Pulmonary Vasculitis

 Overview

Pulmonary manifestations of the systemic vasculitides range from mild upper respiratory tract symptoms to devastating alveolar hemorrhage. Although the lungs are infrequently the only organ system involved, respiratory symptoms often prompt patients to seek medical attention. Often, these issues are only part of a larger systemic process, and it is in this context that we address the various systemic vasculitides.

Vasculitis can occur as either a primary or secondary event. Secondary vasculitis occurs in the setting of another underlying illness, such as the capillaritis that can be seen in SLE, whereas primary vasculitis is a vasculitic syndrome that occurs in the absence of another illness and is usually without identifiable etiology.

Since the original description of the first systemic vasculitis by Kussmaul and Maier in 1866, the nomenclature and classification of these disorders have undergone significant evolution. In 1992, the Chapel Hill Consensus Conference established a standardized method of classification based mainly on histopathologic criteria and on the size of the vessels involved. Furthermore, the discovery of ANCA has significantly influenced the diagnosis and classification of the vasculitides and has provided insight into the possible mechanisms through which these processes progress.

Epidemiology

Primary systemic vasculitides are rare, and epidemiologic studies have been difficult given the changing nomenclature and classification systems. Overall, the frequency of diagnosis has increased over the years, although this may reflect the fact that vasculitic syndromes are being more readily recognized. Giant cell arteritis is the most frequently encountered vasculitis, with an annual incidence of 13 per 1 million adults, followed by rheumatoid arthritis-associated vasculitis (12.5 per million) and then by the small-vessel vasculitides, Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS).

Wegener's Granulomatosis

WG is a multisystem disease that affects small to medium vessels. Originally described as a variant of polyarteritis nodosa (PAN), the findings of a progressive granulomatous process involving the upper and lower respiratory tract as well as other organ systems led Wegener to believe that he had discovered a unique vasculitic syndrome. Although the classic Wegener's triad consisted of necrotizing granulomatous inflammation of the respiratory tract, generalized necrotizing vasculitis of the small arteries and veins, and necrotizing glomerulonephritis, fewer than half of the originally described cases fulfilled these criteria. The evolving process of disease classification and diagnosis has resulted in the 1992 Chapel Hill international consensus statement that WG is a granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to medium-sized vessels.

Clinical Presentation

Before current therapy, the mortality associated with untreated WG was nearly universal, with a mean survival time of 5 mos. WG can occur at any age, but the mean age of onset is approximately 40 yrs. It affects men and women equally and has a predilection for Caucasians. The initial presentation is usually insidious, with generalized complaints of malaise, fatigue, weight loss, and upper respiratory symptoms. After this, patients may develop symptoms involving multiple organ systems.

Ear, nose, and throat involvement occurs in up to 99% of cases of WG. Chronic rhinitis, epistaxis, nasal crusting, and chronic sinusitis are commonly reported, and destruction of the nasal cartilage leads to the nasal septal perforation or saddle nose deformity that is associated with the disease. Ulcerations of the oropharynx and gingival hyperplasia also occur, as can the strawberry gingival hyperplasia that is rare but pathognomonic of WG.

Tracheobronchial ulcerations, intraluminal inflammatory pseudotumor, and bronchomalacia can occur, resulting in symptoms that can be confused with asthma, and scarring from these lesions can result in significant airway obstruction.

Necrotizing granulomas, cavitary lesions, and scattered nodules are the primary pulmonary manifestations of WG and are usually clinically insignificant, although mild hemoptysis can occur. Capillaritis in the lung is a result of the generalized vasculitic component of WG and can result in diffuse alveolar hemorrhage with an associated mortality of nearly 50%. This clinical presentation is indistinguishable from that which can occur in Goodpasture's syndrome or in microscopic polyangiitis.

