eMedicine Specialties > Pediatrics: General Medicine > Pulmonology

Wegener Granulomatosis: Differential Diagnoses & Workup

Author: Rudolph P Valentini, MD, Director of Dialysis Services, Associate Professor, Department of Pediatrics, Division of Pediatric Nephrology, Wayne State University; Vice Chief of Staff, Children's Hospital of Michigan
Coauthor(s): Debbie S Toder, MD, Director of Cystic Fibrosis Center, Department of Pediatrics, Division of Pulmonary Medicine, Assistant Professor, Wayne State University and Children's Hospital of Michigan
Contributor Information and Disclosures

Updated: Mar 5, 2009

Differential Diagnoses

Anti-GBM Antibody Disease
Legionella Infection
Mixed Connective Tissue Disease
Systemic Lupus Erythematosus

Other Problems to Be Considered

Pediatrics, Henoch-Schönlein-Purpura
Other antineutrophil cytoplasmic autoantibodies (ANCA)-associated small vessel vasculitides (ie, Microscopic Polyangiitis, Churg-Strauss Syndrome)
Rheumatoid arthritis with systemic vasculitis
Mixed cryoglobulinemia
Renal vein thrombosis with pulmonary embolism

Workup

Laboratory Studies

• General laboratory findings in Wegener granulomatosis (WG)
  • Nonspecific laboratory abnormalities include anemia, thrombocytosis, and leukocytosis in 30-60% of adults.
  • Marked eosinophilia is rare.
  • Rheumatoid factor is positive in a low titer in two thirds of patients, whereas antinuclear antibody is present in 10-20% of patients.
  • Serum complement levels are within the reference range or increased.
  • Westergren erythrocyte sedimentation rate and C-reactive protein are elevated in 90% of patients with active and generalized disease.
• Antineutrophil cytoplasmic autoantibody (ANCA)
  • The most specific serologic tests are autoantibodies directed against cytoplasmic constituents of neutrophils and monocytes. A cytoplasmic staining pattern on indirect immunofluorescence (cANCA) is characteristic.
  • More specific antibody assays, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA), have been used to determine the antigen at which these ANCAs are directed.
  • The antigen toward which the cANCA is directed most often is proteinase 3, which is contained in the azurophilic granules of the neutrophil. The cANCA test is not specific for proteinase 3 because other neutrophil proteins, such as bacteriocidal/permeability increasing (BPI) protein and, more rarely, myeloperoxidase, can stain similarly. Moreover, antiproteinase 3 antibodies are not specific for Wegener granulomatosis because they are found in other forms of vasculitis.
  • Generally, performance of both indirect immunofluorescent ANCA testing and more specific ANCA testing is recommended in the clinical setting of vasculitis.
  • Despite some limitations, when used appropriately, the ANCA test provides a tool that can aid greatly in the diagnosis of small vessel vasculitis. Circulating cANCAs are detected in 90% of patients with active generalized (sinopulmonary, renal) Wegener granulomatosis and also in 40-70% of patients with active regional (sinopulmonary) disease. By contrast, approximately 30-40% of patients in remission have a positive cANCA. This emphasizes the need to treat the patient with a clinical relapse, not a positive ANCA test result.
  • Clinical entities classified as small vessel vasculitis include Wegener granulomatosis, microscopic polyangiitis (MPA), and Churg-Strauss syndrome. All are forms of small vessel vasculitis with multiorgan involvement and are associated with ANCA.
  • In contrast to Wegener granulomatosis, the indirect immunofluorescence staining pattern in MPA and Churg-Strauss syndrome is often perinuclear (pANCA). 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, myeloperoxidase, lactoferrin, lysozyme, elastase, cathepsin G) from the cytoplasm to the nuclear region. Myeloperoxidase is the antigen at which these autoantibodies are most often directed in the setting of small vessel vasculitis. This antibody can be observed in MPA, Churg-Strauss syndrome, idiopathic crescentic glomerulonephritis (GN), and, occasionally, in Wegener granulomatosis.
  • A positive finding on a pANCA 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 HIV and endocarditis. Because of the variability of the pANCA target antigen, more specific antibody testing is recommended strongly. A positive pANCA test result should only be used to diagnose small vessel vasculitis when used in conjunction with a positive antimyeloperoxidase titer in the setting of high clinical suspicion.
  • 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 cANCA test result in patients with only sinusitis has a posttest probability of 7-16% of correctly diagnosing Wegener granulomatosis. In patients with sinusitis, pulmonary infiltrates or nodules, and active urinary sediment with RBC casts, a positive cANCA test finding has a posttest probability of Wegener granulomatosis of 98%. Moreover, ANCA tests should not be used to correlate with clinical disease in those with established diagnoses of vasculitis.

