Pulmonary manifestations of anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis

Inflammation and necrosis of blood vessel walls occurs in a dozen or so primary vasculitic disorders. An attempt to classify these diverse forms of vasculitis resulted in the Chapel Hill international consensus definitions, which used vessel size as the determinant of classification [1]. Wegener's granulomatosis, microscopic polyangiitis and Churg–Strauss syndrome are described as small vessel vasculitides and are commonly associated with anti-neutrophil cytoplasmic antibodies (ANCA). The incidence of ANCA-associated vasculitis is 20 per million population occurring more often in an elderly population (peak age 55 to 70 yr) [2]. Prevalence rates are far higher since the introduction of successful immunosuppressant treatment regimes. Of the three entities, Churg–Strauss syndrome is the least common (1–3 per million population). Some studies of ANCA-associated vasculitis have suggested that pulmonary involvement is associated with a poor outcome [3, 4]. The diagnosis of ANCA-associated vasculitis is made on the basis of the clinical findings, by biopsy of a relevant involved organ and the presence of ANCA. Testing for ANCA using both indirect immunofluoresence and antigen-specific enzyme-linked immunosorbent assay is recommended, and provides high sensitivity (approximately 99%) and good specificity (approximately 70%) in those with generalized Wegener's or microscopic polyangiitis [5]. ANCA testing may, however, be less sensitive in patients with more limited disease or Churg–Strauss syndrome [6]. Wegener's granulomatosis classically represents a triad of inflammation and vasculitis of the upper and lower airway with glomerulonephritis. Microscopically there is vascular change including fibrinoid necrosis, inflammatory cell infiltrate with neutrophils, lymphocytes and plasma cells with granuloma formation [7]. In contrast, the pathology of Churg–Strauss syndrome is characterized by necrotizing vasculitis, eosinophilic tissue infiltrates and both intra- and extravascular granulomata [8]. Microscopic polyangiitis differs in that it is a small vessel vasculitis without evidence of respiratory tract granulomatous inflammation. The aetiology of these diseases remains unknown; however, significant advances have been made in understanding disease pathogenesis (several very good reviews have recently been published [9, 10]). The strong association of vasculitis with ANCA suggests an autoimmune disease and that these antibodies are directly pathogenic. ANCA activate cytokine-primed neutrophils and monocytes, which express the ANCA antigens, myeloperoxidase (MPO) and proteinase 3 (PR3), on the surface. Neutrophils respond by increasing adhesion to cytokine-activated endothelial cells, generating a respiratory burst, releasing proteolytic granule contents and secreting pro-inflammatory cytokines, resulting in destruction of the alveolar walls. Animal models support the view that these autoantibodies are pathogenic. Xiao et al. [11] immunized MPO knockout mice with murine MPO. Anti-MPO antibodies, purified from the serum of the immunized MPO knockout mice, were injected intravenously into both Rag2 knockout (which lack T and B cells) and wild-type recipients. The recipient mice developed pauci-immune focal necrotizing crescentic nephritis, demonstrating that anti-MPO antibodies alone were sufficient to cause disease. Another murine model using passive transfer of anti-murine PR3 showed exacerbation of local cutaneous inflammation following administration of tumour necrosis factor (TNF) compared with mice without anti-PR3 antibodies. Passive transfer of anti-PR3 antibodies alone did not induce vasculitis or granuloma formation [12]. ANCA, however, are not in themselves sufficient to induce disease in humans as patients may have ANCA but no evidence of disease activity. Endothelial cells are also important in localizing inflammation. Endothelial cells develop an activated phenotype with enhanced expression of adhesion molecules that promotes interaction with circulating leucocytes. ANCA activation can convert rolling neutrophils to stationary adherent cells and increase transmigration [13]. Release of pro-inflammatory mediators, including nitric oxide, reactive oxygen species and proteolytic enzymes, might all contribute to damage to the vessel wall seen in vasculitis. Activation of endothelial cells and neutrophils is important for the early development of vasculitic lesions, and progression is accompanied by