Pulmonary Medicine

Pulmonary Vasculitis (Necrotizing granulomatous vasculitis, Churg-Strauss syndrome, Microscopic polyangiitis)

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What every physician needs to know:

Pulmonary vasculitis is characterized by inflammation and destruction of pulmonary vasculature with subsequent tissue necrosis. These disorders can be divided into those that are part of a systemic autoimmune vasculitis and secondary cases. Secondary pulmonary vasculitis can be associated with a number of diverse etiologies, including infection, drug reactions, connective tissue disease, and malignancy. Systemic lupus erythematosus, mixed connective tissue disease, and antiphospholipid syndrome are the common connective tissue diseases associated with pulmonary vasculitis.

Systemic vasculitis is traditionally divided into large-vessel, medium-vessel, and small-vessel vasculitis. Pulmonary vasculitis affects small vessels—principally capillaries, but also arterioles and venules. More recently the small-vessel vasculitides have been divided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) and immune-complex mediated vasculitides.

The AAV include granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis), eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss Syndrome), and microscopic polyangiitis (MPA). They are systemic vasculitides that may include pulmonary vasculitis. There is also a lung-only AAV termed isolated pauciimune pulmonary capillaritis. The immune complex mediated vasculitides are Henoch-Schönlein purpura, IgA nephropathy, Behçet's disease, and essential cryoglobulinemia. As they do not typically have lung manifestations except in extremely rare cases, they will not be the focus of this chapter.

The diagnosis of vasculitis is a challenge because of the significant overlap in clinical, radiographic, and laboratory features with multiple disease processes, particularly infection and drug reactions. As a result, there is often a delay in establishing the diagnosis of vasculitis. Once a diagnosis of vasculitis is established, immunosuppressive therapy is usually required.

The intensity of the immunosuppressive therapy is determined by disease severity and the degree of organ damage at the time of diagnosis. Therapy is initially geared toward inducing remission, followed by maintenance therapy with frequent evaluation for drug toxicity, infectious complications, and disease relapse.

Classification:

See Table 1.

Table 1.

The Vasculitides.
Primary Vasculitis Small-vessel vasculitisNecrotizing granulomatous vasculitis (NGV)Microscopic polyangiitis (MPA)Churg-Strauss syndrome (CSS)Medium-vessel vasculitisPolyarteritis nodosaKawasaki diseaseLarge-vessel vasculitisTakayasu arteritisGiant cell arteritis
Immune-complex mediated vasculitis Goodpasture's syndromeHenoch-Schönlein purpuraBehçet's diseaseEssential cryoglobulinemiaIgA nephropathy
Secondary vasculitis Autoimmune Disease SLE Rheumatoid arthritis Antiphospholipid antibody syndrome InfectionDrug-inducedInflammatory bowel diseaseHypocomplementemic urticarial vasculitisParaneoplastic

Are you sure your patient has pulmonary vasculitis? What should you expect to find?

The diagnosis of systemic vasculitis can be challenging to make, as the symptoms can be nonspecific, and so a high index of suspicion is required to make the diagnosis. The most common manifestation of pulmonary vasculitis is diffuse alveolar hemorrhage (DAH). DAH in conjunction with other manifestations of systemic vasculitis (see section below on common findings) should trigger a workup to establish a diagnosis. DAH is the manifestation common to all types of systemic vasculitis, but it is not always present. Other findings of pulmonary vasculitis, described below, include pulmonary nodules, cavities, and asthma.

What are the most common findings associated with pulmonary vasculitis?

Diffuse Alveolar Hemorrhage

The predominant clinical manifestation of pulmonary vasculitis is DAH. Though hemoptysis is the most frequent symptom of DAH, about a third of patients do not present with hemoptysis. Non-specific infiltrates seen on CXR or CT scan in a patient who is short of breath may often be the only clue of DAH. A bronchoscopy should be performed in cases of suspected DAH, and serial bronchoalveolar lavages (BAL) should get progressively bloodier. Microscopic evaluation of the BAL fluid yields hemosiderin-laden macrophages.

Cavitary or Nodular Lung Disease

Nodular or cavitary lung diseases are most commonly caused by infection or malignancy. However, in the appropriate clinical setting, these findings may suggest AAV, specifically GPA. Evidence that nodular or cavitary lung disease is not the result of malignancy or infection significantly raises the possibility of vasculitis.

