CGD - Chronic Granulomatous Disease

Definition and pathogenesis

Definition: Inborn errors of phagocyte NADPH oxidase leading to impaired respiratory burst and defective production of reactive oxygen species, with resultant inability to effectively kill certain bacteria and fungi.

Pathogenesis: Mutations in genes encoding components of the NADPH oxidase complex impair superoxide generation in neutrophils and macrophages, promoting persistent infections and granulomatous inflammation.

Genetics and epidemiology

Genetics: Most cases are X‑linked from pathogenic variants in CYBB (gp91phox); autosomal recessive forms arise from defects in CYBA, NCF1, NCF2, or NCF4 (p22, p47, p67, p40 subunits respectively).

Incidence: Rare; population estimates vary by region but commonly cited around 1:200,000 to 1:250,000 live births.

Clinical infections and typical presentation

• Predisposing organisms: Infections are classically due to catalase‑positive organisms including Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia complex, Nocardia species, and molds such as Aspergillus.
• Sites of infection: Frequent skin and soft tissue infections, suppurative lymphadenitis, pneumonia, pulmonary abscesses, osteomyelitis, and hepatic abscesses.
• Age at presentation: Most children present in the first years of life, though milder or late‑presenting forms occur depending on residual oxidase activity.

Gastrointestinal involvement

Gastrointestinal disease is common and can be a dominant clinical problem, particularly in X‑linked forms.

• Prevalence: GI involvement reported in roughly one‑third to one‑half of series; higher frequency seen with more severe mutations.
• Granulomatous lesions: Noncaseating granulomas may affect any segment from oral cavity to anorectum and can cause strictures or pyloric obstruction.
• Mimics of Crohn disease: Macroscopic and histologic findings (transmural inflammation, granulomas, fissures, fistulae) are often indistinguishable from Crohn disease.
• Fistulizing disease: Enteric fistulae and perianal disease can occur and may require surgical management.
• Hypomorphic variants and VEOIBD: Partial‑function mutations can present primarily as very early‑onset inflammatory bowel disease without a history of recurrent infections.

Diagnosis

Screening tests

Flow cytometric dihydrorhodamine (DHR) assay or nitroblue tetrazolium testing evaluates neutrophil oxidative burst; abnormal test supports CGD diagnosis.

Genetic confirmation

Targeted sequencing of NADPH oxidase component genes identifies causal variants and clarifies inheritance, carrier status, and prognosis.

Histopathology

Biopsies commonly show granulomatous inflammation with mixed inflammatory infiltrates; microbiologic stains and cultures should be pursued to exclude infections.

Treatment and preventive strategies

• Antimicrobial prophylaxis: Continuous trimethoprim‑sulfamethoxazole for bacterial prophylaxis and azole antifungal prophylaxis (eg, itraconazole, posaconazole) to reduce fungal risk.
• Interferon‑gamma: Subcutaneous interferon‑γ reduces infection frequency in many patients and is frequently used as adjunctive therapy.
• Management of inflammatory GI disease: Corticosteroids are effective for acute control; steroid‑sparing immunomodulators may be used cautiously with infectious risk mitigation and specialist input.
• Biologics and infection risk: Anti‑TNF agents can control severe inflammation but substantially increase risk of invasive infection and require careful multidisciplinary consideration.
• Curative therapy: Hematopoietic stem cell transplantation is curative and increasingly offered for patients with severe infectious or inflammatory complications; gene therapy is an emerging option at select centers.

Prognosis and follow-up

Prognosis has improved with prophylaxis, early aggressive treatment of infections, and curative cellular therapies. Lifelong surveillance for infectious, inflammatory, and obstructive GI complications is essential, with coordinated care among immunology, gastroenterology, infectious disease, and surgery when needed.

Clinical pearls