eMedicine Specialties > Otolaryngology and Facial Plastic Surgery > Granulomatosis Diseases

Wegener Granulomatosis

Author: Neil Tanna, MD, MBA, Staff Physician, Division of Otolaryngology-Head and Neck Surgery, The George Washington University
Coauthor(s): Charles A Elmaraghy, MD, Assistant Professor, Department of Otolaryngology-Head and Neck Surgery, Ohio State University Medical Center; Douglas R Sidell, MD, Resident Physician, Department of Otolaryngology-Head and Neck Surgery, University of California at Los Angeles Medical Center; John Boone, MD, Consulting Staff, Department of Otolaryngology, Naval Hospital Oak Harbor
Contributor Information and Disclosures

Updated: Mar 24, 2008

Introduction

Background

Wegener granulomatosis (WG) is a multisystem disease characterized by necrotizing granuloma of the upper and lower respiratory tracts, disseminated vasculitis, and glomerulonephritis. The German pathologist Friedrich Wegener first described the disease in 1936. In 1954 Godman and Churg more fully delineated the disease and established the three main clinical criteria of WG. Clinical manifestations and organ involvement of the disease vary widely. The etiology of WG remains unknown, although evolving evidence supports an autoimmune cause. This article presents an overview of WG, with an emphasis on its otolaryngologic features.

For further reading on Wegener granulomatosis, please see the eMedicine articles in our Radiology, Rheumatology, Pediatrics, Dermatology, and Neurology sections.

Pathophysiology

The cause of WG is unknown. Increasing circumstantial evidence supports the concept that WG is an autoimmune disease and that antineutrophil cytoplasmic antibodies (ANCA) play a role in its pathogenicity. This evidence may be summarized as follows: (1) positive findings for ANCA were 97% in a study of WG that used both indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA), (2) titers for ANCA correlate with disease activity and predict relapses, and (3) the disease responds to immunosuppressive therapy. Additional findings that support an autoimmune etiology include elevated levels of immunoglobulin A (IgA) and immunoglobulin E (IgE) in patients with WG, as well as a possible association with HLA-B8 and HLA-DR2.¹

Granular cytoplasmic staining pattern ANCA (c-ANCA) has been strongly associated with WG. The principal target of c-ANCA is protease-3 (PR3), an enzyme stored in the azurophilic granules of neutrophils and monocytes. A smaller number of patients with WG have a perinuclear staining pattern ANCA (p-ANCA), which is directed against myeloperoxidase (MPO), another azurophilic antigen.

In vitro studies show that activation by ANCA of these surface antigens stimulates degranulation of the leukocytes and the release of toxic oxygen radicals and lysosomal enzymes. This activation of ANCA and its target antigens must be primed with proinflammatory cytokines by an as yet unidentified mechanism. Further, neutrophils activated by ANCA have been found to directly damage endothelial cells in vitro.

However, in vivo studies have not provided direct evidence linking ANCA to the pathogenesis of WG, and an animal model of PR3-ANCA–induced vasculitis has not been found. Some have theorized that the circulation of immune complexes composed of antineutrophil antibodies and neutrophil degranulation products result in widespread multiorgan dysfunction. Additionally, a possible role of an infectious agent in the pathogenesis of WG has been conjectured because of the success of trimethoprim-sulfamethoxazole in treating early manifestations of the disease. Chronic nasal carriage of Staphylococcus aureus has been determined to be a more common finding in patients with WG when compared with unaffected individuals. Some have suggested that staphylococci activate neutrophils by releasing a leukocyte-stimulating factor, thereby inducing fibrinoid necrosis of the interstitial tissues.^1,2

Frequency

United States

The prevalence of WG in the United States is estimated at 3 cases per 100,000 population.

International

The prevalence of WG in Europe is estimated at 5 cases per 100,000 population. Higher incidences have been reported in northern compared to southern Europe.

Race

While all racial groups are affected, WG is a disease that predominantly affects whites. African Americans account for only 2-3% of patients with WG.³

Sex

Both sexes are affected equally.

