Otolaryngologic Manifestations of Granulomatosis With Polyangiitis

Granulomatosis with polyangiitis (GPA), formerly known as Wegener granulomatosis (WG), commonly involves otolaryngologic manifestations; more than 70% of presenting symptoms take the form of nasal, sinus, ear, or tracheal manifestations (see Table 1, below). Upper respiratory tract involvement generally precedes pulmonary or renal involvement. Otolaryngologic presenting symptoms of GPA are often misdiagnosed as infectious or allergic in etiology. ^{[1, 2]}

Table 1. Profile of Organ Involvement in Granulomatosis with polyangiitis (GPA)* (Open Table in a new window)

In a retrospective study by Carnevale et al of patients with GPA, 16 of the report’s 19 subjects (84.2%) presented with head and neck manifestations. Among those 16 individuals, the three most common types of presenting symptoms were sinonasal (56.3%), laryngotracheal (31.3%), and otologic (25%), with sinonasal involvement being the disease’s first manifestation in 7 patients (43.8%). ^[4]

The classic triad of full-blown granulomatosis with polyangiitis 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 including the following:

• Head and neck alone

• Head and neck and pulmonary

• Head and neck, pulmonary, and renal ^{[5, 6]}

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.

A retrospective United Kingdom study by Thayakaran et al found that in patients with GPA, the group whose symptoms were relatively limited to otolaryngologic manifestations and cough (designated as cluster 1) had a lower mortality rate (12.2%) than did patients with generalized nonrenal disease (cluster 2; 21%) and those with renal-predominant disease (cluster 3; 29.8%). Nonetheless, the mortality rate for cluster 1 was 68% greater than for members of the general population without GPA. In addition, a number of cluster-1 patients had developed symptoms indicative of systemic disease by 1-year follow-up, including dermatologic, musculoskeletal, ocular, non-specific abdominal, and gastrointestinal manifestations. ^[7]

A retrospective study by Lally et al suggested that rituximab significantly reduces the otolaryngologic manifestations of GPA. The study, which involved 99 patients with GPA, found that the likelihood of active otolaryngologic disease in patients treated with rituximab was 11-fold less than for those who received other treatments, such as methotrexate, azathioprine, cyclophosphamide, or trimethoprim-sulfamethoxazole. ^[8]

For further information on this topic, see the Medscape Drugs & Diseases article Granulomatosis with Polyangiitis (GPA, formerly Wegener Granulomatosis), as well as Neurologic Granulomatosis with Polyangiitis (formerly called Wegener's) and Dermatologic Manifestations of Granulomatosis With Polyangiitis.

The nose and paranasal sinuses are involved in up to 80% of granulomatosis with polyangiitis (GPA) cases. Involvement can vary from mild obstruction to nasal collapse. ^{[9, 1]} Sinonasal involvement of GPA 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 affects 40-50% of patients with sinonasal disease. ^{[9, 2]} Secondary true bacterial or fungal sinusitis is common.

Although GPA is generally less destructive than sinonasal lymphoma, osteocartilaginous destruction may be revealed by the following:

• Saddle nose deformity ^[10]

• Septal perforation

• Pain at the nasal dorsum, which suggests chondritis

Osteocartilaginous destruction does not correlate closely with active disease.

A retrospective study by D’Anza et al examining sinonasal imaging findings (from computed tomography [CT] scanning and magnetic resonance imaging [MRI]) in GPA suggested that although such imaging demonstrates nonspecific findings, the existence of septal erosion, mucosal thickening, and bony changes increase the likelihood that GPA is present. The study reported that mucosal thickening, bony destruction, and septal erosion occurred in 87.7%, 59.9%, and 59.4% of patients, respectively. ^[11]

A study by Proft et al suggested that olfactory and gustatory function are significantly reduced in individuals with GPA. The study included 44 patients with GPA who underwent chemosensory function tests, with the senses of smell and taste in these individuals found to be diminished in comparison with healthy controls. The level of olfactory function was similar to that found in rheumatoid arthritis, which, according to the investigators, may indicate that chemosensory impairment is common in systemic autoimmune disease. ^[12]

Otologic involvement occurs in 25-40% of patients during the course of granulomatosis with polyangiitis (GPA). Otitis media occurs in 40-70% of cases with otologic involvement. Otitis media may be the presenting feature and sole manifestation of GPA. It is the most common form of ear involvement in GPA and may 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 GPA require tympanostomy during the course of their disease. ^[9] Suppurative otitis media or mastoiditis may supervene, with symptoms that manifest as chronic otorrhea and postauricular pain.

