Pulmonary Vasculitis: A Comprehensive Review for the Practicing Internist

Dr Neeraj Manikath , claude.ai

Abstract

Pulmonary vasculitis represents a diagnostically challenging group of disorders characterized by inflammation of pulmonary vessels. Early recognition is critical as delayed diagnosis can result in irreversible organ damage or death. This review provides a practical approach to suspecting pulmonary vasculitis, understanding current classification systems, and navigating the diagnostic pathway. We highlight clinical pearls, diagnostic pitfalls, and evidence-based management strategies essential for postgraduate trainees and practicing internists.

Keywords: Pulmonary vasculitis, ANCA-associated vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, classification, diagnosis

Introduction

Systemic vasculitides affecting the lungs pose unique diagnostic challenges due to their protean manifestations, overlap with infectious and malignant processes, and potential for rapid clinical deterioration. The lung is preferentially involved in small-vessel vasculitides, particularly the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV).¹ However, medium and large-vessel vasculitides can also affect pulmonary circulation, adding to diagnostic complexity.

The reported incidence of AAV ranges from 13-20 cases per million population annually, with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) being the most common forms affecting the lungs.² Understanding when to suspect these conditions and how to classify them appropriately is fundamental to improving outcomes in what remains a group of disorders with significant morbidity and mortality.

When to Suspect Pulmonary Vasculitis: Clinical Red Flags

Pearl #1: The Triad of Hemoptysis, Hematuria, and Lung Infiltrates

This classic triad should immediately raise suspicion for pulmonary-renal syndrome, most commonly seen in AAV and anti-glomerular basement membrane (anti-GBM) disease.³ However, the absence of renal involvement does not exclude pulmonary vasculitis—approximately 20% of GPA cases present with isolated pulmonary disease.⁴

Clinical Presentations Warranting High Suspicion

1. Pulmonary Hemorrhage Syndromes

Diffuse alveolar hemorrhage (DAH) presents with hemoptysis (though absent in 30% of cases), falling hemoglobin, and diffuse ground-glass opacities on imaging
Hack: Sequential bronchoalveolar lavage (BAL) showing progressively bloodier returns (classic "serial bloody BAL") confirms DAH even without hemoptysis⁵
DAH with normal kidney function: Consider MPA, isolated pulmonary capillaritis, or drug-induced vasculitis

2. Cavitary Lung Lesions

Multiple bilateral nodules with cavitation are highly suggestive of GPA
Oyster: Not all cavitary lesions in vasculitis are from the vasculitis itself—always exclude superimposed infection, particularly invasive fungal disease and tuberculosis in immunosuppressed patients⁶

3. Unexplained Airway Disease

Subglottic stenosis, particularly in young to middle-tolerated women, should prompt evaluation for GPA
Chronic cough, dyspnea, or wheeze unresponsive to asthma therapy may indicate tracheobronchial involvement
Pearl #2: Tracheobronchial involvement occurs in 15-55% of GPA cases but may precede systemic manifestations by months to years⁷

4. Constitutional Symptoms with Pulmonary Infiltrates

Fever, weight loss, arthralgias, and malaise accompanying pulmonary findings suggest systemic disease
Hack: If a patient with "pneumonia" isn't improving after 48-72 hours of appropriate antibiotics and has unexplained systemic features, broaden the differential to include vasculitis

5. Multi-organ Involvement

Simultaneous involvement of upper respiratory tract (sinusitis, epistaxis, nasal crusting), lungs, and kidneys is pathognomonic for GPA
Peripheral neuropathy (mononeuritis multiplex) with pulmonary disease suggests systemic vasculitis, particularly MPA or eosinophilic granulomatosis with polyangiitis (EGPA)⁸

Pearl #3: Age and Gender Clues

While vasculitis can occur at any age, certain patterns help:

GPA: Peak incidence 45-60 years, slight male predominance
EGPA: Mean age 40-50 years, equal gender distribution, virtually always with asthma history
MPA: Slightly older demographic (50-60 years)
Takayasu arteritis: Young women <40 years, predominantly Asian descent⁹

Laboratory Red Flags

High-Yield Screening Tests:

