eMedicine Specialties > Otolaryngology and Facial Plastic Surgery > Granulomatosis Diseases

Wegener Granulomatosis

Neil Tanna, MD, MBA, Staff Physician, Division of Otolaryngology-Head and Neck Surgery, The George Washington University
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

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

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.

Differential Diagnoses

Other Problems to Be Considered

Strawberry gums
Gingival hyperplasia induced by drugs (eg, phenytoin anticonvulsants, some calcium channel blockers, cyclosporine, conjugated estrogens)
Sarcoidosis
Tuberculosis
Churg-Strauss
Polyarteritis nodosa
Scurvy (vitamin C deficiency)
Neoplastic processes (squamous cell carcinoma, leukemia, Kaposi sarcoma)
Nasal substance abuse

Workup

Laboratory Studies

• Diagnosis of WG is made on the basis of clinical features, the presence of raised c-ANCA titers, and histopathologic confirmation. Researchers at the American College of Rheumatology proposed 4 criteria for the diagnosis of WG:
  1. Oral ulcers or nasal discharge
  2. Abnormal chest radiography (nodules, fixed infiltrates, or cavities)
  3. Microhematuria (>5 red blood cells per high power field) or red cell casts in urine sediment³
  4. Granulomatous inflammation on biopsy
• They associated 2 of 4 positive criteria with a sensitivity of 88.2% and a specificity of 92%.⁸ Diagnosis may be difficult in early stages when the disease is localized. Early diagnosis is crucial so that effective treatment can intervene before pulmonary and renal involvement takes it toll.
• Laboratory tests: Nonspecific findings include an elevated erythrocyte sedimentation rate (ESR) and leukocytosis, normocytic normochromic anemia, and thrombocytosis.
• Renal function tests
• Urinalysis - Hematuria, RBC casts, proteinuria
• Elevated creatinine, decreased creatinine clearance
• Antineutrophil cytoplasm antibodies
  • Serum immunoglobulin G (IgG) autoantibodies are directed against proteinase-3. (See Pathophysiology for a detailed description of the presumed role of c-ANCA in WG.)
  • Techniques include IIF and ELISA.
  • Sensitivity is 90% in generalized WG and 70% in localized WG. Sensitivity can be increased if both IIF and ELISA techniques are obtained.
  • Specificity is 90%.
  • Titers of c-ANCA have been known to correlate with disease activity in more than 85% of WG cases. C-ANCA levels may therefore be used to follow the course of the disease, although it does not always correlate to treatment response.³
• The best tools for the diagnosis of WG include a high index of suspicion, elevated titers of c-ANCA, and generous biopsy samples of involved sites. Although testing for c-ANCAs remains controversial as a clinical diagnostic tool, it is often the diagnostic feature in patients with nonspecific biopsies.

Imaging Studies

• Biopsy: Even after the discovery of serologic c-ANCA studies, biopsy remains an essential tool in the diagnosis of WG. In mild cases of WG, ANCA may be negative in up to 40% of individuals. However, although specific, biopsy has been demonstrated to have a significant false-negative rate. A negative predictive value of nearly 75% was demonstrated in one study. To decrease the rate of false negative results, some have suggested that biopsies are both adequate in depth and width, with margins of normal tissue included in the specimen. Although low sensitivity may discourage repeat biopsies, some authors maintain that serial biopsies should be considered based on high levels of clinical suspicion. When considering head and neck involvement, biopsies from the paranasal sinuses have been shown to yield results with the highest sensitivity.^1,3

Histologic Findings

WG is typically described by 3 basic histopathologic features: (1) vasculitis of small vessels, (2) granulomatous changes, and (3) focal necrosis. However, diagnosis may be difficult to confirm by the biopsy of head and neck lesions. The small amount of tissue available at most involved otolaryngologic sites often makes it difficult to identify all the histopathologic features of WG.

Additionally, the more classic features are frequently obscured by acute and chronic inflammatory changes, such as pseudoepitheliomatous hyperplasia, multinucleated giant cells, microabscesses, and an inflammatory infiltrate of neutrophils and eosinophils. As a result, biopsies of otolaryngologic lesions may not conclusively confirm the diagnosis and often are only suggestive of WG. The larger the biopsy, the greater the likelihood of obtaining a firm diagnosis. A biopsy of at least 5 mm is recommended.