Skin findings in WG include papules, vesicles, palpable purpura, ulcers, or subcutaneous nodules. Leukocytoclastic vasculitis is the most common manifestation and occurs in up to 50% of patients. Other skin lesions such as pyoderma gangrenosum and granulomatous skin lesions, although rare, have been reported.

Nervous system involvement is believed to be secondary to vasculitis of the vasa nervorum and presents most frequently as mononeuritis multiplex. Other possible findings include cranial neuritis, cerebral vasculitis, or granulomatous infiltration, although these occur infrequently.

Renal disease caused by capillaritis can be irreversible if left untreated. The focal segmental necrotizing glomerulonephritis on biopsy can be indistinguishable from that found in microscopic polyangiitis, Goodpasture's syndrome, or SLE. Immunofluorescence microscopy is used to distinguish the former two pauciimmune (little to no immune deposits) glomerulonephritides from Goodpasture's syndrome and the granular pattern of immune deposits in SLE.

Diagnosis

The diagnosis of WG is a clinicopathologic one and usually begins with initial lab data and a chest x-ray (CXR). CBC, serum chemistry panel, urinalysis with microscopy, ESR, and ANCA should be obtained on all patients with suspected vasculitis. Leukocytosis, anemia, elevations in ESR (~100 mm/hr), and an active urinary sediment with RBCs and RBC casts can all be seen in active small-vessel vasculitis. CXR findings include lung nodules and masses with or without cavitation and, less frequently, pleural effusions, mass lesions, and pleural or mediastinal pseudotumors. High-resolution CT scanning has been used for further investigation of abnormalities on CXR and has increased the sensitivity in diagnosing WG in the appropriate clinical setting.

Flexible fiber-optic bronchoscopy is used both to inspect the tracheobronchial tree and to acquire tissue through biopsy to assist in making the diagnosis of WG. Ulcerating tracheobronchitis as well as cobblestoning of the mucosa have been described, and secondary scarring as the result of the healing of these lesions can lead to stenosis, airway obstruction, bronchomalacia, and postobstructive pneumonia. Although only approximately 20% of biopsy samples obtained by fiber-optic bronchoscopy may be diagnostic of WG, bronchoscopic findings coupled with the appropriate clinical scenario and lab data can save patients from undergoing an open-lung biopsy.

The histopathologic hallmarks of WG are vasculitis, necrosis, and granulomatous inflammation of small and medium vessels such as arterioles, arteries, capillaries, and venules. The lung and the upper respiratory tract offer the highest sensitivity and specificity for biopsy sampling, although size and the presence or absence of concurrent immunosuppressive therapy may affect the diagnostic quality of the specimen. Renal biopsy characteristically shows glomerulonephritis but does not distinguish WG from other small-vessel vasculitides.

ANCA have been identified as possible mechanisms of pathogenesis in the systemic vasculitides. ANCA directed against serine protease 3 cause a cytoplasmic immunofluorescence pattern and have a sensitivity of 28 to 92% and a specificity as high as 80 to 100% in WG. Serum ANCA levels have been shown to vary during the course of WG, although serial measurements in patients have not shown reliability in assessing disease course or predicting relapse.  Diffuse Alveolar Hemorrhage, for more information on ANCA.

Treatment

For prognostic and therapeutic purposes, it is helpful to separate WG into limited and generalized disease. Limited disease has been used to describe cases that do not affect the kidneys and reflects pathology caused mainly by necrotizing granulomas and not by active vasculitis. Generalized disease implies pathology marked predominantly by vasculitis and is applicable any time there is evidence of end-organ disease or impending organ failure. The limited phase of WG results in minimal morbidity, is characterized by constitutional symptoms, and is usually marked by modest increases in inflammatory markers such as CRP and ESR. In the generalized vasculitic phase, elevations in CRP and ESR are marked, as are other acute-phase reactants. If left untreated, the limited phase of WG may progress to the generalized phase, although this is not universal.