Patients may have direct involvement by GPA 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 can lead to extensive tympanic scarring or granulomatous occlusion that results in persistent conductive hearing.

Primary middle ear involvement occurs in only 10% of GPA patients with otologic involvement. It is sometimes mistaken for otologic tuberculosis. The condition improves only with the use of glucocorticoid or cytotoxic agents.

Edema or erythema of the auricle may occur in 15% of GPA patients with otologic signs and symptoms. Pinna involvement resembles relapsing polychondritis. The condition responds to treatment with glucocorticoids or cytotoxic agents.

With regard to eosinophilic GPA (also known as Churg-Strauss syndrome), a literature review by Ashman et al found that the most common presenting otologic signs and symptoms in study patients were hearing loss (76%), otitis media with effusion (44%), vertigo (22%), tinnitus (21%), and chronic otitis media (20%). ^[13]

Hearing loss

Conductive hearing loss is the most common audiologic finding in GPA. It is caused by otitis media or, less frequently, by direct GPA 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. ^{[9, 5]}

Secondary infection extending to the inner ear is an alternative etiology of sensorineural hearing loss.

Vertigo or dysequilibrium

Vertigo or dysequilibrium is rarely reported in GPA. Possible causes include the following:

• Vasculitis of the vestibular inner ear

• Granulomatous neuritis of the vestibular portion of cranial nerve VIII (CN VIII)

• Vestibular deposition of immune complexes

• Central cerebral or cerebellar involvement by GPA

Facial paralysis is exceedingly rare as a presenting sign. It may be associated with primary granulomatosis with polyangiitis (GPA) 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 has also been reported in the absence of otologic GPA involvement. ^[5]

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 occurs in up to 6% of patients. Mucosal ulcerations are the most common oral lesions. These are usually buccal but may occur on the tongue, palate, or pharynx (see the image below). Ulcers are persistent, not recurrent.

Gingivae are striking red, with variably described white, yellow, or blue areas. Characteristic strawberry gingival hyperplasia has been suggested by some authors to be pathognomonic of GPA and may present as an early manifestation of the disease. ^[5]

There is delayed healing of oral wounds. In time, underlying bone can be involved, leading to tooth mobility or tooth loss.

Less common oral lesions include oroantral fistula, osteonecrosis of the palate, and labial mucosal nodules.

Oral biopsies are infrequently positive, but they remain important in the role of early diagnosis. ^{[9, 6]} Histologic features may be nonspecific. Characteristic GPA features of vasculitis and necrotizing granulomas are typically lacking on biopsy findings. Instead, pseudoepitheliomatous hyperplasia, multinucleated giant cells, and inflammatory infiltrates are more common.

Manifestations of laryngotracheal involvement in granulomatosis with polyangiitis (GPA) may range from subtle hoarseness to stridor and life-threatening obstruction. Subglottic stenosis is the most characteristic and serious laryngeal lesion. It occurs in 16-20% of all patients with GPA and up to 50% of pediatric patients with GPA, ^[14] and can be the only presenting manifestation of GPA.

Some researchers have recommended that all patients with subglottic stenosis be evaluated for the presence of cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) and perinuclear ANCA (p-ANCA) as part of the routine laboratory workup.

Most patients with subglottic stenosis have generalized GPA. Although GPA is known to contribute to airway narrowing, the disease course of subglottic stenosis is thought to run independent of that involving GPA.

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. Chronic scarring is thought to be the result of a recurrent insult such as laryngopharyngeal reflux in the presence of GPA, rather than ongoing microvasculitis alone.

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 GPA in 5-15% of biopsies. ^[14]

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 been shown to be another effective means of managing subglottic stenosis that is refractory to medical treatment. ^[14]

Involvement of the salivary glands is rare in granulomatosis with polyangiitis (GPA). ^[6] It typically occurs early in the course of the disease.

Extensive involvement of the salivary glands may produce sufficient destruction to simulate Sjögren syndrome. When involved, submandibular or parotid glands not uncommonly exhibit massive enlargement.

Diagnostic considerations include the following:

• Strawberry gums

• Gingival hyperplasia induced by drugs (eg, phenytoin anticonvulsants, some calcium channel blockers, cyclosporine, conjugated estrogens)

• Sarcoidosis

• Tuberculosis

• Churg-Strauss syndrome

• Polyarteritis nodosa

• Scurvy (vitamin C deficiency)

• Neoplastic processes (squamous cell carcinoma, leukemia, Kaposi sarcoma)

• Nasal substance abuse