Chronic Granulomatous Disease - CGD

Diagnostic Algorithm

  Immunodeficiency Evaluation for Chronic Infections in Adults and Older Children Testing Algorithm

  Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm

Clinical Background

Chronic granulomatous disease (CGD) is a leukocyte function defect where phagocytic cells ingest but do not digest bacteria due to a malfunction of a nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase system. CGD is characterized by severe, recurring infections with granuloma formation.

Epidemiology

• Incidence – 1/250,000 births
• Age – mean diagnosis from birth to 65 years
• Sex – M>F by 85%

Inheritance

• Both X-linked (65-70%) and autosomal recessive forms
  • X-linked form involves mutations in the 13 exons encoding the 91-kD heavy chain of cytochrome b558 in the CYBB gene
• Most common (20-25%) autosomal recessive form involves mutations in the 47-kD cytosolic oxidase component on chromosome 7
• Two other autosomal recessive forms make up 5-10% of cases and involve the 67-kD cytosolic factor encoded on chromosome 1 and the 22-kD light chain of cytochrome b558 in the CYBA gene

Pathophysiology

• Function of neutrophils
  • Neutrophils are the first line of defense against bacterial and fungal infections
  • Neutrophils migrate to the site of infection where phagocytosis occurs at which time microbicidal reactive oxygen products are generated
  • Neutrophil granules fuse to the phagosome; other non-oxidative factors are added and assist in killing microorganisms
• CGD is a result of abnormalities of neutrophils and macrophages, which cause 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 and are produced by catalase-positive microorganisms and fungal organisms (yeasts, molds)
  • Disorder makes patients susceptible to infectious organisms that may be nonpathogenic in the normal host
• Genetic mutations within the CYBB or CYBA genes result in a 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 forms of X-linked CGD
• Gastrointestinal – nausea, diarrhea, vomiting, colitis with inflammatory bowel disease (IBD)-like manifestations
• Genitourinary – urethral strictures, bladder granulomas
• Pulmonary – encapsulated pneumonias
• Skin and musculoskeletal – lymphadenitis, skin and visceral abscesses, osteomyelitis
• Infections
  • Eventual chronic obstructive granulomas form at sites of infection
  • Characterized by bacterial and fungal infections
• Increased tendency toward development of certain autoimmune diseases
  • IBD-like manifestations with colitis, blood in stool and granuloma in GI tract

Treatment

• Early diagnosis and aggressive therapy, including use of interferon gamma and fungal and bacterial prophylaxis, markedly improves prognosis
• Recent studies indicate successful results in transplanted patients with gene therapy as a future possibility
  • Bone marrow and stem cell transplant may be curative

Diagnosis

Indications for Testing

• Severe and recurrent bacterial and fungal (yeast/mold) infections, presence of granulomas, colitis, pneumonias, osteomyelitis, lymphadenitis

Laboratory Testing

• Neutrophil oxidative burst assay (DHR) via flow cytometry – disease indicated by absence or significant alteration of activity
• Other, less-reliable tests include measurement of superoxide production, ferrocytochrome reduction, nitroblue tetrazolium test
• Non-specific testing – to rule out other disorders
  • Serum quantitative immunoglobulins
  • Complement activity enzyme immunoassay
  • CBC with differential
  • Myeloperoxidase stain
  • Neutrophil receptor profile
• Genetic testing
  • Molecular methods (PCR) to identify mutations via high-resolution melting analysis are offered on a research basis; contact appropriate medical director/laboratory

Differential Diagnosis

• Chronic recurrent infections
  • Hypogammaglobulinemia
  • Complement deficiency
  • Leukocyte adhesion deficiency type 1
  • Hyper IgE syndrome (Job syndrome)
  • Kostmann agranulocytosis
  • Autoimmune neutropenia
  • Myeloperoxidase deficiency
  • Innate immune deficiency
  • Wiskott-Aldrich syndrome
  • Severe combined immunodeficiency
  • HIV/AIDS
• Bowel disease
  • IBD
• Granulomatous
  • Sarcoidosis

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory