What are the clinical presentation and management of Chronic Granulomatous Disease (CGD)?

Chronic Granulomatous Disease: Clinical Presentation and Management

Chronic Granulomatous Disease (CGD) is characterized by recurrent severe bacterial and fungal infections due to defects in phagocytic oxidative metabolism, requiring prophylactic antimicrobials, interferon-gamma therapy, and consideration of hematopoietic stem cell transplantation for definitive treatment. 1, 2

Clinical Presentation

Common Infections and Sites

• Recurrent life-threatening infections with catalase-positive bacteria and fungi due to defective phagocyte function and impaired intracellular killing 2, 3
• Infections commonly involve the lungs, skin, lymph nodes, liver, gastrointestinal tract, and viscera 1
• Gingivostomatitis is a characteristic manifestation 1
• Spinal cord infections can occur, though rare, and may mimic tuberculosis 4
• Granuloma formation in affected tissues is characteristic due to defective degradation of inflammatory mediators 5

Common Pathogens

• Staphylococcus aureus - most common bacterial pathogen 2
• Aspergillus species - particularly concerning fungal pathogen 2
• Other significant pathogens include Candida species, Nocardia species, Burkholderia species, Serratia species, and Salmonella species 2
• Invasive aspergillosis is a major concern requiring aggressive management 1

Laboratory Findings

• Laboratory evaluation may show neutropenia, normal neutrophil counts, or marked neutrophilia 1
• Functional studies reveal defects in oxidative metabolism, the hallmark of CGD 1
• Neutrophil chemiluminescence and intracellular killing assays are severely depressed 3
• Genetic testing can identify mutations in genes encoding the five subunits of the NADPH oxidase enzyme complex 2

Age of Presentation

• Most commonly diagnosed in early childhood 2
• Can rarely present in adulthood, with some cases first diagnosed in the fifth decade of life 4

Management Approaches

Antimicrobial Prophylaxis

• Antibacterial prophylaxis with trimethoprim-sulfamethoxazole is recommended to prevent bacterial infections 2, 5
  • Dosing for children: 5 mg/kg daily or twice daily (based on trimethoprim component)
  • Dosing for adults: 160 mg daily or twice daily (based on trimethoprim component) 1
• Antifungal prophylaxis with itraconazole is strongly recommended (A-II) 1
• Posaconazole is a favorable alternative for antifungal prophylaxis (A-III) 1

Immunotherapy

• Recombinant interferon-gamma (rIFN-γ) is strongly recommended as prophylaxis in CGD patients (A-II) 1
• rIFN-γ has been shown to decrease the risk of severe infections (including fungal infections) in CGD by approximately 70% 1
• The mechanism involves augmentation of functional properties of phagocytic cells through upregulation of chemotaxis, phagocytosis, and oxidative metabolism 1
• Some controversy exists about its routine use in prophylaxis 1

Management of Acute Infections

• Prompt identification and aggressive treatment of infections is essential 5
• For invasive aspergillosis, voriconazole is the first-line treatment (AII) 1
• Surgical debridement of infected tissue should be considered when lesions are localized 1
• For refractory invasive fungal infections, granulocyte transfusions can be considered in neutropenic patients (weak recommendation; low-quality evidence) 1

Definitive Treatment

• Hematopoietic stem cell transplantation (HSCT) from an HLA-identical donor is currently the only proven curative treatment for CGD 2, 5
• HSCT should be considered for selected patients with severe or recurrent life-threatening infections 5
• Gene-replacement therapy remains experimental with major obstacles and risks, though it has shown some transitory benefits in a few cases 5

Management of Inflammatory Complications

• Adolescent and adult CGD is increasingly characterized by inflammatory complications 5
• Granulomatous lung disease and inflammatory bowel disease may require immunosuppressive therapy 5, 6
• Progressive developing granulomas may require early immunosuppressive therapy in addition to anti-infectious treatment 4

Special Considerations

Diagnosis in Adults

• CGD should be considered in adult patients with recurrent granulomatous infections or atypical presentations of common infections 4
• Appropriate CGD diagnostics are recommended in adult patients with unclear granulomatous diseases of the nervous system 4

Monitoring and Follow-up

• Regular monitoring for infection and inflammatory complications is essential 5
• Secondary prophylaxis is recommended for patients who have had a previous episode of invasive aspergillosis, especially during periods of immunosuppression (A-IIt) 1

Pitfalls to Avoid

• Delay in diagnosis due to lack of awareness of the disease in adult patients 4
• Inadequate prophylaxis leading to life-threatening infections 2
• Failure to consider CGD in patients with recurrent infections with catalase-positive organisms 3
• Underestimating the importance of both anti-infectious and anti-inflammatory approaches to management 4, 5