Treatment

Medical Care

Immunosuppression using a combination of glucocorticoids and cyclophosphamide is the mainstay for treatment of generalized WG. Complete remission or a marked improvement is seen in more than 90% of cases. However, patients receiving such therapy experience relatively high incidences of relapse (50%) and drug-related toxicity (40%).

The substitution of methotrexate in place of cyclophosphamide after the former has induced remission has gained favor because of methotrexate's lower toxicity profile. In combination with glucocorticoids, methotrexate may also play a role in the initial treatment of limited disease. Trimethoprim-sulfamethoxazole (TMP-SMZ) may be of benefit to reduce relapses and may be useful as a sole agent in patients with extremely limited disease. As a prophylactic measure to reduce Pneumocystis carinii infections, recommendations for TMP-SMZ also include all patients who are taking cyclophosphamide or methotrexate and prednisone. The use of cotrimoxazole during remission periods as a means to control infection and improve quality of life in both localized and generalized WG patients has also been reported with good results.^2,4

Intravenous immunoglobulin (IVIG): Some positive results have been demonstrated using IVIG in patients with cases of WG that are refractory to immunosuppressive treatment.⁴

Plasmapheresis: Plasma exchange has been used with WG patients who are dialysis dependent and those who have rapidly progressive glomerulonephritis (RPGN).^2,4

Medication

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Glucocorticoids

These are used in combination with cytotoxic agents. Glucocorticoids are ineffective when used alone in generalized WG. Palliation of limited disease may be achieved by using glucocorticoids alone, but relapses and progression are common.

Prednisone (Deltasone, Meticorten, Orasone)

Used as an immunosuppressant in the treatment of autoimmune disorders and vasculitis. By reversing increased capillary permeability and suppressing PMN activity, may decrease inflammation.
Tapering of glucocorticoids precedes that of the cytotoxic agent.

Dosing

Adult

1 mg/kg/d PO

Pediatric

Not established

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; and fungal or tubercular skin infections; GI disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Cytotoxic agents

These agents treat by inhibiting key factors responsible for deregulated cell proliferation.

Cyclophosphamide (Cytoxan, Neosar)

Used in combination with glucocorticoids in treatment of generalized WG.

Dosing

Adult

2 mg/kg/d PO

Pediatric

Not established

Interactions

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones
Chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Life-threatening conditions, such as renal failure and pulmonary hemorrhage, may occur; initiate at 3-5 mg/kg/d PO, then taper to usual dose; use leukocyte count to titer subsequent doses; continue for 1 y following clinical remission; toxicities include dose-related bone marrow suppression, hemorrhagic cystitis, bladder fibrosis, transitional cell carcinoma of the bladder, increased incidence of lymphoma

Methotrexate (Folex PFS, Rheumatrex)

Used as substitute for cyclophosphamide after initial remission of the disease to reduce toxicity and relapse. May also have a role in combination with GC in initial treatment of patients with limited disease.

Dosing

Adult

1 double-strength tab PO bid

Pediatric

Not established

Interactions

PO aminoglycosides may decrease absorption and blood levels of concurrent PO methotrexate (MTX); activated charcoal lowers levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives contained in some vitamins may decrease response to MTX
Coadministration with NSAIDs may be fatal; indomethacin and phenylbutazone can increase MTX plasma levels; may decrease phenytoin serum levels
Probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase effects and toxicity of MTX; may increase plasma levels of thiopurines

Contraindications

Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Monitor CBCs monthly and liver and renal function q1-3mo during therapy (monitor more frequently in initial dosing, dose adjustments, or risk of elevated MTX levels, eg, dehydration); has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems
Discontinue if significant drop in blood counts; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly with MTX (possibility of increased toxicity with NSAIDs, eg, salicylates, not yet tested)

Antibiotics

Therapy must cover all likely pathogens in the context of this clinical setting.

Trimethoprim-sulfamethoxazole (Bactrim, Bactrim DS, Septra, Septra DS)

Presumed to act by reducing microorganisms, serving as an antigenic primer in the pathogenesis of WG. May be beneficial for reducing relapses in patients with limited upper respiratory tract disease. Therapeutic role, if any, to be determined. Used in prophylaxis of Pneumocystis carinii.

