Version January 2024
INTRODUCTION — "Classic" granulomatosis with polyangiitis (GPA) is a form of systemic vasculitis (polyangiitis) with necrotizing granulomatous inflammation of the upper and lower respiratory tracts, systemic necrotizing vasculitis, and necrotizing glomerulonephritis [1,2]. Microscopic polyangiitis (MPA) is a necrotizing vasculitis without granulomatous inflammation that predominantly affects small vessels (ie, capillaries, venules, or arterioles) and can present with pulmonary capillaritis or in the context of interstitial lung disease [3]. Both MPA and GPA are considered ANCA-associated vasculitides, although ANCA testing may be negative in some patients.
The major features of respiratory tract involvement in GPA and MPA will be reviewed here. Issues related to the approach to and management of systemic vasculitides, as well as the pathogenesis, clinical manifestations, diagnosis, therapy, and outcomes in GPA and MPA are discussed separately.
●(See "Overview of and approach to the vasculitides in adults".)
●(See "Overview of the management of vasculitis in adults".)
●(See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)
●(See "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis".)
●(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy".)
CLINICAL FEATURES — Patients with granulomatosis with polyangiitis (GPA) typically have both upper airway and pulmonary involvement, although a minority may have just one or the other [1]. Nonspecific complaints of fever, anorexia, weight loss, and malaise are often present [4,5]. Microscopic polyangiitis (MPA) affecting the respiratory tract is most often associated with alveolar hemorrhage [6,7]. The clinical manifestations of GPA and MPA outside the respiratory tract are discussed separately.
In the past, the term "limited" GPA was used to describe patients with clinical findings isolated to the upper respiratory tract or lungs, which occurs in approximately one-fourth of cases. The term was confusing, as "limited" disease could be severe. The current practice is to describe the locations of organ involvement and the severity of disease at each location. Thus, a patient can have "severe" disease in the lungs in the presence of antineutrophil cytoplasmic antibody (ANCA)-associated diffuse alveolar hemorrhage with mild extrapulmonary involvement [8]. Many patients with disease limited to upper respiratory tract or lungs subsequently develop systemic involvement [9].
Nasal, sinus, and ear disease — Among patients with GPA, approximately 90 percent have nasal, sinus, or ear involvement, compared with 35 percent of patients with MPA, who have sensorineural hearing loss [10-12]. Nasal, sinus, and ear involvement may be present without other disease manifestations for weeks to months before progressing to more generalized, "vasculitic" disease.
The most common presenting symptoms and signs of GPA or MPA related to the nares, sinuses, and ears include the following [1,13-18]:
●Nasal crusting
●Sinus pain
●Chronic rhinosinusitis
●Nasal obstruction
●Smell disturbances
●Purulent/bloody nasal discharge
●Excessive tearing (ie, epiphora)
●Formation of sinus mucoceles (benign, epithelium-lined cysts filled with mucus)
●Conductive and/or sensorineural hearing loss
Patients often present with symptoms of nasal congestion and purulent nasal discharge suggestive of a sinus infection that has failed to resolve with appropriate antibiotic therapy. Chronic rhinosinus involvement with GPA can lead to nasal septal perforation, saddle nose deformity, serous otitis, hearing loss, and nasocutaneous fistulae [13,19,20]. Nasal polyposis is not seen in GPA. Adjacent structures may also be involved (eg, orbital pseudotumor with proptosis and vision impairment, oral ulcers) [21].
Airway and lung involvement — The most common respiratory symptoms in GPA and MPA are cough, hemoptysis (due to alveolar hemorrhage and/or tracheobronchial disease), dyspnea, and pleuritic pain. The severity of symptoms and signs varies considerably from asymptomatic (one-third of patients) to acute and fulminant alveolar hemorrhage with respiratory failure. Among patients with GPA, it is unusual for pulmonary symptoms to occur in the absence of upper respiratory tract symptoms or signs. The specific clinical manifestations vary depending on whether the patient has tracheobronchial disease, lung parenchymal nodules, interstitial lung disease, or alveolar hemorrhage.
Tracheobronchial disease — Tracheobronchial involvement with GPA has several manifestations, including tracheal and bronchial stenosis, mass lesions (inflammatory pseudotumors), tracheobronchial malacia, and tracheoesophageal fistulae [17,19]. Associated symptoms include dyspnea, stridor, cough, sputum production, and hemoptysis.
●Subglottic stenosis is the most common manifestation of tracheobronchial GPA; reported frequencies vary from 8 to 50 percent [17,22-25]. In a referral population, 22 percent of patients with GPA had subglottic stenosis [22]. Subglottic stenosis may be the sole manifestation of GPA and may be severe enough to necessitate tracheostomy [19,26]. Stridor is a sign of severe subglottic obstruction and requires urgent evaluation. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults", section on 'Diagnostic evaluation and initial management'.)
●Bronchial ulceration and stenosis are less common than tracheal stenosis and may be asymptomatic or cause dyspnea, hemoptysis, and/or symptoms of postobstructive pneumonia. Bronchial disease is almost always associated with GPA disease elsewhere.
●Mass lesions in the trachea and bronchi due to GPA can ulcerate leading to hemoptysis or cause airway obstruction leading to dyspnea and postobstructive infections.
●Uncommonly, bronchial involvement leads to airflow limitation or bronchiectasis, with productive cough, hemoptysis, wheezes, or crackles [19,27,28]. (See "Clinical manifestations and diagnosis of bronchiectasis in adults", section on 'Clinical features'.)
Lung parenchymal nodules — Lung parenchymal nodules usually do not cause symptoms, although patients often have constitutional or upper airway symptoms, as described above.
