Chronic Granulomatous Disease
Chronic Granulomatous Disease: Excerpt from The 5-Minute Pediatric Consult
Mathew Fogg, MD
Chronic Granulomatous Disease - BASICS
Chronic Granulomatous Disease - description
Rare inherited defect involving phagocytes. The defective phagocytes (neutrophils and monocytes) have a decreased or absent ability to generate reactive oxygen intermediates, leaving the host susceptible to recurrent bacterial and fungal infections.
Chronic Granulomatous Disease - epidemiology
Chronic Granulomatous Disease - prevalence
~1 in 500,000 individuals
Chronic Granulomatous Disease - risk factors
Chronic Granulomatous Disease - genetics
- Gene mutations may occur spontaneously and are inherited as an X-linked variant or autosomal recessive variant.
- Mutations may occur in any 1 of the 4 subunits of the neutrophil NADPH oxidase complex.
Chronic Granulomatous Disease - pathophysiology
- Associated defects involve the NADPH oxidase complex of the neutrophil.
- Neutrophils in chronic granulomatous disease (CGD) have an impaired ability to combat infection via an impaired respiratory burst.
- The NADPH oxidase complex is composed of 4 subunits, any of which may be defective in CGD.
- 60% of patients with CGD have a defect in the gp91-phox subunit, which is inherited in an X-linked manner.
- 33% of patients have a defect in the p47-phox subunit, which is inherited in an autosomal recessive manner.
- Defects occur less frequently in the p22-phox and p67-phox subunits.
Chronic Granulomatous Disease - etiology
CGD is not acquired; it is inherited as an X-linked variant or as an autosomal variant.
Chronic Granulomatous Disease - DIAGNOSIS
Chronic Granulomatous Disease - signs & symptoms
- General goal: Decide whether the patient’s type of infections (osteomyelitis, perirectal abscess) and infecting organisms are consistent with the diagnosis of CGD.
- Order a DCF or DHR assay.
- If abnormal, initiate sulfamethoxazole/trimethoprim prophylaxis.
Chronic Granulomatous Disease - history
- Usually present <2 years of age with marked lymphadenopathy, hepatosplenomegaly, draining lymph nodes, and pneumonias
- Tend to develop infections with unusual organisms, such as Staphylococcus aureus, S. epidermidis, Serratia marcescens, Pseudomonas, Escherichia coli, Candida, Aspergillus, Nocardia, and Salmonella
- Disease is inherited in an X-linked and autosomal recessive pattern. Therefore, there may be other affected family members.
- Mother with lupus: There is a higher incidence of lupus in females who are carriers for CGD.
Chronic Granulomatous Disease - physical exam
- Skin abscess or boils: Patients develop frequent skin infections.
- Mucous membrane and perirectal infections: Patients commonly develop infections at mucous membrane and epidermal junctions, especially in the perirectal area.
- Lymphadenopathy: Patients commonly develop lymphadenopathy and draining lymph nodes.
- Hepatosplenomegaly: Common finding in patients with CGD
- Abnormal lung examination: Pulmonary disease common in patients with CGD
Chronic Granulomatous Disease - tests
Chronic Granulomatous Disease - lab
- Nitroblue tetrazolium test:
- Older test for CGD, no longer widely used by immunologists
- Neutrophils from normal individuals can reduce the dye, resulting in a color change. Neutrophils from patients with CGD cannot reduce the dye, and it remains colorless.
- Neutrophils and monocytes from patients with CGD 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 nitroblue tetrazolium in this study.
- Results may be inaccurate if not performed by experienced technician.
- DCF or DHR assay:
- Can directly measure the production of hydrogen peroxide using a fluorescent label and flow cytometry
- Patients with CGD have decreased hydrogen peroxide production.
- DHR and DCF are very similar tests.
- Immunoblotting: Can be used to quantify the amount of each NADPH subunit present
Chronic Granulomatous Disease - differencial diagnosis
- Infectious: Infections are related to the immune deficiency.
- Genetic/Metabolic:
- Leukocyte glucose-6-phosphate dehydrogenase deficiency
- Myeloperoxidase deficiency
- Humoral immune deficiencies
- Complement deficiencies
Chronic Granulomatous Disease - TREATMENT
Chronic Granulomatous Disease - special therapy
Bone marrow transplant: CGD has been cured in patients with matched transplants.