Urinalysis: Active sediment (RBC casts, dysmorphic RBCs, proteinuria) indicates glomerulonephritis
Complete blood count:
- Anemia disproportionate to clinical status suggests DAH
- Eosinophilia >10% or >1.5 × 10⁹/L raises suspicion for EGPA¹⁰
Inflammatory markers: Markedly elevated ESR (>100 mm/hr) and CRP suggest active vasculitis
Renal function: Rising creatinine with active urine sediment mandates urgent evaluation

Oyster: Normal inflammatory markers do not exclude vasculitis—approximately 10-15% of patients with active AAV have normal acute phase reactants.¹¹

Classification of Pulmonary Vasculitis

The 2012 Chapel Hill Consensus Conference Classification

The current gold standard classification system categorizes vasculitides by vessel size, which has both pathophysiologic and clinical relevance.¹² This system replaced the 1994 Chapel Hill nomenclature and incorporated ANCA testing into diagnostic criteria.

Large-Vessel Vasculitis

1. Takayasu Arteritis

Granulomatous arteritis affecting the aorta and major branches
Pulmonary artery involvement in 50-80% of cases, though often asymptomatic¹³
Imaging (CT angiography, MR angiography, or PET-CT) shows arterial wall thickening, stenosis, or aneurysms
Hack: Check blood pressure in all four limbs; >10 mmHg difference between arms suggests subclavian involvement

2. Giant Cell Arteritis

Rarely affects lungs; thoracic aortic involvement possible
Consider in elderly patients (>50 years) with new respiratory symptoms and temporal headache/jaw claudication

Medium-Vessel Vasculitis

Polyarteritis Nodosa (PAN)

Necrotizing arteritis of medium arteries without glomerulonephritis or vasculitis in small vessels
Pulmonary involvement is notably absent in classic PAN (if present, consider another diagnosis)
Pearl #4: PAN can be associated with hepatitis B infection; always check HBsAg¹⁴

Small-Vessel Vasculitis

This category includes the most common forms of pulmonary vasculitis.

A. ANCA-Associated Vasculitides (AAV)

1. Granulomatosis with Polyangiitis (GPA, formerly Wegener's)

Classic triad: Upper airway, lungs, kidneys
ANCA pattern: c-ANCA (anti-PR3) in 65-90%, p-ANCA (anti-MPO) in 10-25%
Histology: Necrotizing granulomatous inflammation, vasculitis
Pulmonary manifestations:
- Nodules (50-70%, often cavitary)
- Masses or infiltrates (30-50%)
- DAH (7-45%)
- Pleural effusion (20%)
- Endobronchial disease (15-55%)⁴

Pearl #5: Negative ANCA does not exclude GPA—up to 10% of patients with active disease are ANCA-negative, particularly those with limited disease.¹⁵

2. Microscopic Polyangiitis (MPA)

Necrotizing vasculitis with few or no immune deposits affecting small vessels
ANCA pattern: p-ANCA (anti-MPO) in 50-75%, c-ANCA in 35%
No granulomas (key distinguishing feature from GPA)
Pulmonary manifestations:
- DAH most common (30-55%)
- Interstitial lung disease (ILD) in 30-50%¹⁶
Hack: MPA-associated ILD often shows usual interstitial pneumonia (UIP) pattern on HRCT, mimicking idiopathic pulmonary fibrosis; check ANCA in all cases of "IPF" especially if younger or with atypical features

3. Eosinophilic Granulomatosis with Polyangiitis (EGPA, formerly Churg-Strauss)

Eosinophil-rich granulomatous inflammation involving respiratory tract, with necrotizing vasculitis
Almost always preceded by asthma (mean duration 8-10 years before systemic symptoms)
ANCA pattern: p-ANCA (anti-MPO) in 30-40% only
Diagnostic criteria (American College of Rheumatology):
1. Asthma
2. Eosinophilia >10%
3. Mononeuropathy or polyneuropathy
4. Migratory pulmonary infiltrates
5. Paranasal sinus abnormality
6. Extravascular eosinophils on biopsy
- Four of six criteria = 85% sensitivity, 99.7% specificity¹⁷

Pearl #6: EGPA has two phenotypes:

