Chronic Granulomatous Disease

Notes

Immunodeficiency Disorders | Immunology | Paediatrics | Primary Immunodeficiency | Primary Immunodeficiency Disorders

Overview

Chronic granulomatous disease (CGD) is a rare, inherited primary immunodeficiency characterised by defective function of the NADPH oxidase enzyme complex in phagocytes, leading to failure of the oxidative burst required for intracellular killing of pathogens. This results in recurrent, often life-threatening bacterial and fungal infections, particularly with catalase-positive organisms, and predisposes to granuloma formation that can obstruct hollow viscera.

CGD affects approximately 1 in 200,000–250,000 live births worldwide, with around two-thirds of cases inherited in an X-linked pattern and the remainder autosomal recessive. The condition typically presents in infancy or early childhood, although milder phenotypes may present later, and survival has improved significantly with advances in prophylaxis and haematopoietic stem cell transplantation.

Definition

NADPH oxidase: Enzyme complex in neutrophils/monocytes that generates superoxide radicals for microbial killing.
Oxidative burst: Rapid release of reactive oxygen species (ROS) by phagocytes during pathogen killing.
Granuloma: Organized collection of macrophages and immune cells formed in response to persistent infection.
Immunodeficiency: Impaired ability of the immune system to defend against infections.

Anatomy & Physiology

Phagocytes (neutrophils, monocytes, macrophages) engulf pathogens.
NADPH oxidase catalyses conversion of oxygen → superoxide → hydrogen peroxide → reactive oxidants for killing.
Defect in CGD → impaired oxidative burst → intracellular survival of catalase-positive organisms.

Remember

Catalase-negative organisms (e.g., Streptococcus) are less problematic, as they generate hydrogen peroxide that host cells can use. Catalase-positive organisms (e.g., Staphylococcus, Serratia, Aspergillus) are particularly dangerous.

Aetiology

Genetic defect in NADPH oxidase complex subunits:
- X-linked: CYBB gene mutation encoding gp91^phox.
- Autosomal recessive: Mutations in p22^phox, p47^phox, p67^phox, p40^phox.

Risk Factors

Family history of primary immunodeficiency.
Male sex (higher risk due to X-linked inheritance).

Pathophysiology

Genetic mutation → defective NADPH oxidase → failure of oxidative burst.
Phagocytes ingest but cannot kill catalase-positive organisms.
Persistent infection → granuloma formation (immune attempt to contain).
Chronic inflammation damages tissues → obstruction (e.g., GI or urinary tract).

Think

CGD is a failure of “killing after ingestion” — different from neutropenia (failure to recruit) or leukocyte adhesion deficiency (failure to enter tissues).

Clinical Manifestations

Recurrent infections: pneumonia, lymphadenitis, skin/soft tissue abscesses, osteomyelitis.
Pathogens involved are catalase-positive organisms (Staph aureus, Serratia, Burkholderia, Aspergillus, Nocardia)
Granuloma-related obstruction: GI/urinary tract (e.g., gastric outlet obstruction, bladder outflow obstruction).
Poor wound healing.
Failure to thrive in children.

Remember

Aspergillus pneumonia is a red flag for CGD in children.

Remember

CGD has a normal neutrophil count, but defective killing of bacteria.

Diagnosis

Screening: Dihydrorhodamine (DHR) flow cytometry test (preferred) or nitroblue tetrazolium (NBT) test (historical).
Confirmatory: Genetic testing of NADPH oxidase components.
Supportive labs:
- normal neutrophil count
- normal immunoglobulins
- raised inflammatory markers during infections.
Imaging: chest X-ray/CT for pneumonia, abscesses.

Differential Diagnosis (DDx)

Condition	Key Feature	Differentiation from CGD
Leukocyte adhesion deficiency	Delayed cord separation, recurrent bacterial infections, no pus	Normal oxidative burst
Severe congenital neutropenia	Very low neutrophil counts	CGD has normal counts
Hyper-IgE syndrome (Job’s)	Eczema, coarse facies, high IgE	DHR test normal
Cystic fibrosis	Bronchiectasis, pancreatic insufficiency	Positive sweat chloride test

Treatment

Infection prophylaxis:
- Trimethoprim-sulfamethoxazole (for bacteria).
- Itraconazole/voriconazole (for fungi).
Immunotherapy: Interferon-γ shown to reduce infections.
Curative: Haematopoietic stem cell transplantation (HSCT).
Supportive: Prompt aggressive treatment of infections, surgical drainage of abscesses.

Think

HSCT offers potential cure, but timing and donor availability are key.

Complications & Prognosis

Complications

Chronic lung disease
Obstructive granulomas
Sepsis
Recurrent liver abscesses.

Prognosis

Markedly improved with prophylaxis and HSCT; survival into adulthood common with modern therapy.
Before prophylaxis, median survival was <10 years; now many patients live into adulthood.

References

Holland SM. Chronic granulomatous disease. Clin Rev Allergy Immunol. 2010;38(1):3–10.
Kuhns DB, Alvord WG, Heller T, et al. Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med. 2010;363:2600–10.
Marciano BE, Spalding C, Fitzgerald A, et al. Common severe infections in chronic granulomatous disease. Clin Infect Dis. 2015;60(8):1176–83.
Rider NL, Jameson MB, Creech CB. Chronic granulomatous disease: Epidemiology, pathophysiology, and genetic basis of disease. J Pediatric Infect Dis Soc. 2018;7(suppl_1):S2–S5.
van den Berg JM, van Koppen E, Ahlin A, et al. Chronic granulomatous disease: the European experience. PLoS One. 2009;4(4):e5234.