Granulomatosis with Polyangiitis (Wegener Granulomatosis) Workup

Updated: Dec 02, 2017
  • Author: Christopher L Tracy, MD; Chief Editor: Herbert S Diamond, MD  more...
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Workup

Approach Considerations

Routine laboratory tests are nonspecific in granulomatosis with polyangiitis (GPA). Elevated blood urea nitrogen (BUN) and creatinine levels may signal renal involvement. Hypoalbuminemia may be present. Serum complement levels are within the reference range or increased. [53]

Mild normochromic normocytic anemia is present in 50% of patients. A peripheral blood smear may show schistocytes and burr cells. Leukocytosis is also common, with a neutrophil predominance. Eosinophilia is not a feature of GPA but rather of allergic granulomatous angiitis (Churg-Strauss syndrome).

Westergren erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are elevated in 90% of patients with active and generalized disease. They may decrease in response to treatment.

In patients with renal involvement, urinalysis may show non-nephrotic–range to nephrotic-range proteinuria, microscopic hematuria, and the presence of red blood cell (RBC) casts consistent with underlying glomerulonephritis.

Rheumatoid factor is positive in a low titer in two thirds of patients, whereas antinuclear antibody is present in 10-20% of patients. Hypergammaglobulinemia may be present.

Whether tissue diagnosis is always required for GPA remains controversial. As the therapy for severe GPA is not benign, tissue diagnosis is recommended if a biopsy site is available, provided that the patient understands the risks of the procedure.

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ANCA Detection

Antineutrophil cytoplasmic antibodies (ANCAs) can be detected with serologic assays. The 2 types of assays in common use are immunofluorescence (IF) and enzyme immunoassay.  A 2017 position paper by an international consensus panel stated that high-quality immunoassays are the preferred screening method for the diagnosis of ANCA-associated vasculitis, and that screening does not categorically require indirect IF assays. [54]

Three types of IF patterns are recognized: C-ANCA (cytoplasmic antibody), P-ANCA (perinuclear antibody), and atypical ANCA. (See the images below.)

C-ANCA immunofluorescence pattern. Staining for an C-ANCA immunofluorescence pattern. Staining for antineutrophil cytoplasmic antibody by indirect immunofluorescence shows heavy cytoplasmic staining, whereas nuclei are nonreactive. Image courtesy of K. Orr, MD.
P-ANCA immunofluorescence pattern. Perinuclear ant P-ANCA immunofluorescence pattern. Perinuclear antineutrophil cytoplasmic antibody staining pattern by indirect immunofluorescence shows perinuclear staining, whereas cytoplasm is nonreactive. Image courtesy of K. Orr, MD.

IF represents a qualitative ANCA assay, and significant inter-reader variability exists. Enzyme-linked immunosorbent assay (ELISA) provides target antigen-specific characterization of ANCA (ie, anti-PR3 and anti-myeloperoxidase [MPO]) and should be used to confirm IF findings. Combining IF and ELISA enhances the sensitivity and specificity of a diagnosis of AAV to 96% and 98.5%, respectively. [24] Only ANCAs directed against PR3 or MPO have been associated with primary vasculitic syndromes.

C-ANCA directed against PR3 is most specific for GPA. According to the WGET trial, IF shows positive C-ANCA results in 88% of all patients with GPA. IF shows positive C-ANCA results in 87% of patients with severe disease and in 90% of those with limited disease. [10] Using both IF and ELISA, ANCA is detectable in nearly 100% of patients with active generalized GPA. [24]

Some patients with GPA express P-ANCA specific for MPO. Analysis of the WGET cohort demonstrated that IF showed positive P-ANCA results in 13% of patients with severe disease; 10%of patients with limited disease were P-ANCA–positive. [10] A few patients with GPA are ANCA-negative, although this fraction appears to be exceedingly small. [11, 19]

Rising C-ANCA titers may herald a relapse in some patients with GPA, but this relationship is unreliable. Thus, patients with rising ANCA titers should not be treated with cytotoxic medications in the absence of signs, symptoms, or other objective evidence of disease relapse. [23, 38]