Interstitial lung disease — Various types of interstitial lung disease (ILD) can be seen in GPA, although ILD is more commonly associated with MPA [29-32]. Sometimes, evidence of ILD precedes the appearance of systemic vasculitis [4,29,31,33].
In a series of 144 patients with MPA, fibrosing interstitial lung disease was noted in 12 percent at disease onset and 15 percent in long-term follow-up [3]. In most of the patients with computed tomography images, the pattern was felt to resemble usual interstitial pneumonia (UIP) most closely.
A retrospective study identified 204 patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and ILD, of whom 91 percent had MPA and 7 percent had GPA. The radiographic pattern (based on 2013 American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines [34]) was consistent with UIP or possible UIP in 75 percent, nonspecific interstitial pneumonia (NSIP) in 19 percent, organizing pneumonia in 1.5 percent, and unclassifiable ILD in 10 percent [35]. Patients did not undergo surgical biopsy for histologic confirmation. While p-ANCA positivity predominated in this cohort, patients with NSIP radiographic pattern had a higher likelihood of c-ANCA positivity (15 percent) than those with radiographic UIP or possible UIP (3.3 percent).
A cross-sectional Italian national study of 95 consecutive patients (56 affected by MPA and 39 by GPA) also showed that NSIP pattern was more frequently observed in c-ANCA positive patients (61 percent of cases), while the UIP pattern was more often observed in p-ANCA positive patients (48 percent) [36]. ILD was found at diagnosis in two-thirds of patients and was the first clinical manifestation (preceding vasculitis) in 22 percent of cases.
Alveolar hemorrhage — Diffuse alveolar hemorrhage (DAH) is a prominent and life-threatening pulmonary manifestation of ANCA-associated vasculitis (AAV) [37-39]. It is estimated to occur in 5 to 45 percent of patients with AAV and may be the presenting finding [40-42]. As an example, among 144 patients with MPA, 22 percent had alveolar hemorrhage at the time of presentation; it occurred subsequently in another 4 percent [3]. DAH accompanied by glomerulonephritis is a form of pulmonary-renal syndrome [43]. (See "The diffuse alveolar hemorrhage syndromes" and "Glomerular disease: Evaluation and differential diagnosis in adults".)
Patients with alveolar hemorrhage due to GPA or MPA typically present with the rapid onset of dyspnea and may also have cough, hemoptysis, anemia, and/or hypoxemia. Untreated, they may progress rapidly to respiratory failure. Associated constitutional symptoms and evidence of skin, neurologic, and renal involvement are common; nonspecific prodromal symptoms may precede presentation by days to weeks [5].
Pulmonary artery stenosis — A few cases of proximal pulmonary artery stenosis have been reported in patients with GPA or MPA and attributed to involvement of the arterial wall [44,45]. The patients presented with progressive dyspnea, and the diagnosis was made with computed tomographic pulmonary angiography [45]. Pulmonary artery pressures may or may not be elevated on transthoracic Doppler echocardiography [44,45].
EVALUATION — The evaluation of patients with suspected upper or lower respiratory tract involvement with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) requires a combination of clinical assessment, serologic testing, pulmonary function testing, sinus and chest imaging, bronchoscopy, and tissue biopsy.
Approach — The order of testing and speed with which it is performed depends in part on the pattern of symptoms and acuity of illness. However, it is important to establish a diagnosis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis expeditiously, as a prompt diagnosis allows the initiation of therapy that may be life-saving and organ-sparing. The results of initial testing, presence of extra-respiratory or co-morbid disease, and local expertise also influence the choice and order of procedures. Whenever possible, the least invasive biopsy site is selected (eg, skin, nares). As examples:
●If the patient presents with dyspnea and diffuse radiographic opacities, an expedited evaluation is necessary to enable rapid initiation of treatment. Testing includes routine laboratory tests, urinalysis, testing for ANCA, anti-glomerular basement membrane antibodies, and antinuclear antibodies (table 1). (See 'Laboratory tests' below.)
If the patient's condition allows, high resolution computed tomography (HRCT) is obtained to guide bronchoalveolar lavage (BAL). Urgent bronchoscopy is performed with a careful airway survey (to exclude ulcerations, stenosis, or mass) and BAL in a radiographically involved area to assess for alveolar hemorrhage, infection, or malignancy. In general, biopsy confirmation of GPA or MPA is highly desirable, but individual patients may be deemed to be poor surgical candidates for lung biopsy. As alternatives, less invasive sites may be used for tissue confirmation (eg, skin, kidney) or empiric therapy may be initiated on the basis of serologic results and BAL showing hemorrhage. (See 'Bronchoscopy' below and "The diffuse alveolar hemorrhage syndromes", section on 'Diagnostic evaluation'.)
●For patients who present with pulmonary nodules, a positive ANCA test result, and renal insufficiency, but no cutaneous manifestations, the choice between a lung or kidney biopsy is often debated. When pulmonary nodules are peripheral, we typically proceed with a video-assisted thoracoscopic lung biopsy. Transbronchial biopsies are generally not helpful due to insufficient sample size. On the other hand, a patient with progressive renal insufficiency may require a kidney biopsy to fully characterize their kidney disease and guide treatment. If the kidney biopsy shows pauci-immune glomerulonephritis, a lung biopsy may not be necessary. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)
●If upper respiratory tract disease (eg, nasal obstruction, sinus opacification, crusting, bloody nasal discharge) is prominent and the patient does not have constitutional symptoms, the initial diagnostic evaluation usually includes testing for ANCAs and a sinus CT scan (if not already performed). A positive ANCA test result should be followed by additional laboratory testing (eg, complete blood count with differential, urinalysis, creatinine) and appropriate chest imaging studies. If sinus disease is extensive, biopsy of involved nasal or sinus tissue usually follows, but may be nondiagnostic. Further evaluation is aimed at obtaining histopathologic confirmation at another site, such as the skin, kidney, or lungs depending on the results of careful skin examination, laboratory testing, and chest imaging.
