Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes (neutrophils, monocytes, macrophages and eosinophils) resulting from impaired killing of bacteria and fungi^[1].

Epidemiology

CGD is rare (prevalence approximately 1 in 250,000)^[2]. CGD is caused by pathogenic variants in one of five genes that encode the subunits of phagocyte NADPH oxidase: biallelic pathogenic variants in CYBA, NCF1, NCF2 and NCF4 cause autosomal recessive CGD (AR-CGD), and mutation of CYBB causes X-linked CGD^[1].

• The most common is an X-linked condition with mutation at the Xp21.1 locus^[3].
• Autosomal recessive cytochrome b-positive CGD type I. There is mutation at gene locus 7q11.23^[4].
• The type II has mutation at gene locus 1q25^[5].
• There is also an autosomal recessive cytochrome b-negative CGD caused by an abnormality at gene map locus 16q24^[6].
• The rarest is autosomal dominant cytochrome-b-positive form of CGD of childhood and much less is known about this than the others^[7].

Presentation^{[1, 8]}

CGD may present any time from infancy to late adulthood but the vast majority of affected individuals are diagnosed before age 5 years.

CGD is characterised by severe recurrent bacterial and fungal infections and dysregulated inflammatory response resulting in granuloma formation and other inflammatory disorders such as colitis.

Infections typically include pneumonia, lymphadenitis, liver abscess, osteomyelitis and skin abscesses or cellulitis. Granulomas typically involve the bladder and gastrointestinal tract (often initially the pylorus and later the oesophagus, jejunum, ileum, caecum, rectum and perirectal area).

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.

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^[9].

Vascular damage to the liver can result in non-cirrhotic portal hypertension^[10].

Female carriers of the condition may have discoid lupus erythematosus or Jessner lymphocytic infiltrate. 

Investigation

• CGD is diagnosed by tests that measure neutrophil superoxide production via the NADPH oxidase complex. The dihydrorhodamine (DHR) test has largely replaced the nitroblue tetrazolium (NBT) test^[1].
• 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^[11].
• CXR and CT imaging are very valuable in the diagnosis and management of pulmonary and hepatosplenic infections.

Management^[1]

The use of antimicrobial prophylaxis and therapy has greatly improved overall survival. Management includes aggressive and prolonged administration of antibiotics and prednisone.

Treatment of manifestations

A definitive microbiological diagnosis is essential. Long courses of antimicrobials are often needed for adequate treatment. Abscesses may require percutaneous drainage or excisional surgery. Simultaneous administration of antimicrobials and corticosteroids can help resolve the associated heightened inflammatory response, including colitis.

Prevention of primary manifestations

Allogeneic haematopoietic stem cell transplantation (HSCT) is the only known cure for CGD. However, the indications for and timing of HSCT are yet to be resolved.

Antibacterial and antifungal prophylaxis is currently the main method of prevention. Immunomodulatory therapy with interferon gamma (IFN-gamma) is part of the prophylactic regimen in many centres.

Agents and circumstances to avoid include decayed organic matter (eg, mulching, gardening, leaf raking, house demolition, as inhalation of fungal spores can result in fulminant pneumonitis), BCG vaccination and blood transfusions that are Kell antigen-positive.

Surveillance

Regular follow-up visits can aid in early detection and treatment of asymptomatic or minimally symptomatic infections and non-infectious complications such as colitis, pulmonary granulomas and pulmonary fibrosis.

Evaluation of relatives at risk

Early diagnosis of relatives at risk allows for prompt initiation of antimicrobial prophylaxis and other treatment.

Genetic testing

Molecular genetic carrier testing and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant(s) in a family are known. Other carrier and prenatal testing options may be available if the pathogenic variant(s) in the family are not known.

Prevention

• 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^[12].

Prognosis

• 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 2-3% per year.
• X-linked form of CGD has been noted to carry a poorer prognosis compared to autosomal recessive variants. However, evidence suggests that the outcome in CGD is determined by the amount of residual NADPH oxidase activity irrespective of the mode of inheritance^[13].
• Fungal infections are a poor prognostic factor^[14].
• The development of portal hypertension is also an adverse prognostic sign^[10].
• A UK study found an estimated survival of 88% at 10 years but 55% at age 30 years^[15].
• 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)^[16].