Further considerations in P-ANCA testing

In contrast to GPA, the indirect IF staining pattern in microscopic polyangiitis and allergic granulomatous angiitis is often perinuclear (P-ANCA). This is an artifactual phenomenon that occurs during the ethanol fixation process of neutrophils, resulting in the displacement of the basic positively charged proteins (eg, MPO, lactoferrin, lysozyme, elastase, cathepsin G) from the cytoplasm to the nuclear region. MPO is the antigen at which these autoantibodies are most often directed in the setting of small-vessel vasculitis. This antibody can be observed in microscopic polyangiitis, allergic granulomatous angiitis, idiopathic crescentic glomerulonephritis, and, occasionally, GPA.

A positive finding on a P-ANCA test alone can be observed in a number of other diseases that would not qualify as small-vessel vasculitis. These include inflammatory bowel disease, Kawasaki disease, polyarteritis nodosa, Felty syndrome, and infections such as human immunodeficiency virus (HIV) infection and endocarditis. Because of the variability of the P-ANCA target antigen, more specific antibody testing is recommended strongly. A positive P-ANCA test result should be used to diagnose small vessel vasculitis only when it is used in conjunction with a positive antimyeloperoxidase titer in the setting of high clinical suspicion.

Cautions

In summary, be cautious not to equate a positive ANCA test result with disease. When used appropriately, the ANCA test is a very powerful test with high degrees of sensitivity and specificity; however, when used in the wrong setting, it can lead to misdiagnosis with resultant inappropriate treatment using potentially toxic therapy. Indeed, a positive C-ANCA test result in patients with only sinusitis has a posttest probability of 7-16% of correctly diagnosing GPA. In patients with sinusitis, pulmonary infiltrates or nodules, and active urinary sediment with RBC casts, a positive C-ANCA test finding has a posttest probability of GPA of 98%. Moreover, ANCA tests should not be used to correlate with clinical disease in patients with established diagnoses of vasculitis.

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Radiography and CT Scanning

Findings on chest radiography are abnormal in two thirds of adults with GPA. The most common radiologic findings are single or multiple nodules and masses. Nodules are typically diffuse, and approximately 50% are cavitated. (See the images below.)

Granulomatosis with polyangiitis. Bilateral nodule Granulomatosis with polyangiitis. Bilateral nodules observed on a plain chest radiograph in a patient with hemoptysis and hematuria. Image courtesy of G. Eschun, MD.
This 42-year-old man presented with hemoptysis, we This 42-year-old man presented with hemoptysis, weight loss, and night sweats. He was diagnosed with the limited form of granulomatosis with polyangiitis.
Granulomatosis with polyangiitis. This patient pre Granulomatosis with polyangiitis. This patient presented with massive hemoptysis. No nodules are identified on the chest radiograph, although a subsequent CT scan showed several noncavitating nodules.
Shown is a chest radiograph of an 11-year-old girl Shown is a chest radiograph of an 11-year-old girl who presented with an upper respiratory tract infection, myalgias, and arthralgias for 1 month, followed by an abrupt presentation with pallor, hemoptysis, and hypertension. Her bilateral fluffy infiltrates are suggestive of a pulmonary hemorrhage. She had an antineutrophil cytoplasmic autoantibody (ANCA)–positive pauci-immune necrotizing and crescentic glomerulonephritis associated with her pulmonary hemorrhage. Supportive therapy consisted of mechanical ventilation and hemodialysis along with immunosuppressive therapy. Her anti–glomerular basement membrane antibody test result was negative. Nearly 2 years later, she had a serum creatinine of 0.7mg/dL and no residual pulmonary disease.
An 11-year-old girl presented with an upper respir An 11-year-old girl presented with an upper respiratory tract infection, myalgias, and arthralgias for 1 month followed by an abrupt presentation with pallor, hemoptysis, and hypertension. She had an antineutrophil cytoplasmic autoantibody (ANCA)–positive pauci-immune necrotizing and crescentic glomerulonephritis associated with her pulmonary hemorrhage. A follow-up chest radiograph obtained several days later shows a complete resolution of her pulmonary infiltrates. This rapid resolution is more consistent with hemorrhage than with pneumonia.
Bilateral cavitating nodules in a patient with gra Bilateral cavitating nodules in a patient with granulomatosis with polyangiitis.

