Chronic Granulomatous Disease

Clinical characteristics: 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 responses 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. While CGD may present anytime from infancy to late adulthood, the vast majority of affected individuals are diagnosed before age five years. Use of antimicrobial prophylaxis and therapy has greatly improved overall survival.

Diagnosis/testing: The diagnosis of CGD is established in a proband with suggestive findings by identification of pathogenic variant(s) in one of six genes that encode or permit assembly of the subunits of phagocyte NADPH oxidase: biallelic pathogenic variants in CYBA, CYBC1, NCF1, NCF2, and NCF4 cause autosomal recessive CGD; pathogenic variants of CYBB cause X-linked CGD.

Management: 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: Lifelong daily antibacterial and antifungal prophylaxis is recommended; immunomodulatory therapy with interferon gamma (IFN-gamma) is part of the prophylactic regimen in many centers.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known cure for CGD and is associated with excellent overall and event-free survival, especially when performed with matched donors at a younger age.

Surveillance: Screening labs every 3-4 months in a healthy individual with CGD can aid in early detection and treatment of asymptomatic or minimally symptomatic infections and noninfectious 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) live bacterial vaccines including bacille Calmette-Guérin (BCG) vaccination and Salmonella typhi 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.

Genetic counseling: CGD associated with a pathogenic variant in CYBB is inherited in an X-linked manner. CGD associated with biallelic pathogenic variants in CYBA, CYBC1, NCF1, NCF2, or NCF4 is inherited in an autosomal recessive manner.

1. 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. Heterozygous females are typically not affected with CGD but are at substantial risk for inflammatory conditions. Once the CYBB pathogenic variant has been identified in an affected family member, molecular genetic heterozygote detection for at-risk female relatives is possible.

2. Autosomal recessive CGD. If both parents are known to be heterozygous for an autosomal recessive CGD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the CGD-causing pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk relatives is possible.

Once the CGD-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. (Other prenatal testing options may be available if the pathogenic variant[s] in the family are not known.)