Laboratory tests
Routine laboratory tests — Laboratory testing, other than the ANCA, is generally nonspecific in GPA and MPA. Nonetheless, a complete blood count with differential, blood urea nitrogen (BUN), creatinine, and urinalysis are obtained in virtually all patients with suspected GPA or MPA. For patients with respiratory insufficiency and diffuse radiographic opacities, we also obtain liver and muscle enzymes, antiglomerular basement membrane (anti-GBM) antibodies, antinuclear antibodies (ANA), cryoglobulins, complement (C4), hepatitis serology, HIV screen, and blood cultures to assess potential vasculitic involvement of other organs and to exclude other processes in the differential diagnosis (table 1). (See "Overview of and approach to the vasculitides in adults", section on 'Laboratory tests'.)
For patients with nasal ulcerations or a saddle nose deformity, a toxicology screen for cocaine may be appropriate. The saddle nose deformity of syphilis is congenital and thus serologic testing for syphilis is not necessary in patients with acquired saddle nose deformity. (See "Cocaine use disorder: Epidemiology, clinical features, and diagnosis".)
Common hematologic abnormalities in GPA include a normochromic, normocytic anemia, leukocytosis, and thrombocytosis (>400,000/mm3) [1]. Peripheral eosinophilia is uncommon in GPA and MPA. Marked elevation of the erythrocyte sedimentation rate (>100 mm/hour by Westergren method) and an increase in C-reactive protein (CRP) are common, but nonspecific. A lack of elevation in sedimentation rate or CRP does not exclude GPA or MPA.
The plasma creatinine and urinalysis are normal in limited GPA. In contrast, patients with classic GPA or MPA typically show a variable elevation in plasma creatinine concentration, mild to moderate proteinuria, and an active urine sediment with red cells, white cells, and red cell and other cellular casts.
Antineutrophil cytoplasmic antibodies — An indirect immunofluorescent assay for ANCAs is performed in any adult patient who presents with symptoms or signs suggestive of a vasculitis. (See 'Clinical features' above and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Granulomatosis with polyangiitis'.)
More than 90 percent of patients with active GPA or MPA and both lung and kidney involvement have ANCAs in the serum. In some circumstances (eg, nondiagnostic biopsy findings), a positive ANCA may provide the only clue to the correct diagnosis. However, in limited forms of GPA, ANCA testing may be negative. Conversely, a positive ANCA needs confirmatory testing with antigen-specific enzyme-linked immunosorbent assays (ELISAs) and (almost always) tissue histopathology.
The majority of patients with GPA have autoantibodies directed against serine proteinase 3 (PR3), known as PR3-ANCA (C-ANCA), that are associated with diffuse cytoplasmic staining; a minority have autoantibodies directed against myeloperoxidase (MPO), known as MPO-ANCA (P-ANCA), that are associated with a perinuclear staining pattern. MPO-ANCA are also found in microscopic polyarteritis, pauci-immune glomerulonephritis, eosinophilic granulomatosis with polyangiitis (EGPA), and the drug-induced ANCA-associated vasculitis. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)
Confirmation of the presence of autoantibodies to PR3 or MPO by the specific ELISAs leads to substantially higher specificity and positive predictive values than the indirect immunofluorescence assay. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Solid-phase immunoassays'.)
The individual types of ANCA (PR3 or MPO) are often associated with particular patterns on computed tomography (CT). In a case series of 129 patients with ANCA-positive vasculitis and positive serology, 81 (63 percent) were PR3-ANCA positive and 48 (37 percent) were MPO-ANCA positive, and one patient was positive for both PR3 and MPO [46]. On CT, PR3-ANCA was associated with central airways and nodular disease; MPO-ANCA was associated with a usual interstitial pneumonia pattern and bronchiectasis. Alveolar hemorrhage, pleural effusion, lymph node enlargement, and pulmonary venous congestion were more common in MPO-ANCA positive patients. (See 'Computed tomography' below.)
ANCA-positivity during follow-up is associated with systemic relapses and may reflect ongoing GPA activity, while undetectable ANCA during the clinical course of the disease is associated with longer relapse-free survival. Unfortunately, the titers are not consistent enough to allow GPA or MPA management based on serial measurement of ANCA levels alone. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease", section on 'Monitoring by the clinician'.)
Pulmonary function tests — Pulmonary function tests (PFTs), including flow volume loops, are obtained in ambulatory patients with symptoms or signs of airway or lung involvement in GPA or MPA to assess the presence of airway involvement and the severity of lung function impairment. (See "Overview of pulmonary function testing in adults" and "Diffusing capacity for carbon monoxide".)
Data regarding PFT results in GPA and MPA are limited [1,47].
●The most frequent abnormality is airflow obstruction and may be caused by diffuse airway involvement, focal tracheal or bronchial stenosis or lobar collapse
●Reduced lung volumes and diffusing capacity for carbon monoxide (DLCO) are seen in interstitial lung disease
●Reduced lung volumes are found when diffuse interstitial involvement is present
●The DLCO may be markedly increased in the presence of active alveolar hemorrhage, although these patients are often too dyspneic to perform PFTs
●Lung function frequently improves following treatment, although the diffusing capacity may not return to normal
Flow volume loop tracings may show flattening of the expiratory loop in patients with intrathoracic tracheal stenosis or flattening of the inspiratory loop in extrathoracic subglottic stenosis when the area of narrowing is still pliable or flattening of both inspiratory and expiratory loops when the airway lesion is tightly stenotic (figure 1). (See "Flow-volume loops", section on 'Abnormal inspiratory loop'.)
