Chronic Granulomatous Disease (CGD)

Epidemiology

General Epidemiology

  • Prevalence: rare (occurs 1 in 200k live births)
  • Sex: affects mostly males (as most mutations are X-linked)
  • Age of Presentation: most cases present in pediatric population
    • Approximately 76% of Cases are Diagnosed Before Age 5
    • Approximately 10% of Cases are Diagnosed in Second Decade of Life (Teens)
    • However, the Clinical Presentation Can Vary Considerably and the Age of First Severe Infection May Occur in Adulthood
    • Age of Onset Varies with Genetics: for unclear reasons, autosomal recessive variants have later age of onset than X-linked variants

Disease Associations

  • In Contrast to Many Other Immunodeficiency States, Chronic Granulomatous Disease is Not Believed to Be Associated with an Increased Risk of Neoplasia

Genetics and Etiology

X-Linked Recessive

  • Frequency: accounts for 65% of cases
  • Defects
    • Defect in NADPH Oxidase 91-kDa Plasma Membrane Subunit
      • Involved in Forming the b-558 Heterodimeric Cytochrome Plasma Membrane Protein
  • Clinical Manifestations
    • X-Linked Pattern of Inheritance Has Earlier Onset of Disease, More Severe Clinical Manifestations, and Higher Mortality Rate Than the Autosomal Recessive Pattern of Inheritance: for unclear reasons

Autosomal Recessive

General Comments

  • Frequency: accounts for 35% of cases
  • Defects
    • Defect in NADPH Oxidase 22-kDa Plasma Membrane Subunit
      • Accounts for <5% of All CGD Cases
      • Involved in Forming the b-558 Heterodimeric Cytochrome Plasma Membrane Protein
    • Defect in NADPH Oxidase 40-kDa Cytoplasmic Subunit
      • Defect in this Gene Has Been Associated with Severe Inflammatory Bowel Disease in a Single Child with Impaired Respiratory Burst Activity
    • Defect in NADPH Oxidase 47-kDa Cytoplasmic Subunit
      • Accounts for 25% of All CGD Cases
      • Involved in Forming a Cytoplasmic Protein, Which Interacts with the Cytochrome Following Cell Activation
    • Defect in NADPH Oxidase 67-kDa Cytoplasmic Subunit
      • Accounts for <5% of All CGD Cases
      • Involved in Forming a Cytoplasmic Protein, Which Interacts with the Cytochrome Following Cell Activation
  • Clinical Manifestations
    • Autosomal Recessive Pattern of Inheritance Has Later Onset of Disease, Less Severe Clinical Manifestations, and Lower Mortality Rate Than the X-Linked Recessive Pattern of Inheritance: for unclear reasons

Physiology

Defective NADPH Oxidase in Neutrophil and Mononuclear Phagocytes

  • Impaired Respiratory Burst Oxidase Activity, Resulting in Impaired Hydrogen Peroxide (H2O2) Synthesis (Hydrogen Peroxide and Chloride are Substrates for Neutrophil and Mononuclear Phagocyte Myeloperoxidase, Resulting in the Synthesis of Hypochlorite, Which Has a Bactericidal Effect)
    • Inability to Defend Against a Specific Subset of Catalase-Positive Organisms: catalase allows organisms to degrade their own hydrogen peroxide
    • Intact Defense Against Streptococcus: as this organism produces hydrogen peroxide, providing the phagocyte with the oxidant which it is unable to synthesize
    • Excessive Inflammatory Reaction: due to abnormal inability to degrade antigens and chemoattractants -> inability to turn off local inflammatory process
    • Granuloma Formation: due to impaired killing of intracellular organisms by macrophages

Diagnosis

Nitroblue Tetrazolium Test (NBT) (see Nitroblue Tetrazolium Test)

  • Older Test: no longer used in many labs
  • Nitroblue Tetrazolium Test: abnormal
    • Failure of the patient’s activated neutrophils to reduce NBT is virtually pathognomonic of CGD
  • False-Positive Test