Therapy for WG is tailored to individual cases and is managed according to disease activity. Treatment for WG can be divided into remission induction and remission maintenance. The current standard therapy for generalized disease combines the use of oral cyclophosphamide (2 mg/kg/day) and prednisone (1 mg/kg/day). The prednisone is tapered over the following 2 to 3 mos after a therapeutic response is achieved, after which it can be discontinued if remission persists. Cyclophosphamide is continued for 3 mos and is then followed by remission maintenance therapy. If the disease relapses, the protocol is reinitiated. Using this regimen, a complete remission rate of 75 to 93% can be achieved. Although effective, current therapy is not without its drawbacks. Nearly half of patients undergoing cyclophosphamide therapy develop some form of toxicity, including hemorrhagic cystitis, bladder cancer, and myelodysplasia.

For limited disease, methotrexate (MTX) has been successfully used and is preferred for its small side effect profile and limited toxicity. A study conducted by the NIH found that a significant complication of MTX and prednisone therapy was Pneumocystis jiroveci pneumonia, and therefore, prophylaxis with TMP-SMX is now mandatory. TMP-SMX alone has been used with success in treating limited forms of WG but appears to be ineffective in treating generalized disease. TMP-SMX has been shown to significantly reduce the relapse rate when used as adjunctive therapy and therefore is included in most regimens used to treat WG. It is unclear if the antimicrobial or immunomodulatory effects of TMP-SMX are responsible for its activity in treating WG. Remission maintenance for WG is an area of active research. Current regimens consist of MTX alone, although azathioprine has shown promise as well. Other agents such as mycophenolate and leflunomide are currently undergoing investigation.

Microscopic Polyangiitis

Microscopic polyangiitis is a necrotizing vasculitis affecting small vessels. Although their clinical courses may be similar, MPA, WG, and PAN are generally distinguished by the lack of granulomatous involvement of the upper respiratory tract in MPA and by the involvement of small vessels only in PAN. This latter distinction is important to establish early on, as disease course and treatment response differ between the two syndromes.

Similar to WG, MPA can present at nearly any age, with a mean of approximately 50 yrs. Men and women appear to be affected equally, although some studies suggest a female predominance. The main clinical feature of MPA is renal involvement, with the presence of a rapidly progressive necrotizing glomerulonephritis in nearly 90% of cases. Again, this feature is pathologically indistinguishable from that occurring in other small-vessel vasculitides. Clinical manifestations vary from mild hemoptysis with transient pulmonary infiltrates on CXR to massive hemoptysis and diffuse alveolar hemorrhage. Pulmonary-renal failure may be the initial presentation in fulminant MPA, necessitating hemodynamic and respiratory support as well as hemodialysis. Although MPA has been reported as the most common pulmonary-renal syndrome, cutaneous, peripheral nerve, and GI manifestations may also be present.

Diagnosis

The diagnostic approach to the patient with suspected MPA is similar to that described for the initial evaluation of WG. Perinuclear ANCA (p-ANCA), an antibody directed against myeloperoxidase, is found in 80% of patients with microscopic polyangiitis. p-ANCA generates a perinuclear immunofluorescence pattern. See Chap. 19, Diffuse Alveolar Hemorrhage, for more information on ANCA.

Treatment

Relapses are common in MPA, but they are rare in classic PAN, and therefore distinguishing between the two early on can significantly affect the duration of therapy. PAN characteristically affects small and medium muscular arteries and causes renovascular HTN, microaneurysms, and renal infarcts, whereas the capillaritis in MPA yields a rapidly progressive glomerulonephritis that is uncommon in PAN.

Although the success of remission induction in MPA remains high, many patients experience disease relapse after therapy is discontinued or during the tapering of remission maintenance. As in WG, cyclophosphamide and oral corticosteroids are the mainstay of therapy. Relapses are generally milder than the initial presentation, although some may be severe with end-organ damage. Although cyclophosphamide is effective in treating active disease, it has not been shown to prevent relapses. Patients with mild relapse may be managed by increasing the dose of oral corticosteroids, whereas major relapse necessitates the reintroduction of initial therapy. In cases of treatment failure, plasma exchange may be considered. IV immunoglobulin G has been used in refractory cases with limited success.

