Chronic granulomatous disease (CGD) is an uncommon primary immunodeficiency affecting the innate immune system and is characterized by recurrent and severe infections.

Epidemiology

• Incidence - 1/200,000 births
• Age - early presentation with mean age of diagnosis between 0 and 8 years
• Sex - males predominate (85%)

Inheritance

• Both X-linked (65-70%) and autosomal recessive forms
• Involves mutations in the 13 exons encoding the CYBB gene

Pathophysiology

• Neutrophils are the first line of defense against bacterial and fungal infections
• Neutrophils migrate to the site of infection where phagocytosis then occurs
• Neutrophil granules fuse to the phagosome and microbicidal reactive oxygen products are generated
• CGD involves defective microbicidal oxidant production secondary to a defect in the neutrophil respiratory burst
  • Defects result in decreased production of superoxide, hydrogen peroxide, hydroxyl radical and hypochlorite ion within neutrophil and macrophages
  • Most common infections are bacterial infections produced by catalase-positive microorganisms and fungal organisms
  • Disorder makes patients susceptible to infectious organisms that may be nonpathogenic in normal host
• Molecular defects associated with disease result in malfunction of one of the phagocyte NADPH oxidase components

Clinical Presentation

• Clinical manifestations usually appear very early in childhood, but may not present until later in life, especially with autosomal recessive or variant form of sex-linked CGD
• Gastrointestinal - nausea, diarrhea, vomiting, inflammatory bowel disease-like manifestations
• Genitourinary - urethral strictures, bladder granulomas
• Pulmonary - pneumonia
• Skin and musculoskeletal - lymphadenitis, skin and visceral abscesses, osteomyelitis
• Eventual chronic obstructive granulomas form at sites of infection
• Increased tendency toward development of certain autoimmune diseases
  • Sarcoidosis
  • Inflammatory bowel disease granulomas are somewhat different from CGD associated IBD manifestations
  • Rheumatoid arthritis

Treatment

• Early diagnosis and aggressive therapy, including use of interferon gamma and fungal prophylaxis, improves prognosis
• Recent studies indicate successful results in transplant patients

Diagnosis

• Indications for testing - severe and recurrent infections, presence of granulomas
• Laboratory Testing
  • Neutrophil oxidative burst assay (DHR) via flow cytometry - disease indicated by absence of activity
  • Other less-reliable tests include measurement of superoxide production, ferrocytochrome reduction, nitroblue tetrazolium test (NBT)
• Genetic testing
  • Molecular methods (PCR) to identify mutations via high-resolution melting analysis