Imaging Studies

• Chest radiography
  • Chest radiography should be performed in all patients with respiratory symptoms. Chest radiography should be performed likewise in patients with GN and the clinical suspicion for a systemic vasculitis.
  • Asymptomatic pulmonary infiltrates or nodules can be observed on chest radiography.
  • Findings on chest radiography are abnormal in two thirds of adults with Wegener granulomatosis.
  • The most characteristic finding is single or multiple pulmonary nodules with or without cavitation.
• Chest CT imaging: As expected, this test is more sensitive than chest radiography when evaluating involvement of the lung parenchyma.
• Sinus CT imaging
  • This is the radiographic test of choice to evaluate sinus disease.
  • Findings on thin section sinus CT imaging are abnormal in more than 90% of adults with Wegener granulomatosis. A similar number would be expected in the pediatric population, based on an 83% incidence of sinusitis reported by Rottem et al (1993).¹⁰

Other Tests

• In patients old enough to cooperate, spirometry, plethysmography, and diffusion 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.
• 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.
• A decreased diffusion capacity is a common finding in Wegener granulomatosis, but the diffusion capacity may still fall within the reference range.
• In alveolar hemorrhage, the single breath diffusion capacity is increased.

Procedures

• Renal biopsy
  • Although findings on a renal biopsy are often negative for the presence of granulomas in Wegener granulomatosis, renal biopsy is nonetheless a very useful diagnostic tool, especially in the setting of pulmonary-renal syndrome.
  • A kidney biopsy can usually be performed without incident, even in a relatively unstable patient. This test can help confirm a suspected ANCA-associated small vessel vasculitis in the kidney, such as Wegener granulomatosis, by detecting a pauci-immune necrotizing and crescentic GN.
  • More importantly, a renal biopsy 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.
  • A renal biopsy documenting the focal, necrotizing, and crescentic GN of Wegener granulomatosis is shown in Media file 3.
    
    

    

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

    [ CLOSE WINDOW ]

    

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

• Bronchoscopy
  • Bronchoscopy can demonstrate lesions of the larynx, subglottic space, trachea, and mainstem bronchi. As mentioned, spiral CT imaging has also been used to examine these lesions and is viewed as a complementary modality.
  • Bronchoscopy allows clear views of the mucosa and allows appreciation of dynamic lesions, such as tracheomalacia and bronchomalacia, which are observed in Wegener granulomatosis.
  • Transbronchial biopsy in diffuse lung disease has a low yield of diagnostic findings, presumably because of the geographic nature of the granulomatous inflammation.
• Biopsies of other sites
  • When patients with Wegener granulomatosis present with a limited form with upper airway disease, orbital disease, or pulmonary disease, the differential diagnosis may include infectious and neoplastic diseases and other forms of vasculitis. Biopsies of the nasal mucosa, even when ulcerated, often are not diagnostic.
  • Often, necrosis and granuloma formation are observed but are without the true vasculitis required for definitive diagnosis.
  • Bronchoscopic biopsy of ulcerative or exophytic lesions of the tracheal or bronchial mucosa is more likely to show necrotizing or nonnecrotizing granulomas but often does not demonstrate vasculitis.
  • In the presence of nodules or infiltrates on chest radiography or CT imaging, lung biopsy findings often are diagnostic, and patchy necrosis, granulomatous inflammation, and vasculitis are observed.
  • 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.

Histologic Findings

• Renal biopsy findings reveal few, if any, immune deposits (pauci-immune) on immunofluorescence. Light microscopy reveals a necrotizing and crescentic GN.

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