What is the management and treatment of chronic granulomatous disease (CGD) in a typical male patient with a history of recurrent infections and granulomas?

Management and Treatment of Chronic Granulomatous Disease

Diagnostic Confirmation

Confirm the diagnosis with neutrophil oxidative burst testing and proceed with genetic analysis to establish the molecular defect. 1

• Measure reactive oxygen intermediates (O₂⁻ or H₂O₂) in peripheral blood phagocytes upon in vitro activation with PMA and/or TLR4 ligands 2
• Perform genetic testing to distinguish X-linked (CYBB mutations) from autosomal recessive forms (CYBA, NCF1, NCF2, or CYBC1 mutations) 3, 2
• X-linked CGD accounts for the majority of cases, particularly in male patients with the characteristic presentation 3

Antimicrobial Prophylaxis (Cornerstone of Conservative Management)

All CGD patients require lifelong antimicrobial prophylaxis with both antibacterial and antifungal agents. 4, 5

Antibacterial Prophylaxis

• Trimethoprim-sulfamethoxazole is mandatory: 5 mg/kg daily or twice daily (based on trimethoprim component) for children 4
• This prevents infections with catalase-positive bacteria, particularly Staphylococcus aureus, the most common bacterial pathogen 5, 6

Antifungal Prophylaxis

• Itraconazole is strongly recommended as first-line antifungal prophylaxis 4, 5
• Aspergillus species (particularly A. fumigatus and A. nidulans) represent the leading cause of mortality in CGD, with incidence rates of 26-45% 3
• Invasive aspergillosis is the single most common infectious cause of death 3

Immunomodulatory Therapy

Recombinant interferon-gamma (rIFN-γ) is strongly recommended as prophylaxis for all CGD patients. 1, 4, 7

• FDA-approved specifically for reducing frequency and severity of serious infections in CGD 7
• Administered subcutaneously three times weekly 7
• Reduces risk of severe infections (including fungal infections) by approximately 70% 4
• Demonstrated 67% reduction in relative risk of serious infection in the pivotal trial 7
• Treatment benefit was consistent across all subgroups regardless of inheritance pattern, age, or concurrent prophylactic antibiotic use 7

Management of Acute Infections

For invasive aspergillosis, initiate voriconazole immediately as first-line therapy. 4

• Voriconazole is the recommended first-line treatment for invasive aspergillosis in CGD 4
• Consider surgical debridement for localized, accessible lesions (sinusitis, cutaneous disease, focal abscesses) 1, 4
• Aggressive antimicrobial therapy is required for deep-seated infections and abscesses with granuloma formation, which are hallmark presentations 3

Monitoring for Complications

Monitor closely for inflammatory complications, particularly colitis and suppurative lymphadenitis with granuloma formation. 3, 4

• Colitis may develop as part of the inflammatory phenotype, resembling Crohn's disease 3, 2
• Gingivostomatitis is a characteristic manifestation requiring aggressive treatment 4
• Pneumatoceles may develop, particularly with Aspergillus infections 3
• Granulomatous inflammation can affect the gastrointestinal and genitourinary tracts 2, 8

Secondary Prophylaxis

Patients with prior invasive aspergillosis require indefinite secondary prophylaxis, especially during any periods of additional immunosuppression. 4

• Continue antifungal prophylaxis to prevent recurrence 4
• This is particularly critical if the patient requires subsequent immunosuppressive therapy 1

Definitive Curative Therapy

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment and should be considered, particularly for patients with persistent infections or severe autoinflammation. 5, 2, 8, 9

• HSCT can achieve event-free survival of at least 80% even with unrelated donors when performed without active infections 9
• Optimal outcomes occur in patients without ongoing infections or inflammation at the time of transplant 2
• Gene therapy with lentiviral vectors is emerging as an alternative for patients without matched donors 8, 9
• Conservative management alone leaves most patients with lifelong challenges of recurrent infections, autoinflammation, and failure to thrive 2

Critical Pitfalls to Avoid

• Never delay antimicrobial prophylaxis: Both antibacterial and antifungal prophylaxis must be initiated immediately upon diagnosis 4, 5
• Do not omit interferon-gamma: This is FDA-approved and has demonstrated clear mortality benefit 7
• Recognize that conservative treatment is palliative, not curative: Only cellular therapies (HSCT or gene therapy) can cure CGD 2, 9
• Maintain strict adherence to prophylaxis: The natural history has been dramatically improved by prophylactic measures, with overall survival now around 90% reaching into adulthood 8