Chronic Granulomatous Disease (CGD)

Chronic granulomatous disease is a genetically heterogeneous immunodeficiency disorder resulting from an inability of phagocytes to kill microbes that they have ingested. It is caused by any of several defects in the NADPH oxidase enzyme complex which generates the respiratory burst that is lethal to the micro-organism.

There are a number of variations of this disease.

• The commonest is an X-linked condition with mutation at the Xp21.1 locus. It is designated by OMIM as #306400.¹
• Autosomal recessive cytochrome b-positive chronic granulomatous disease (CGD) type I. There is mutation at gene locus 7q11.23 and designated #233700.²
• The type II has mutation at gene locus 1q25 and designated #233710.³
• There is an autosomal recessive cytochrome b-negative chronic granulomatous disease caused by an abnormality at gene map locus 16q24 and designated #233690.⁴
• The rarest is autosomal dominant cytochrome-b-positive form of chronic granulomatous disease of childhood and much less is known about this than the others.⁵

The frequency of all types is probably around 1 in 220,000 to 500,000 births.

A review of the condition⁶ found that:

• 76% were the X-linked variety
• 18% were autosomal recessive cytochrome b-positive chronic granulomatous disease type I
• 4% were autosomal recessive cytochrome b-positive chronic granulomatous disease type II
• 3% were autosomal dominant cytochrome-b-positive chronic granulomatous disease
• The autosomal dominant form is extremely rare

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.

• Most present in early childhood but more benign variants may present later. Over 75% present before the age of 5 years.
• The X-linked form is by far the commonest and affects boys. In the 1950s the description was of:
  • Hypergammaglobulinemia
  • Hepatosplenomegaly
  • Lymphadenopathy in boys who invariably died in the first decade of life
• In 1965, a report of 16 males in 8 families with a syndrome of chronic suppurative lymphadenitis, chronic dermatitis, chronic pulmonary disease and hepatosplenomegaly found an invariable fatal outcome.⁷
• Hypergammaglobulinaemia was often present.
• The phagocytes can ingest staphylococci but not kill them.
• They are susceptible to both bacterial and fungal infection and 20% suffer fungal infection. The commonest fungi are Aspergillus fumigatus, Torulopsis glabrata (Candida glabrata), and Candida albicans.
• Pneumonia is the commonest presentation of fungal infection.
• Infecting bacteria tend to be catalase positive although Pseudomonas aeruginosa can be killed by a different mechanism. Burkholderia cepacia (also 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 occur 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
• Osteomyelitis
• Septicaemia
• Aspergillus infection 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.

Female carriers of the condition may suffer from discoid lupus erythematosus or a skin conditon that resembles it.⁸ The degree in reduction of superoxide production was closely related to the manifestations of clinical disease.⁹ There seem to be 2 populations of leucocytes in heterozygous females.¹⁰

• 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 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.
• CXR and CT imaging are very valuable in the diagnosis and management of pulmonary and hepato-splenic infections.

• Antimicrobial prophylaxis, early and aggressive treatment of infections, and interferon gamma are the basis of treatment.
• Co-trimoxazole is the drug of choice for daily prophylaxis. It has a wide spectrum without affecting the incidence of fungal infection nor upsetting the anaerobic flora of the gut and it is well concentrated in the phagocytes
• Itraconazole looks more promising than ketoconazole in preventing fungal infection¹¹ but good RCTs are difficult in rare diseases. This one took 10 years to recruit 39 patients.
• High doses of interferon gamma are advocated during acute infection and they may well be beneficial for long term prophylaxis¹² but it is very expensive and not used routinely in Europe.
• With granuloma formation intravenous antibiotics and low dose steroids seem beneficial
• There is limited experience with bone marrow transplants but where possible it would seem to offer a cure for the disease.¹³ Stem cells treatment has not been greatly used but results seem very promising¹⁴
• Gene therapy carries great hope¹⁵

Prenatal diagnosis is possible. Fetal blood sampling was used in 1984¹⁶ but a PCR technique was used in 1992 to permit diagnosis from chorionic villus sampling.¹⁷

• This disease is variable in terms of severity but prognosis has certainly improved over the last 20 years.
• When it was first described in the 1950s, death before 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.