Dosing

Adult

Septra DS: 1 tab PO bid

Pediatric

Not established

Interactions

May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly patients; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine

Contraindications

Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Patients taking methotrexate can safely receive TMP-SMZ 3 times weekly for prophylaxis of P carinii, but they should not receive TMP-SMZ twice daily because this combination has been associated with severe pancytopenia; discontinue at first appearance of rash or sign of adverse reaction; obtain CBCs frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, administer 5-15 mg/d leucovorin); caution in folate deficiency (eg, chronic alcoholism, elderly age, current anticonvulsant therapy, malabsorption syndrome); hemolysis may occur in G-6-PD deficiency; AIDS patients may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); give fluids to prevent crystalluria and stone formation

Follow-up

Prognosis

Untreated WG has a rapid fatal course with a mean survival of 5 months. Death most frequently results from renal failure. Pulmonary complications are the second leading cause of mortality. Therapy with glucocorticoids and cytotoxic agents produces clinical improvement in more than 90% of patients; complete remission occurs in 75%. However, relapses are common, and WG is still associated with a mortality rate of 20%.

Miscellaneous

Medicolegal Pitfalls

The early diagnosis of WG can be difficult, similar to that in many multisystem diseases. Symptoms can be nonspecific at initial presentation; however, early diagnosis is important to prevent renal and pulmonary complications. A high index of suspicion combined with generous biopsy samples of available tissue and the use of c-ANCA best ensures that the diagnosis is not missed and treatment not delayed.

References

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16. Yumoto E, Saeki K, Kadota Y. Subglottic stenosis in Wegener's granulomatosis limited to the head and neck region. Ear Nose Throat J. Aug 1997;76(8):571-4. [Medline].

Keywords

Wegener granulomatosis, WG, Wegener's granulomatos, granuloma, respiratory tracts, disseminated vasculitis, glomerulonephritis

Contributor Information and Disclosures

Author

Neil Tanna, MD, MBA, Staff Physician, Division of Otolaryngology-Head and Neck Surgery, The George Washington University
Neil Tanna, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, American Medical Association, and Medical Society of the District of Columbia
Disclosure: Nothing to disclose.

Coauthor(s)

Charles A Elmaraghy, MD, Assistant Professor, Department of Otolaryngology-Head and Neck Surgery, Ohio State University Medical Center
Charles A Elmaraghy, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American Medical Association, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Douglas R Sidell, MD, Resident Physician, Department of Otolaryngology-Head and Neck Surgery, University of California at Los Angeles Medical Center
Disclosure: Nothing to disclose.

John Boone, MD, Consulting Staff, Department of Otolaryngology, Naval Hospital Oak Harbor
John Boone, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery
Disclosure: Nothing to disclose.

Medical Editor

David J Terris, MD, FACS, Porubsky Professor and Chairman, Department of Otolaryngology, Medical College of Georgia
David J Terris, MD, FACS is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngology-Head and Neck Surgery, American Association for the Advancement of Science, American Bronchoesophagological Association, American College of Surgeons, American Head and Neck Society, Federation of American Societies for Experimental Biology, International Association of Endocrine Surgeons, Phi Beta Kappa, Radiation Research Society, Society of University Otolaryngologists-Head and Neck Surgeons, and Triological Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Peter S Roland, MD, Professor, Department of Neurological Surgery, Professor and Chairman, Department of Otolaryngology-Head and Neck Surgery, Director of Clinical Center for Auditory, Vestibular and Facial Nerve Disorders, Chief of Pediatric Otology, University of Texas Southwestern Medical Center; Adjunct Professor of Communicative Disorders, School of Human Development.
Peter S Roland, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngic Allergy, American Academy of Otolaryngology-Head and Neck Surgery, American Auditory Society, American Laryngological Rhinological and Otological Society, American Neurotology Society, American Otological Society, North American Skull Base Society, and Society of University Otolaryngologists-Head and Neck Surgeons
Disclosure: Alcon labs Honoraria Speaking and teaching; GSK Honoraria Speaking and teaching; Advanced Bionics Honoraria Board membership; Cochlear corp Honoraria Board membership; Med El corp travel grants Speaking and teaching; Insight vision Consulting fee Consulting

CME Editor

Christopher L Slack, MD, Otolaryngology-Facial Plastic Surgery, Private Practice, Associated Coastal ENT; Medical Director, Treasure Coast Sleep Disorders
Christopher L Slack, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Arlen D Meyers, MD, MBA, Professor, Department of Otolaryngology-Head and Neck Surgery, University of Colorado School of Medicine
Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and American Head and Neck Society
Disclosure: Advanced Headache Intervention Consulting fee Consulting; Covidien Corp Consulting fee Consulting

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