16, 2, p Appearance colorless (gas) very pale blue (liquid) Standard atomic weight 15. ... Lewis electron configuration of superoxide. ... A pathogen or infectious agent is a biological agent that causes disease or illness to its host. ... H&E section of non-caseasting granuloma seen in the colon of a patient with Crohns disease In medicine (anatomical pathology), a granuloma is a group of epithelioid macrophages surrounded by a lymphocyte cuff. ...

This condition was first described in 1959 as "a fatal granulomatosis of childhood"^[3]. 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^[4]. Year 1959 (MCMLIX) was a common year starting on Thursday (link will display full calendar) of the Gregorian calendar. ... Year 1967 (MCMLXVII) was a common year starting on Sunday (link will display full calendar) of the 1967 Gregorian calendar. ...

Pathophysiology

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^[1]. Image File history File links Download high resolution version (800x610, 382 KB)Two segmented neutrophil granulocytes, surrounded by red blood cells. ... Image File history File links Download high resolution version (800x610, 382 KB)Two segmented neutrophil granulocytes, surrounded by red blood cells. ... Neutrophil granulocytes (commonly referred to as neutrophils) are a class of white blood cells and are part of the immune system. ... â€œRed cellâ€ redirects here. ... This article does not cite any references or sources. ... Monocyte A monocyte is a leukocyte, part of the human bodys immune system that protect against blood-borne pathogens and move quickly to sites of infection in the tissues. ... A macrophage of a mouse stretching its arms to engulf two particles, possibly pathogens Macrophages (Greek: big eaters, makros = long, phagein = eat) are white blood cells, more specifically phagocytes, acting in the nonspecific defense as well as the specific defense system of vertebrate animals. ... Ribbon diagram of the enzyme TIM, surrounded by the space-filling model of the protein. ... Reactive oxygen species (ROS) include oxygen ions, free radicals and peroxides both inorganic and organic. ... Phyla/Divisions Actinobacteria Aquificae Bacteroidetes/Chlorobi Chlamydiae/Verrucomicrobia Chloroflexi Chrysiogenetes Cyanobacteria Deferribacteres Deinococcus-Thermus Dictyoglomi Fibrobacteres/Acidobacteria Firmicutes Fusobacteria Gemmatimonadetes Nitrospirae Omnibacteria Planctomycetes Proteobacteria Spirochaetes Thermodesulfobacteria Thermomicrobia Thermotogae Bacteria (singular, bacterium) are a major group of living organisms. ... Steps of a macrophage ingesting a pathogen: a. ... Lewis electron configuration of superoxide. ... Reactive oxygen species (ROS) include oxygen ions, free radicals and peroxides both inorganic and organic. ...

Genetics

Most cases of chronic granulomatous disease are transmitted as a mutation on the X chromosome and are thus called an "X-linked trait"^[5]. The affected gene on the X chromosome codes for the gp91 protein p91-PHOX (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^[6]^[7]. â€¹ The template below (Expand) is being considered for deletion. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... P91-PHOX is a glycoprotein associated with chronic granulomatous disease. ... Possible meanings: Kachin Defense Army Kentucky Distillers Association Kongsberg Defence & Aerospace This page expands a three-character combination which might be any or all of: an abbreviation, an acronym, an initialism, a word in English, or a word in another language. ... A glycoprotein is a macromolecule composed of a protein and a carbohydrate (an oligosaccharide). ... In genetics, the term recessive gene refers to an allele that causes a phenotype (visible or detectable characteristic) that is only seen in a homozygous genotype (an organism that has two copies of the same allele). ...

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. Homozygote cells are diploid or polyploid and have the same alleles at a locus (position) on homologous chromosomes. ... Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive hereditary disease featuring nonimmune hemolytic anemia in response to a number of causes. ...

Image File history File links No higher resolution available. ... X-linked Recessive inheritance From http://ghr. ... Image File history File links No higher resolution available. ...