Upper Airway Disease

Upper airway disease, including otitis, sinusitis, and rhinitis, is present in > 90% of patients with GPA. Tracheal stenosis is present in 10-30% of patients, and ulcerative or destructive lesions should alert the clinician to the possibility of vasculitis. Tracheobronchial and endobronchial lesions occur in 10-50% of patients with GPA.

Adult Onset Asthma

Asthma with eosinophilia is a near-universal finding in EGPA that often presents several years prior to the diagnosis of vasculitis. Asthma that is steroid-dependent or refractory to standard medical therapy can suggest the diagnosis.

Extrapulmonary Manifestations of Systemic Vasculitis

Systemic vasculitis can cause nonspecific constitutional symptoms such as fever, weakness, and weight loss. In addition, the kidneys, nervous system, and skin are also common target organs in all AAV.

Rapidly progressive glomerulonephritis (RPGN) is characterized by a 50% loss of renal function in less than 3 months and by histopathology revealing crescents in a least half of glomeruli. When renal failure and microscopic hematuria are seen, a microscopic examination of urine should be performed to look for red blood cell casts. Disorders that present with pulmonary-renal syndrome, a combination of RPGN and DAH, include AAV, SLE, and Goodpasture's syndrome. RPGN is nearly always present in MPA, only rarely in EGPA, and sometimes in GPA. Notably, there are many other causes of RPGN that have no lung involvement.

Mononeuritis multiplex, defined by the presence of peripheral nerve abnormalities in 2 or more distributions, is suggestive of small-vessel vasculitis. Other nervous system abnormalities include paresthesias, weakness, pain, and functional deficiencies such as foot drop. Mononeuritis multiplex is also typically found in the medium-vessel vasculitis, polyarterteritis nodosa (PAN). It should be noted that PAN does not cause pulmonary vasculitis.

Palpable purpura is a finding of non-blanching purplish discolorations that signify a cutaneous vasculitis. It is a nonspecific finding, as it can be associated with AAV, as well as drug reactions, cryoglobulinemia, infections, rheumatologic disorders, and malignancy.Granulomatosis with Polyangiitis (GPA), formerly Wegener’s disease

Among the AAV syndromes, GPA is the most common. The syndrome is characterized by a combination of upper and lower respiratory tract disease along with renal disease. Upper airway disease with sinusitis, otitis, epistaxis, and subglottic and/or tracheal stenosis occurs in 70-95% of patients. The presence of ulcerating or destructive lesions is highly suggestive.

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

EGPA is characterized by a classic triad of asthma, eosinophilia, and necrotizing vasculitis. The presence of asthma, peripheral blood eosinophilia with elevated IgE levels, pulmonary eosinophilia in BAL fluid, and the presence of eosinophils in tissue, make it unique amongst AAV, and also make it difficult to identify as a manifestation of vasculitis. EGPA is the rarest of the three AAVs, and DAH is rarely seen in EPGA. Migratory ground glass lesions on CT are the characteristic lower respiratory tract finding in EGPA.

Cardiac involvement is more common in EGPA than the other AAVs, occurring in 15-50% of patients, and it is disproportionately associated with high mortality. Gastrointestinal involvement with pain, infarction, hemorrhage, and viscus perforation are also more common in EGPA than other AAVs.

Microscopic Polyangiitis (MPA)

RPGN is nearly always present in MPA, and MPA is the most common pulmonary-renal syndrome. In contrast to GPA with its classic upper airway findings and cavitary lesions and EGPA with its asthma and ground glass opacities, MPA does not have features that distinguish it from other AAV aside from its very high rate of renal involvement. What does distinguish MPA from GPA and MPA is the absence of granulomas on biopsy.

Beware: there are other diseases that can mimic pulmonary vasculitis:

Signs and symptoms of vasculitis can overlap significantly with other conditions, including infection, malignancy, connective tissue disease, drug toxicity, and venous thromboembolic disease. DAH has myriad etiologies, and pulmonary capillaritis (suggestive of vasculitis) must be differentiated from diffuse alveolar damage and bland hemorrhage (e.g., coagulopathy, mitral stenosis, inhalation injury, drug-associated disease).

How and/or why did the patient develop pulmonary vasculitis?