Diffuse alveolar opacities due to diffuse alveolar hemorrhage (DAH), atelectasis, and obstructive pneumonia caused by bronchial stenosis may also be seen. Findings on computed tomography (CT) scans and high-resolution CT (HRCT) scans include consolidation, patchy or diffuse ground-glass opacities, or both. (See the images below.)

Diffuse alveolar hemorrhage in a 21-year-old man w Diffuse alveolar hemorrhage in a 21-year-old man with granulomatosis with polyangiitis. Image courtesy of the US Government.
Diffuse alveolar hemorrhage in a 21-year-old man w Diffuse alveolar hemorrhage in a 21-year-old man with granulomatosis with polyangiitis. Image courtesy of the US Government.

Additional CT scan findings include stenoses of the larynx or tracheobronchial tree, bronchial wall thickening, bronchiectasis, pleural thickening or effusion, and lymphadenopathy.

Sinus radiography

Opacification, bony destruction, and mucosal thickening are reported, but these signs are not specific to GPA. (See the image below.)

Extensive thickening of the maxillary sinuses in a Extensive thickening of the maxillary sinuses in a patient with granulomatosis with polyangiitis. The patient also had intermittent epistaxis.

Sinus CT scanning

This is the radiographic test of choice to evaluate sinus disease. Findings on thin-section sinus CT scans are abnormal in more than 90% of adults with GPA. A similar number would be expected in the pediatric population, based on an 83% incidence of sinusitis reported by Rottem et al. [55]

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Pulmonary Testing

In patients old enough to cooperate, spirometry, plethysmography, and diffusing capacity should be performed as soon as possible to identify abnormalities and provide a baseline.

Good inspiratory and expiratory loops should be obtained. If these are flattened, subglottic stenosis or other causes for central airway obstruction should be suspected.

Because most pediatric subglottic stenosis is not found initially, spirometry, particularly with a good baseline flow volume loop, can be used to screen noninvasively for this development.

Spirometry may show either restrictive or obstructive patterns, and the diffusing capacity of lung for carbon monoxide (DLCO) may be decreased or increased, as in the case of DAH. [2]

Although a decreased diffusing capacity is a common finding in GPA, it may still fall within the reference range. In alveolar hemorrhage, the single-breath diffusing capacity is increased.

In adults, limitation to flow and decrease of the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) are the most common pulmonary function test abnormalities. Focal and interstitial infiltrates and peripheral mass lesions produce decreased lung volumes.

Bronchoscopy

This study is helpful in the evaluation of alveolar hemorrhage, infection, airway disease, and endobronchial lesions.

Transbronchial biopsy in diffuse lung disease has a low yield of diagnostic findings, presumably because of the geographic nature of the granulomatous inflammation. Bronchoscopy may also be used as needed for palliative measures for narrowed airways (ie, stents). [56]

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Biopsy

The diagnosis of GPA is generally confirmed with tissue biopsy from a site of active disease, and renal and lung biopsies are most specific for GPA. However, sampling error may occur, and histopathologic findings can be nonspecific. Tissue diagnosis may not be required if the clinical gestalt is convincing and a site for biopsy is not apparent or would be too invasive to obtain. For example, the finding of leukocytoclastic vasculitis in the setting of pulmonary nodules and PR3-ANCA may be sufficient for the diagnosis.

Renal biopsy may be easier to perform than lung biopsy and has a greater diagnostic yield. The typical renal lesion of GPA is segmental crescentic necrotizing glomerulonephritis with little or no immunoglobulin or complement deposition (pauci-immune). Generally, vasculitis is not observed, but this histology helps in establishing the diagnosis. Renal biopsy findings cannot be used to distinguish between GPA and microscopic polyarteritis. (See the image below.)

