How is granulomatosis with polyangiitis (Wegener granulomatosis) diagnosed?

Diagnosis of Granulomatosis with Polyangiitis (Wegener Granulomatosis)

The diagnosis of granulomatosis with polyangiitis requires the integration of characteristic clinical features (upper/lower respiratory tract and renal involvement), positive PR3-ANCA serology (present in 80-90% of cases), and histopathological confirmation of necrotizing vasculitis with granulomatous inflammation whenever tissue can be obtained. 1, 2

Clinical Presentation: Key Diagnostic Features

Upper Respiratory Tract Manifestations (>90% of patients)

• Persistent nasal symptoms: crusting, stuffiness, epistaxis (nosebleeds), and sinus pain are the most common presenting features 1
• Chronic rhinosinusitis with possible nasal polyps, often progressing to nasal septal perforation in advanced cases 1
• Otitis media with associated hearing loss 1
• Subglottic stenosis develops in 5-23% of treated patients, presenting with persistent cough, wheezing, and dyspnea that may be misdiagnosed as asthma 1

Lower Respiratory Tract Involvement

• Pulmonary infiltrates and nodules are common, with cough and hemoptysis occurring in >95% of patients with lower respiratory disease 1
• Diffuse alveolar hemorrhage can occur in severe cases, manifesting as diffuse alveolar infiltrates on imaging 1
• Tracheobronchial stenosis occurs in 15% of patients 1

Renal Involvement (Hallmark Feature)

• Pauci-immune necrotizing crescentic glomerulonephritis is the characteristic renal pathology 1
• Manifests as proteinuria, hematuria, red cell casts, and varying degrees of kidney failure 1
• Present in approximately 70% of classical cases 3

Other Systemic Manifestations

• Peripheral neuropathy (often mononeuritis multiplex pattern) 1
• Skin lesions including palpable purpura 1
• Ocular manifestations including scleritis 1
• Constitutional symptoms: fever, malaise, weight loss, arthralgia, and myalgia 1

Laboratory Diagnostic Workup

ANCA Testing (Critical Diagnostic Tool)

• PR3-ANCA (c-ANCA) is detected in 80-90% of GPA cases and is highly specific for this diagnosis 1, 2
• Both PR3-ANCA and MPO-ANCA should be tested using high-quality antigen-specific enzyme-linked immunosorbent assays (ELISA), not just immunofluorescence patterns alone 2, 3
• Important caveat: In disease limited to the sinonasal tract, ANCA may be negative, complicating diagnosis 1
• The likelihood of positive ANCA increases with more widespread and severe clinical involvement 1

Additional Laboratory Tests

• Complete blood count with differential (may show anemia, leukocytosis) 2, 3
• Elevated inflammatory markers: ESR (typically ≈60 mm/hr) and CRP 1, 3
• Renal function tests: creatinine and BUN to assess kidney involvement 1
• Urinalysis: looking for hematuria, proteinuria, and red cell casts 2, 4

Imaging Studies

Chest Imaging

• Chest CT is more sensitive than conventional radiographs for detecting pulmonary nodules, infiltrates, and cavitary lesions 2
• Look for multiple, bilateral nodules or masses, often with cavitation 1

Sinus Imaging

• Sinus CT should be performed when upper respiratory tract involvement is suspected, showing mucosal thickening and bony erosion 2

Additional Imaging

• MRI is useful for detecting CNS lesions, pachymeningitis, retro-orbital lesions, or subglottic inflammation 2

Histopathological Confirmation

Biopsy Strategy

• Tissue biopsy is the gold standard for definitive diagnosis and should be obtained whenever possible 2, 5
• Choose biopsy sites based on clinical involvement: kidney, lung, skin, or nasal mucosa 2
• Critical limitation: Nasal mucosal biopsies frequently lack sufficient diagnostic features; therefore, tissue from other involved organs (lung or kidney) is often necessary for definitive confirmation 1, 6

Characteristic Histopathological Features

• Classic triad: necrotizing vasculitis, necrotizing granulomatous inflammation, and necrosis 6, 5
• Kidney biopsy typically shows crescentic necrotizing glomerulonephritis 1
• Common features in small biopsies: microabscesses and scattered multinucleated giant cells in a highly inflammatory background 6

Diagnostic Criteria and Classification

No Single Diagnostic Criterion

• There are no universally accepted diagnostic criteria; diagnosis is based on the combination of clinical features, ANCA positivity, and histopathology 2, 5
• Classification criteria exist but should not be used as diagnostic criteria (1990 ACR criteria, 2022 ACR-EULAR criteria) 7

American College of Rheumatology Classification (for reference)

• Requires 2 of 4 criteria: positive biopsy for granulomatous vasculitis, urinary sediment with red blood cells, abnormal chest radiograph, and oral/nasal inflammation 4
• Important: These are classification criteria for research, not diagnostic criteria for clinical practice 7

Differential Diagnosis

Key Conditions to Exclude

• Eosinophilic Granulomatosis with Polyangiitis (EGPA): distinguished by asthma, blood eosinophilia >10%, elevated IgE, and predominantly MPO-ANCA (when ANCA-positive, only 30-40% are ANCA-positive) 1, 2
• Microscopic Polyangiitis: typically lacks granulomatous inflammation and upper airway involvement 2
• Polyarteritis Nodosa: ANCA-negative medium-vessel vasculitis 1
• IgA vasculitis and cryoglobulinaemia: show immune deposits on biopsy, which are absent in GPA 7
• Infections: particularly tuberculosis and fungal infections that can mimic granulomatous inflammation 6
• Malignancy: lung cancer should be considered in the differential of pulmonary manifestations 1

Disease Activity Assessment

• Birmingham Vasculitis Activity Score (BVAS) is the primary validated tool for assessing disease activity across multiple organ systems 1, 2
• Five-Factor Score (FFS) predicts mortality risk in established vasculitis 2

Common Diagnostic Pitfalls and How to Avoid Them

1. Misdiagnosing subglottic stenosis as asthma: Investigate with flow-volume loops showing abnormal inspiratory and expiratory patterns 1
2. Relying solely on nasal biopsy: These are often non-diagnostic; obtain tissue from lung or kidney when possible 1, 6
3. Making treatment decisions based on ANCA titers alone: ANCA should be interpreted in the context of clinical features 2
4. Missing limited disease: ANCA may be negative in localized upper respiratory disease 1
5. Overlooking the need for prompt ANCA testing: In patients with chronic rhinosinusitis, epistaxis, systemic symptoms, and renal abnormalities, ANCA testing should be performed immediately to avoid diagnostic delay 1