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Chronic granulomatous disease (CGD) is a genetically heterogeneous immunodeficiency disorder resulting from an inability of phagocytes to kill bacteria and fungi that they have ingested. It is caused by any of several defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex which normally generates increased oxygen consumption (the 'respiratory burst'), essential for the clearance of phagocytosed micro-organisms.
There are a number of variations of this disease.
- The most common is an X-linked condition with mutation at the Xp21.1 locus.
- Autosomal recessive cytochrome b-positive CGD type I. There is mutation at gene locus 7q11.23.
- The type II has mutation at gene locus 1q25.
- There is also an autosomal recessive cytochrome b-negative CGD caused by an abnormality at gene map locus 16q24.
- The rarest is autosomal dominant cytochrome-b-positive form of CGD of childhood and much less is known about this than the others.
Serious disease is rarely autosomal dominant as it is self-destructive in that it kills the affected person before he or she can reproduce.
Despite the heterogenicity of this disease, the clinical picture is remarkably similar.
CGD usually presents in the first two years of life, but the presentation is occasionally delayed into the second decade of life. Initial features often involve the skin - eg, recurrent pyodermas causing perianal, axillary or scalp abscesses. Other features include fever, diarrhoea, osteomyelitis, pulmonary abscesses and granulomas, spleen abscesses, liver abscesses, lymphadenopathy and hepatosplenomegaly.
- People with CGD are susceptible both to bacterial and fungal infection and 20% suffer fungal infection. The most common fungi are Aspergillus fumigatus, Candida glabrata and Candida albicans.
- Pneumonia is the most common presentation of fungal infection.
- Infecting bacteria tend to be catalase positive. Catalase breaks down endogenous hydrogen peroxide normally produced by phagocytes. In normal circumstances these bacteria are killed by other oxygen radicals which are lacking in CGD. Pseudomonas aeruginosa can be killed by a non-oxidative mechanism although Burkholderia cepacia (previously known as Pseudomonas cepacia) does tend to be a problem.
- A staphylococcal liver abscess in a child should prompt suspicion of the disease.
Common presentations include:
- Skin infections occurring in 60 to 70%.
- Pneumonia or lung abscesses.
- Suppurative lymphadenitis.
- Diarrhoea from enteritis.
- Abscess around the anus or rectum or in the liver or spleen.
- Aspergillus infection, which may be mild or indolent at the outset.
- Granulomas of the skin.
Presentation with lymphadenopathy, hepatosplenomegaly, growth failure and stigmata of chronic skin infections is less common now, as infection can be much more effectively treated.
- There are several versions of the phagocytic oxidase activity test. The colourless nitroblue tetrazolium (NBT) is reduced to blue formazan by the activity of the phagocyte oxidase (phox) enzyme system. More recently, flow cytometry tests have provided a way to quantify the activity in the cells.
- Genetic testing is required because of the high incidence of new mutations and the difficulty of differentiating between an X-linked and an autosomal recessive in an affected male without a significant pedigree. Currently, mutations can be identified in nearly all patients and in about 90% of mothers of affected children. Prenatal screening using direct genetic sequencing of material obtained by chorionic villus sampling is now possible.
- CXR and CT imaging are very valuable in the diagnosis and management of pulmonary and hepatosplenic infections.
Management includes aggressive and prolonged administration of antibiotics and prednisone.
- Antibiotic prophylaxis is usually with continuous trimethoprim-sulfamethoxazole. Significant recent progress towards newer antibiotics (eg, linezolid) will allow survival of most patients into adulthood. All bacterial infections should be treated aggressively with broad-spectrum systemic antibiotics.
- Continuous antifungal therapy with itraconazole is effective in preventing infection by aspergillus. Amphotericin should be added for established invasive aspergillosis. Newer antifungals (eg, voriconazole and posaconazole) may well prove helpful.
- Interferon-gamma therapy improves neutrophil and monocyte function and is beneficial as lifelong therapy for infection prophylaxis. High doses of interferon-gamma are advocated during acute infection.
- Non-infectious granulomas may resolve spontaneously, and they rarely require systemic corticosteroid therapy unless vital organs are affected.