recruitment of T cells and monocytes. Several studies have suggested that T cells can proliferate to myeloperoxidase or proteinase 3 [14, 15], and that they remain activated, with increased activation markers CD25 and HLA-DR on circulating T cells [16, 17], despite disease remission. These studies suggest that T cells contribute to the relapsing–remitting nature of ANCA-associated vasculitis. Within the respiratory tract of patients with Wegener's granulomatosis, accumulation of monocytes and T and B cells often manifest as granuloma. Although granulomatous inflammation is a characteristic response to intracellular pathogens (for review see [18]), attempts to isolate an infectious pathogen in Wegener's granulomatosis have failed. Studies in patients with Wegener's granulomatosis have shown an excessive Th1 response with significant production of interferon-γ and TNF [19, 20] similar to granuloma formation associated with infection. CD28-negative CD4-positive T cells are a major source of these cytokines in granuloma of patients with Wegener's granulomatosis, and are uncommon in normal individuals [21, 22]. The excessive production of TNF and interferon-γ could serve to initiate and perpetuate the granulomatous inflammation characteristic of Wegener's granulomatosis. Interestingly, exposure to silica, which may also result in granuloma formation, is associated with an increased risk of ANCA-associated vasculitis [23]. Environmental and genetic factors also influence disease pathogenesis (for review see [24]). There are no strong HLA associations with ANCA-associated vasculitis but patients with α1-anti-trypsin deficiency have an increased risk of disease and increased disease severity [25, 26]. Drug exposure may also precipitate ANCA-associated vasculitis, including exposure to propylthiouracil, minocycline and penicillamine [27, 28]. Infectious agents have long been suspected of playing a role in development of vasculitis. Chronic nasal carriage of Staphylococcus aureus appears to confer significant risk for disease relapse, and pulmonary infection frequently triggers a relapse [29–30]. Observations of Churg–Strauss syndrome in cases of parasitic disease (e.g. ascaris, trichinosis) suggest that in many cases hyper-responsiveness to an antigenic stimulus underlies the syndrome. A number of cases of Churg–Strauss syndrome have been reported following the introduction of leokotriene receptor antagonists. However, of 126 cases, 88% developed disease during a period of steroid tapering, suggesting that these drugs may not in themselves cause disease [31]. Like Wegener's granulomatosis and microscopic polyangiitis, Churg–Strauss syndrome is not associated with deposition of immune complexes. Activated eosinophils are able to induce activation of vascular endothelial cells and may be directly responsible for some of the classical disease features of Churg–Strauss syndrome by virtue of the release of stored cationic proteins. Thirty to fifty per cent of cases are associated with ANCA, particularly in those with evidence of vasculitis. The pathogenic role of these antibodies is unclear, but they may act to amplify inflammation. Cytokine profiles on the cells involved in Churg–Strauss syndrome are contradictory, but a Th2 cytokine profile may predominate. Interleukin-5 and TNF are elevated in the bronchoalveolar lavage. Pulmonary involvement is a characteristic feature of both Wegener's granulomatosis and Churg–Strauss syndrome, less so in microscopic polyangiitis. The lung is the most commonly affected organ in Wegener's granulomatosis with evidence of involvement in over 90% of patients during the course of their disease; in 9% it is the only organ affected. Pulmonary involvement ranges from subclinical changes evidenced by high-resolution computer tomography (HRCT) chest scans [32] and the finding of haemosiderin-laden macrophages in bronchoalveolar lavage fluid (BALF) to devastating haemoptysis [32]. Wegener's granulomatosis can affect all parts of the respiratory tract, resulting in the variety of symptoms illustrated in Table 1. However, asymptomatic pulmonary involvement is common, occurring in over 30% of cases [33]. Approximately 5% of patients will have a fulminant presentation requiring assisted ventilation. Clinical manifestations of pulmonary vasculitis Clinical manifestations of pulmonary vasculitis Churg–Strauss syndrome classically, although not always, presents with three distinct clinical phases of asthma, tissue eosinophilia and vasculitis. The phasic development of disease with