Chronic Granulomatous Disease - medication
- Antibiotic prophylaxis: Trimethoprim- sulfamethoxazole is the antibiotic of choice, because both components are concentrated in the neutrophil and for its bacterial spectrum.
- Recombinant interferon-γ:
- Reserved for patients with severe disease
- May decrease the incidence of infection
- Acute infections:
- Broad-spectrum IV antibiotics: Should be a low threshold to start this therapy. Severe infections should be treated with broad-spectrum IV antibiotics until an organism is identified. Good initial antibiotics include IV penicillins, aminoglycosides, and antipseudomonal antibiotics.
- Amphotericin B: 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: Reserved for severe infections; efficacy is controversial.
Chronic Granulomatous Disease - FOLLOW UP
Chronic Granulomatous Disease - disposition
Chronic Granulomatous Disease - issues for referral
Factors that may help alert you to make a referral:
- New diagnosis of CGD:
- Immunologists can assist with antibiotic prophylaxis and with parameters for when to seek medical attention.
- Can help identify which genetic variant is responsible for the patient’s disease
- Pregnant carrier for CGD:
- Immunologists can help with prenatal diagnosis.
- Some centers may consider in utero bone marrow transplantation for an affected fetus.
- Fever or suspected infection: Patients with CGD tend to develop infections in unusual sites with unusual organisms. An immunologist can help with the evaluation and appropriate antibiotic coverage.
Chronic Granulomatous Disease - prognosis
- Survival beyond the 4th decade is common.
- Bone marrow transplantation is curative.
Chronic Granulomatous Disease - complications
These patients have an increased susceptibility to bacterial and fungal infections that usually are not pathogenic in normal hosts:
- 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
The diagnosis of CGD should be considered in patients with:
- Recurrent lymphadenitis
- Staphylococcal hepatic abscess
- Aspergillus or Nocardia pneumonia
- Serratia marcescens osteomyelitis
- Infections with Pseudomonas cepacia
- Salmonella sepsis
- Perirectal abscesses
- Brain abscesses
Chronic Granulomatous Disease - patient monitoring
- CGD is a lifelong disease.
- Patients tend to develop chronic lung disease; therefore, pulmonary function studies should be followed at least annually.
- Liver disease is also common; therefore, liver function studies should also be followed at least annually.
- Female carriers should be observed for signs of lupus erythematosus.
Chronic Granulomatous Disease - bibliography
- Horwitz ME, Barrett AJ, Brown MR, et al. Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft. N Engl J Med. 2001;344:881–888.
- Jirapongsananuruk O, Malech HL, Kuhns DB, et al. Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease, based on the dihydrorhodamine 123 assay. J Allergy Clin Immunol. 2003;111:374–379.
- Kamani N, Douglas SD. Natural history of chronic granulomatous disease. Diagn Clin Immunol. 1988;5:314–317.
- Schappi MG, Klein NJ, Lindley KJ, et al. The nature of colitis in chronic granulomatous disease. J Pediatr Gastroenterol Nutr. 2003;36:623–631.
- Hernandez M, Bastian JF. Immunodeficiency in childhood. Curr Allergy Asthma Rep. 2006;6(6):468–474.
- Fleisher TA. Back to basics: Primary immune deficiencies: Windows into the immune system. Pediatr Rev. 2006;27(10):363–372.
Chronic Granulomatous Disease - CODES
Chronic Granulomatous Disease - icd9
288.1 Functional disorders of polymorphonuclear neutrophils (Chronic [childhood] granulomatous disease)
Chronic Granulomatous Disease - FAQ
- Q: What do the infecting organisms have in common?
- A: Patients with CGD are most susceptible to catalase-positive organisms.
- Q: Are all CGD 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 be done only in a limited number of research laboratories, and the testing is not commercially available. Testing involves chorionic villus sampling, and it can be done only on families in which the specific mutation has been mapped.
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Book Source Details
- Book Title: The 5-Minute Pediatric Consult
- Author(s): M. William Schwartz MD; et al.
- Year of Publication: 2008
- Copyright Details: The 5-Minute Pediatric Consult, Copyright © 2008 Lippincott Williams & Wilkins.
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Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.
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More About This Book:
Title: The 5-Minute Pediatric Consult
Authors: M. William Schwartz MD; et al.
Publisher: Lippincott Williams & Wilkins
Copyright: 2008
ISBN: 0-7817-7577-9
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