Dihydrorhodamine Test (see Dihydrorhodamine Test)

  • Newer Test: currently used in most labs
  • Dihydrorhodamine Test: abnormal
  • Technique: patient’s neutrophils are incubated with catalase + dihydrorhodamine 123 (DHR), then stmulated with the mitogen, phorbol 12-myristate 13-acetate (PMA) -> DHR oxidation to rhodamine is assessed using flow cytometry, giving a stimulation index (index of stimulated vs unstimulated cells)

Immunoblot (Western Blot) of Neutrophil Proteins

  • Confirmatory Test: elucidates the specific missing subunit

Gene Sequencing

  • Usually Also Performed

Clinical Manifestations

Dental Manifestations

Dermatologic Manifestations

  • Cellulitis/Impetigo (see Cellulitis)
  • Chronic Inflammation of Nares: nasal crusting
  • Seborrheic Dermatitis
  • Skin Abscess (see Skin Abscess)

Gastrointestinal/Hepatic Manifestations

Neurologic Manifestations

Otolaryngologic Manifestations

Pulmonary Manifestations

Other Manifestations


Vaccination

  • xxxxx

Treatment

Chronic Antimicrobial Prophylaxis

  • Sulfamethoxazole-Trimethoprim (Bactrim, Septra) (see Sulfamethoxazole-Trimethoprim)
    • Bacterial Prophylaxis
  • Itraconazole (see Itraconazole)
    • Indicated for Fungal Prophylaxis
    • Potential Hepatotoxicity May Limit its Use

Subcutaneous Interferon-γ-1b (Actimmune) (see Interferon Gamma-1b)

  • Pharmacology
    • Will not Increase the Respiratory Burst of Neutrophils in Patients Who are Totally Lacking the Ability to Generate Superoxide
    • Believed to Increase Neutrophil/Monocyte Expression of Fc Receptors, Adhesion Molecules, and HLA-DR, Enhancing Microbial Clearance
    • In X-linked Cases, Interferon-γ Enhances Granulocyte Cytochrome b Expression, Enhancing Superoxide Generation
  • Clinical Efficacy
    • Useful to Decrease the Number of Serious Bacterial and Fungal Infections
  • Administration: 3x per week
  • Disadvantages
    • Cost
    • Need for Administration by Injection
  • Adverse Effects: both of which may be decreased by acetaminophen pre-treatment and administering interferon gamma-1b before bedtime

Systemic Corticosteroids (see Corticosteroids)

  • Indications
    • Used in Some Cases (for a Few Weeks) to Resolve the Granulomatous Process (Particularly in Cases with Obstructive Granulomas)

Allogeneic Hematopoietic Stem Cell Transplant (SCT) (see Hematopoietic Stem Cell Transplant)

  • May be Curative
  • Unresolved Issues Related to Stem Cell Transplantation
    • Proper Degree of Immune Ablation Prior to Stem Cell Transplant
    • Proper Degree of T-cell Depletion of the Allograft
    • Appropriate Prophylaxis to Prevent Graft vs Host Disease (see Graft vs Host Disease)

Gene Therapy

  • Experimental

Prognosis

  • Mortality Rate: with current prophylaxis, mortality has decreased to 2 deaths per 100 patients per year, with life expectancy extended well into adulthood

Insurability

  • In California, Children with Pre-Existing Conditions Cannot Be Denied Coverage
  • Children Can Currently Remain on Their Parents Insurance Coverage Until Age 26
  • California Children’s Services (CCS): children up to age 21 can get health care (provided that their parents meet the financial criteria of income <$40k per year, medical expenses >20% of family’s adjusted gross income, or qualifications for Medi-Cal with full benefits or Healthy Families Insurance)

References

  • Invasive pulmonary infection due to Scedosporium apiospermum in two children with chronic granulomatous disease. Clin Infect Dis. 1998;27(6):1437 [MEDLINE]