Oxygenation is initially assessed with pulse oximetry. A reduced oxygen saturation can be caused by pulmonary hemorrhage, infection, thromboembolism, or fluid overload. For patients with progressive respiratory impairment, arterial blood gas analysis is usually obtained.
Imaging
Sinus computed tomography — Multiplanar computed tomography (MDCT) is the preferred imaging modality for evaluating chronic rhinosinusitis and suspected rhinosinus involvement by GPA or MPA in patients with nasal symptoms, facial pain/pressure, hyposmia, or anosmia [48,49]. In addition, sinus CT is often obtained in patients with suspected GPA even in the absence of nasal or sinus complaints. In a case series of 28 patients with sinonasal GPA, the most common findings on sinus CT were mucosal thickening in the nasal cavity and paranasal sinuses in 61 and 75 percent, respectively [48]. Other findings included bony destruction of the nasal cavity (57 percent), bony destruction of the paranasal sinuses (54 percent), subtotal sinus opacification (25 percent), and bony thickening (sclerosing osteitis) of the paranasal sinuses (18 percent). (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis", section on 'Sinus CT'.)
Chest radiograph — A chest radiograph is typically obtained in patients with respiratory symptoms or extrapulmonary features that suggest vasculitis. If a chest CT will be obtained promptly, the chest radiograph can be omitted. The vast majority of patients with GPA have an abnormal chest radiograph, although the appearance is highly variable. The radiographic findings usually include one or more of the following [50]:
●Nodules that may be cavitary
●Reticular markings
●Diffuse hazy opacities, sometimes with an air bronchogram
●Lobar or segmental atelectasis
●Pleural opacities
●Hilar adenopathy (uncommon)
No clear differences are noted between the chest radiograph manifestations of limited and classic GPA, except that alveolar hemorrhage generally occurs in the setting of systemic vasculitis (classic GPA or MPA) [50].
Depending on the case series, the most commonly reported chest radiograph findings are nodules (20 to 90 percent) and patchy or diffuse opacities (20 to 50 percent) [27,41,50,51]. Pulmonary nodules may be single or multiple and range in diameter from 1 to 10 cm [52]. The nodules are typically diffuse in distribution and may be cavitary [41,53]. Margins may be well-circumscribed or ill-defined.
Focal segmental opacities and/or atelectasis can also occur, often distal to a site of endobronchial involvement (eg, stenosis or a mass) produced by the granulomatous inflammatory process. Other less common findings include pleural effusions, hilar adenopathy, spontaneous pneumothorax (induced by rupture of a subpleural cavitary nodule), and the presence of a fungus ball (eg, aspergilloma) in a cavity.
Computed tomography — HRCT scans of the chest are obtained in virtually all patients undergoing an evaluation for GPA or MPA and in patients with hemoptysis or an abnormal chest radiograph. Chest HRCT imaging is helpful in disclosing lesions not seen on the plain chest radiograph and in identifying previously unsuspected cavitary nodules (image 1) or central airway lesions [50].
Common CT findings in GPA include multiple pulmonary nodules (generally less than 10 in number) (image 2 and image 3) and ground glass or consolidative opacities that are patchy or diffuse (due to diffuse pulmonary hemorrhage or active vasculitis) [43,50,53]. Nodules range in size from a few millimeters to 10 cm. Approximately 30 to 50 percent of nodules are cavitary and 17 percent are diffuse opacities [4,50,54]. Less common findings include a reticular pattern, interlobular septal thickening, honeycombing, bronchiectasis, hilar adenopathy, and pleural effusions [19,43,50,53].
Among patients with MPA, common abnormalities on HRCT include ground glass opacities, reticular markings, interlobular septal thickening, bronchiolitis, bronchial wall thickening, and bronchiectasis [55]. Areas of consolidation, honeycombing, nodular densities, and pleural abnormalities are less common.
Chest HRCT scanning can also identify the presence of other findings that may suggest the diagnosis of vasculitis, including [50,53,56]:
●Blood vessels leading to nodules and cavities (feeding vessels)
●Small, peripheral, wedge-shaped densities suggesting pulmonary microinfarction
●Cuffing of the bronchovascular bundle in a lobar segmental and subsegmental distribution, often associated with narrowing of the bronchial lumen
●Enlarged, irregular, and stellate-shaped peripheral pulmonary arteries (the "vasculitis" sign) [57]
●Previously unsuspected tracheal or bronchial stenosis (image 2)
When central airway obstruction due to subglottic or tracheal stenosis is suspected, MDCT scanning with two and three dimensional reconstruction can provide thin-section, high-spatial resolution images of the airway [58]. Advantages of MDCT over axial or helical CT imaging include identification of subtle areas of narrowing and a more precise estimate of the craniocaudal extent of stenotic lesions. This technology also allows for noninvasive follow-up of airway lesions during the course of therapy. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults", section on 'Diagnostic evaluation and initial management'.)
Certain CT findings may be associated with particular autoantibodies, as described above. (See 'Antineutrophil cytoplasmic antibodies' above.)
Bronchoscopy — The most common indications for bronchoscopy in patients with suspected GPA are to assess and biopsy endobronchial disease and perform BAL. BAL is performed in patients with diffuse parenchymal opacities on chest imaging to identify alveolar hemorrhage, if present, and to obtain samples for microbiologic and cytologic analysis. Transbronchial lung biopsy may identify an alternate diagnosis, but the sample size does not allow for a positive diagnosis of GPA [59].