Churg-Strauss Syndrome

CSS is a rare vasculitis affecting small and medium vessels. The hallmarks of CSS are asthma, hypereosinophilia, and necrotizing vasculitis.

CSS affects men and women equally and can present at any age. The clinical course has been described in three phases. The first consists of a prodrome of allergic rhinitis and asthma, which may last up to 20 yrs, followed by peripheral and tissue eosinophilia, which characterize the second phase. The third phase consists of an extensive vasculitis that can affect the nerve, lung, heart, GI tract, and kidney and can be life-threatening. Although variability has been reported in the order of these phases, the American College of Rheumatology has found them 95% sensitive and specific for CSS when coupled with histopathologic evidence of vasculitis. In the absence of proven vasculitis, the prodromal phase is indistinguishable from typical asthma, and the eosinophilia of the second phase may be confused with eosinophilic pneumonia, Loeffler's syndrome, or eosinophilic gastroenteritis.

The unifying pulmonary manifestation in CSS is a history of asthma, but allergic rhinitis, sinusitis, and nasal polyps are also commonly seen. The majority of patients have been treated with oral corticosteroids for symptoms of asthma before the diagnosis of CSS, a feature that can delay the diagnosis. Radiographic findings are widespread and nonspecific, consisting of transient pulmonary infiltrates, peripheral parenchymal infiltrates, cavitating pulmonary nodules, and pleural effusions.

Mononeuritis multiplex is the most distinguishing and common extrapulmonary manifestation of CSS, affecting up to 75% of patients. 

Cardiovascular involvement is another common feature and is responsible for a significant proportion of the morbidity and mortality associated with the disease. Manifestations include ECG abnormalities, congestive heart failure, eosinophilic myocarditis, coronary vasculitis, and pericardial effusions resulting in cardiac tamponade.

Renal involvement occurs most commonly as a focal and segmental necrotizing glomerulonephritis and usually does not result in fulminant renal failure.

Abdominal pain is nearly universal in the latter phases and is caused by eosinophilic or vasculitic involvement of the GI tract. Other GI findings include pancreatitis, GI perforation, or hemorrhage.

Cutaneous involvement in CSS is also common and includes purpura, livedo reticularis, and subcutaneous nodules.

Diagnosis

The diagnosis of CSS rests mainly on establishing an active vasculitis given the appropriate clinical setting of asthma and hypereosinophilia. Every effort should be made to obtain tissue before beginning potentially toxic therapy. The utility of ANCA testing is not as well defined in CSS as in WG or MPA, although p-ANCA may be positive in 50% of patients. It is important to note that a positive p-ANCA should be confirmed with ELISA for myeloperoxidase, as other neutrophil antigens resulting in a positive p-ANCA have a low sensitivity in CSS.

The American College of Rheumatology has published the following criteria for the diagnosis of CSS once the establishment of vasculitis has been made: asthma, eosinophilia >10% of the total WBC count, mono- or polyneuropathy, migratory pulmonary infiltrates, paranasal sinus abnormality, and extravascular eosinophils. These criteria are 85% sensitive and 99% specific for the diagnosis of CSS when four of the six are positive in the setting of an active vasculitis.

Treatment

Glucocorticoids are the mainstay of treatment of CSS vasculitis. The role of cyclophosphamide and other cytotoxic agents is less clear in CSS than in WG or MPA, although they have been used in addition to corticosteroids in refractory cases and in cases with neurologic or cardiac involvement. Hydroxyurea has been used to treat severe eosinophilia, and despite aggressive therapy, some patients with CSS may remain refractory.