Age

The mean age at diagnosis is 40 years, although patients may present at nearly any age. The age range is 8-99 years.¹

Clinical

History

The typically described triad of full-blown WG consists of the following:

• Necrotizing granulomatous inflammation of the upper and lower respiratory tracts
• Systemic vasculitis of small arteries and veins
• Focal glomerulonephritis

Not all patients show involvement of all 3 areas, and virtually any organ system can be involved. Both limited and systemic variations of the disease have been described, with variations including the following:

1. Head and neck alone
2. Head and neck and pulmonary
3. Head and neck, pulmonary, and renal^2,4

The clinical course can be rapid or indolent.

Constitutional signs and symptoms, such as fever, weight loss, and fatigue, are common, but rarely dominate the clinical picture.

Profile of Organ Involvement, as summarized by Langford and Hoffman⁵

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The upper respiratory tract is the area most often involved at initial presentation and generally precedes pulmonary or renal involvement. Greater than 70% of presenting symptoms involve nasal, sinus, ear, or tracheal manifestations. These presenting symptoms of WG are commonly misdiagnosed as infectious or allergic in etiology.^3,6

Physical

• Sinonasal involvement: The nose and paranasal sinuses are involved in up to 80% of WG cases. Involvement can vary from mild obstruction to nasal collapse.^1,3
  • Sinonasal involvement of WG is often misdiagnosed in its early stages as chronic rhinitis or sinusitis.
  • Nasal signs and symptoms include mucosal edema with obstruction, rhinorrhea, ulcerations, crusting, and epistaxis.
  • Chronic sinusitis (40-50% of patients with sinonasal disease)^1,6
  • Secondary true bacterial or fungal sinusitis is common.
  • Although WG is generally less destructive than sinonasal lymphoma, osteocartilaginous destruction may be revealed by the following:
    • Saddle nose deformity
    • Septal perforation
    • Pain at the nasal dorsum, which suggests chondritis
• Osteocartilaginous destruction does not correlate well with active disease.
• Otologic involvement: This occurs in 25-40% of patients during the course of WG.
• Otitis media (40-70% of cases with otologic involvement).
  • Otitis media may be the presenting feature and sole manifestation of WG.
  • This is the most common form of ear involvement in WG. Otitis media can antedate upper and lower airway disease by months.
  • Serous otitis media is the most prevalent type and is usually secondary to associated nasal disease and subsequent eustachian tube dysfunction.
  • Up to 30% of patients with WG require tympanostomy during the course of their disease.¹
  • Suppurative otitis media or mastoiditis may supervene, with symptoms that manifest as chronic otorrhea and postauricular pain.
• Primary middle ear involvement
  • Patients may have direct involvement by WG of the middle ear and/or mastoid mucosa, with resultant necrotizing granuloma and vasculitis.
  • Primary middle ear involvement produces middle ear granulation tissue, tympanic perforation, and chronic suppurative drainage.
  • It is present in only 10% of patients with WG and otologic involvement and is sometimes mistaken for otologic tuberculosis.
  • The condition improves only with the use of glucocorticoid or cytotoxic agents.
  • It results in persistent conductive hearing loss because of extensive tympanic scarring or granulomatous occlusion.
• Hearing loss
  • Conductive hearing loss is the most common audiologic finding. It is caused by otitis media or, less frequently, by direct WG involvement of the middle ear.
  • Sensorineural hearing loss is less common. The cause is unclear; suggested mechanisms include cochlear nerve compression by adjacent granuloma, cochlear immune-complex deposition, and local vasculitis that involves cochlear vessels. Sensorineural hearing loss is usually bilateral and profound, with a flat audiometric pattern. Progression is generally rapid; however, the condition is occasionally reversible with glucocorticoids or cytotoxic agents.^1,2
  • Secondary infection extending to the inner ear is an alternative etiology of sensorineural hearing loss.
