Basics
Description
Chronic granulomatous disease (CGD) is a rare, primary immunodeficiency caused by a genetic defect that results in an inability of phagocytes to generate superoxide, which is important in microbial killing. Affected individuals are susceptible to recurrent, life-threatening bacterial and fungal infections.
Epidemiology
Incidence
1:200,000 to 1:250,000 live births in the United States and Europe. Rates in other countries vary depending on ethnic practices and degree of intermarriage.
Risk Factors
Genetics
- Mutations in any of the 5 genes that code for the 5 subunits of the phagocyte NADPH oxidase complex (phox) can result in CGD.
- Mutations in the gp91phox subunit are responsible for 65% of cases and are inherited in an X-linked manner (1/3 of these cases are the result of a de novo mutation).
- Mutations in p47phox, p22phox, p67phox, and p40phox subunits account for the remaining cases and have an autosomal recessive inheritance.
- Mutations in the p47phox subunit are the most common cause of autosomal recessive CGD (25% of all cases).
Pathophysiology
- Phagocytes (neutrophils, monocytes, and macrophages) require NADPH oxidase to generate reactive oxygen species (ROS) in a process called the respiratory burst.
- During this process, the NADPH oxidase complex transfers an electron to molecular oxygen forming superoxide, which is eventually converted to hydrogen peroxide.
- Superoxide plays a significant role in killing bacterial and fungal pathogens both directly and through the activation of more important intraphagosomal proteases.
- The clinical phenotype of CGD is related to the level of residual superoxide production; patients who have higher levels of superoxide production have better long-term survival rates.
- Only the X-linked subunit gp91phox is phagocyte specific, and patients with defects in the autosomal subunits may also have other abnormalities such as vascular disease, diabetes, and inflammatory bowel disease.
Etiology
CGD is the result of a spontaneous or inherited genetic mutation that is present at birth.
Diagnosis
History
- Patients most commonly present in early childhood with recurrent or severe bacterial or fungal infections of the lung, skin, lymph nodes, liver, bones, and blood.
- Patients may also have a history of failure to thrive, diarrhea, anemia, abnormal wound healing, or granulomatous inflammation.
- Infecting organisms are typically catalase producing; however, catalase alone does not appear to be a significant virulence factor in animal models.
- Most common organisms include Staphylococcus aureus, Burkholderia (Pseudomonas) cepacia, Serratia marcescens, Nocardia, Aspergillus, Salmonella, Bacillus Calmette-Gu ©rin (BCG), Mycobacterium, Klebsiella pneumoniae, and Candida.
- Obtain a good maternal family history given that most common inheritance is X-linked. There may also be family history of lupus, especially maternal.
Physical Exam
- Skin and mucosa
- Dermatitis, cellulitis, impetigo, abscesses, stomatitis, gingivitis
- HEENT
- Conjunctivitis, chorioretinitis, sinusitis
- Lymphatic
- Lymphadenopathy, suppurative lymphadenitis
- Respiratory
- Gastrointestinal
- Gastric outlet obstruction hepatomegaly, splenomegaly, colitis, diarrhea, malabsorption, perirectal abscess, fistulae
- Genitourinary
- Urethral strictures, urinary tract infections
Diagnostic Tests & Interpretation
Lab
- Dihydrorhodamine 123 (DHR) test
- Uses flow cytometry to directly measure NADPH oxidase function in phagocytes
- Phagocytes take up nonfluorescent DHR. Oxidation by a normal functioning NADPH oxidase complex causes DHR to fluoresce, which is identified by flow cytometry.
- More sensitive and quantitative than older nitroblue tetrazolium (NBT) test
- Can identify NADPH positive and negative subpopulations of phagocytes, easily identifying a carrier of CGD
- May be falsely positive in patients with myeloperoxidase deficiency and SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome
- NBT test
- Historical test for CGD that is no longer widely used by immunologists
- Neutrophils with a normal NADPH complex can reduce the dye, resulting in a color change from yellow to dark blue. Neutrophils from patients with CGD cannot reduce the dye, and it remains colorless.
- Color change is assessed with microscopy, and results may be inaccurate if not performed by experienced technician.
- Genetic testing
- A diagnosis of CGD should be confirmed with genetic testing to identify the specific genetic defect.
- Identification of specific mutation can better predict the patient's clinical course.
- Identification of specific mutation is necessary for a future prenatal diagnosis.
Imaging
Obtain chest radiograph, ultrasound, CT scan, or MRI as appropriate to aid in the diagnosis and evaluation of acute infections.
Differential Diagnosis
- Genetic/metabolic
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency
- Glutathione synthetase (GS) deficiency
- Cystic fibrosis
- Immunology
- Myeloperoxidase deficiency
- Hyper IgE syndrome
- Humoral immunodeficiencies
- IRAK4 deficiency
- MyD88 deficiency
- Gastrointestinal
- Inflammatory bowel disease
Treatment
Medication
- Trimethoprim-sulfamethoxazole (TMP-SMX)
- First line for antibacterial prophylaxis; also can be used for the treatment of acute bacterial infections
- Prophylaxis dosing: 5 mg/kg/24 h TMP PO divided b.i.d., maximum 320 mg b.i.d.
