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Chronic granulomatous disease

Chronic granulomatous disease (CGD), also known as Bridges–Good syndrome, chronic granulomatous disorder, and Quie syndrome,[1] 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 due to defective phagocyte NADPH oxidase) used to kill certain ingested pathogens.[2] This leads to the formation of granulomas in many organs.[3] CGD affects about 1 in 200,000 people in the United States, with about 20 new cases diagnosed each year.[4][5]

Chronic granulomatous disease

Bridges–Good syndrome, chronic granulomatous disorder, Quie syndrome

Immunology Edit this on Wikidata

This condition was first discovered in 1950 in a series of four boys from Minnesota, and in 1957 it was named "a fatal granulomatosus of childhood" in a publication describing their disease.[6][7] 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.[8] Bernard Babior made key contributions in linking the defect of superoxide production of white blood cells, to the cause of the disease. In 1986, the X-linked form of CGD was the first disease for which positional cloning was used to identify the underlying genetic mutation.

pneumonia

of the skin, tissues, and organs

abscesses

septic arthritis

osteomyelitis

/fungemia

bacteremia

superficial skin infections such as or impetigo

cellulitis

Genetics[edit]

Most cases of chronic granulomatous disease are transmitted as a mutation on the X chromosome and are thus called an "X-linked trait".[9] The affected gene on the X chromosome codes for the gp91 protein p91-PHOX (91 is the weight of the protein in kDa; the gp means glycoprotein). CGD can also be transmitted in an autosomal recessive fashion (via CYBA, NCF1, NCF2 and NCF4) which affect other PHOX proteins. The type of mutation that causes both types of CGD are varied and may be deletions, frame-shift, nonsense, and missense.[14][15]


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.[16]

The (NBT) test is the original and most widely known test for chronic granulomatous disease.[20][21] It is negative in CGD, meaning that it does not turn blue. The higher the blue score, the better the cell is at producing reactive oxygen species. This test depends upon the direct reduction of NBT to the insoluble blue compound formazan by superoxide which is produced by normal peripheral blood neutrophils stimulated in vitro; NADPH oxidase catalyzes the aforementioned reaction and NADPH is oxidized in the same reaction. 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.

nitroblue-tetrazolium

Dihydrorhodamine (DHR) 123 test: In this test the respiratory burst of the neutrophils is stimulated with myristate acetate (PMA), resulting in oxidation of dihydrorhodamine 123 (nonfluorescent derivative of rhodamine) to rhodamine 123 (green fluorescent compound), which can be measured by flow cytometry.[22] This test is abnormal in patients with chronic granulomatous disease (i.e., there is no shift in fluorescence with stimulation). Moreover, its quantitative nature allows to differentiate oxidase-positive from oxidase-negative phagocyte subpopulations in CGD carriers and identify deficiencies in gp91phox and p47phox.[17] Modest residual production of reactive oxygen intermediates (ROI) as assessed by DHR 123 test, is associated with significantly less severe illness and a greater likelihood of long-term survival than patients with little residual ROI production.[23] On the other hand, in the case of complete myeloperoxidase deficiency, DHR test gives abnormal results (false positive for CGD) because the DHR signal yielded by flow cytometry depends on intact NADPH oxidase activity as well as the presence of a myeloperoxidase (MPO); however, NBT test demonstrates normal production of superoxide.[24]

phorbol

Prognosis[edit]

There are currently no studies detailing the long term outcome of chronic granulomatous disease with modern treatment. Without treatment, children often die in the first decade of life. The increased severity of X-linked CGD results in a decreased survival rate of patients, as 20% of X-linked patients die of CGD-related causes by the age of 10, whereas 20% of autosomal recessive patients die by the age of 35.[33]
Recent experience from centers specializing in the care of patients with CGD suggests that the current mortality has fallen to under 3% and 1% respectively.[34] CGD was initially termed "fatal granulomatous disease of childhood" because patients rarely survived past their first decade in the time before routine use of prophylactic antimicrobial agents. The average patient now survives at least 40 years.[17]

Epidemiology[edit]

CGD affects about 1 in 200,000 people in the United States, with about 20 new cases diagnosed each year.[4][5]


Chronic granulomatous disease affects all people of all races; however, there is limited information on prevalence outside of the United States. One survey in Sweden reported an incidence of 1 in 220,000 people,[35] while a larger review of studies in Europe suggested a lower rate: 1 in 250,000 people.[33]

History[edit]

This condition was first described in 1954 by Janeway, who reported five cases of the disease in children.[36] In 1957 it was further characterized as "a fatal granulomatosus of childhood".[6][7] 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.[8] Use of antibiotic prophylaxis, surgical abscess drainage, and vaccination led to the term "fatal" being dropped from the name of the disease as children survived into adulthood.

Research[edit]

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.[37]


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 and efficacy of this therapy were unknown.[38]


In 2012, a 16-year-old boy with CGD was treated at the Great Ormond Street Hospital, London with an experimental gene therapy that temporarily reversed the CGD and allowed him to overcome a life-threatening lung disease.[39]