its distinct pathological findings suggests the evolution of disease over time. Chronic asthma requiring long term steroids often precedes the vasculitic phase by 8–10 yr. With the onset of vasculitic phase, the severity of the asthma and exacerbations increase, although in rare cases these episodes may actually decrease. Allergic rhinitis is a common finding in Churg–Strauss syndrome [34] along with involvement of the nasal and paranasal sinuses (e.g. nasal obstruction, recurrent sinusitis and nasal polyposis) which may precede asthma. Lung involvement is also common in microscopic polyarteritis. Lung haemorrhage occurs in up to a third of patients. Some patients with microscopic polyarteritis may present clinical, radiological and functional findings consistent with an interstitial process mimicking idiopathic pulmonary fibrosis [35]. Diffuse alveolar haemorrhage (DAH) occurs as a consequence of pulmonary capillaritis in the ANCA-associated vasculitides, and is an important cause of morbidity and mortality in this condition [36]. It can also arise as a result of a major bleed from endobronchial disease. Published series, report the incidence of DAH as 7–45% in Wegener's granulomatosis [7, 33, 37] and 10–30% in microscopic polyangiitis [38]. It is rare in Churg–Strauss syndrome [6], but almost invariable in isolated pauci-immune pulmonary capillaritis [39]. The acute mortality associated with DAH and underlying vasculitis is approximately 60%, six times greater than vasculitis without pulmonary haemorrhage [37, 40]. Haemoptysis and dyspnoea are the commonest clinical presentations of DAH [39]. However, approximately one-third of patients may have significant alveolar haemorrhage without reporting episodes of haemoptysis. Other features suggestive of DAH include new alveolar shadowing on the chest radiograph in the absence of heart failure or infection with or without a falling haematocrit. Increases in carbon monoxide gas transfer (KCO) of 30% or more from baseline, due to increased haemoglobin–carbon monoxide binding, is seen acutely almost universally [37]. Fibreoptic bronchoscopy may show diffuse blood staining throughout the endobronchial tree. Additional bronchoscopic features include increasing blood staining of sequential aliquots of bronchoalveolar lavage fluid and haemosiderin-laden macrophages [32]. Transbronchial biopsy or thoracoscopic lung biopsy is rarely required, but may be indicated in patients who present with diffuse alveolar haemorrhage in whom the underlying aetiology has not been identified by other means. With experienced operators, the risk of open lung biopsy in ventilated patients is relatively low [41]. Subglottic stenosis occurs in approximately 10–20% of patients with Wegener's granulomatosis, and can present as its only manifestation [33]. Moreover, the stenotic segments may persist or progress despite control of the disease elsewhere in the body [42]. Subglottic stenosis in Wegener's granulomatosis affects woman more frequently than men. Symptoms range from cough and shortness of breath to life-threatening stridor. Initial diagnosis can be confused with other pulmonary diseases, especially asthma. Voice changes can occur with glottic involvement. Some patients with Wegener's granulomatosis also develop distal endobronchial disease which can lead to wheezing, stridor and dyspnoea. The diagnosis of subglottic stenosis is made on bronchoscopy, flexible pernasal laryngoscopy or radiological imaging of the larynx. Macroscopically, Wegener's granulomatosis appears as a red, friable circumferential narrowing below the vocal cords. Biopsy yield from the involved area is low and typically reveals non-specific inflammation [42]. Histological confirmation is more likely to come from the nasal mucosa. Severity is determined from clinical history, and measurement of the length and diameter of the stenosed segment using three-dimensional CT reconstruction or magnetic resonance imaging (MRI) of the trachea. Flow-loop studies allow sequential assessment of severity. Accurate assessment of disease activity within the lungs can be difficult since disease activity correlates poorly with pulmonary symptoms. A plain chest radiograph is routinely obtained to monitor disease activity in the lungs. Typical findings on plain radiograph include bilateral, multiple rounded opacities ranging from a few millimetres to 10 cm in diameter. There is commonly cavitation of these nodules (Fig. 1). Chest X-ray of patient with active Wegener's demonstrating cavitating lesions. High-resolution