What is the appropriate diagnostic workup for a patient suspected of myeloperoxidase (MPO) anti‑neutrophil cytoplasmic antibody (ANCA)‑associated systemic vasculitis?

Diagnostic Workup for MPO-ANCA-Associated Systemic Vasculitis

Initial Serologic Testing

Order both MPO-ANCA and PR3-ANCA antigen-specific immunoassays (ELISA) simultaneously as the gold standard diagnostic test; these should be performed together with indirect immunofluorescence (IIF) for optimal diagnostic accuracy. 1, 2

• MPO-ANCA detected by ELISA is the primary diagnostic marker, with approximately 90% of small-vessel vasculitis cases testing positive for either MPO or PR3 antibodies 1
• The combination of IIF (showing p-ANCA pattern) plus MPO-ANCA ELISA achieves 99.4% specificity, though sensitivity drops to 31.5% when both are required 2
• Using the combined ANCA testing system (PR3/c-ANCA + MPO/p-ANCA) increases sensitivity to 85.5% while maintaining 98.6% specificity 2
• P-ANCA positivity occurs in 26-48% of EGPA cases, increasing to 75% when renal involvement is present 3

Essential Laboratory Evaluation

Obtain the following baseline tests to assess organ involvement and disease activity:

• Urinalysis with microscopy specifically examining for dysmorphic red blood cells and red cell casts, which indicate glomerulonephritis 1
• Serum creatinine and GFR estimation to detect rapidly declining renal function (creatinine >4 mg/dL is a critical red flag requiring urgent intervention) 1
• Complete blood count looking for marked peripheral eosinophilia (>1500 cells/μL or >10%) in suspected EGPA, anemia, or leukocytosis 3, 1
• Inflammatory markers (CRP and ESR) recognizing that 10% of AAV patients may have normal values 1
• Chest radiograph or high-resolution CT to identify pulmonary infiltrates, nodules, ground-glass opacities (86% in EGPA), or bronchial wall thickening 3

Tissue Biopsy Strategy

Obtain tissue biopsy from the most accessible affected organ to confirm vasculitis, particularly when ANCA is negative or clinical suspicion remains high despite negative serology. 1

• Kidney biopsy yields 91.5% diagnostic confirmation in granulomatosis with polyangiitis and provides prognostic information 1
• Skin biopsy of active purpuric or necrotic lesions can reveal typical vasculitic changes 1
• Lung or sinus tissue biopsy may show eosinophilic infiltration (35-100% in EGPA), though necrotizing vasculitis and eosinophilic granulomas are rarely seen in sinonasal tissue 3
• Nerve biopsy can confirm vasculitis in patients presenting with mononeuritis multiplex 1

Imaging Studies

Perform targeted imaging based on clinical presentation:

• Sinus CT typically shows pan-opacification with Lund-Mackay scores of 9-17 in EGPA; look for ethmoid erosion, widened intercanthal distance, or mucocele formation 3
• High-resolution chest CT is superior to plain radiography (detects abnormalities in 64% vs. chest X-ray), revealing "fluffy" or nodular migratory infiltrates, peripheral nodules (25%), and bronchiectasis (66%) 3

Differential Diagnosis Workup

Systematically exclude mimicking conditions before confirming vasculitis, especially in ANCA-negative cases. 1

The EGPA Consensus Task Force recommends these additional tests 3:

• Serologic testing for toxocariasis and HIV to exclude parasitic and infectious causes
• Specific IgE and IgG for Aspergillus species plus sputum/bronchoalveolar lavage culture to rule out allergic bronchopulmonary aspergillosis
• Serum tryptase and vitamin B12 to exclude hypereosinophilic syndrome
• ANA, anti-dsDNA, complement levels to distinguish from systemic lupus erythematosus, Sjögren's syndrome, or rheumatoid arthritis 1

Assessment of Multi-Organ Involvement

Once vasculitis is confirmed, evaluate for poor prognostic features 3:

• Cardiac assessment including ECG, echocardiography, and troponin (myocardial involvement portends worse prognosis in ANCA-negative EGPA)
• Neurologic examination for peripheral neuropathy or mononeuritis multiplex (more common in MPO-ANCA-positive patients) 3, 4
• Gastrointestinal evaluation if abdominal symptoms are present
• Pulmonary function tests and bronchoalveolar lavage when indicated

Critical Clinical Pitfalls

• Do not delay immunosuppressive therapy while awaiting biopsy results if MPO-ANCA or PR3-ANCA is positive and clinical presentation is compatible with life- or organ-threatening vasculitis (pulmonary-renal syndrome, rapidly progressive glomerulonephritis) 1
• Recognize that approximately 10% of true AAV patients are persistently ANCA-negative; these patients require the same treatment but diagnosis depends heavily on tissue biopsy confirmation 1, 5
• A negative ANCA does not exclude EGPA, particularly in patients with the head and neck phenotype who are more often ANCA-negative 3
• MPO-ANCA-positive patients typically present with glomerulonephritis, peripheral neuropathy, and purpura, while ANCA-negative patients more commonly have myocardial, respiratory, and gastrointestinal involvement 3, 4

Referral and Management Coordination

Transfer patients to specialized vasculitis centers that offer rapid ANCA testing, expert histopathology interpretation, access to rituximab/cyclophosphamide protocols, and intensive care/hemodialysis capabilities 1