Pulmonary Vasculitis Update Part 1: Clinical Features & Diagnosis (Review, AJRCCM)

Pulmonary Vasculitis Update / Review
Part 1: Clinical Features & Diagnosis
(Go to Part 2: Treatment and Prognosis)

by Brett Ley, MD

Vasculitides are disorders of inflammation and necrosis of the blood vessel wall. Pulmonary vasculitides can present in multiple ways: with alveolar hemorrhage, infiltrates, nodules, cavities, or airway disease. They are categorized by the size of vessel involved (small, medium, and large), the underlying immunologic mechanism (pauci-immune, immune-complex mediated), and associated systemic disease. The nomenclature for pulmonary vasculitides has recently been revised by the 2012 International Chapel Hill Consensus Conference.

Although many forms of vasculitis have the potential to involve the lungs, the ANCA-associated vasculitides (AAVs) are a group of small-vessel vasculitides that commonly involve the respiratory tract and are the focus of a recent review in AJRCCM by Stephen Frankel and Marvin Schwartz. They include:

• Granulomatosis with polyangiitis (GPA), no longer called Wegener’s granulomatosis because of the namesake’s ties to the Nazi party
• Microscopic polyangiitis (MPA)
• Churg-Strauss Syndrome (CSS), a.k.a Eosinophilic Granulomatosis with Polyangiitis (EGPA)
• Idiopathic pauci-immune pulmonary capillaritis (IPIPC)

Epidemiology of Pulmonary Vasculitis

ANCA-associated vasculitis is rare (overall incidence 15-20 cases/million/year and prevalence 90-300 cases/million/year). Granulomatosis with polyangiitis is more common than microscopic polyangiitis in Europe & North America, while MPA appears to be more common than GPA in Japan & China. Churg-Strauss syndrome is quite rare, even less common than both GPA & MPA. There appears to be some element of genetic predisposition. Survival rates are decreased compared to the general population (RR 2.6) with 1, 2, and 5 year survival rates of 88, 85, and 78% overall. Poor prognostic factors include older age, greater disease activity, alveolar hemorrhage, cardiac involvement, and proteinase-3 positivity.

Clinical Presentation and Diagnosis of Pulmonary Vasculitis

Classification criteria for vasculitides have been developed by the American College of Rheumatology in 1990, and the Chapel Hill Consensus Conference in 1994, recently revised in 2012. However, the authors emphasize that these criteria are not meant to be used as diagnostic criteria, but rather that the diagnosis is made clinically through the integration of clinical, laboratory, radiographic, and pathology data.

Clinical scenarios that should prompt the consideration of ANCA-associated vasculitis include:

1. Diffuse alveolar hemorrhage
2. Tracheal or subglottic stenosis
3. Pulmonary nodules and cavities
4. Glomerulonephritis
5. Destructive or ulcerating upper airway disease
6. Mononeuritis multiplex
7. Retroorbital mass
8. Palpable purpura
9. For Churg-Strauss: severe or refractory adult-onset asthma, peripheral eosinophilia, or eosinophilic pneumonia

ANCA-Associated Pulmonary Vasculitis: The Players

Granulomatosis with Polyangiitis (formerly Wegener’s) commonly affects the upper respiratory tract (>85%) (otitis, hearing loss, sinusitis, epistaxis, nasal septal perforation, mastoiditis, and saddle nose deformity), lower respiratory tract (>80%) (cough, dyspnea, chest discomfort, hemoptysis, diffuse alveolar hemorrhage, pulmonary nodules, cavities, and infiltrates), and tracheobronchial tree (50-60%) (stenosis, ulceration).

Microscopic polyangiitis less commonly involves the upper respiratory tract (<15%) and lower respiratory tract (diffuse alveolar hemorrhage in up to 30%, but also infiltrates, pulmonary artery aneurysms, fibrosis, and airway disease).

Constitutional symptoms and extrapulmonary involvement (renal, cutaneous, musculoskeletal, ocular, cardiovascular, and peripheral nerves) occur in both granulomatous polyangiitis and microscopic polyangiitis. Glomerulonephritis and constitutional symptoms are particularly common in both, and are nearly the rule in microscopic polyangiitis.

Idiopathic pauci-immune pulmonary capillaritis:  Think of IPIPC as “lung-limited microscopic polyangiitis” presenting as isolated diffuse alveolar hemorrhage.

Churg-Strauss Syndrome is characterized by the triad of asthma, eosinophilia, and vasculitis, described to occur in three phases of disease:

1. Prodromal, allergic/atopic phase: manifest as asthma and rhinosinusitis
2. Eosinophilic phase: tissue eosinophilic inflammation including eosinophilic pneumonia
3. Vasculitic phase: palpable purpura and mononeuritis multiplex

In Churg-Strauss, asthma generally precedes vasculitis by an average of 7-8 years and is often severe and steroid-dependent. Upper airway disease (70-90%) is generally non-destructive (in contrast to GPA) manifest as chronic rhinosinusitis. Pulmonary infiltrates occur at some point in 70-90% and are patchy, bilateral, and migratory. Extrapulmonary manifestations are common, but cardiac involvement (30-50%) is responsible for half the mortality (cardiomyopathy, myocarditis, coronary aneurysms, conduction system disease, and sudden cardiac death).

Anti-Neutrophil Cytoplasmic Antibodies (ANCAs)

Anti-neutrophil cytoplasmic antibodies (ANCAs) are, as the AAV name suggests, characteristic of these diseases, but importantly, are not required for their diagnosis, if histopathology and clinical features are diagnostic. ANCAs are not only markers of disease but are also involved in pathogenesis by promoting neutrophil migration to, and degranulation in, vessel walls; and they may correlate (to some degree) with disease activity.

• c-ANCA = neutrophil cytoplasmic staining by indirect immunofluorescence. It is associated with antibodies specifically directed at proteinase 3 (PR 3) that are detected via ELISA. They are found in GPA with 85-90% sensitivity and 95% specificity when disease is generalized. Sensitivity is decreased when disease is limited (60%) or in remission (40%).
• p-ANCA = neutrophil perinuclear staining. It is commonly associated with antibodies specifically directed against myeloperoxidase (MPO), again detected by ELISA, which are associated with MPA and CSS. But the p-ANCA picture is less clear-cut than that of c-ANCA: 1) p-ANCA is associated with antibodies against other neutrophil antigens besides MPO and 2) p-ANCA/MPO are both less sensitive for MPA (50-75%) and CSS (35-50%) and less specific (may be found in other diseases).

Histopathology is usually required to confirm a pulmonary vasculitis diagnosis, especially considering the likely side effects of heavy immunosuppressive treatments and the need to rule out infection as the leading differential diagnosis. Don’t forget that tissue specimens should be sent for microbiologic studies in addition to histopathology and immunofluorescence staining.

• The role of bronchoscopy is mainly to evaluate for diffuse alveolar hemorrhage, infection, and large airway complications. Transbronchial biopsies are usually not diagnostic, but endobronchial biopsies may be helpful in tracheobronchial disease.
• Skin and sinus biopsy are minimally invasive but lower yield.
• Renal biopsy and surgical lung biopsy are probably the highest yield.

With much thanks to:

Stephen K Frankel, Marvin I Schwartz. The Pulmonary Vasculidities. AJRCCM 2012;186:216-224.