ANCA-positive: More vasculitic features (glomerulonephritis, peripheral neuropathy, purpura)
ANCA-negative: More eosinophilic tissue infiltration (cardiac involvement, which is the leading cause of death)¹⁸

Oyster: Leukotriene receptor antagonists (montelukast) have been associated with EGPA, but this likely represents unmasking rather than causation as corticosteroids are tapered.¹⁹

B. Anti-GBM Disease (Goodpasture's Syndrome)

Rapidly progressive glomerulonephritis plus DAH from antibodies against type IV collagen
Not a true vasculitis but clinically overlaps
Anti-GBM antibodies diagnostic
10-40% have concurrent ANCA positivity ("double-positive" patients have worse prognosis)²⁰

C. Immune Complex Small-Vessel Vasculitides

1. IgA Vasculitis (Henoch-Schönlein Purpura)

Rare pulmonary involvement (DAH in <5%)
More common in children; suspect in adult with palpable purpura, arthritis, abdominal pain, and glomerulonephritis

2. Cryoglobulinemic Vasculitis

Associated with hepatitis C in 80-90%
Pulmonary involvement uncommon but includes DAH, ILD

3. Anti-C1q Vasculitis (Hypocomplementemic Urticarial Vasculitis)

Chronic urticaria, arthritis, and complement consumption
Pulmonary manifestations: obstructive lung disease, DAH (rare)

Diagnostic Approach: A Stepwise Strategy

Step 1: Clinical Syndrome Recognition

Pattern recognition is crucial:

Pulmonary-renal syndrome → AAV, anti-GBM, or SLE
Asthma + eosinophilia + systemic symptoms → EGPA
Cavitary nodules + upper airway disease → GPA
DAH + rapidly progressive glomerulonephritis → MPA or anti-GBM

Step 2: Serologic Evaluation

Essential Tests:

ANCA testing (by both immunofluorescence and ELISA)
- Immunofluorescence patterns:
  - c-ANCA (cytoplasmic): Anti-PR3 antibodies → GPA
  - p-ANCA (perinuclear): Anti-MPO antibodies → MPA or EGPA
- ELISA confirms specificity (anti-PR3, anti-MPO)
- Hack: Always order both IF and ELISA; IF alone has false positives, ELISA alone may miss atypical patterns²¹
Anti-GBM antibodies
ANA, anti-dsDNA, complement levels (to exclude SLE)
Rheumatoid factor, cryoglobulins (if clinical suspicion)
Hepatitis B and C serology (PAN, cryoglobulinemic vasculitis)

Pearl #7: ANCA Testing Pitfalls

Drug-induced ANCA (levamisole-adulterated cocaine, hydralazine, propylthiouracil, minocycline)—usually atypical ANCA patterns²²
Infections (endocarditis, tuberculosis) can cause false-positive ANCA
Always interpret ANCA in clinical context

Step 3: Imaging

High-Resolution CT Chest:

GPA findings:
- Multiple bilateral nodules (90% have at least one >2 cm)
- Cavitation in 50%
- Ground-glass opacities (DAH)
- Tracheobronchial thickening or stenosis
MPA findings:
- Ground-glass opacities (DAH)
- Reticular opacities, honeycombing (ILD)
EGPA findings:
- Peripheral ground-glass opacities
- Consolidation
- Bronchial wall thickening (asthmatic component)

Oyster: "Tree-in-bud" pattern suggests infection, not vasculitis—always investigate further.²³

Step 4: Tissue Diagnosis

Biopsy remains the gold standard when feasible.

Biopsy Site Selection:

Lung biopsy (surgical or transbronchial cryobiopsy)
- Highest yield in nodular disease
- Surgical lung biopsy preferred for definitive diagnosis
- Hack: If both kidneys and lungs affected, biopsy the kidney—safer and often diagnostic
Kidney biopsy
- Essential if glomerulonephritis present
- Pauci-immune crescentic glomerulonephritis supports AAV
Upper airway biopsy (nasal, sinus)
- Low yield (15-25%) but safe and easily accessible
- May show granulomatous inflammation in GPA
Skin biopsy (if palpable purpura present)
Nerve/muscle biopsy (if mononeuritis multiplex present)