The etiology of AAV, like most other autoimmune diseases, is not known. Case findings of AAV have increased significantly with the advent of ANCA testing in the last 20-30 years. With regard to specific AAV, GPA has an annual incidence of 4.9-10.5 per million, CSS from 0.5-4.2 per million, and MPA from 2.7-11.6 per million.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Laboratory Testing

When a patient presents with potential pulmonary vasculitis, labs for systemic vasculitis should be sent, specifically ANA, ANCA, anti-myeloperoxidase antibody (MPO), and anti-proteinase 3 (PR3) antibody. Additionally, evaluation for connective tissue disease should take place, with antinuclear antibodies, rheumatoid factor, and disease-specific antibodies (e.g., anti-dsDNA, anti-Smith, anti-RNP, and antibodies for antiphospholipid antibody syndrome). Goodpasture disease, which is an autoimmune disorder against glomerular basement membrane, can also present with the combination of DAH and RPGN, so in the proper clinical setting, sending anti-glomerular basement membrane antibodies should also be considered.

Antinuclear Cytoplasmic Antibodies

Our understanding of the role that ANCA testing plays in the diagnosis of vasculitis has advanced immensely since the 1980s. Immunofluorescent staining of ethanol-fixed neutrophils shows a diffuse pattern in the cytoplasm of patients with GPA (cytoplasmic pattern, or c-ANCA), while a perinuclear pattern is most commonly noted in patients with MPA and pauci-immune glomerulonephritis (perinuclear pattern, or p-ANCA). Though EGPA is classified as an AAV, the rate of ANCA positively is relatively low in this condition, about 30-50%.

c-ANCA is most commonly directed against a proteinase (PR3) in azurophilic granules, while p-ANCA is most commonly directed against myeloperoxidase (MPO) and is known to have a more diverse group of intracellular targets (i.e., lactoferrin, cathepsin, elastase, lysozyme, bacterial permeability protein).

When applied to at-risk populations, c-ANCA has a sensitivity of 85-90% and specificity of 90-95% in active systemic GPA. In organ-limited disease, the sensitivity decreases to 65-86%.

p-ANCA is often positive in ulcerative colitis and Crohn’s disease, and is also commonly positive in drug-induced skin vasculitis.

What imaging studies will be helpful in making or excluding the diagnosis of pulmonary vasculitis?

Imaging studies in pulmonary vasculitis are fairly non-specific. The DAH characteristic of GPA and MPA appears as diffuse alveolar infiltrates on CXR or CT scan. DAH must be diagnosed via bronchoscopy in these cases. GPA can also present with pulmonary nodules and cavities seen on imaging. Meanwhile, EGPA is characterized by migratory areas of ground-glass opacities on CT scan. These opacities will typically be seen in different areas of the lung on serial imaging. Pulmonary vasculitis can also result in pulmonary fibrosis, but this is rare overall.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of pulmonary vasculitis?

Serial pulmonary function tests are helpful in patients with bronchiectasis in GPA, or pulmonary infiltrates in EGPA or MPA. It has classically been taught that the finding of an elevated diffusion capacity for carbon monoxide (DLCO) to 30% above baseline can suggest a diagnosis of alveolar hemorrhage, but the critically ill nature of many patients with DAH makes DLCO testing impractical.

What diagnostic procedures will be helpful in making or excluding the diagnosis of pulmonary vasculitis?

Bronchoscopy

Bronchoscopy plays several important roles in the diagnosis of pulmonary vasculitis, including evaluation for DAH, malignancy, infection, and eosinophilia and assessing for ulcerative and stenotic upper airway and endobronchial disease. Lower respiratory samples can be obtained by BAL and should be sent for culture, cytology, and cell count with differential. Endobronchial or transbronchial biopsies can be helpful in excluding infections and malignancy, but the small size of the acquired tissue specimen limits diagnostic accuracy. Transbronchial biopsies should not be performed in patients with severe DAH or respiratory failure, owing to a high complication rate.

Tissue biopsy

ANCA positivity and the appropriate clinical context can be enough to make a diagnosis of AAV. However, tissue biopsy is often necessary to diagnose vasculitis definitively. Considerations regarding the biopsy site include the accessibility of involved organs, the morbidity/mortality associated with the procedure, and the likelihood of obtaining diagnostic tissue. EGPA and GPA are both granulomatous diseases, whereas MPA does not feature granulomas on biopsy. EGPA is further distinguished by the presence of eosinophils in tissue specimens.