CT scanning of the chest offers a more sensitive imaging technique in ANCA-positive vasculitis. High-resolution CT has a higher sensitivity in detecting nodules and masses; these are an important radiographic finding as the probability of having active lung disease is significantly increased when they are present [32] (Fig. 2). Table 2 outlines the broad range of HRCT abnormalities seen in Wegener's granulomatosis [43]. Once a patient has started upon treatment, radiological abnormalities and pulmonary symptoms become even more challenging, as pulmonary infections affect up to 50% of cases at some point [44]. Clearly, there is a very broad differential diagnosis for these infiltrates [45–47]. Furthermore, since vasculitis patients are at increased risk of cancer, new pulmonary lesions need appropriate investigation [48]. CT findings in areas in 57 patients with Wegener's granulomatosis Adapted from Lohrmann et al. [43]. CT findings in areas in 57 patients with Wegener's granulomatosis Adapted from Lohrmann et al. [43]. HRCT chest image of a cavitating pulmonary mass in a patient with Wegener's. Radiographic abnormalities in patients with Churg–Strauss syndrome are also varied [49–51] with the chest X-ray revealing changes from transient focal areas of consolidation to more extensive peripheral opacities similar to those found in eosinophilic pneumonia. Other manifestations include pulmonary haemorrhage and pleural effusion, which may be present in up to 30% of cases. As with Wegener's granulomatosis, pulmonary abnormalities are better assessed by HRCT but the pattern is non-specific. Abnormalities of pulmonary function can be varied in vasculitis according to which part of the respiratory tract is involved. Airflow obstruction is common in Churg–Strauss syndrome but is also seen in patients with Wegener's granulomatosis, with small airway involvement in both diseases. The chest X-ray is often normal in these patients (7/12 in one study) [52]. Parenchymal involvement can lead to either reduced gas transfer from interstitial involvement or increased gas transfer when there is pulmonary haemorrhage. Central airway obstruction due to subglottic stenosis gives a classical flow volume loop appearance (see Fig. 3). Respiratory muscle weakness may also be present even in those without obvious lung involvement [52]. Flow volume loop showing typical flow limitation due to a fixed subglottic stenosis. Little is known regarding the long-term effects on lung function in patients with early lung involvement. Previous vasculitic lung disease may cause persistent scarring and loss of the alveolar capillary bed. CT changes of ground glass opacification often resolve without scarring; however, one-third of nodules, masses and consolidation may heal with scarring and development of fibrosis. Small studies have suggested that patients may be with obstruction, pulmonary fibrosis and reduced have also shown that patients with pulmonary involvement are more likely to have reduced transfer factor and [52]. and bronchoalveolar lavage can be in patients with vasculitis. and biopsy of endobronchial disease and is in other lavage typically a in Wegener's granulomatosis with active disease and vasculitis. In some cases with granulomatous lavage may be macrophages are suggestive of pulmonary which is often Transbronchial are in Wegener's granulomatosis patients they are from lung areas tissue confirmation of granulomatous inflammation is to the can be obtained from the upper respiratory tract, by endobronchial or biopsy or thoracoscopic The upper respiratory tract in approximately of patients lung biopsy provides with a high yield [7]. The pathological of necrotizing granulomatous inflammation and necrotizing vasculitis throughout the lung is suggestive of Wegener's granulomatosis. However, these features are not seen in biopsy and biopsy may It is important to that the absence of the typical features of Wegener's granulomatosis not the ANCA-associated vasculitis has a 90% mortality within 2 due to respiratory failure of disease be to disease severity. In those with organ and (see Table 3). is and risk of morbidity is on A suggested that 3 to to is as as a more course of The of has been in ANCA-associated vasculitis. A suggested that may be less with effects than and that it is at least as at but at the risk of a higher relapse In those without organ involvement may be used as an however, this may be at the of increased relapse be in those with significant for vasculitis for vasculitis are the of treatment