Chronic Granulomatous Disease (CGD)

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 Dcade 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
  • Lack of Association with Neoplasia: CGD is not associated with an increased risk of neoplasia (in contrast to many other immunodeficiency states)

Genetics and Etiology

X-Linked Recessive (65% of cases)

  • General Comments: for unclear reasons, patients with this genetic etiology have more severe clinical manifestations, earlier onset of disease, and higher mortality rates than those with autosomal recessive variants of CGD
  • Defect in NADPH Oxidase 91-kDa Plasma Membrane Subunit: involved in forming the b-558 heterodimeric cytochrome plasma membrane protein

Autosomal Recessive (35% of cases)

  • General Comments: for unclear reasons, patients with this genetic etiology have less severe clinical manifestations, later age of onset, and lower mortality rate than those with X-linked variants of CGD
  • Defect in NADPH Oxidase 22-kDa Plasma Membrane Subunit: accounts for <5% of 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 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 CGD cases
    • Involved in forming a cytoplasmic protein, which interacts with the cytochrome following cell activation

Physiology

  • Defective NADPH Oxidase in Neutrophil and Mononuclear Phagocytes: impaired respiratory burst oxidase activity -> impaired hydrogen peroxide (H2O2) synthesis (hydrogen peroxide and chrloride are substrates for neutrophil and mononuclear phagocyte myeloperoxidase, resulting in 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)

  • 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
    • Positive NBT test can also be seen in very severe glucose-6-phosphate dehydrogenase deficiency (these patients will also have severe hemolytic anemia) (see Glucose-6-Phosphate Dehydrogenase Deficiency, [[Glucose-6-Phosphate Dehydrogenase Deficiency]])

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

Clinical Manifestations

Dental Manifestations

Dermatologic Manifestations

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

Gastrointestinal/Hepatic Manifestations

  • Gastroenteritis (see Gastroenteritis, [[Gastroenteritis]])
  • Hepatic Abscess (Pyogenic Liver Abscess, [[Pyogenic Liver Abscess]])
  • Obstructive Granulomas of Gastrointestinal Tract
  • Peri-Anal Abscess

Neurologic Manifestations

Otolaryngologic Manifestations

Pulmonary Manifestations

Other Manifestations

  • Lymphadenopathy (see Lymphadenopathy, [[Lymphadenopathy]])
  • Lymphadenitis (see Lymphadenopathy, [[Lymphadenopathy]]): with suppurative drainage
  • Obstructive Granulomas of Genitourinary Tract
  • Osteomyelitis (see Osteomyelitis, [[Osteomyelitis]])
  • Sepsis (see Sepsis, [[Sepsis]])

Treatment

Chronic Antimicrobial Prophylaxis

  • Sulfamethoxazole-Trimethoprim (Bactrim, Septra) (see Sulfamethoxazole-Trimethoprim, [[Sulfamethoxazole-Trimethoprim]]): bacterial prophylaxis
  • Itraconazole (see Itraconazole, [[Itraconazole]]): may be used in some cases for fungal prophylaxis
    • However, potential hepatotoxicity typically limits its use to treatment of fungal infections, rather than fungal prophylaxis

Subcutaneous Interferon Gamma-1b (Actimmune) (see Interferon Gamma-1b, [[Interferon Gamma-1b]])

  • Pharmacology
    • Will not increase the respiratory burst of neutrophils from 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 gamma 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
    • Fever (see Fever, [[Fever]])
    • Myalgias (see Myalgias, [[Myalgias]])

Systemic Corticosteroids (see Corticosteroids, [[Corticosteroids]])

  • Indications: used in some cases (for a few weeks) to resolve the granulomatous process (particularly in cases with obstructive granulomas)

Allogeneic Bone Marrow Transplant/Stem Cell Transplant (see Bone Marrow Transplant/Stem Cell Transplant, [[Bone Marrow 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, [[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

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