Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) 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 nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex which normally generate increased oxygen consumption (the 'respiratory burst'). essential for the clearance of phagocytosed micro-organisms. ¹

There are a number of variations of this disease.

• The most common is an X-linked condition with mutation at the Xp21.1 locus.²
• Autosomal recessive cytochrome b-positive CGD type I. There is mutation at gene locus 7q11.23.³
• The type II has mutation at gene locus 1q25.⁴
• There is also an autosomal recessive cytochrome b-negative CGD caused by an abnormality at gene map locus 16q24.⁵
• The rarest is autosomal dominant cytochrome-b-positive form of CGD of childhood and much less is known about this than the others.⁶

One Dutch study found a prevalence of all types of 1:250,000.⁷ A UK study found a prevalence of 7.5/million for 1990-1999 and 8.5/million for 1980-1989.⁸

A review of the condition⁹ found that:

• 76% were the X-linked variety
• 18% were autosomal recessive cytochrome b-positive CGD type I
• 4% were autosomal recessive cytochrome b-positive CGD type II
• 3% were autosomal dominant cytochrome-b-positive CGD
• 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 most common and affects boys. In the 1950s the description was of:
  • Hypergammaglobulinaemia
  • 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.¹⁰
• Hypergammaglobulinaemia was often present.
• The phagocytes can ingest staphylococci but not kill them.
• They 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.¹¹ Pseudomonas aeruginosa can be killed by a non-oxidative mechanism although Burkholderia cepacia (previously known as Pseudomonas cepacia) does tend to be a problem.¹²
• 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
• Osteomyelitis
• Septicaemia
• Aspergilloid 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.

Vascular damage to the liver can result in non-cirrhotic portal hypertension.¹³

Female carriers of the condition may suffer from discoid lupus erythematosus or a skin condition that resembles it.¹⁴ The degree in reduction of superoxide production was closely related to the manifestations of clinical disease.¹⁵ There seem to be 2 populations of leucocytes in heterozygous females.¹⁶

• 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. Pre-natal screening using direct genetic sequencing of material obtained by chorionic villus sampling is now possible.¹⁷
• 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 has been 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. A significant recent progress towards newer antibiotics (e.g. linezolid) will allow survival of most patients into adulthood.¹⁸
• Itraconazole looks more promising than ketoconazole in preventing fungal infection but good RCTs are difficult in rare diseases.¹⁹ This one took 10 years to recruit 39 patients. Newer antifungals (e.g. voriconazole and posaconazole) may well prove helpful.¹⁸
• High doses of interferon-gamma are advocated during acute infection and they may well be beneficial for long-term prophylaxis but it is very expensive and not used routinely in Europe.²⁰
• With granuloma formation, intravenous antibiotics and low-dose steroids seem beneficial.
• Peripheral blood stem cell or bone marrow transplantation, while curative, have 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.²¹
• Gene therapy has, within the last 5-10 years, become more and more of a reality and may be realised by the end of this decade.²¹

Prenatal diagnosis is possible. Fetal blood sampling was used in 1984 but a polymerase chain reaction (PCR) technique was used in 1992 to permit diagnosis from chorionic villus sampling.^22,23

Family screening can lead to early intervention, prophylaxis and appropriate genetic counselling.²⁴

• 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. The mortality ranges from 3% to 5% per year.²¹
• Fungal infections are a poor prognostic factor.²⁵
• The development of portal hypertension is also an adverse prognostic sign.¹³
• A UK study found an estimated survival of 88% at 10 years but 55% at age 30 years.⁸
• 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).⁷