Wegener Granulomatosis Workup

  • Author: Patricia J Papadopoulos, MD; Chief Editor: Herbert S Diamond, MD   more...
 
Updated: May 9, 2012
 

Approach Considerations

Routine laboratory tests are nonspecific in Wegener granulomatosis (WG). 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.[43]

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 WG but rather of 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 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 WG remains controversial. As the therapy for severe WG is not benign, tissue diagnosis is recommended if a biopsy site is available, given that the patient understands the risks of the procedure.

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ANCA Detection

ANCAs can be detected with serologic assays. The 2 types of assays in common use are immunofluorescence (IF) and enzyme immunoassay. 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 anC-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 antP-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-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.[19] Only ANCAs directed against PR3 or MPO have been associated with primary vasculitic syndromes.

C-ANCA directed against PR3 is most specific for Wegener granulomatosis (WG). According to the WGET trial, IF shows positive C-ANCA results in 88% of all patients with WG. IF shows positive C-ANCA results in 87% of patients with severe disease and in 90% of those with limited disease.[5] Using both IF and ELISA, ANCA is detectable in nearly 100% of patients with active generalized WG.[19]

Some patients with WG 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. Ten percent of patients with limited disease were P-ANCA–positive.[5] A few patients with WG are ANCA-negative, although this fraction appears to be exceedingly small.[6, 14]

Rising C-ANCA titers may herald a relapse in some patients with WG, 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.[18, 32]

Further considerations in P-ANCA testing

In contrast to Wegener granulomatosis, the indirect IF staining pattern in microscopic polyangiitis and Churg-Strauss syndrome 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, 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 microscopic polyangiitis, Churg-Strauss syndrome, idiopathic crescentic glomerulonephritis, and, occasionally, Wegener granulomatosis.

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 Wegener granulomatosis. 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 Wegener granulomatosis 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 Wegener granulomatosis (WG). 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.)

Wegener granulomatosis. Bilateral nodules observedWegener granulomatosis. 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, weThis 42-year-old man presented with hemoptysis, weight loss, and night sweats. He was diagnosed with the limited form of Wegener granulomatosis. Wegener granulomatosis. This patient presented witWegener granulomatosis. 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 girlShown 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 respirAn 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 WegBilateral cavitating nodules in a patient with Wegener granulomatosis.

Diffuse alveolar opacities due to 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 wDiffuse alveolar hemorrhage in a 21-year-old man with Wegener granulomatosis, part 1. Image courtesy of the US Government. Diffuse alveolar hemorrhage in a 21-year-old man wDiffuse alveolar hemorrhage in a 21-year-old man with Wegener granulomatosis, part 2. 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 WG. (See the image below.)

Extensive thickening of the maxillary sinuses in aExtensive thickening of the maxillary sinuses in a patient with Wegener granulomatosis. 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 Wegener granulomatosis. A similar number would be expected in the pediatric population, based on an 83% incidence of sinusitis reported by Rottem et al.[44]

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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.[40]

Although a decreased diffusing capacity is a common finding in Wegener granulomatosis, 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).[45]

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Biopsy

The diagnosis of Wegener granulomatosis (WG) is generally confirmed with tissue biopsy from a site of active disease, and renal and lung biopsies are most specific for WG. 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 WG 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 WG and microscopic polyarteritis. (See the image below.)

A renal biopsy specimen from a 13-year-old girl wiA 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 WG, 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 WG 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 WG.

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.[46] Prospective studies are needed.

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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 Wegener gLung biopsy specimen from a patient with Wegener granulomatosis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD. Lung biopsy specimen from a patient with Wegener gLung biopsy specimen from a patient with Wegener granulomatosis 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 oFocal glomerulonephritis with crescent formation on renal biopsy specimen, characteristic of Wegener granulomatosis.

Skin

Leukocytoclastic vasculitis is most commonly reported.