During the airway survey, careful attention is needed to identify areas of friable mucosa, ulceration, masses, or stenosis. Biopsy of endobronchial lesions may yield histopathology compatible with GPA, although the specimen size may be too small to make a definitive diagnosis of GPA [59]. Endobronchial biopsy is, however, useful for excluding other diseases such as endobronchial malignancy, tuberculosis, or sarcoidosis.
For patients with multiple pulmonary nodules, bronchoscopy with BAL is useful to evaluate for fungal or mycobacterial infection, but the nodules are usually inaccessible to transbronchial biopsy.
When performing BAL to assess for alveolar hemorrhage, three sequential wedged lavages with 50 to 60 mL aliquots are performed in a single area. When alveolar hemorrhage is present, the returned lavage aliquots are progressively more hemorrhagic. Hemosiderin-laden macrophages are often identified on Prussian blue staining of cells from the BAL fluid, although this latter finding does not differentiate alveolar hemorrhage from diffuse alveolar damage. (See "The diffuse alveolar hemorrhage syndromes", section on 'Bronchoalveolar lavage' and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Hemorrhagic BAL'.)
Biopsy — Tissue confirmation of GPA or MPA is highly desirable, even among patients with a compatible clinical presentation and positive serology, due to the potential toxicity of treatment. The choice of a biopsy site must be individualized based on the accessibility of specific sites of disease and whether the patient would tolerate the planned procedure. (See 'Approach' above.)
Lung biopsy — The main indication for lung biopsy is the evaluation of single or multiple pulmonary nodules, particularly when extrapulmonary disease is absent or not accessible to biopsy [60]. Even when GPA is strongly suspected (eg, positive ANCA), infection and metastatic disease affecting the lung must be fully excluded prior to initiating immunosuppressive therapy for GPA. (See 'Histopathology' below.)
Most patients with diffuse alveolar hemorrhage identified by diffuse radiographic opacities and a BAL showing hemorrhage are poor candidates for lung biopsy. Lung biopsy is generally not recommended in this setting, especially when unexplained anemia, a positive ANCA, and an elevated DLCO (>150 percent predicted or an increase of more than 30 percent over baseline) are present. (See "The diffuse alveolar hemorrhage syndromes", section on 'Biopsy'.)
When ANCA-associated vasculitis is suspected in a patient with interstitial lung disease, the choice between lung or kidney biopsy must be made individually. It is often a difficult decision to obtain surgical lung biopsy in this setting. Importantly, when the lung is clinically involved, surgical lung biopsy usually provides definitive pathologic evidence.
Generally, transthoracic needle biopsies, like transbronchoscopic biopsies, are too small for making a definitive diagnosis of GPA, although they may be performed to identify other processes (eg, infection, tumor) in the differential diagnosis. Instead, lung tissue is obtained via video-assisted thoracoscopic surgery or thoracotomy. The decision between these techniques depends on the location and size of nodules and radiographic opacities and also local expertise. Smaller, more peripheral nodules and diffuse disease are more amenable to a thoracoscopic approach, while larger more central lesions may require a thoracotomy. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)
Nasal or sinus biopsy — Nasal and sinus biopsies are performed as part of the evaluation and treatment of nasal obstruction due to soft tissue masses and chronic sinusitis, even though the findings are often nonspecific [13,15,16,61]. As an example, functional endoscopic sinus surgery is often performed for symptoms and signs of recurrent or persistent sinusitis and sinus biopsies are obtained in the course of the procedure. Areas of nasal mucosal ulceration or soft tissue mass are biopsied when present. Biopsies are also indicated when septal perforation, bony erosion, or collapse of the nasal bridge are noted [13,15,21]. Samples are also sent for special stains and culture (eg, fungal, mycobacterial), as well as histopathology (table 2). (See 'Histopathology' below and "Chronic rhinosinusitis with nasal polyposis: Management and prognosis", section on 'Surgical management'.)
Histopathology — Histopathologic findings in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) vary with the location and type of involvement in the respiratory tract and elsewhere. The histopathology of renal GPA and MPA are discussed separately.
●Chronic rhinosinusitis – Histopathologic examination of nasal and sinus tissue involved by GPA typically reveals extensive tissue necrosis and infiltration with a mixed population of inflammatory cells; necrotizing granulomas are occasionally present in GPA, but not MPA. Direct evidence of vasculitis is rarely seen in pathologic specimens from the upper respiratory tract [62-65].
●Tracheobronchial disease – Tracheobronchial GPA disease includes subglottic and lower tracheal and bronchial stenoses, tracheal and endobronchial mass lesions, and, less commonly, tracheobronchial malacia, follicular bronchiolitis, and bronchiolitis obliterans [19,27,66]. The histopathologic findings of the various forms of bronchiolitis are discussed separately. (See "Overview of bronchiolar disorders in adults".)
The initial lesion in tracheal and bronchial stenosis appears to be a circumferential area of friable mucosa and ulceration [19]. Fibrotic scarring may occur during the resolution phase, and result in stenosis or, less commonly, tracheomalacia, or bronchiectasis. Biopsies of areas of airway stenosis due to GPA often reveal nonspecific inflammation typical of granulation tissue or fibrotic scarring, but rarely show vasculitis [19,67].
Biopsies of tracheal and bronchial masses often show fibrinoid necrosis, microabscesses, and infiltration by epithelioid histiocytes and neutrophils without clear vasculitis [68].
●Pulmonary parenchymal nodules – The characteristic lung parenchymal lesions of GPA are firm, hemorrhagic to yellow-gray spherical nodules, ranging in size from 0.3 to 12 cm with an average size of 2.4 cm [50]. Central necrosis, more friable than caseous, may be present, resulting in cavities in 25 to 50 percent of nodules [62].
