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PULMONARY VASCULITIS

DEFINITION & INTRODUCTION

• Primary vasculitis — heterogeneous syndromes of unknown etiology sharing clinical response to immunosuppressive therapy
• Secondary vasculitis — occurs in the context of a defined underlying disorder (SLE, RA, infections) or as an incidental histopathologic finding

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CLASSIFICATION (Chapel Hill 2012 Consensus Nomenclature)

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PATHOGENESIS OF ANCA-ASSOCIATED VASCULITIS

• PR3-ANCA / C-ANCA — cytoplasmic immunofluorescence pattern; characteristic of GPA (>80% positive)
• MPO-ANCA / P-ANCA — perinuclear pattern; predominates in MPA and EGPA

1. ANCA activation of primed neutrophils → release of oxygen radicals and proteolytic enzymes → endothelial apoptosis
2. ANCA enhance neutrophil adhesion to endothelial cells via upregulation of adhesion molecules
3. Genetic predisposition: HLA-DP association with PR3-ANCA; HLA-DQ with MPO-ANCA
4. Epigenetic modifications increase expression of PR3 and MPO on neutrophil surfaces

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I. GRANULOMATOSIS WITH POLYANGIITIS (GPA) — Formerly Wegener Granulomatosis

Definition

Epidemiology

• Annual incidence: ~10–12 per million; predominantly whites and northern Europeans
• Can affect any age; incidence plateaus after age 50

Pulmonary Manifestations

1. Diffuse Alveolar Hemorrhage (DAH) from pulmonary capillaritis — presents as hemoptysis, falling Hb, bilateral ground-glass opacities
2. Necrotizing granulomatous nodules/masses (most common form) — typically bilateral, may cavitate

• Tracheobronchial involvement in 15–55%, more common in women; presents with cough, wheezing, hemoptysis, subglottic stenosis
• Organizing pneumonia pattern can occur

Histopathology

• Small necrotizing microabscesses → coalesce → geographic basophilic necrosis with palisading histiocytes and scattered giant cells
• Granulomatous vasculitis when inflammation extends into vessel walls (secondary to granulomatous inflammation, distinct from capillaritis)
• Background: mixed infiltrate (lymphocytes, plasma cells, giant cells, eosinophils)
• Sarcoid-like non-necrotizing granulomas are NOT found in GPA

Diagnosis

• Serology: C-ANCA/PR3-ANCA positive >80%
• Lab: Elevated ESR/CRP, anemia, elevated creatinine, hematuria, proteinuria
• Imaging: Bilateral nodules, masses, cavities ± ground-glass infiltrates (DAH)
• Biopsy: VATS lung biopsy (highest yield for isolated lung disease); transbronchial biopsy supports diagnosis in ~50% combined with ANCA; renal biopsy shows pauci-immune focal segmental necrotizing glomerulonephritis with crescents

Differential Diagnosis

• Infections (fungal, Nocardia), organizing pneumonia, metastatic disease, lymphomatoid granulomatosis (EBV-related T-cell-rich B-cell lymphoma — an important mimic), lymphoproliferative disorders

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II. MICROSCOPIC POLYANGIITIS (MPA)

Key Features

• Necrotizing small vessel vasculitis without granuloma formation — this separates MPA from GPA
• No upper airway involvement (sinusitis, nasal disease absent — their presence suggests EGPA or GPA)
• Kidneys most affected (up to 80%) — pauci-immune focal segmental necrotizing glomerulonephritis with crescents
• DAH from pulmonary capillaritis affects 10–30% of patients
• MPA is the most frequent cause of pulmonary-renal syndrome
• Association with ILD (interstitial lung disease) increasingly recognized, particularly with MPO-ANCA

Serology

• P-ANCA/MPO-ANCA positive in 40–80%; C-ANCA/PR3-ANCA less common
• Histopathologically indistinguishable from GPA capillaritis

Treatment

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III. EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS (EGPA) — Formerly Churg-Strauss Syndrome

Definition

Three Clinical Phases

1. Prodromal phase: Allergic rhinitis, nasal polyposis, sinusitis, adult-onset asthma
2. Eosinophilic phase: Peripheral blood and tissue eosinophilia (typically 5,000–20,000/μL); eosinophilic pneumonia, gastroenteritis
3. Vasculitic phase: Small vessel vasculitis — mononeuritis multiplex (75%), palpable purpura, cardiomyopathy (60% — major cause of death), renal involvement (25%)

