Chronic Granulomatous Disease - Neutrophil Oxidative Burst

Chronic Granulomatous Disease - Neutrophil Oxidative Burst

 

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

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

Treatment

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

See Also