Chronic Granulomatous Disease

Chronic granulomatous disease (CGD), as the name implies, is a chronic disorder that is characterized by granuloma formation. This disorder is a consequence of defective phagocytic cells that are unable to produce bactericidal superoxide because of a defect in nicotinamide adenine dinucleotide phosphate (NADPH), the oxidase responsible for the respiratory burst in phagocytic leukocytes. The diagnosis is made by testing neutrophil function for superoxide production. Patients with CGD are at increased risk of life-threatening infections with fungi and catalase-positive bacteria. Inflammatory complications such as CGD colitis are also possible. The introduction of antimicrobial prophylaxis and the use of azole antifungals has increased the overall life expectancy of these patients.

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Epidemiology and Etiology

Epidemiology

  • Equally identified in all ethnicities and races
  • Estimated incidence: approximately 1 case per 200,000 people per year
  • Predominant in males (65%–70% of cases are from an X-linked mutation)
  • Mortality:
    • Most patients survive until adulthood.
    • Mortality elevated after age > 10 years
    • X-linked form of the disease is associated with the highest mortality and morbidity.

Etiology

Chronic granulomatous disease (CGD) is caused by mutations in the genes encoding for constituents of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase: 

  • Gp91phox (X-linked disorder)
  • P47phox (NCF1 gene found on chromosome 7, autosomal inheritance)
  • P22phox (autosomal recessive)
  • P67phox (autosomal recessive)

Pathophysiology

Normal phagocytosis pathway

  • Neutrophils phagocytose bacteria and other pathogens
  • ↑ Oxygen consumption 
  • Produce different reactive oxidant species, which are bactericidal 

Pathophysiology of CGD

The NADPH-oxidase enzyme is impaired in phagocytic cell → ↓ production of superoxide anion O2, which affects other oxidants. This enzyme is responsible for the inability to fight infections.

  • Catalase-positive microorganisms are implicated in life-threatening infections:
    • Burkholderia cepacia
    • Aspergillus
    • Candida albicans
    • Staphylococcus aureus
    • Nocardia spp.
  • Although Pseudomonas aeruginosa is catalase-positive, it is killed by neutrophils in CGD patients.
  • Catalase-negative microorganisms can still be killed by phagocytes.
Process of phagocytosis in neutrophils

Process of phagocytosis in neutrophils:
A deficiency in NADPH oxidase results in an inability to produce superoxide, which diminishes the cell’s ability to destroy catalase-positive microorganisms.

Image by Lecturio. License: CC BY-NC-SA 4.0

Clinical Presentation

General presentation

Most CGD patients are < 5 years of age, and the severity is variable (depending on the genetic defect). Clinical presentation can include:

  • Growth failure
  • Abnormal wound healing
  • Infections

Infections

Patients may experience repeated infections caused by bacterial and fungal pathogens.

  • Patients exhibit few clinical symptoms and signs despite the severity of infection
  • Viral infection response is normal
  • An infectious etiology should always be searched for in any child presenting with a fever.
  • Types of infections include:
    • Pneumonia
    • Abscesses (perianal, perirectal, liver)
    • Suppurative adenitis
    • Osteomyelitis
    • Bacteremia/fungemia
    • Superficial skin infections (cellulitis/impetigo)

Inflammatory and other manifestations

  • Granulomata: mostly in GI and genitourinary tracts
  • GI manifestations:
    • Diarrhea 
    • Colitis
    • Proctitis
    • Fistulae 
    • Vomiting
    • Constipation
  • Hepatic:
    • Elevated liver enzymes
    • Hepatitis
    • Liver abscesses 
    • Portal hypertension
  • Ophthalmic:
    • Chorioretinal lesions (mostly X-linked CGD)
  • Pulmonary:
    • Bronchiectasis
    • Chronic fibrosis

Diagnosis

General evaluation

  • Hypergammaglobulinemia → chronic inflammation
  • ↓ Circulating B cells
  • CD4 T-cell lymphocytopenia
  • Anemia of chronic disease
  • ↑ Markers of inflammation (erythrocyte sedimentation rate (ESR) and CRP)
  • Hypoalbuminemia
  • Imaging studies are dictated according to the presenting infectious process.

Specific laboratory evalution

Neutrophil function tests should be done:

  • Nitroblue tetrazolium test: normal phagocytes reduce NBT to blue formazan 
  • Dihydrorhodamine (DHR) test:
    • More accurate than nitroblue tetrazolium test for the diagnosis of CGD
    • DHR results: phagocytes are unable to ↓ DHR in the fluorescent active compound, rhodamine
    • The extent of conversion varies based on the genetic mutation.

Molecular genetic testing and genotyping:

  • Indicated in familial cases of CGD
  • Can be used on chorionic villus sampling for previously identified mutations

Biospy

  • Performed when granulomas form
  • Histologic examination: 
    • Necrotic centers
    • Layers of histiocytes and macrophages

Management

  • Hematopoietic stem cell transplantation from a HLA-compatible donor
  • Antimicrobial prophylaxis (trimethoprim–sulfamethoxazole is considered 1st-line treatment)
  • Aggressive treatment of current infections 
    • Skin infections: IV ciprofloxacin
    • Fungal pneumonia: voriconazole or posaconazole for up to 6 months
  • Administration of interferon-gamma
  • Surgical drainage of abscesses
  • Gene therapy is undergoing extensive research and development.

Differential Diagnosis

  • Cystic fibrosis (CF): autosomal recessive disorder. Most carriers of the CF gene are asymptomatic, and the disease manifests as an exocrine gland dysfunction that involves multiple organ systems but usually results in chronic respiratory infections, pancreatic enzyme insufficiency, and associated complications in untreated patients. Pulmonary involvement occurs in 90% of patients who survive the neonatal period. End-stage lung disease is the principal cause of death
  • Hyperimmunoglobulin E syndrome (HIES): first described as Job syndrome in 1966. Hyperimmunoglobulin E syndrome is characterized by recurrent skin abscesses, recurrent pneumonia with pneumatocele, eczematous dermatitis, and elevated serum IgE levels. HIES was initially reported to have an autosomal dominant inheritance pattern, but cases with autosomal recessive inheritance and sporadic cases have been reported
  • Crohn’s disease (in patients with inflammation limited to the rectum): idiopathic, chronic regional enteritis that most commonly affects the terminal ileum but has the potential to affect any part of the GI tract from mouth to anus. CD is defined by transmural inflammation that lacks continuity along the intestine (skip areas). In some cases, CD has nonnecrotizing granulomas containing epithelioid histiocytes. Patients present with typical signs of CD including abdominal pain, bloody diarrhea, and in severe cases by intestinal fistulas, intramural abscesses, and bowel obstruction.

References

  1. Zerbe CS, Marciano BE, Holland SM. (2021). Chronic granulomatous disease: pathogenesis, clinical manifestations, and diagnosis. UpToDate. Retrieved March 22, 2021, from https://www.uptodate.com/contents/chronic-granulomatous-disease-pathogenesis-clinical-manifestations-and-diagnosis
  2. Fischer, A. (2018). Primary Immune Deficiency Diseases. In Jameson JL, et al. (Ed.), Harrison’s Principles of Internal Medicine (20th ed., ch. 344).

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