Chronic Granulomatous Disease - CGD

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 – preferred test; disease indicated by absence or significant alteration of activity
• Other, less-reliable tests – measurement of superoxide production, ferrocytochrome reduction, nitroblue tetrazolium test
• Nonspecific testing to rule out other disorders
  • Serum quantitative immunoglobulins – rule out hypogammaglobulinemia
  • Complement activity enzyme immunoassay – rule out complement deficiency
  • CBC with differential – rule out other causes of chronic infection (neutropenic disorders)
  • Leukocyte adhesion deficiency panel – rule out leukocyte adhesion deficiency
• Genetic testing
  • Molecular methods (PCR) to identify mutations via high-resolution melting analysis 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
  • Celiac disease
• Granulomatous disease
  • Sarcoidosis
  • Infection 
    • Mycobacterium tuberculosis

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 the 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

• X-linked form – 60-70%
  • Involves mutations in the 13 exons encoding the 91-kD heavy chain of cytochrome b558 in the CYBB gene
    • Typically earlier onset and more severe disease than autosomal recessive CGD
• Autosomal recessive forms
  • Most common form (NCF1 gene)(20-25%) involves mutations in the 47-kD cytosolic oxidase component on chromosome 7
  • Two other autosomal recessive forms (5-10%) 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
  • First line of defense against bacterial and fungal infections
  • Migrate to the site of infection – phagocytosis occurs, which generates microbicidal reactive oxygen products
  • Neutrophil granules fuse to the phagosome
  • Other nonoxidative factors are added that assist in killing microorganisms
• CGD – result of abnormalities of neutrophils and macrophages
  • Cause defective microbicidal oxidant production secondary to a defect in the neutrophil respiratory burst
  • Result in decreased production of superoxide, hydrogen peroxide, hydroxyl radical, and hypochlorite ion within neutrophil and macrophages
  • Defect causes susceptibility to infections from organisms that may be nonpathogenic in an immunocompetent individual
    • Most common infections – bacterial produced by catalase-positive microorganisms and fungal organisms (yeasts, molds)
• Genetic mutations within the CYBB or CYBA genes – result in a malfunction of one of the phagocyte NADPH oxidase components

Clinical Presentation

• Signs and symptoms usually appear very early in childhood
  • May not present until later in life, especially with mild cases or autosomal recessive/variant forms of X-linked CGD
• Gastrointestinal – nausea, diarrhea, vomiting, colitis with inflammatory bowel disease (IBD)-like manifestations (blood in stool, granuloma in GI tract)
• 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

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

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Chronic Granulomatous Disease (NCF1) Exon 2 GT Deletion 2006366 Method: High Resolution Melt Analysis	Confirm diagnosis of autosomal recessive CGD
Chronic Granulomatous Disease, X-Linked (CYBB) Gene Scanning with Reflex to Sequencing 2006361 Method: High Resolution Melt Analysis	Confirm diagnosis of X-linked CGD
Leukocyte Adhesion Deficiency Panel 2004359 Method: Semi-Quantitative Flow Cytometry	Rule out leukocyte adhesion deficiency Panel measures CD11b, CD15, and CD18 on neutrophils

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