• Vertigo or dysequilibrium: This is a rare symptom reported in WG and is possibly due to vasculitis of the vestibular inner ear, granulomatous neuritis of the vestibular portion of CN VIII, vestibular deposition of immune complexes, or central cerebral or cerebellar involvement by WG.
• Pinna involvement
  • Edema or erythema of the auricle may occur.
  • Incidence is 15% in cases of WG with otologic signs and symptoms.
  • Pinna involvement resembles relapsing polychondritis.
  • The condition responds to treatment with glucocorticoids or cytotoxic agents.
• Facial paralysis
  • Facial paralysis is exceedingly rare as a presenting sign.
  • This condition may be associated with primary WG of the middle ear or mastoid.
  • It is caused by necrotizing vasculitis of the vasa nervorum or neuritis due to granulomatous involvement of the middle ear.
  • Most cases resolve or improve with cytotoxic therapy; however, permanent facial paralysis secondary to delayed treatment has been reported. Facial neuropathy was also reported in the absence of otologic WG involvement.²
  • Multiple cranial neuropathies may exist. Involvement of cranial nerves (CNs) VI, VII, IX, and XII have been reported in patients with large cranial base lesions and destruction of the petrous portion of the temporal bone.
• Oral or pharyngeal involvement: This occurs in up to 6% of patients. Oral biopsies are infrequently positive, yet remain important in the role of early diagnosis.^1,4
• Mucosal ulcerations
  • Mucosal ulcerations are the most common oral lesions.
  • These are usually buccal but may occur on the tongue, palate, or pharynx.
  • Ulcers are persistent, not recurrent.
  • Biopsy usually reveals necrotizing vasculitis, but histologic features may be nonspecific.
• Strawberry gums
  • This is characteristic erythematous, friable, granular hyperplasia of gingiva.
  • Gingivae are striking red, with variably described white, yellow, or blue.
  • Characteristic strawberry gingival hyperplasia has been suggested by some authors to be pathognomonic of WG and may present as an early manifestation of the disease.²
  • A delayed healing of oral wounds is present.
  • In time, underlying bone can be involved, leading to tooth mobility or tooth loss.
  • Characteristic WG features of vasculitis and necrotizing granulomas are typically lacking on biopsy findings. Instead, pseudoepitheliomatous hyperplasia, multinucleated giant cells, and inflammatory infiltrates are more common.
• Less common oral lesions: These include oroantral fistula, osteonecrosis of the palate, and labial mucosal nodules.
• Laryngotracheal involvement: Symptoms may range from subtle hoarseness to stridor and life-threatening obstruction.
• Subglottic stenosis: The immediate subglottic region of the trachea is particularly susceptible to narrowing secondary in part to laryngopharyngeal reflux, limited blood supply, and turbulent airflow. This narrowing of the upper airway is associated with scarring and can result in airway compromise.
  • This is the most characteristic and serious laryngeal lesion.
  • Subglottic stenosis can be the only presenting manifestation of WG.
  • Subglottic stenosis occurs in 16-20% of all patients with WG and up to 50% of pediatric patients with WG.⁷
  • Some have recommended that all patients with subglottic stenosis be evaluated for the presence of c-ANCA and p-ANCA as part of the routine laboratory workup.
  • Although WG is known to contribute to airway narrowing, the disease course of subglottic stenosis is thought to run independent of that involving WG.
  • Most patients with subglottic stenosis have generalized WG.
  • Direct laryngoscopy may show edematous mucosa or bland scar.
  • Biopsy specimens generally demonstrate only fibrosis and inflammation, without evidence of vasculitis. Subglottic specimens have been reported as showing evidence of WG in 5-15% of biopsies.⁷
  • Chronic scarring is thought to be the result of a recurrent insult such as laryngopharyngeal reflux in the presence of WG, rather than ongoing microvasculitis alone.
  • Only 20% of involved cases diminish with immunotherapy; 80% remain fixed or irreversible because of chronic fibrosis.
  • Treatment includes intralesional corticosteroids, tracheotomy, or surgical reconstruction.
  • Methylprednisolone acetate injection combined with serial passage of blunt dilators has shown to be another effective means by which subglottic stenosis that is refractory to medical treatment may be managed.⁷
