Advances in treatment for chronic granulomatous disease
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Advances in treatment for chronic granulomatous disease Elizabeth M. Kang · Harry L. Malech
Published online: 20 September 2008 © Springer Science+Business Media, LLC 2008
Abstract Chronic granulomatous disease (CGD) is a rare congenital disorder resulting from a failure of neutrophils to produce oxidases. Patients are therefore prone to recurrent infections from various organisms including fungi and atypical bacteria. The mortality in patients with the X-linked form of CGD, the most common type, ranges from 3% to 5% per year and although management of infections has improved with advances in antimicrobial therapies, better methods are needed to be able to cure these patients. Peripheral blood stem cell or bone marrow transplantation, while curative, is not widely used due to the episodic nature of the infections and the belief by many that conservative management is preferable to the risks of transplantation. Still, as will be discussed, improvements in the Weld are making allogenic transplantation more desirable and tilting the risk beneWt ratio in favor of this modality. Additionally, gene therapy, which has been a long touted method to cure CGD, has within the last 5–10 years become more and more of a reality and may be realized by the end of this decade. Keywords Chronic granulomatous disease · Gene therapy · Allogeneic transplantation · Autoimmune complications · Antibiotic prophylaxis · Interferon gamma
Background Chronic granulomatous disease, or CGD, is a congenital disorder with an estimated prevalence of 1/200,000 in the United States, but ranges to as low as 1/450,000 in other countries. [1, 2]. The disease arises from a defect in one of the four NADPH oxidases necessary for microbicidal oxidant production. As a result, patients are highly susceptible to catalase-positive infections including fungi, as well as developing granulomata and autoimmune complications. E. M. Kang (&) National Institutes of Health, Building 10-Room 6-3752, 10 Center Drive, Bethesda, Maryland 20892, USA e-mail: [email protected] H. L. Malech National Institutes of Health, Building 10-Room 5-3750, 10 Center Drive, Bethesda, Maryland 20892, USA
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Immunol Res (2009) 43:77–84
The most common form of this disease, consisting of 65–75% of cases, arises from mutations in the gp91 phox gene located on the X chromosome. The autosomal forms aVect the p47 phox gene (about 20% of the cases) or either the p67 phox or the p22 phox genes (remaining 5%), found on chromosomes 7, 1, and 16, respectively. The level of oxidase production appears to correlate with morbidity and mortality and patients with the X-linked form have a death rate estimated at 3–5% per year. The p22 phox mutations are biochemical isomorphs of the X-linked form. In both cases, the entire heterodimeric cytochrome b558 is missing or defective and the mortality rate is thus similar. Patients with the p67 deWciency also seem to have higher mortality compared to the p47 phox patients who have the best mortality rate estimated at 1–2% per year [3].
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