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Contributor Information and Disclosures
Author

Patricia J Papadopoulos, MD  Key Clinical Faculty, Rheumatology Service, Department of Medicine, Walter Reed National Military Medical Center; Assistant Professor of Medicine, Uniformed Services University of the Health Sciences

Patricia J Papadopoulos, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and American College of Rheumatology

Disclosure: Merck Ownership interest Own stock

Chief Editor

Herbert S Diamond, MD  Adjunct Professor of Medicine, Division of Rheumatology, University of Pittsburgh School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa

Disclosure: Merck Ownership interest Other; Smith Kline Ownership interest Other; Zimmer Ownership interest Other

Additional Contributors

Michael R Bye, MD Professor of Clinical Pediatrics, Division of Pulmonary Medicine, Columbia University College of Physicians and Surgeons; Attending Physician, Pediatric Pulmonary Medicine, Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University Medical Center

Michael R Bye, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Heidi Connolly, MD Associate Professor of Pediatrics and Psychiatry, University of Rochester; Director, Pediatric Sleep Medicine Services, Strong Sleep Disorders Center

Heidi Connolly, MD is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Elliot Goldberg, MD Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine

Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology

Disclosure: Nothing to disclose.

Robert John O'Brian, MD Staff Rheumatologist, National Naval Medical Center

Robert John O'Brian, MD is a member of the following medical societies: American College of Rheumatology

Disclosure: Nothing to disclose.

Girish D Sharma, MD Associate Professor of Pediatrics, Rush Medical College; Director, Section of Pediatric Pulmonology and Rush Cystic Fibrosis Center, Rush University Medical Center

Girish D Sharma, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Thoracic Society, and Royal College of Physicians of Ireland

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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

Debbie S Toder, MD is a member of the following medical societies: American Academy of Pediatrics and American Thoracic Society

Disclosure: Nothing to disclose.

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

Rudolph P Valentini, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, and American Society of Pediatric Nephrology

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Robert E Wolf, MD, PhD Professor Emeritus, Department of Medicine, Louisiana State University Health Sciences Center at Shreveport; Chief, Rheumatology Section, Medical Service, Overton Brooks Veterans Administration Medical Center of Shreveport

Robert E Wolf, MD, PhD is a member of the following medical societies: American College of Rheumatology, Arthritis Foundation, and Society for Leukocyte Biology

Disclosure: Nothing to disclose.

Acknowledgments

The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, or the US Government. Additionally, this publication does not imply the Federal or Department of Defense endorsement of any product.

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Lung biopsy specimen from a patient with Wegener granulomatosis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD.
Lung biopsy specimen from a patient with Wegener granulomatosis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD.
Saddle nose deformity in a 26-year-old man with Wegener granulomatosis. Image courtesy of P. Papadopoulos, MD.
Focal glomerulonephritis with crescent formation on renal biopsy specimen, characteristic of Wegener granulomatosis.
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 antineutrophil cytoplasmic antibody staining pattern by indirect immunofluorescence shows perinuclear staining, whereas cytoplasm is nonreactive. Image courtesy of K. Orr, MD.
Goodpasture syndrome: Linear deposition of immunoglobulin G and C3 are observed on a renal biopsy specimen from a patient with Goodpasture syndrome. Immunofluorescence staining. Image courtesy of K. Orr, MD.
Extensive thickening of the maxillary sinuses in a patient with Wegener granulomatosis. The patient also had intermittent epistaxis.
Wegener granulomatosis. 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, weight loss, and night sweats. He was diagnosed with the limited form of Wegener granulomatosis.
Bilateral cavitating nodules in a patient with Wegener granulomatosis.
Wegener granulomatosis. This patient presented with massive hemoptysis. No nodules are identified on the chest radiograph, although a subsequent CT scan showed several noncavitating nodules.
Diffuse alveolar hemorrhage in a 21-year-old man with Wegener granulomatosis, part 1. Image courtesy of the US Government.
Diffuse alveolar hemorrhage in a 21-year-old man with Wegener granulomatosis, part 2. Image courtesy of the US Government.
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 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.
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).
 
 
 
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