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:

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. This article is about human pneumonia. ... Look up Abscess in Wiktionary, the free dictionary. ... Septic arthritis is the invasion of the joint space by an infectious agent. ... Osteomyelitis is an infection of bone, usually caused by pyogenic bacteria or mycobacteria. ... Bacteremia (BacterÃ¦mia in British English, also known as blood poisoning or toxemia) is the presence of bacteria in the blood. ... Fungemia (also called Candidemia/Candedemia and Invasive Candidiasis) is the presence of fungi or yeasts in the blood. ... Image File history File links Download high resolution version (2100x1430, 1705 KB)The conidiophore of the fungal organism Aspergillus fumigatus. ... Image File history File links Download high resolution version (2100x1430, 1705 KB)The conidiophore of the fungal organism Aspergillus fumigatus. ... Aspergillus fumigatus is a fungus of the genus Aspergillus, and it is one of the most common Aspergillus species to cause disease in humans with a weakened immune response. ... Binomial name Rosenbach 1884 Staphylococcus aureus , (literally Golden Cluster Seed) the most common cause of staph infections, is a spherical bacterium, frequently living on the skin or in the nose of a person, that can cause a range of illnesses from minor skin infections (such as pimples, boils, and cellulitis... Binomial name Escherichia coli T. Escherich, 1885 Escherichia coli (usually abbreviated to E. coli) is one of the main species of bacteria that live in the lower intestines of warm-blooded animals (including birds and mammals) and are necessary for the proper digestion of food. ... Klebsiella pneumoniae is a gram-negative rod-shaped bacteria, and clinically the most important member of the Klebsiella genus of Enterobacteriaceae. ... Species Aspergillus caesiellus Aspergillus candidus Aspergillus carneus Aspergillus clavatus Aspergillus deflectus Aspergillus flavus Aspergillus fumigatus Aspergillus glaucus Aspergillus nidulans Aspergillus niger Aspergillus ochraceus Aspergillus oryzae Aspergillus parasiticus Aspergillus penicilloides Aspergillus restrictus Aspergillus sojae Aspergillus sydowi Aspergillus terreus Aspergillus ustus Aspergillus versicolor Aspergillus is a genus of around 200 filamentous fungi... Candida can have various meanings: Candida is a comedic play by George Bernard Shaw published in 1898 that satirizes socialist reformers in the Church of England. ...

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. Aspergillus fumigatus is a fungus of the genus Aspergillus, and it is one of the most common Aspergillus species to cause disease in humans with a weakened immune response. ...

Most people with CGD are diagnosed in childhood, usually before age 5 ^[5]. Early diagnosis is important since these people can be placed on antibiotics to ward off infections before they occur.

Laboratory findings

The nitroblue-tetrazolium (NBT) test is the original and most widely-known test for chronic granulomatous disease.^[8] It is negative in CGD, and positive in normal individuals. 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. Nitro blue tetrazolium chloride (NBT) is chemical. ... Lewis electron configuration of superoxide. ...

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. Staphylococcus aureus - Antibiotics test plate. ...

Physicians often prescribe the antibiotic trimethoprim-sulfamethoxazole to prevent bacterial infections^[9]. This drug also has the benefit of sparing the normal bacteria of the digestive tract. Fungal infection is commonly prevented with itraconazole^[10], although a newer drug of the same type called voriconazole may be more effective^[11]. The use of this drug for this purpose is still under scientific investigation. Co-trimoxazole is a bacteriostatic antibiotic combination of trimethoprim and sulfamethoxazole, in the ratio of 1 to 5, used in the treatment of a variety of bacterial infections. ... Itraconazole (marketed as SporanoxÂ® by Janssen Pharmaceutica) is a triazole antifungal agent that is prescribed to patients with fungal infections. ... Voriconazole (VfendÂ®, Pfizer) is a triazole antifungal medication used to treat serious fungal infections. ...

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^[12]. Interferons (IFNs) are natural proteins produced by the cells of the immune system of most vertebrates in response to challenges by foreign agents such as viruses, bacteria, parasites and tumor cells. ... Interferon-gamma (IFN-Î³) is a dimerized soluble cytokine that is the only member of the type II class of interferons. ... hi â€œFDAâ€ redirects here. ...

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^[13]. Diagram that shows the development of different blood cells from hematopoietic stem cell to mature cells Haematopoiesis (from Ancient Greek: haima blood; poiesis to make) (or Hematopoiesis in the United States) is the formation of blood cellular components. ...

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^[14]. Mouse embryonic stem cells with fluorescent marker. ... This article does not cite any references or sources. ...

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.^{[citation needed]}

References

^ ^a ^b Heyworth P, Cross A, Curnutte J (2003). "Chronic granulomatous disease.". Curr Opin Immunol 15 (5): 578-84. PMID 14499268.
^ 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.
^ 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
^ Baehner, RL, Nathan, DG. Leukocyte oxidase: a defective activity in chronic granulomatous disease. Science 1967; 155:835. PMID 6018195.
^ ^a ^b 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ Sabo J, Abdel-Rahman S (2000). "Voriconazole: a new triazole antifungal.". Ann Pharmacother 34 (9): 1032-43. PMID 10981251.
^ (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.
^ 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.
^ 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.

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