A renal biopsy specimen from a 13-year-old girl wi A renal biopsy specimen from a 13-year-old girl with antineutrophil cytoplasmic antibody (C-ANCA)–positive pulmonary renal syndrome. Seven weeks after presenting with sinusitis, she presented with an acute abdomen, pulmonary hemorrhage, and acute renal failure (creatinine 4.9mg/dL). This biopsy specimen shows a necrotizing and crescentic glomerulonephritis (Silver stain).

Although findings on a renal biopsy are often negative for the presence of granulomas in GPA, renal biopsy is nonetheless a very useful diagnostic tool, especially in the setting of pulmonary-renal syndrome.

Importantly, renal biopsy with indirect immunofluorescent staining allows exclusion of anti–glomerular basement membrane (GBM) antibody disease in the setting of a pulmonary renal syndrome. Because of the importance of treating anti-GBM with plasma exchange, this therapy is often started empirically and continued until this disease can be ruled out.

Lung biopsy is performed in the absence of renal involvement by either open or thoracoscopic lung biopsy. Biopsy may reveal the entire histologic spectrum of GPA to include vasculitis and granulomatous inflammation. Chronic infections should be excluded.

In the setting of pulmonary hemorrhage, pulmonary biopsy is much more risky. If the cause of a new infiltrate is unclear, bronchoscopy can be used to confirm the presence of blood. Lavage fluid is bloody and contains hemosiderin-laden macrophages. Stains and cultures should be obtained to rule out infection.

Upper respiratory tract tissue biopsies (nose, sinuses, subglottic region) are frequently nondiagnostic, yielding only nonspecific acute and chronic inflammation in up to 50% of biopsy samples. Upper respiratory tract biopsies demonstrate the full pathologic triad of granulomatous inflammation, vasculitis, and necrosis in only about 15% of cases. However, in the correct clinical context, finding only parts of this triad in an upper respiratory tract biopsy may support the diagnosis of GPA.

Peripheral nerve biopsy can be considered if signs or symptoms such as paresthesias or mononeuritis multiplex are present.

A retrospective study suggested that even in the absence of myalgias or creatine kinase elevation, a muscle biopsy can aid in the diagnosis of systemic vasculitides because biopsy findings can reveal necrotizing or nonnecrotizing vasculitis. [57] A prospective study found that muscle biopsy is a safe method for diagnosing small- or medium-vessel vasculitis, with a sensitivity of 57% overall, and sensitivity of 75% in patients presenting with peripheral neuropathy. [58]

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Histologic Findings

Lung

Histologic examination of lung samples may reveal the classic triad of parenchymal necrosis, vasculitis, and granulomatous inflammation characterized by an inflammatory infiltrate composed of neutrophils, lymphocytes, plasma cells, histiocytes, and eosinophils. (See the images below.)

Lung biopsy specimen from a patient with granuloma Lung biopsy specimen from a patient with granulomatosis with polyangiitis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD.
Lung biopsy specimen from a patient with granuloma Lung biopsy specimen from a patient with granulomatosis with polyangiitis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD.

Pulmonary vasculitis may affect arteries, veins, and capillaries, is pauci-immune, and can be granulomatous or nongranulomatous. Vasculitis causes vessel wall necrosis with infiltration by neutrophils, which degenerate and become surrounded by palisading histiocytes and multinucleated giant cells. The neutrophilic debris coalesces into irregularly bordered microabscesses, which can become extensive areas of "geographic" necrosis.

Kidney

Segmental pauci-immune crescentic necrotizing glomerulonephritis is typically seen. The earliest histologic abnormalities include thrombotic changes in the glomerular capillary loops. The finding of granulomatous inflammation in renal biopsy samples is unusual. Generally, vasculitis is not observed in renal biopsy specimens. (See the image below.)

Focal glomerulonephritis with crescent formation o Focal glomerulonephritis with crescent formation on renal biopsy specimen, characteristic of granulomatosis with polyangiitis.

Skin

Leukocytoclastic vasculitis is most commonly reported.

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