Chronic Granulomatous Disease

Chronic granulomatous disease is an inherited disorder of phagocyte NADPH oxidase, which prevents production of reactive oxygen species needed to kill certain bacteria and fungi. It causes recurrent life threatening infections and inflammatory granulomas.

The incidence is about 1 in 200 000 to 250 000 births. About 65% of cases are X-linked (CYBB, gp91phox), and the remainder are autosomal recessive (CYBA, NCF1, NCF2, NCF4). Presentation is usually in the first year or two of life, but it may be delayed in autosomal recessive disease.

Typical pathogens are catalase positive organisms: Staphylococcus aureus, Aspergillus species, Burkholderia cepacia complex, Serratia marcescens, Nocardia species, Salmonella and Klebsiella.

Pathophysiology.

Failure of the respiratory burst means phagocytes can ingest but not kill catalase positive organisms. Persistent infection and impaired regulation of inflammation lead to granuloma formation.

Defective neutrophil apoptosis and clearance cause excessive inflammation and autoimmune features, including colitis.

• Recurrent pneumonia (often Aspergillus), lymphadenitis with suppuration, skin abscesses, and liver abscess (Staphylococcus aureus).
• Osteomyelitis (Serratia, Aspergillus), and perianal abscess.
• Inflammatory granulomas causing gastric outlet or urinary tract obstruction, and Crohn like colitis.
• Growth failure, discoid lupus like rash, aphthous ulcers and chorioretinal lesions.

Red flags.

• Fungal pneumonia, liver abscess or osteomyelitis from unusual organisms.
• Severe infection after BCG vaccination.
• Obstructive granuloma or severe colitis.

• Dihydrorhodamine 123 flow cytometry (neutrophil oxidative burst), which is the preferred screening test. A nitroblue tetrazolium test can also be used. Results are absent or reduced.
• Genetic testing to determine the type, with carrier testing in the family.
• Imaging (chest CT, abdominal ultrasound or CT, MRI) to locate infection. Biopsy and culture of lesions, and fungal biomarkers.
• Inflammatory markers and bowel evaluation when colitis is suspected.

Differential diagnosis. Other primary immunodeficiencies (leucocyte adhesion deficiency, hyper-IgE syndrome, Mendelian susceptibility to mycobacterial disease), cystic fibrosis, Crohn disease, tuberculosis, and malignancy.

Prophylaxis.

• Co-trimoxazole 5 mg/kg/day of the trimethoprim component as a single daily dose or in 2 divided doses.
• Itraconazole 5 mg/kg once daily (maximum 200 mg) as antifungal prophylaxis, with monitoring of levels and liver function.
• Interferon gamma 50 micrograms/m2 SC 3 times each week (1.5 micrograms/kg for body surface area of 0.5 m2 or less).

Treatment of infection.

• Early, aggressive investigation and prolonged antimicrobial therapy, directed by culture.
• Invasive aspergillosis: voriconazole IV (9 mg/kg every 12 hours on day 1, then 8 mg/kg every 12 hours; oral 9 mg/kg every 12 hours in children 2 to 12 years) or liposomal amphotericin B 3 to 5 mg/kg daily, with monitoring of drug levels. Surgical drainage or resection of abscesses. Granulocyte transfusions in life threatening infection.
• Corticosteroids: prednisolone 1 mg/kg/day short course for obstructive granulomas or severe colitis, together with antimicrobial cover.

Definitive therapy. Haematopoietic stem cell transplantation is curative and is considered for severe disease or recurrent infection, ideally with a matched donor before organ damage. Gene therapy is under development.

Monitoring. Infections, growth, liver function, drug levels, inflammatory complications and bone health. Avoid exposure to mulch, compost, hay and damp environments.

Referral and escalation. Refer to a paediatric immunology service at diagnosis.