What is the workup for Granulomatosis with Polyangiitis (GPA), formerly known as Wegener's granulomatosis?

Diagnostic Workup for Granulomatosis with Polyangiitis (GPA)

The diagnostic workup for Granulomatosis with Polyangiitis requires comprehensive laboratory testing, imaging studies, and often tissue biopsy to confirm the diagnosis and assess organ involvement, with ANCA testing being essential for all suspected cases. 1

Initial Baseline Investigations

Laboratory Studies

• Complete blood count with differential - to assess for anemia, leukocytosis, and eosinophilia
• Comprehensive metabolic panel - to evaluate kidney function (BUN, creatinine)
• Urinalysis and urine protein-to-creatinine ratio - to detect hematuria, proteinuria
• Inflammatory markers - ESR and CRP to assess disease activity
• ANCA testing - both immunofluorescence and ELISA for:
  • PR3-ANCA (c-ANCA) - highly specific for GPA, present in approximately 90% of systemic forms 2
  • MPO-ANCA (p-ANCA) - less commonly associated with GPA 1

Imaging Studies

• Chest radiograph and/or high-resolution CT - to identify pulmonary nodules, infiltrates, cavities
• Sinus CT scan - to evaluate for sinusitis, bony erosion, and mucosal thickening
• Abdominal ultrasonography - to assess for organ involvement

Specialist Evaluations

• ENT consultation with nasal endoscopy - to evaluate upper airway involvement
• Ophthalmologic examination - to assess for ocular manifestations
• Pulmonary function tests - to evaluate lung function

Targeted Investigations Based on Clinical Presentation

For Renal Involvement

• 24-hour urine collection for protein and creatinine clearance
• Kidney biopsy - gold standard for confirming renal involvement showing pauci-immune necrotizing crescentic glomerulonephritis 3

For Pulmonary Involvement

• Bronchoalveolar lavage (BAL) - if pulmonary infiltrates or hemorrhage present
• Lung biopsy - if diagnosis remains uncertain, showing granulomatous inflammation and vasculitis

For ENT Involvement

• Audiometry - if hearing loss is present
• Functional endoscopic sinus surgery (FESS) - for diagnostic tissue sampling
• Nasal/sinus biopsy - though often non-diagnostic 1

For Neurological Involvement

• EMG/ENG studies - for peripheral neuropathy
• Brain/spinal MRI - if CNS involvement suspected
• Nerve biopsy (sural nerve) - in cases of mononeuritis multiplex

Important Diagnostic Considerations

1. Tissue biopsy is strongly recommended to establish a new diagnosis of GPA, though the diagnostic yield varies by site 1:

   • Lung biopsies typically have the highest yield
   • Nasal/sinus biopsies often have lower diagnostic yield but are more accessible
   • Kidney biopsy shows pauci-immune necrotizing glomerulonephritis

2. ANCA testing is crucial but has limitations:

   • PR3-ANCA is highly specific for GPA but may be negative in limited forms
   • Approximately 10% of systemic GPA cases are ANCA-negative 2
   • ANCA status may influence clinical phenotype and prognosis 1

3. Differential diagnosis must exclude:

   • Other ANCA-associated vasculitides (microscopic polyangiitis, EGPA)
   • Other granulomatous diseases (sarcoidosis, tuberculosis)
   • Infections (fungal, bacterial)
   • Malignancies
   • IgG4-related disease 1

Clinical Pearls and Pitfalls

• Do not delay treatment while awaiting biopsy results in patients with rapidly progressive disease, especially with positive ANCA serology and compatible clinical presentation 3

• Biopsy of sino-nasal mucosa/polyps is often non-diagnostic despite being commonly affected sites 1

• PR3-ANCA positive patients more frequently have lung nodules and skin manifestations, while MPO-ANCA positive patients more commonly present with glomerulonephritis 1

• Limited forms of GPA may be ANCA-negative in up to 50% of cases, making diagnosis more challenging 2

• Consider GPA in patients with the combination of upper respiratory tract, pulmonary, and renal involvement, particularly with ANCA positivity 3

By following this systematic diagnostic approach, clinicians can establish a timely diagnosis of GPA, assess disease extent, and initiate appropriate therapy to improve outcomes and reduce mortality.