• Gene mutations may occur spontaneously and are inherited as an X-linked variant, or autosomal recessive variant.
• Mutations may occur in any one of the four subunits of the neutrophil NADPH oxidase complex:
  • gp91-phox: X chromosome
  • p22-phox: chromosome 16
  • p47-phox: chromosome 7
  • p67-phox: chromosome 1

• Prevalence: approximately 1 in 500,000 individuals

• Recurrent skin infections
• Sepsis
• Chronic lung disease (secondary to recurrent infections)
• Chronic liver disease (secondary to recurrent infections)
• Chronic osteomyelitis of large and small bones
• Malabsorption
• Systemic and discoid lupus erythematosus: increased incidence in female carriers

• Recurrent lymphadenitis
• Staphylococcal hepatic abscess
• Aspergillus or Nocardia pneumonia
• Serratia marcescens osteomyelitis
• Infections with Pseudomonas cepacia
• Salmonella sepsis
• Perirectal abscesses
• Brain abscesses

• Leukocyte glucose-6-phosphate dehydrogenase deficiency
• Myeloperoxidase deficiency
• Humoral immune deficiencies
• Complement deficiencies

• Chronic granulomatous disease is not acquired; it is inherited as an X-linked variant or as an autosomal variant.

Question: At what age did the patient present?
Significance: Patients with chronic granulomatous disease usually present before 2 years of age with marked lymphadenopathy, hepatosplenomegaly, draining lymph nodes, and pneumonias.

Question: What is the infecting organism?
Significance: Patients with chronic granulomatous disease tend to develop infections with unusual organisms, such as: S. aureus, S epidermidis, S. marcescens, Pseudomonas, Escherichia coli, Candida, Aspergillus, Nocardia, and Salmonella.

Question: Are there other affected family members?
Significance: Chronic granulomatous disease is inherited in an X-linked and autosomal recessive pattern. Therefore, there may be other affected family members.

Question: Does the mother have lupus?
Significance: There is a higher incidence of lupus in females who are carriers for chronic granulomatous disease.

Finding: Skin abscess or boils
Significance: Patients with chronic granulomatous disease develop frequent skin infections.

Finding: Mucous membrane and perirectal infections
Significance: Patients with chronic granulomatous disease commonly develop infections at mucous membrane and epidermal junctions, especially in the perirectal area.

Finding: Lymphadenopathy
Significance: Patients with chronic granulomatous disease commonly develop lymphadenopathy and draining lymph nodes.

Finding: Hepatosplenomegaly
Significance: Hepatosplenomegaly is a common finding in patients with chronic granulomatous disease.

Finding: Abnormal lung examination
Significance: Pulmonary disease is common in patients with chronic granulomatous disease.

• General goal: Decide whether the patient’s type of infections (osteomyelitis, perirectal abscess, etc.) and infecting organisms are consistent with the diagnosis of chronic granulomatous disease.
• Order a nitroblue tetrazolium (NBT) test.
• If abnormal, initiate sulfamethoxazole/trimethoprim prophylaxis.

Test: The NBT
Significance: The NBT is the most widely available test for chronic granulomatous disease. Neutrophils from normal individuals can reduce the dye, resulting in a color change. Neutrophils from patients with chronic granulomatous disease cannot reduce the dye, and it remains colorless. Neutrophils and monocytes from patients with chronic granulomatous disease have an impaired hexose monophosphate shunt. Therefore, they have a decreased conversion of NADP to NADPH, and a decreased oxidative burst, which results in an inability to reduce the NBT in this study.

Test: The 2,7 Dichlorofluorescin (DCF)
Significance: DCF can directly measure the production of hydrogen peroxide utilizing a fluorescent label and flow cytometry. Patients with chronic granulomatous disease have decreased hydrogen peroxide production.

Test: Immunoblotting
Significance: Immunoblotting can be used to quantify the amount of each NADPH subunit present.

• A new diagnosis of chronic granulomatous disease: An immunologist can assist with antibiotic prophylaxis and with parameters for when to seek medical attention, and they can help identify which genetic variant is responsible for the patient’s disease.
• Pregnant carrier for chronic granulomatous disease: An immunologist can help with prenatal diagnosis. Furthermore, some centers may consider in utero bone marrow transplantation for an affected fetus.
• Fever or suspected infection: Patients with chronic granulomatous disease tend to develop infections in unusual sites with unusual organisms. An immunologist can help with the evaluation and appropriate antibiotic coverage.

• Antibiotic prophylaxis: Trimethoprim-sulfamethoxazole is the antibiotic of choice, because both components are concentrated in the neutrophil, and for its bacterial spectrum.
• Recombinant gamma interferon: This is reserved for patients with severe disease. This therapy may decrease the incidence of infection.
• Bone marrow transplant: Chronic granulomatous disease has been cured in patients with matched transplants.
• Acute infections:
  • Broad-spectrum intravenous antibiotics: There should be a low threshold to start this therapy. Severe infections should be treated with broad-spectrum intravenous antibiotics until an organism is identified. Good initial antibiotics include intravenous penicillins, aminoglycosides, and antipseudomonal antibiotics.
  • Amphotericin B: This should not be withheld if a fungal infection is suspected, or if the patient’s clinical status is deteriorating despite broad-spectrum antibiotics.
  • Leukocyte transfusions: These are reserved for severe infections, and efficacy is controversial.

Q: How do you interpret an NBT test reported as 50% of normal?
A: This is generally consistent with a carrier state. The carrier is not at increased risk for infection. However, carrier females have an increased risk of developing lupus.

Q: What do the infecting organisms have in common?
A: Patients with chronic granulomatous disease are most susceptible to catalase-positive organisms.

Q: Are all chronic granulomatous disease patients with fever admitted automatically?
A: No. It is true that these patients are more prone to invasive and systemic infections, but these patients are not admitted with every febrile episode (especially if there is evidence of a minor bacterial or viral infection). However, subtle signs of an invasive infection must be taken very seriously, and these patients are certainly admitted.

Q: Can a prenatal diagnosis be made?
A: Yes. However, currently this can only be done in a limited number of research laboratories, and the testing is not commercially available. Testing involves chorionic villus sampling, and it can only be done on families in which the specific mutation has been mapped.

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