How should infections be managed in patients with chronic granulomatosis polyangitis (CGPA) who are on immunosuppressive therapy?

Managing Infections in Granulomatosis with Polyangiitis on Immunosuppressive Therapy

All patients with granulomatosis with polyangiitis (GPA) receiving cyclophosphamide and/or rituximab must receive Pneumocystis jirovecii prophylaxis with sulfamethoxazole-trimethoprim (800 mg-160 mg on alternate days or 400 mg-80 mg daily), and pre-treatment screening for hepatitis B and HIV is mandatory. 1

Understanding the Infection Risk

Patients with GPA face a dual infection risk that compounds mortality:

• Disease-related immunosuppression: GPA itself causes immune dysregulation that increases infection susceptibility even before treatment begins 2
• Treatment-related immunosuppression: Cyclophosphamide and rituximab dramatically amplify infection risk, with respiratory tract infections being particularly common 3, 4
• Early mortality: Infections during the first year of treatment represent one of the main causes of death in GPA patients 3

The infection risk is significantly higher in GPA compared to other autoimmune conditions like SLE, even when controlling for immunosuppression intensity 4.

Mandatory Prophylaxis and Screening

Pre-Treatment Requirements

Before initiating cyclophosphamide or rituximab:

• Screen for chronic infections: Hepatitis B virus and HIV testing is strongly recommended 1
• This prevents reactivation of latent infections that could be fatal under immunosuppression 1

Pneumocystis Prophylaxis (Non-Negotiable)

• Sulfamethoxazole-trimethoprim dosing: 800 mg-160 mg on alternate days OR 400 mg-80 mg daily 1, 2
• Indications: All patients receiving cyclophosphamide and/or rituximab 1, 5, 6
• Additional benefit: This regimen also provides protection against certain bacterial infections, including some E. coli strains 2

Managing Active Infections While Treating GPA

When infection develops during GPA treatment, a careful balance is required:

For Severe Infections (e.g., Pneumonia)

• Temporarily suspend immunosuppressive therapy except glucocorticoids until infection is controlled 6
• Continue glucocorticoids at the minimum effective dose to prevent vasculitis flare while treating infection 6
• Consider IVIG bridge therapy: Intravenous immunoglobulin (2 g/kg divided over 5 days) can serve as temporary bridge therapy when conventional immunosuppressants must be held 6

After Infection Control

• Resume definitive GPA therapy once infection is controlled 6
• For severe GPA: rituximab (375 mg/m² weekly for 4 weeks) plus glucocorticoids is preferred over cyclophosphamide 6
• For non-severe GPA: methotrexate, azathioprine, or mycophenolate mofetil with glucocorticoids 6

Vaccination and Immunoglobulin Monitoring

Cyclophosphamide and rituximab impair humoral vaccine responses and can cause clinically significant secondary hypogammaglobulinemia:

• Timely vaccination according to current recommendations before initiating therapy 1
• Monitor quantitative IgG serum concentrations regularly 1
• Passive immunization if necessary for patients with hypogammaglobulinemia 1

Long-Term Infection Surveillance

• Continuous monitoring for infections is recommended as a standard comorbidity assessment in all GPA patients 1, 2
• Lymphopenia monitoring: Marked lymphopenia (not just neutropenia) is associated with increased infection risk and should be tracked 4
• Highest risk period: The intensive/induction phase of treatment carries a 13.3-fold increased relative risk of major infection 4

Critical Pitfalls to Avoid

• Never completely discontinue all immunosuppression during infection: This can trigger severe vasculitis flare; maintain at least glucocorticoids 6
• Never omit PCP prophylaxis: This is the most preventable cause of mortality in immunosuppressed GPA patients 5, 6
• Never ignore lymphopenia: Focus only on neutropenia misses a major infection risk factor 4
• Never delay infection screening: Pre-treatment screening for hepatitis B and HIV is not optional 1

Risk Factors for Major Infections

The following factors significantly increase infection risk and warrant heightened vigilance:

• Methylprednisolone use: 11.1-fold increased relative risk 4
• Cyclophosphamide use: 2.0-fold increased relative risk 4
• Intensive/induction phase: 13.3-fold increased relative risk 4
• Marked lymphopenia: Significantly associated with major infections 4
• Respiratory tract involvement: GPA patients have more respiratory infections than other vasculitis patients 4