Pearl #8: A negative biopsy does not exclude vasculitis—patchy distribution means sampling error is common. Clinical judgment and serologic findings often suffice to initiate treatment in life-threatening situations.²⁴

Step 5: Bronchoscopy with BAL

Confirms DAH (progressively bloodier aliquots, hemosiderin-laden macrophages)
Excludes infection
Transbronchial biopsy typically non-diagnostic for vasculitis but may show capillaritis

Treatment Considerations and Prognostic Factors

Induction Therapy for Severe AAV

Standard regimen: Cyclophosphamide + high-dose corticosteroids

Cyclophosphamide: 15 mg/kg IV every 2-3 weeks or 2 mg/kg/day oral
Methylprednisolone: 500-1000 mg/day × 3 days for organ-threatening disease
Followed by prednisone 1 mg/kg/day with taper²⁵

Alternative: Rituximab (375 mg/m² weekly × 4 weeks or 1000 mg × 2 doses)

Non-inferior to cyclophosphamide in RAVE and RITUXVAS trials
May be superior in relapsing disease²⁶,²⁷

Adjunctive: Plasma exchange for severe DAH or rapidly progressive glomerulonephritis (controversial; PEXIVAS trial showed no mortality benefit but reduced ESKD risk)²⁸

Maintenance Therapy

Options include:

Rituximab (500 mg every 6 months or CD19-guided dosing)
Azathioprine (2 mg/kg/day)
Methotrexate (20-25 mg/week for non-organ-threatening disease)
Mycophenolate mofetil (2-3 g/day)

Duration: Minimum 18-24 months, often longer depending on relapse risk²⁹

Monitoring for Relapse

Risk factors for relapse:

PR3-ANCA positivity (higher relapse rate than MPO-ANCA)
Upper airway involvement
Persistent ANCA positivity during remission
Subglottic stenosis
Pulmonary nodules³⁰

Pearl #9: Rising ANCA titers during remission predict relapse in only 40% of cases; clinical assessment remains paramount.³¹

Emerging Concepts and Future Directions

Complement Pathway in AAV

Recent recognition that complement activation is critical in AAV pathogenesis has led to novel therapeutics:

Avacopan (C5a receptor antagonist): FDA-approved as adjunctive therapy, allows corticosteroid dose reduction³²
Particularly valuable in diabetes, osteoporosis, or other steroid-intolerant conditions

Biomarkers

Promising biomarkers under investigation:

Urinary monocyte chemoattractant protein-1 (MCP-1): Correlates with renal disease activity
Serum-soluble CD163: Marker of alternative macrophage activation
ANCA epitope specificity: Certain PR3 epitopes associated with worse outcomes³³

Practical Pearls Summary

Always check urinalysis in any suspected pulmonary vasculitis
Serial bloody BAL confirms DAH even without hemoptysis
Tracheobronchial involvement in GPA may precede systemic disease by years
MPA-associated ILD can mimic idiopathic pulmonary fibrosis
ANCA-negative GPA occurs in 10% of cases
EGPA phenotypes differ by ANCA status
ANCA testing requires both IF and ELISA
Negative biopsy doesn't exclude vasculitis
Rising ANCA titers don't always predict relapse
Kidney biopsy is safer than lung biopsy when both organs involved

Conclusion

Pulmonary vasculitis remains a diagnostic challenge requiring high clinical suspicion, systematic evaluation, and often multidisciplinary collaboration. Understanding current classification systems, recognizing clinical red flags, and appropriately utilizing diagnostic modalities are essential skills for the practicing internist. Early diagnosis and prompt treatment are crucial to preventing irreversible organ damage and improving outcomes. As our understanding of disease mechanisms evolves and novel therapeutics emerge, the prognosis for patients with pulmonary vasculitis continues to improve, making early recognition and accurate classification more important than ever.