• Salivary involvement: Extensive involvement of the salivary glands may produce sufficient destruction to simulate Sjögren syndrome. When involved, massive enlargement of the submandibular or parotid glands is not uncommon. This is typically an early, albeit rare, manifestation.⁴
• Nonotolaryngologic involvement
• Pulmonary involvement
  • This occurs in 45% of patients at presentation and in 90% during the course of the disease.
  • Lung parenchyma, bronchioles, bronchi, and the trachea may become involved.
  • Cough, hemoptysis, pleuritis, and dyspnea are the most common pulmonary signs.
  • One third of patients with radiographically demonstrable pulmonary disease do not have signs or symptoms of lower respiratory tract involvement.
  • Classic chest radiographic findings include bilateral multiple parenchymal nodes (+/- cavitation), or airway disease that simulates pneumonia. Less common findings include hilar or mediastinal adenopathy and pleural effusion.
  • Pulmonary morbidity is significant and may include obstruction, fibrosis, lobar collapse, pneumonia, or hemorrhage.
• Renal involvement
  • Renal involvement occurs in 15% of patients at presentation and 70-75% of patients during the entire course of the disease.³
  • Most patients are asymptomatic until the point of advanced uremia.
  • It is the usual cause of death in WG and the most important prognostic feature.
  • Laboratory tests include urinalysis and renal function tests. Urinalysis is performed to evaluate urinary sediment (eg, RBC casts, hematuria, proteinuria) and is the most useful screening tool. Renal function tests are performed to evaluate for a rise in serum creatinine levels and a decrease in creatinine clearance.
  • Histopathologic renal findings include focal glomerulonephritis, necrotizing crescent formation, frank vasculitis (less common), and granulomata (rare).
  • If renal insufficiency is untreated, it progresses rapidly from asymptomatic mild focal glomerulonephritis to fulminant end-stage renal failure. Mean survival time is 5 months. Even when appropriately treated, chronic renal insufficiency is not uncommon.
• Ocular involvement
  • This occurs in 50-75% of patients with WG, and involvement is commonly bilateral.^1,6
  • This may be the only symptom in nonsystemic WG.
  • Conjunctivitis, keratitis, episcleritis, uveitis, retinal artery occlusion, and optic neuritis may occur.
  • Patients may have proptosis caused by a retroorbital pseudotumor or an extension of sinonasal disease into the orbit.
  • Ocular disease responds to immunosuppressive treatment in most cases.
• Musculoskeletal involvement
  • Arthralgias and myalgias are the most common manifestations, occurring in two thirds of patients.
  • Monoarticular or polyarticular arthritis is less common. Because the rheumatoid factor is often positive in WG, it is sometimes misdiagnosed as rheumatoid arthritis.
• Skin involvement
  • Incidence during the course of disease is 40-50%.
  • Subcutaneous nodules, papules, vesicles, ulcers, petechiae, pyogenic gangrenosum, and Raynaud phenomenon have been reported.
  • Skin involvement rarely dominates the clinical picture.
  • It parallels disease activity in other organs.
  • Cutaneous manifestations generally respond to topical anti-inflammatory agents.
• Neurologic involvement
  • Incidence during the course of the disease is up to 20%.
  • Peripheral neuropathy is the most common single neurologic feature, with 16% incidence, and mononeuritis multiplex.
  • The incidence of cranial neuropathy is 6%. CNs II, VI, and VII are most commonly affected; CNs IX, X, and XII are less commonly affected (see Otologic involvement, above).
  • Other neurologic manifestations include seizures, cerebritis, stroke syndromes, and granulomas extending from the sinuses, which may affect the pituitary gland, resulting in diabetes insipidus.
• Other uncommon signs and symptoms
• Gastrointestinal signs and symptoms include abdominal pain, diarrhea, and bleeding.
• Genitourinary signs and symptoms include cystitis, ureteral obstruction, and urethritis.
• Cardiac signs and symptoms include coronary arteritis, pericarditis, and congestive myopathy.

Causes

The etiology of WG remains unknown, although evolving evidence supports an autoimmune cause.

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