How to differentiate between an active infection and a relapse in Granulomatosis with Polyangiitis (GPA)?

Differentiating Between Active Infection and Relapse in Granulomatosis with Polyangiitis (GPA)

To differentiate between active infection and relapse in Granulomatosis with Polyangiitis (GPA), clinicians should perform a comprehensive disease activity assessment using validated clinical tools rather than relying solely on laboratory biomarkers, as no single biomarker reliably correlates with disease activity or predicts relapse. 1

Clinical Assessment

• GPA relapse is defined as the recurrence of clinical signs or symptoms attributable to active disease following a period of remission 1
• The need for an increase in glucocorticoid dosage or initiation/increase of immunosuppressive therapy should be considered a relapse 1
• Distinguish between systemic relapse (vasculitis affecting organs) and respiratory relapse (isolated exacerbation of asthma and ENT manifestations) 1

Key Differentiating Features

Signs of Relapse

• Recurrence of characteristic GPA manifestations such as:
  • ENT symptoms (sinusitis, crusting rhinorrhea) 2
  • Pulmonary nodules or infiltrates 2
  • Worsening renal function with active urinary sediment 3
  • Skin manifestations (purpura, nodules) 1
• Response to immunosuppressive therapy rather than antimicrobials 4
• Possible rise in ANCA titers (though not definitive) 1

Signs of Infection

• Fever, chills, and other systemic inflammatory response signs 5
• Focal signs of infection (productive cough, dysuria, etc.) 5
• Positive cultures or other microbiological evidence 5
• Response to antimicrobial therapy 5
• No improvement or worsening with increased immunosuppression 5

Diagnostic Approach

Clinical Evaluation

• Before confirming relapse, re-evaluate the primary diagnosis, exclude other etiologies (especially infection), check treatment appropriateness, and assess patient compliance 6
• Distinguish active disease from irreversible damage using tools like the Vasculitis Damage Index 1

Laboratory Assessment

• No biomarker reliably correlates with disease activity or predicts relapse in GPA 1
• ANCA monitoring is advisable in patients with previous positivity, but ANCA titers don't clearly associate with disease activity 1
• Complete blood count, inflammatory markers (ESR, CRP), and renal function tests should be assessed 5
• Appropriate cultures and infectious disease workup when infection is suspected 5

Imaging and Functional Studies

• Appropriate imaging (chest radiography, CT scans) and functional studies (pulmonary function tests, echocardiography) should be performed based on clinical presentation 1
• Compare with baseline studies to identify new or worsening findings 5

Management Algorithm

If Relapse is Confirmed

• For severe systemic relapses (organ-threatening manifestations):

  • Rituximab or cyclophosphamide with glucocorticoids is recommended 1
  • Rituximab (375 mg/m² once weekly for 4 weeks) plus glucocorticoids is first-line for remission re-induction 7, 8
  • For patients who relapsed while on rituximab maintenance, consider switching to cyclophosphamide 7

• For non-severe systemic relapses:

  • Optimize glucocorticoid therapy 1
  • Consider adding mepolizumab for minor relapses 1

• For respiratory relapses:

  • Follow a stepwise approach: optimize topical therapies, increase oral glucocorticoids, consider mepolizumab 1
  • Consider functional endoscopic sinus surgery for relapsing ENT disease 1

If Infection is Confirmed

• Appropriate antimicrobial therapy based on identified pathogen 5
• Consider temporary reduction in immunosuppression if infection is severe 5
• Resume appropriate immunosuppression after infection control 5

Common Pitfalls and Caveats

• Don't base treatment decisions solely on ANCA titer results 7
• An increase in inflammatory markers without accompanying clinical manifestations should not be considered a relapse 1
• Patients on immunosuppression may have blunted inflammatory responses to infection 5
• Consider opportunistic infections in immunosuppressed patients (Pneumocystis jirovecii, fungal infections) 7
• Prophylaxis against Pneumocystis jirovecii pneumonia is recommended for patients receiving rituximab or cyclophosphamide 7

Follow-up and Monitoring

• Regular assessment of disease activity using clinical parameters 7
• Monitor for treatment-related complications 7
• For patients with MPO-ANCA positivity at disease onset, serum ANCA monitoring is advisable as persistence, rise, or reappearance might justify more frequent clinical assessment 1