References

Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med. 1997;337(21):1512-1523.
Watts RA, Scott DGI. Epidemiology of the vasculitides. Curr Opin Rheumatol. 2003;15(1):11-16.
Salama AD, Levy JB, Lightstone L, Pusey CD. Goodpasture's disease. Lancet. 2001;358(9285):917-920.
Cordier JF, Valeyre D, Guillevin L, et al. Pulmonary Wegener's granulomatosis: a clinical and imaging study of 77 cases. Chest. 1990;97(4):906-912.
De Lassence A, Fleury-Feith J, Escudier E, et al. Alveolar hemorrhage: diagnostic criteria and results in 194 immunocompromised hosts. Am J Respir Crit Care Med. 1995;151(1):157-163.
Seo P, Stone JH. The antineutrophil cytoplasmic antibody-associated vasculitides. Am J Med. 2004;117(1):39-50.
Polychronopoulos VS, Prakash UB, Golbin JM, et al. Airway involvement in Wegener's granulomatosis. Rheum Dis Clin North Am. 2007;33(4):755-775.
Guillevin L, Pagnoux C, Seror R, et al. The Five-Factor Score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort. Medicine (Baltimore). 2011;90(1):19-27.
Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11.
Comarmond C, Pagnoux C, Khellaf M, et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis Study Group cohort. Arthritis Rheum. 2013;65(1):270-281.
Finkielman JD, Lee AS, Hummel AM, et al. ANCA are detectable in nearly all patients with active severe Wegener's granulomatosis. Am J Med. 2007;120(7):643.e9-14.
Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11.
Yamada I, Nakagawa T, Himeno Y, et al. Takayasu arteritis: evaluation of the thoracic aorta with CT angiography. Radiology. 1998;209(1):103-109.
Guillevin L, Mahr A, Callard P, et al. Hepatitis B virus-associated polyarteritis nodosa: clinical characteristics, outcome, and impact of treatment in 115 patients. Medicine (Baltimore). 2005;84(5):313-322.
Finkielman JD, Merkel PA, Schroeder D, et al. Antiproteinase 3 antineutrophil cytoplasmic antibodies and disease activity in Wegener granulomatosis. Ann Intern Med. 2007;147(9):611-619.
Homma S, Matsushita H, Nakata K. Pulmonary fibrosis in myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitides. Respirology. 2004;9(2):190-196.
Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum. 1990;33(8):1094-1100.
Sablé-Fourtassou R, Cohen P, Mahr A, et al. Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome. Ann Intern Med. 2005;143(9):632-638.
Harrold LR, Patterson MK, Andrade SE, et al. Asthma drug use and the development of Churg-Strauss syndrome (CSS). Pharmacoepidemiol Drug Saf. 2007;16(6):620-626.
Levy JB, Turner AN, Rees AJ, Pusey CD. Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med. 2001;134(11):1033-1042.
Savige J, Gillis D, Benson E, et al. International Consensus Statement on Testing and Reporting of Antineutrophil Cytoplasmic Antibodies (ANCA). Am J Clin Pathol. 1999;111(4):507-513.
Pendergraft WF, Niles JL. Trojan horses: drug culprits associated with antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. Curr Opin Rheumatol. 2014;26(1):42-49.
Lohrmann C, Uhl M, Kotter E, Burger D, Ghanem N, Langer M. Pulmonary manifestations of Wegener granulomatosis: CT findings in 57 patients and a review of the literature. Eur J Radiol. 2005;53(3):471-477.
Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116(6):488-498.
de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009;150(10):670-680.
Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-232.
Jones RB, Tervaert JW, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010;363(3):211-220.
Walsh M, Merkel PA, Peh CA, et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N Engl J Med. 2020;382(7):622-631.
Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003;349(1):36-44.
Booth AD, Almond MK, Burns A, et al. Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study. Am J Kidney Dis. 2003;41(4):776-784.
Tomasson G, Grayson PC, Mahr AD, Lavalley M, Merkel PA. Value of ANCA measurements during remission to predict a relapse of ANCA-associated vasculitis--a meta-analysis. Rheumatology (Oxford). 2012;51(1):100-109.
Jayne DRW, Merkel PA, Schall TJ, Bekker P; ADVOCATE Study Group. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med. 2021;384(7):599-609.
Kemna MJ, Damoiseaux J, Austen J, et al. ANCA as a predictor of relapse: useful in patients with renal involvement but not in patients with nonrenal disease. J Am Soc Nephrol. 2015;26(3):537-542.