Pulmonary Manifestations of Other Vasculitides

Giant cell arteritis is a disease of large and medium vessels that predominantly affects the elderly. It is more common among Caucasians and is the most common vasculitis in this population. Respiratory symptoms such as cough, hoarseness, or throat pain may be the presenting symptom in as many as 25% of cases, and diagnostic studies such as pulmonary function tests and CXRs may be normal. Treatment is with prednisone, which usually results in resolution of symptoms.

Takayasu's arteritis has been classically described in young Asian females. The aorta and its major branches are affected, and manifestations include mild pulmonary HTN, fistula formation between pulmonary artery branches and bronchial arteries, and nonspecific inflammatory interstitial lung disease. The diagnosis is best made using CT or magnetic resonance angiography, which demonstrate pulmonary artery stenoses and occlusion in nearly half of all patients. Initial treatment consists of glucocorticoids and immunosuppression, and methotrexate and vascular bypass are options in severe or refractory cases.

Behcet's syndrome is a relapsing multisystem disorder characterized by recurrent oral ulcerations and at least two of the following: genital ulcers, uveitis, cutaneous nodules or pustules, or meningoencephalitis. Cough, fever, dyspnea, and chest pain may be the initial respiratory symptoms, although massive hemoptysis is perhaps the most significant complication.

Immune-complex deposition is believed to be the underlying mechanism in the vasculitis of Behcet's syndrome. Characteristic lung findings include pulmonary artery aneurysms, which result from destruction of the elastic lamina. Erosion of bronchi can result in arterial-bronchial fistulae, producing massive hemoptysis with an associated mortality of nearly 40%. Other manifestations include recurrent venous thrombosis as well as pneumonia and bronchial occlusion.

CT and magnetic resonance angiography have replaced pulmonary angiography in the diagnosis of Behcet's syndrome. Methotrexate, colchicine, chlorambucil, and cyclosporine have all been used with prednisone to treat Behcet's, and the combination of prednisone and azathioprine or cyclophosphamide has been shown to improve pulmonary artery aneurysms. Aspirin at 81 mg/day may be considered for the prevention of recurrent venous thrombosis but should be avoided in any patient with known pulmonary involvement.

Both SLE and rheumatoid arthritis are associated with a secondary vasculitis that is believed to be immune complex mediated. Complications of these syndromes include the presence of rheumatoid nodules in rheumatoid arthritis and pulmonary HTN and alveolar hemorrhage that tends to be more severe in SLE and can be the initial disease manifestation. With a mortality >50% in some case series, treatment of alveolar hemorrhage in SLE with the combination of plasmapheresis and pulse-dose cyclophosphamide has met with limited success.

Necrotizing sarcoid granulomatosis is differentiated from sarcoidosis by its extensive vasculitis and necrosis, the paucity for extrapulmonary involvement, and for the radiographic findings of pulmonary masses, nodules, and pleural involvement, which are less commonly seen in sarcoidosis. Well-circumscribed granulomas are prominent in this disease, and the vasculitis may be epithelioid-granulomatous, with histiocytes and multinucleated giant cells reminiscent of giant cell arteritis, or lymphocytic without granuloma formation. The clinical onset of this syndrome is subacute, and patients may complain of nonspecific respiratory symptoms such as cough, dyspnea, or wheezing. Alternatively, the diagnosis is incidental and made radiographically in asymptomatic patients. The prognosis is good, with spontaneous resolution in some cases. Further therapy is similar to that for chronic pulmonary sarcoidosis and consists of oral corticosteroids.

Key Points to Remember

• Although the lungs are infrequently the only organ system involved in cases of vasculitis, respiratory symptoms are often what prompt patients to seek medical attention. Often, these issues are only part of a larger systemic process.
• The discovery of ANCA has significantly influenced the diagnosis and classification of vasculitides and has provided insight into the possible mechanisms responsible for these diseases.
• WG is classically described as a triad of sinusitis, pneumonitis, and glomerulonephritis, although <50% of cases meet all three criteria.
• The hallmarks of CSS are asthma, hypereosinophilia, and necrotizing vasculitis.