- Has been shown to decrease frequency and severity of infections in CGD patients
- Itraconazole
- First line for antifungal prophylaxis
- Prophylaxis dosing: 5 mg/kg PO daily, maximum 200 mg daily
- Interferon gamma-1b
- Effective in reducing the frequency and severity of infections when used prophylactically; however, it is unclear how much additional benefit is gained when used in conjunction with TMP-SMX and itraconazole prophylaxis
- Prophylaxis dosing: 50 mcg/m2 subcutaneously 3 times weekly
- Ciprofloxacin
- Should be started prophylactically before any invasive procedure and continued for at least 24 hours afterward
- Prophylaxis dosing: 7.5 mg/kg PO q12h, maximum 500 mg q12h
- Acute infections
- Broad-spectrum IV antimicrobials: Severe infections should be treated empirically until a specific organism is identified. Treatment should cover both gram-negative and gram-positive bacteria along with fungi.
- First line: TMP-SMX, fluoroquinolones, and voriconazole
- Carbapenems, vancomycin, and amphotericin B may be considered depending on site or severity of infection.
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 establish the specific molecular diagnosis of the patient and offer genetic counseling for the future
- Can discuss treatment options, including the possibility of hematopoietic stem cell transplant
- Fever or suspected infection
- Patients with CGD tend to develop infections in unusual sites with unusual organisms. Both an infectious disease specialist and an immunologist can help with the evaluation and appropriate treatment of infections.
- Gastrointestinal symptoms or malabsorption
- Gastroenterologists can help identify and treat strictures, obstruction, and colitis.
- The diagnosis of CGD should be considered in patients with
- Recurrent lymphadenitis
- Staphylococcal hepatic abscess
- Infections with Burkholderia cepacia, Serratia marcescens, Nocardia, or Aspergillus
- Salmonella sepsis
- Perirectal or deep tissue abscesses
- Colitis in infancy
- Granulomatous lesions of the gastrointestinal or genitourinary systems
Complementary & Alternative Therapies
- Hematopoietic stem cell transplant (HSCT)
- HSCT can be a definitive cure for CGD.
- Younger patients with absence of preexisting overt infection have the best prognosis.
- Gene therapy
- May be an effective treatment of CGD in the future; however, currently still in research phase
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- Regular screening blood tests
- CBC with differential and LFTs should be performed every 6 months to monitor for any adverse effects of prophylactic medications.
- CRP and ESR should be performed regularly and at times of acute infection.
- Pulmonary function testing should be followed annually to screen for chronic lung disease.
- Patients should be screened regularly by ophthalmology for chorioretinal lesions.
- Closely monitor CGD patients and carriers for signs of systemic lupus erythematosus and other autoimmune disorders.
Prognosis
- CGD is a lifelong disease.
- Survival beyond the 4th decade is now common with antimicrobial prophylaxis and early and aggressive treatment of infections.
- Successful HSCT is curative.
Complications
CGD patients have an increased susceptibility to bacterial and fungal infections that usually are not pathogenic in normal hosts:
- Recurrent infections (see previous sections)
- 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
Additional Reading
- Cole T, Pearce MS, Cant AJ, et al. Clinical outcome in children with chronic granulomatous disease managed conservatively or with hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2013;132(5):1150-1155. [View Abstract]
- Damen GM, van Krieken JH, Hoppenreijs E, et al. Overlap, common features, and essential differences in pediatric granulomatous inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2010;51(6):690-697. [View Abstract]
- Holland SM. Chronic granulomatous disease. Hematol Oncol Clin North Am. 2013;27(1):89-99. [View Abstract]
- Kuhns DB, Alvord WG, Meller T, et al. Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med. 2010;363(27):2600-2610. [View Abstract]
- Song E, Jaishankar GB, Saleh H, et al. Chronic granulomatous disease: a review of the infectious and inflammatory complications. Clin Mol Allergy. 2011;9(1):10. [View Abstract]
Codes
ICD09
- 288.1 Functional disorders of polymorphonuclear neutrophils
ICD10
- D71 Functional disorders of polymorphonuclear neutrophils
SNOMED
- 387759001 Chronic granulomatous disease (disorder)
FAQ
- Q: Should patients with CGD receive dental prophylaxis?
- A: Yes. Antibiotic prophylaxis should be started before and continued for the 24 hours after any dental treatment likely to cause bleeding.
- Q: Can patients with CGD receive live viral vaccines?
- A: Yes. The only routine immunization that adults and children with CGD should NOT receive is BCG as it has been associated with disseminated infection.
- Q: Are all CGD patients with fever automatically admitted to the hospital?
- A: No. Although CGD patients are more prone to invasive and systemic infections, they are not necessarily admitted with every febrile episode. If there is evidence of a minor bacterial or viral infection without any concern for a more serious infection, patients may be treated as an outpatient with close monitoring. Subtle signs of an invasive infection must be taken very seriously.
- Q: Can CGD be diagnosed prenatally?
- A: Yes. Testing involves chorionic villus sampling; however, it can only be done on families with a history of CGD in which the specific mutation is known.