in Churg–Strauss however, be in those with more disease. The reported that those with more disease factor when with steroids and but associated with increased effects The most important of are pulmonary haemorrhage and severity of failure at who present with fulminant disease of with either or plasma A of patients with involvement has shown outcome in patients plasma There are no of patients with pulmonary suggest of and has also been used as but a of patients suggested only a transient is associated with significant including failure TNF is to be important in the pathogenesis of ANCA-associated vasculitis, and have suggested a However, a of patients with Wegener's granulomatosis showed no of TNF receptor in disease or of when to and or compared with may have to the outcome of this as more patients with disease or those who treatment were in the The relapse also higher than in reported and of patients may be less in granulomatous inflammation than as but not is in disease studies with are remains an important cause of morbidity and mortality in these patients. be to those for An important risk for infection is a common of The of a appears and not a high risk of a of vasculitis is common despite with 50% of patients within yr. In the of as as however, at there a relapse in both is for However, a has suggested that change to when patients remain may increase the risk of relapse The of following disease is not be for at least 2 following successful remission. In those who remain ANCA or have be to long-term Other have been to in an attempt to In studies has shown in and a with for of is has also been used but is less of in a of 20 patients using following disease with and patient a major relapse and patients relapse in a of yr. were of patients respiratory of patients experienced and developed of the upper respiratory tract by Staphylococcus aureus may increase the risk of disease with reduced the risk of respiratory relapse compared with when to but there a high of is not for at the of to induce in approximately of patients. A of difficult patients are those who frequently relapse, recurrent of a has been reported to induce disease in in those with disease. In a of this also resulted in a in ANCA but without However, disease may relapse on of B cells The and of in disease and of is assessed in a is an immunosuppressant that has been used in acute and models of autoimmune disease. of is not but it may with activation of factor Interestingly, it has a on In an open used to induce in patients with active Wegener's granulomatosis, all of whom were or to blood cells to 3 they were a six over to with no or episodes of A has suggested that of is and in patients to T cells a role in disease is of activated lymphocytes and in patients with Wegener's granulomatosis, with pulmonary patients with patients and in a of patients to relapse and patients one from infection and the other pulmonary haemorrhage following treatment may be in patients with disease. have suggested that may be in patients with Churg–Strauss syndrome In one with three patients with Churg–Strauss syndrome, all patients showed early clinical in pulmonary function studies and of steroid However, be with risk as most patients as less symptoms and may respiratory failure during DAH often which to be associated with a high the of with lower to the of associated lung of in in the of DAH have been seen the patient during may changes in recruitment and of at least six with the of in DAH associated with ANCA-associated vasculitis However, and that is not and may its in the clinical of activated have also been used to DAH to microscopic polyangiitis Although studies are typically normal in patients with there are high of to factor with activated life-threatening and the pulmonary capillary inflammation patients with subglottic is on the severity of the the severity of the activity of the Wegener's granulomatosis and the Subglottic stenosis often despite treatment [42]. Several to the stenosis are including steroid and These have not in the and is to a airway in approximately of cases in almost from symptoms and is Small have suggested that of stenosis is but be only in with appropriate patients with distal endobronchial and are successful in experienced ANCA-positive vasculitis commonly affects the respiratory tract and has a range of The differential diagnosis of all the manifestations is and diagnosis often and Respiratory of vasculitis and its treatment can be and clinical this is in with an The have no of Lung and of and of of and of