GPA is categorized as a small vessel vasculitis, but may affect arteries, arterioles, capillaries, venules, and veins. Microscopically, transmural infiltration of blood vessels with inflammatory cells is noted, associated with granulomatous inflammation in the surrounding tissue [69]. Necrosis of the vessel walls and/or necrosis of inflammatory cells within the vessel walls may be visible. One issue in the histopathologic diagnosis of GPA is that infections (typically granulomatous) can cause vascular inflammation within areas of diffusely inflamed parenchyma and must be differentiated from GPA. The presence of vasculitis in an area of otherwise uninvolved lung tissue ensures that the vascular inflammation is not just a consequence of another inflammatory process [62]. However, this finding is infrequent and the diagnosis of GPA does not require it. A separate finding that favors GPA over infection is necrosis of the vascular media, which is rarely noted when vascular inflammation is caused by infection. Negative special stains and cultures are also evidence against an infectious etiology.
The granulomatous inflammation of GPA is characterized by palisading histiocytes that are oriented with their long axis perpendicular to the necrotic center [62]. A few noncaseating granulomas may be present, but are not prominent. In general, the inflammatory changes associated with GPA are angiocentric, although a rare bronchocentric variant has been described [52]. The infiltrating inflammatory cells include neutrophils, lymphocytes, multinucleated giant cells, and eosinophils, but eosinophils are generally not abundant. However, eosinophilic variants of GPA have been described. In a case series of four patients with a clinical syndrome consistent with GPA, lung biopsy findings otherwise consistent with GPA were associated with eosinophil infiltration, but not peripheral eosinophilia [70]. In a separate case report, peripheral blood and pleural eosinophilia were associated with lung biopsy findings of classic GPA without eosinophil infiltration [71]. Differentiation of the eosinophilic variants of GPA from eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss) was based on clinical and histopathologic correlation. (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Pathology' and "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Diagnostic criteria'.)
Small areas of organizing pneumonia are often seen in association with small suppurative granulomas, foci of bland necrosis, multinucleated giant cells, and microabscesses [66]. Rarely, prominent areas of organizing pneumonia are noted [52,72]. (See "Cryptogenic organizing pneumonia", section on 'Histopathologic diagnosis of organizing pneumonia'.)
●Interstitial lung disease – Typical histopathologic findings of patients with interstitial lung disease and MPA include fibrosis of the alveolar walls and interstitium and honeycombing [73]. Vasculitis is not always demonstrable. In a series of 12 patients, vasculitis involved the pulmonary arterioles in three, the bronchial arteries in three, and capillaries in two [74]. In a separate series of nine patients, the histopathologic pattern in six was consistent with usual interstitial pneumonitis (UIP) without evidence of alveolar hemorrhage or vasculitis; two patients had alveolar hemorrhage, but no evidence of vasculitis [33].
●Alveolar hemorrhage – Pulmonary capillaritis is the key histopathologic finding in GPA and MPA presenting with diffuse alveolar hemorrhage (picture 1 and picture 2); larger vessels are often uninvolved [37,40]. Small punctate neutrophilic aggregates within areas of hemorrhage are a clue to the presence of capillaritis [62]. A mixed inflammatory cell infiltrate is typically present within the interstitium and airspaces, as well as a small vessel leukocytoclastic vasculitis (ie, presence of degenerating neutrophils with formation of nuclear dust in the vessel wall) (image 4). Foamy macrophages and giant cells may be present, but granulomatous inflammation is usually minimal or absent.
Pulmonary capillaritis due to GPA or MPA is differentiated from that due to systemic lupus erythematosus (SLE) or antiglomerular basement membrane (anti-GBM) antibody (Goodpasture's) disease by immunostaining. Granular immune complex deposition is characteristic of SLE and linear IgG deposition along the capillary basement membrane is virtually diagnostic of anti-GBM antibody disease. Immune deposits are absent in MPA. (See "The diffuse alveolar hemorrhage syndromes", section on 'Biopsy' and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis".)
Hemosiderin-laden macrophages, identified by Prussian blue staining that reveals large clumps of hemosiderin, appear in alveoli approximately 48 hours after the onset of hemorrhage are typically noted in the alveoli [62]. The large clumps of hemosiderin differentiate these macrophages from smoker's macrophages, which have a finely stippled pattern of iron deposition in the cytoplasm. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Hemorrhagic BAL'.)
Testing for tuberculosis — We generally perform a tuberculin skin test or blood interferon-gamma release assay (IGRA) as part of the evaluation of patients with suspected GPA, as the clinical features and histopathology of GPA can be difficult to differentiate from granulomatous infections like tuberculosis. However, a positive result on either of these tests does not necessarily indicate active tuberculosis, nor does a negative test exclude active TB. Patients with latent TB infection will require anti-tuberculosis treatment when undergoing immunosuppressive therapy for GPA. (See "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults" and "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection" and "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)
DIAGNOSIS — The diagnosis of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) is established when serologic (ie, antineutrophil cytoplasmic antibody positivity with autoantibodies directed against serine proteinase 3 or myeloperoxidase) and histopathologic evidence of small vessel vasculitis with or without granulomatous inflammation are present in a patient with a compatible clinical presentation. The distinction between GPA and MPA can be difficult and is largely based on the presence or absence of necrotizing granulomatous inflammation on biopsy or radiographic surrogates thereof (lung nodules, cavities, or masses). As GPA and MPA are typically systemic processes, the diagnostic criteria include an assessment of the distribution of involvement in extrarespiratory organ systems (eg, kidneys, nervous system, skin, heart). The full diagnostic criteria for GPA and MPA are discussed separately.
