Chronic Granulomatous Disease
Jennifer W Leiding, MD and Steven M Holland, MD.Author Information
Initial Posting: August 9, 2012; Last Update: February 11, 2016.
Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes (neutrophils, monocytes, macrophages, and eosinophils) resulting from impaired killing of bacteria and fungi. CGD is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory response resulting in granuloma formation and other inflammatory disorders such as colitis. Infections typically involve the lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis); granulomas typically involve the genitourinary system (bladder) and gastrointestinal tract (often the pylorus initially, and later the esophagus, jejunum, ileum, cecum, rectum, and perirectal area). Some males with X-linked CGD have McLeod neuroacanthocytosis syndrome as the result of a contiguous gene deletion. CGD may present any time from infancy to late adulthood; however, the vast majority of affected individuals are diagnosed before age five years. Use of antimicrobial prophylaxis and therapy has greatly improved overall survival.
CGD is diagnosed by tests that measure neutrophil superoxide production via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex: the dihydrorhodamine (DHR) test has largely replaced the nitroblue tetrazolium (NBT) test, the oldest and most recognized diagnostic test for CGD. CGD is caused by pathogenic variants in one of five genes that encode the subunits of phagocyte NADPH oxidase: biallelic pathogenic variants inCYBA, NCF1, NCF2, and NCF4 cause autosomal recessive CGD (AR-CGD); mutation of CYBB causes X-linked CGD.
Treatment of manifestations: A definitive microbiologic diagnosis is essential to proper treatment of infections. Newer azole drugs (voriconazole, posaconazole, isovuconazole) have expanded therapeutic options for fungal infections. Long courses of antimicrobials are often needed for adequate treatment. Abscesses may require percutaneous drainage or excisional surgery. Simultaneous administration of antimicrobials and corticosteroids can help resolve the associated heightened inflammatory response, including colitis.
Prevention of primary manifestations: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known cure for CGD; however, indications for and timing of HSCT are yet to be resolved. Antibacterial and antifungal prophylaxis is the cornerstone of prevention; immunomodulatory therapy with interferon gamma (IFN-gamma) is part of the prophylactic regimen in many centers.
Surveillance: Regular follow-up visits can aid in early detection and treatment of asymptomatic or minimally symptomatic infections and non-infectious complications such as colitis, pulmonary granulomas, and pulmonary fibrosis.
Agents/circumstances to avoid: (1) Decayed organic matter (e.g., mulching, gardening, leaf raking, house demolition) as inhalation of fungal spores can result in fulminant pneumonitis; (2) bacille Calmette-Guérin (BCG) vaccination; (3) Persons with CGD and McLeod neuroacanthocytosis syndrome: blood transfusions that are Kell antigen positive.
Evaluation of relatives at risk: Early diagnosis of relatives at risk allows for prompt initiation of antimicrobial prophylaxis and other treatment.
Pregnancy management: The major concern during the pregnancy of a woman known to have CGD is use of prophylactic antimicrobials: trimethoprim, a folic acid antagonist, is discontinued during pregnancy because of the high risk for birth defects. Although sulfamethoxazole is not known to increase the risk of birth defects in humans, it is typically administered in conjunction with trimethoprim. Data regarding teratogenicity of itraconazole are limited.
CGD associated with a pathogenic variant in CYBB is inherited in an X-linked manner. CGD associated with biallelic pathogenic variants in CYBA, NCF1, NCF2, or NCF4 is inherited in an autosomal recessivemanner.
- X-linked CGD. If the mother of an affected male is heterozygous for a CYBB pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous and will usually not be affected with typical CGD but may have other manifestations including discoid lupus erythematosus and aphthous ulcers.
- AR-CGD. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Molecular genetic carrier testing and prenatal testing for pregnancies at increased risk is possible if the pathogenic variant(s) in a family are known. (Other carrier and prenatal testing options may be available if the pathogenic variant[s] in the family are not known.)