Pulmonary Manifestations

• Pulmonary opacities (eosinophilic pneumonia pattern): ill-defined, migratory, peripheral-predominant ground-glass to consolidation — present in 37–72% on CXR
• DAH is rare (contrast with GPA/MPA)
• Cavitary lesions extremely unusual
• CT: airspace consolidation, centrilobular nodules, bronchial wall thickening

Diagnostic Criteria (Cottin & Cordier)

1. Asthma
2. Peripheral eosinophilia >1500/mm³ and/or alveolar eosinophilia >25%
3. Extrapulmonary clinical manifestations:
   • Mononeuritis multiplex, cardiomyopathy, or palpable purpura, OR
   • Any extrapulmonary manifestation + histopathologic vasculitis on biopsy, OR
   • ANCA (anti-MPO or anti-PR3) positivity

Serology

• MPO-ANCA positive in 40–60% overall; 75–100% in those with renal involvement
• Elevated IgE levels; markedly elevated eosinophils

Histopathology

• Microgranulomas, fibrinoid necrosis, thrombosis of small vessels
• Eosinophilic infiltrates in vessels and extravascular tissues — distinguishes EGPA from GPA/MPA

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IV. OTHER PULMONARY VASCULITIDES

Behçet Disease

• Immune complex–mediated vasculitis affecting vessels of all sizes
• Characterized by oral + genital aphthous ulcers, uveitis, cutaneous lesions
• Pulmonary artery aneurysms are the hallmark — detected by CT/MR angiography
• Massive hemoptysis (often fatal) from erosion of aneurysms into bronchi
• Prognosis: ~1/3 die within 2 years of pulmonary involvement
• Treatment: corticosteroids + cyclophosphamide/azathioprine; TNF-α inhibitors for refractory disease; anticoagulation should be AVOIDED once pulmonary arteritis present

Classic Polyarteritis Nodosa (PAN)

• Affects medium vessels; does NOT cause glomerulonephritis or DAH (no capillary involvement)
• Rare lung hemorrhage via bronchial artery involvement
• Most cases today associated with hepatitis B/C — antiviral therapy is central

Idiopathic Pauci-immune Pulmonary Capillaritis

• Diagnosis of exclusion: capillaritis with no systemic disease, no autoantibodies, no immune deposits
• Histologically identical to AAV; responds to similar immunosuppression

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DIFFUSE ALVEOLAR HEMORRHAGE (DAH) — Unifying Concept

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INVESTIGATIONS SUMMARY

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TREATMENT

Induction of Remission (Severe AAV — GPA/MPA)

• IV methylprednisolone 1 g/day × 3 days, then oral prednisolone 1 mg/kg/day
• Rituximab (375 mg/m² × 4 doses or 2 × 1 g doses) OR cyclophosphamide (IV/oral)
• RAVE trial: Rituximab = cyclophosphamide for induction; rituximab preferred in relapsing disease
• PEXIVAS trial: Plasmapheresis does NOT reduce end-stage renal disease/death; rapid steroid taper equally effective with fewer side effects

Maintenance Therapy

• Once remission achieved: azathioprine, methotrexate, or mycophenolate mofetil
• Low-dose rituximab effective for maintenance (RITAZAREM trial)
• Duration: typically 24–48 months minimum
• PCP prophylaxis (TMP-SMX) for all patients

EGPA

• Glucocorticoids alone sufficient in most cases (prednisone 1 mg/kg/day)
• Add cyclophosphamide for life-threatening manifestations (cardiac, renal, severe neuropathy)
• Anti-IL-5 therapy: Mepolizumab 300 mg SC every 4 weeks — FDA-approved for EGPA
• Anti-IgE therapy with omalizumab for predominantly asthma/sinonasal disease
• Five-factor score (FFS) guides need for cyclophosphamide addition

Limited GPA (upper airway only)

• Oral DMARDs alone (methotrexate + glucocorticoids) without cyclophosphamide

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PROGNOSIS

• Untreated GPA/MPA: mortality approaches 90% within 2 years (mostly from renal/pulmonary failure)
• With treatment: 5-year survival >80%; major causes of death are infection (immunosuppression) and relapse
• Relapse rates: higher with PR3-ANCA than MPO-ANCA; higher in GPA than MPA
• EGPA: 5-year survival >90% with treatment; cardiac involvement is the main mortality determinant
• Behçet pulmonary involvement: poor prognosis; ~1/3 die within 2 years

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QUICK SUMMARY TABLE

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