The diagnosis of GPA or MPA also depends on the exclusion of other diseases in the differential diagnosis, such as sarcoidosis, tuberculosis, antiglomerular basement membrane antibody syndrome, and drug-induced vasculitis, as described below. (See 'Differential diagnosis' below.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of the upper and lower respiratory tract findings associated with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) is broad, but narrows considerably in the presence of a positive antineutrophil cytoplasmic antibody (ANCA), particularly when the enzyme-linked immunoassay shows specific antibodies to proteinase 3 (PR3) or myeloperoxidase (MPO). Diseases that require special consideration when evaluating a patient for possible GPA are described in the following sections. The differential diagnosis of a positive ANCA test is described separately. (See 'Antineutrophil cytoplasmic antibodies' above and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Disease associations'.)
Chronic rhinosinusitis — Several granulomatous processes can cause a similar presentation to that of GPA sinonasal disease, including infections, eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss), sarcoidosis, extranodal NK/T cell nasal lymphoma (previously known as lethal midline granuloma), and others listed in the table (table 2).
Differentiating features include the following:
●The sinonasal disease associated with EGPA is less likely to cause septal perforation or other destructive lesions compared with GPA [75]. Nasal polyposis, which is common in EGPA, is not seen in GPA. While mild peripheral blood eosinophilia can be seen in GPA, prominent peripheral blood eosinophilia (usually 5000 to 9000 eosinophils/microL) and prominent eosinophilic infiltration on histopathology favor EGPA. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)" and "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Pathology'.)
●Sarcoidosis is suggested by the presence of lupus pernio or other typical cutaneous manifestations, and also numerous noncaseating granulomas on nasal or sinus biopsy. Hearing loss is more common in GPA and EGPA than in sarcoidosis. (See "Cutaneous manifestations of sarcoidosis" and 'Histopathology' above.)
●Cocaine-induced midline destructive lesions (CIMDL) can mimic limited GPA and are associated with positive ANCA tests [76,77]. In CIMDL the ANCA may be directed at proteinase 3, myeloperoxidase, or human neutrophil elastase [78-81].
Constitutional symptoms and signs suggestive of ear, orbit, or lung involvement are rare in CIMDL and common in GPA. At least partial destruction of the inferior or middle turbinate and septal perforations are common in CIMDL, but uncommon in GPA [82]. Histopathologically, the presence of extravascular granulomas and giant cells rules out CIMDL [77]. (See 'Histopathology' above.)
●Extranodal NK/T cell nasal lymphoma (previously lethal midline granuloma) is diagnosed by the presence of extensive tissue ulceration and a diffuse and permeative lymphomatous infiltrate with atypical lymphoid cells. The immunophenotype is similar to that of natural killer T cells and Epstein Barr virus genome is virtually always present on in situ hybridization. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type", section on 'Pathologic features'.)
●Immunoglobulin G4 (IgG4)-related disease can cause a midline destructive lesion with nasal septal and palatal perforations that mimics GPA [83]. Biopsy in IgG4-related disease shows lymphoplasmacytic infiltrates and storiform fibrosis without granulomas. Immunohistochemical staining shows IgG4-positive plasma cells. (See "Pathogenesis and clinical manifestations of IgG4-related disease".)
Tracheal stenosis — Subglottic and lower tracheal lesions need to be differentiated from postintubation stenosis, relapsing polychondritis, tracheopathia osteoplastica, urticarial vasculitis, tracheal amyloidosis, cicatricial pemphigoid, and granulomatous infection. Postintubation stenosis is suggested by a history of intubation and the location of stenosis. Relapsing polychondritis is suggested by coexistent auricular and nasal polychondritis and characteristic findings on tracheal CT. The tracheal changes of relapsing polychondritis usually involve long continuous stretches of the tracheobronchial tree, whereas tracheobronchial lesions of GPA are usually localized and segmental [84]. Tracheopathia osteoplastica also has characteristic CT features. GPA is differentiated from the other processes based on serologic, microbiologic, and histopathologic findings. (See "Presentation and diagnostic evaluation of non-life-threatening and nonmalignant subglottic and tracheal stenosis in adults" and "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults", section on 'Diagnostic evaluation and initial management' and "Diagnostic evaluation of relapsing polychondritis", section on 'Computed tomography' and "Radiology of the trachea", section on 'Relapsing polychondritis' and "Radiology of the trachea", section on 'Tracheobronchopathia osteochondroplastica' and "Radiology of the trachea", section on 'Pseudotumors'.)
Pulmonary nodules — The differential diagnosis of multiple pulmonary nodules includes metastatic solid organ malignancy, non-Hodgkin lymphoma, septic emboli, granulomatous infections (eg, Mycobacteria, histoplasmosis, coccidioidomycosis, cryptococcosis, aspergillosis), Paragonimus infection in endemic areas, sarcoidosis, rheumatoid arthritis, lymphomatoid granulomatosis, inflammatory myofibroblastic tumor, silicosis, and coal-worker's pneumoconiosis. Differentiation is based on history of exposures, presence of other features (eg, erosive arthritis, cutaneous lesions), serology, special stains and culture, and histopathology. (See "Diagnostic evaluation of the incidental pulmonary nodule".)