The skin and sinuses, which are often involved, are frequently the most accessible biopsy sites. Upper airway specimens reveal the classic combination of necrosis, granulomatous inflammation, and vasculitis only 15-20% of the time, so skin and upper respiratory sites are useful in supporting the diagnosis of vasculitis but may not allow for definitive diagnosis.

Percutaneous renal biopsy is performed in the setting of acute glomerulonephritis. The histopathologic finding of a segmental, necrotizing glomerulonephritis is highly suggestive of vasculitis. Immunofluorescence should be performed to evaluate for immune-deposition that would suggest immune-complex mediated vasculitis (e.g., IgA deposits in HSP, linear IgG in Goodpasture's syndrome, and clumped IgG in SLE). The absence of immune deposits defines pauci-immune glomerulonephritis, which in the right clinical setting, is consistent with AAV.

Surgical lung biopsy performed via video-assisted thoracoscopic surgery in patients with small-vessel vasculitis identifies diagnostic features in up to 90% of patients. However, this requires general anesthesia and is the most invasive modality of biopsy; it is also generally contraindicated in patients with severe DAH or respiratory failure.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of pulmonary vasculitis?

Tissue should be evaluated by conventional histopathology for evidence of vasculitis, such as vascular necrosis with neutrophilic infiltration of the capillary walls, granulomas or eosinophilic components. In patients with DAH or RPGN, immunofluorescent stains for IgG, IgA, and anti-GBM should be done. Stains to detect acid-fast bacilli and fungi should also be performed.

Cytology from BAL can be helpful if the differential includes malignancy. In DAH, the cytology evaluation of the BAL can demonstrate hemosiderin-laden macrophages.

If you decide the patient has pulmonary vasculitis, how should the patient be managed?

Induction Therapy

Therapy for pulmonary vasculitis requires immunosuppressive treatment with corticosteroids and cytotoxic immunosuppressive agents, with escalating intensity based on disease severity. Patients with severe DAH or RPGN should be treated with high dose “pulse” steroids combined with either cyclophosphamide (CYC) or rituximab (RTX).

Plasmapheresis should be considered for patients with acute renal failure and serum creatinine > 2.5 mg/dL. Alongside pulse steroids, the two agents to consider for induction are IV rituximab or cyclophosphamide (CYC), which can be administered IV in pulse dosing or orally in “continuous” dosing. Though CYC was long considered first line, recent data has shown that RTX is at least as effective as CYC. As RTX carries with it less long-term concerns for cancer risk, we believe it should be the induction agent of choice. Initial induction therapy is geared toward achieving remission, and should be followed by maintenance therapy.

Maintenance Therapy

After remission is achieved, the glucocorticoid dose should be tapered carefully with a goal dose of < 10 mg daily of prednisone by 6 months, with close monitoring of pulmonary parameters, including chest imaging, symptoms of dyspnea or hemoptysis, and pulmonary function testing if indicated.

If CYC is used as induction, a maintenance regimen of either azathioprine or methotrexate should be administered once remission is achieved. More recently, RTX given in intervals as maintenance after induction with CYC has been shown to be efficacious. If RTX is used as induction, it is less clear that a maintenance regimen is needed, but retreatment with RTX in 6-12 month intervals is reasonable, or azathioprine or methotrexate may be considered 6 months after induction.

What is the prognosis for patients managed in the recommended ways?

The mortality rate for untreated patients is thought to be upwards of 90%. Survival has improved significantly compared to older data. The most recent survival data comes from the longitudinal follow-up for the studies demonstrating efficacy of RTX as an induction agent for AAV. In one study, there were only 4 deaths out of 99 patients with GPA or MPA at 18 months. In another study, at 24 months, in GPA or MPA patients with RPGN (some of whom had pulmonary vasculitis), there were 9 deaths out of 44 patients. It should be noted that all of the patients in the second study had RPGN, which worsens the prognosis significantly.

What other considerations exist for patients with pulmonary vasculitis?

Longitudinal monitoring of patients with AAV requires careful evaluation for disease relapse and complications of therapy. The clinician must be cautious that signs or symptoms consistent with a flare of vasculitis may also represent signs of infection or drug toxicity. In addition, the incidence of venous thromboembolic disease in patients with AAV is several times higher than the general population, so it should be considered in the differential diagnosis of a disease flare.

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