- Peripheral blood stem cell or bone marrow transplantation, while curative, has not been widely used due to the episodic nature of the infections. Improvements in the field are tilting the risk-benefit scale of these modalities and making them more desirable.
- Gene therapy has, within a period of 5-10 years, become more and more of a possibility for the future.
- Prenatal diagnosis is possible. The NBT test can be used to identify gene carriers.
- Family screening can lead to early intervention, prophylaxis and appropriate genetic counselling.
- This disease is variable in terms of severity but prognosis has certainly improved over the last few decades.
- When it was first described in the 1950s, death before the age of 10 was usual. Death rates are still highest in infancy but median survival is now 20 to 25 years with a mortality of 2 or 3% per year.
- As a general rule, those with the X-linked form tend to have a more severe disease. The mortality ranges from 3% to 5% per year.
- Fungal infections are a poor prognostic factor.
- The development of portal hypertension is also an adverse prognostic sign.
- A UK study found an estimated survival of 88% at 10 years but 55% at age 30 years.
- One study found that the most prominent reasons for death were pneumonia and pulmonary abscess (18/84 cases), septicaemia (16/84 cases) and brain abscess (4/84 cases).
Further reading & references
- CGD Society
- Assari T; Chronic Granulomatous Disease; fundamental stages in our understanding of CGD; Med Immunol. 2006; 5: 4. [full text]
- Norwicki RJ; Chronic Granulomatous Disease, Medscape, Sep 2012
- Granulomatous Disease, Chronic, X-linked, GCD; Online Mendelian Inheritance in Man (OMIM)
- Autosomal recessive cytochrome b-positive chronic granulomatous disease type I; Online Mendelian Inheritance in Man (OMIM)
- Autosomal recessive cytochrome b-positive chronic granulomatous disease type II; Online Mendelian Inheritance in Man (OMIM)
- Autosomal recessive cytochrome b-negative chronic granulomatous disease; Online Mendelian Inheritance in Man (OMIM)
- Autosomal dominant cytochrome-b-positive chronic granulomatous disease of childhood; Online Mendelian Inheritance in Man (OMIM)
- van den Berg JM, van Koppen E, Ahlin A, et al; Chronic granulomatous disease: the European experience. PLoS One. 2009;4(4):e5234. Epub 2009 Apr 21.
- Jones LB, McGrogan P, Flood TJ, et al; Special article: chronic granulomatous disease in the United Kingdom and Ireland: a comprehensive national patient-based registry. Clin Exp Immunol. 2008 May;152(2):211-8.
- Wolfe LC; Pediatric Chronic Granulomatous Disease, Medscape, Nov 2012
- Zelazny AM, Ding L, Elloumi HZ, et al; Virulence and cellular interactions of Burkholderia multivorans in chronic granulomatous disease. Infect Immun. 2009 Jul 27.
- Feld JJ, Hussain N, Wright EC, et al; Hepatic involvement and portal hypertension predict mortality in chronic granulomatous disease. Gastroenterology. 2008 Jun;134(7):1917-26. Epub 2008 Mar 4.
- Yavuz Koker M, Metin A, Ozgur TT, et al; Prenatal diagnosis of chronic granulomatous disease in a male fetus. Iran J Allergy Asthma Immunol. 2009 Mar;8(1):57-61.
- Seger RA; Modern management of chronic granulomatous disease. Br J Haematol. 2008 Feb;140(3):255-66.
- Kang EM, Malech HL; Advances in treatment for chronic granulomatous disease. Immunol Res. 2009;43(1-3):77-84.
- Bender JM, Rand TH, Ampofo K, et al; Family clusters of variant X-linked chronic granulomatous disease. Pediatr Infect Dis J. 2009 Jun;28(6):529-33.
- Shigemura T, Agematsu K, Yamazaki T, et al; Femoral Osteomyelitis due to Cladophialophora arxii in a Patient with Chronic Granulomatous Disease. Infection. 2009 Aug 7.
Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.
|Original Author: Dr Laurence Knott||Current Version: Dr Colin Tidy||Peer Reviewer: Dr Adrian Bonsall|
|Last Checked: 01/03/2013||Document ID: 1955 Version: 22||© EMIS|