Alveolar hemorrhage — The differential diagnosis of alveolar hemorrhage due to GPA or MPA is broad and includes other vasculitides (eg, cryoglobulinemia, immunoglobulin A vasculitis [Henoch-Schönlein purpura], drug-induced ANCA associated vasculitis), rheumatic diseases (eg, lupus, antiphospholipid antibody syndrome, polymyositis, anti-glomerular basement membrane [GBM] antibody syndrome), anticoagulant therapy, thrombocytopenia, drug-induced lung injury, toxic exposures (eg, trimellitic anhydride), infections, acute respiratory distress syndrome, cardiac dysfunction, and pulmonary infarction (table 3). (See "The diffuse alveolar hemorrhage syndromes", section on 'Clues to a specific etiology' and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Drug-induced ANCA-associated vasculitis'.)
A few medications (eg, hydralazine, propylthiouracil, minocycline) can cause ANCA positivity, alveolar hemorrhage, and glomerulonephritis as part of a drug-induced vasculitis [85,86]. As an example, a number of cases of hydralazine-induced alveolar hemorrhage with crescentic glomerulonephritis have been reported in association with perinuclear ANCA (P-ANCA) positivity (positive myeloperoxidase) [87-89]. Typically, these patients also have positive antinuclear antibodies and antihistone antibodies. (See "Drug-induced lupus".)
COMPLICATIONS — Several studies have identified an increased risk of venous thromboembolic disease among patients with GPA and other ANCA-associated vasculitides, although the cause of hypercoagulability is unclear [90-94]. In one series, the cumulative incidence at 10 years was 4 percent for pulmonary embolism and 7 percent for deep venous thrombosis [93]. Most of the events occurred in the first two years following diagnosis. (See "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis" and "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity".)
TREATMENT — The treatment of GPA and MPA and the management of central airway obstruction and diffuse alveolar hemorrhage are discussed separately. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy" and "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults" and "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults", section on 'Follow-up' and "Management of non-life-threatening, nonmalignant subglottic and tracheal stenosis in adults" and "The diffuse alveolar hemorrhage syndromes", section on 'Treatment'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis".)
SUMMARY AND RECOMMENDATIONS
●Definitions and major characteristics
•Granulomatosis with polyangiitis – "Classic" granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis (polyangiitis) with a predilection for the upper and lower respiratory tracts and the kidneys. A "limited" form, with clinical findings isolated to the upper respiratory tract or the lungs, occurs in approximately one-fourth of cases. Essentially all patients with GPA have upper airway or pulmonary involvement. (See 'Introduction' above and 'Clinical features' above.)
•Microscopic polyangiitis – Microscopic polyangiitis (MPA) is a necrotizing vasculitis without granulomatous inflammation that predominantly affects small vessels (ie, capillaries, venules, or arterioles) and can present with pulmonary capillaritis or interstitial lung disease. It causes rhinosinusitis less commonly than GPA. (See 'Introduction' above and 'Airway and lung involvement' above.)
●Clinical manifestations
•Upper airway involvement – The most common presenting symptoms and signs of GPA and MPA in the upper airway include nasal crusting, sinus pain, chronic rhinosinusitis, nasal obstruction, smell disturbances, purulent/bloody nasal discharge, excessive tearing (ie, epiphora), and sinus mucocele formation. Chronic complications include nasal septal perforation, saddle nose deformity, hearing loss, subglottic stenosis, and tracheal collapse. (See 'Nasal, sinus, and ear disease' above.)
•Pulmonary involvement – The clinical manifestations of pulmonary GPA and MPA include cough, hemoptysis (due to alveolar hemorrhage and/or tracheobronchial disease), dyspnea, and less commonly pleuritic pain. The severity of pulmonary involvement is highly variable. (See 'Airway and lung involvement' above.)
●Laboratory testing – More than 90 percent of patients with both lung and kidney involvement have elevated serum antinuclear cytoplasmic antibodies, but the ANCA may sometimes be negative in limited GPA. In GPA, ANCAs are most often directed against serine protease 3 (PR3, or C-ANCA); in MPA, ANCAs are usually directed to MPO. Direct testing for PR3 and MPO antibodies has much higher specificity and positive predictive value than ANCA immunofluorescence testing. (See 'Antineutrophil cytoplasmic antibodies' above and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Granulomatosis with polyangiitis'.)
●Imaging findings – Computed tomography is the preferred imaging modality for characterizing the upper and lower airways in patients with suspected GPA or MPA. Typical sinus findings include mucosal thickening or opacification in the nasal cavity and paranasal sinuses. Common chest findings include multiple pulmonary nodules and patchy or diffuse areas of ground-glass or consolidative opacities. Reticular changes, interlobular septal thickening, honeycombing, bronchiectasis, pleural effusion, and hilar adenopathy are less commonly seen. (See 'Sinus computed tomography' above and 'Computed tomography' above.)
●Diagnostic criteria – The diagnosis of GPA or MPA is established in patients with a compatible clinical presentation based on the following features (see 'Evaluation' above and 'Histopathology' above):
•Serologic testing (positive ANCA with autoantibodies to serine proteinase 3 or myeloperoxidase)
•Histopathologic evidence of necrotizing vasculitis
•Exclusion of drug-induced vasculitis
●Diagnostic evaluation – The sequence and pace of the evaluation depends on the pattern of symptoms and acuity of illness. Tissue confirmation of GPA or MPA is highly desirable, even among patients with a compatible clinical presentation and positive serology, due to the potential toxicity of treatment. Choice of biopsy site is individualized based on accessibility of involved tissues and expected patient tolerance of the procedure. A prompt diagnosis allows the initiation of therapy that may be lifesaving and organ-sparing. (See 'Evaluation' above and 'Histopathology' above.)
●Treatment – The treatment of GPA, MPA, diffuse alveolar hemorrhage, and central airway obstruction are discussed separately. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy" and "The diffuse alveolar hemorrhage syndromes" and "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults", section on 'Follow-up'.)
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