What is chronic granulomatous disease?

What is Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by defects in the NADPH oxidase enzyme complex, resulting in phagocytes that cannot produce reactive oxygen species (ROS) to kill catalase-positive bacteria and fungi, leading to severe recurrent infections and excessive granulomatous inflammation. 1, 2

Genetic Basis and Inheritance Patterns

CGD is genetically heterogeneous with two inheritance patterns 1, 3:

• X-linked recessive (XR-CGD): Caused by mutations in the CYBB gene encoding the gp91phox protein—this is the most common form 1
• Autosomal recessive (AR-CGD): Caused by mutations in CYBA, NCF1, NCF2, or NCF4 genes encoding p22phox, p47phox, p67phox, and p40phox proteins respectively 1, 3

The defect prevents the respiratory burst in phagocytic leukocytes (neutrophils, monocytes), eliminating their ability to generate superoxide and other ROS critical for microbial killing 4, 3.

Clinical Manifestations

Infectious Complications

Patients experience life-threatening infections with specific pathogens 1, 2:

• Catalase-positive bacteria: Staphylococcus aureus, Burkholderia cepacia, Serratia marcescens, Nocardia species 1
• Fungal infections: Aspergillus species (most common cause of death), Candida species 1, 2
• Deep-seated infections: Lung abscesses, liver abscesses, lymphadenitis, osteomyelitis 5, 1

The American Academy of Allergy, Asthma, and Immunology identifies key clinical presentations warranting CGD evaluation: deep-seated infections with abscess formation and granuloma development, recurrent serious bacterial and fungal infections affecting respiratory tract, skin, and viscera, and gingivostomatitis with severe pyogenic infections 5.

Inflammatory Complications

Excessive inflammation is a hallmark feature 1, 2, 6:

• Granuloma formation: Can occur in any organ, particularly gastrointestinal and genitourinary tracts 1
• CGD colitis: Inflammatory bowel disease-like presentation, often refractory to standard therapies 2, 6
• Gastrointestinal manifestations: Structural changes, dysmotility, liver abscesses, noncirrhotic portal hypertension 6
• Hepatic complications: Liver abscesses and portal hypertension are common 6

Diagnostic Approach

Screening Tests

The American Academy of Allergy, Asthma, and Immunology recommends the nitroblue tetrazolium (NBT) test as the primary screening test for CGD by detecting defective oxidative burst in phagocytic cells 5. The NBT test functions as a screening tool that should be followed by more definitive testing when positive or equivocal 5.

Confirmatory Testing

Multiple assays should be used to confirm diagnosis 5, 4:

• Dihydrorhodamine (DHR) flow cytometry: Visualizes ROS production in individual cells—considered the gold standard confirmatory test 5, 4
• Flow cytometry for NADPH oxidase components: Identifies the specific protein defect 5, 4
• Molecular genetic testing: Confirms the specific gene mutation 5
• Quantitative assays: O2˙- reduction of ferricytochrome c and luminol-enhanced chemiluminescence 4
• Immunoblotting: Identifies the defective phox protein 4

Management Strategies

Prophylactic Therapy

Lifelong antimicrobial prophylaxis is essential 1, 2:

• Antibacterial prophylaxis: Continuous antibiotics to prevent bacterial infections 1, 2
• Antifungal prophylaxis: Azole antifungals have considerably improved overall survival 1, 2
• IFN-γ therapy: Can be considered after early diagnosis to reduce infection frequency 5

Curative Treatment Options

Hematopoietic stem cell transplantation (HSCT) is currently the only definitive curative treatment that can reverse organ dysfunction in CGD 1, 2:

• Pediatric outcomes: Overall survival rates now exceed 90% in children less than 14 years of age 2
• Conditioning debate: Myeloablative conditioning results in more durable myeloid engraftment but with increased toxicity and high rates of graft-versus-host disease 2
• Timing considerations: Early diagnosis through NBT testing enables prompt consideration for HSCT in severe cases 5

Gene therapy is being investigated as an alternative for patients without HLA-matched donors 1, 2:

• Initial trials with retroviral vectors failed due to negligible long-term engraftment and myelodysplastic syndrome from insertional mutagenesis 2
• Current multicenter trials use SIN-lentiviral vectors under myeloid-specific promoters with regulated expression targeting gp91phox 1, 2

Prognosis and Natural History

The implementation of routine antimicrobial prophylaxis and azole antifungals has significantly modified CGD's natural history 1, 2:

• Current survival: Overall survival is now approximately 90%, with patients reaching well into adulthood 1
• Persistent mortality: Life expectancy remains decreased compared to the general population 2
• Morbidity contributors: Inflammatory complications, particularly CGD colitis, are significant contributors to morbidity and are often refractory to standard therapies 2

Early diagnosis through NBT testing followed by confirmatory studies leads to improved survival and disease prognosis by enabling prompt initiation of prophylaxis, IFN-γ therapy, and consideration for HSCT 5.