Chapter 13. Nasal Manifestations of Systemic Disease

General Considerations

Granulomatous and autoimmune diseases are characterized by a systemic chronic inflammatory process and a predilection for particular organ systems. Occasionally, patients may present with florid nasal symptoms such as severe crusting, inflammation, and saddle-nose deformity, which raise suspicion early in the evaluation. However, sinonasal manifestations are often nonspecific, including nasal obstruction, rhinorrhea, and recurrent sinusitis. The practitioner must therefore include these diseases in the differential diagnosis of chronic sinonasal symptoms and assess for systemic manifestations in the history and physical examination.

Although obtaining biopsies of suspicious lesions is critical for establishing a diagnosis, specimens often demonstrate nonspecific chronic inflammation and necrosis. Helpful adjunctive tests include inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), complete blood cell count, various autoimmune serologies, chest X-ray, urinalysis, and bacterial and fungal cultures.

The goals of managing the sinonasal manifestations of these diseases are to provide symptomatic relief of nasal obstruction and crusting and to reduce the incidence and severity of secondary sinusitis from ostial obstruction by reducing mucosal edema and facilitating mucociliary clearance. Patients may also require concurrent systemic therapy.

Wegener's Granulomatosis

Essentials of Diagnosis

• Severe nasal crusting with friable underlying mucosa, septal perforation, and saddle nose deformity.
• ANCA (antineutrophil cytoplasmic autoantibodies), chest X-ray, and urinalysis.
• Nasal biopsy of suspicious lesions; possible renal biopsy.

General Considerations

Wegener's granulomatosis is an idiopathic vasculitic and autoimmune process that typically involves the upper and lower respiratory tracts. It occurs in all age groups and predominantly affects white populations. The spectrum of disease presentation ranges from localized to disseminated forms, but the majority of patients have otolaryngologic manifestations. Classically, Wegener's granulomatosis involves a triad of necrotizing granulomas of the upper and lower airways, glomerulonephritis, and disseminated vasculitis. Upper respiratory tract symptoms may occur in up to 90% of patients, and sinonasal symptoms may be the only systemic manifestation in 30%. The previously undiagnosed patient may present with a pattern of chronic or recurrent sinusitis, managed medically and often surgically with variable clinical improvement.

Clinical Findings

Symptoms and Signs

The more limited, localized form of Wegener's granulomatosis typically presents with a several-week history of upper respiratory infection symptoms that are unresponsive to standard medical treatment, with the presence of serosanguineous nasal drainage and characteristic pain over the dorsum. Nasal exam is notable for significant bilateral nasal crusting with underlying friable mucosa, particularly over the nasal turbinates, with possible extension to the nasopharynx. Septal perforations may be found with progressive disease, and can lead to saddle-nose deformity due to loss of cartilaginous support and a resultant a dorsal concavity. Other potentially involved head and neck sites are (1) the orbit, with nasolacrimal duct obstruction, orbital pseudotumor, episcleritis, or peripheral ulcerative keratitis; (2) the ear, including serous otitis media, with or without mastoiditis, and possible sensorineural hearing loss; and (3) the larynx and trachea, with subglottic stenosis and tracheal stenosis. Oral cavity ulcerations, gingival hyperplasia, and sialadenitis are rare manifestations of Wegener's granulomatosis. Systemic symptoms may include weakness, night sweats, and migratory arthralgias. More advanced systemic disease manifests as clinically significant pulmonary and renal pathology, although most patients have renal involvement, even if it is subclinical.

The classification criteria for Wegener's granulomatosis are the following: (1) oral ulcers and purulent or serosanguineous nasal discharge; (2) abnormal chest X-ray (which may include nodules, cavities, or fixed infiltrates); (3) abnormal urinalysis suggesting renal involvement; and (4) granulomatous inflammation evident on biopsy.

Laboratory Findings

Although the specificity of antineutrophil cytoplasmic antibodies (c-ANCA) for Wegener's granulomatosis is as high as 98%, the sensitivity varies with disease activity and is 90% in patients with active systemic disease, 60% in patients with localized disease, and 30% for patients in a remission phase. Typically, a positive c-ANCA on immunofluorescence is followed by a confirmatory PR3-ANCA (proteinase 3) on enzyme immunoassay. In a majority of patients, c-ANCA titers parallel disease activity and a titer increase may herald relapse. A positive biopsy characterized by necrotizing granulomata, multinucleated giant cells, and palisading histiocytes is highly suggestive of the diagnosis (Figure 13–1).

Treatment

The goals of therapy are to induce remission of active disease, maintain remission, and to control adverse effects of disease. The initial goal of therapy is remission induction with cyclophosphamide (2 mg/kg/day) and high-dose glucocorticoids (prednisone 0.5-1 mg/kg/day). Methotrexate may be used instead of cyclophosphamide in more limited forms of the disease. After 1 month of treatment, steroids can be slowly tapered over several months. Cyclophosphamide should be continued for 6–12 months until symptoms disappear and then switched to a less toxic immunosuppressant, such as methotrexate or azathioprine. Investigational therapies include tumor necrosis factor antagonists (etanercept), T-cell inhibitors (lefunomide), and monoclonal antibody therapy (rituximab). Trimethoprim/sulfamethoxazole may have a role for either the limited form of Wegener's granulomatosis, for pneumocystis pneumonia prophylaxis while on immunosuppressants, or to prevent relapse.

Sinonasal manifestations may be managed medically with low-dose systemic steroids, topical nasal steroids, saline irrigations, and anti-staphylococcal antibiotics when bacterial superinfection is suspected. The role of surgical intervention is limited and may include repair of saddle-nose deformity during a period of remission, septal prosthesis, and conservative endoscopic sinus surgery.

Sarcoidosis

Essentials of Diagnosis

• Chest X-ray (bilateral hilar adenopathy).
• Angiotensin-converting enzyme (ACE) levels positive in 60% of patients with active disease.
• Serum calcium level elevated in 15% of patients.
• Biopsy of suspicious mucosal lesions, labial minor salivary gland, or transbronchial lymph nodes.

General Considerations

The incidence of systemic sarcoidosis is approximately 16.5/100,000 in men and 19/100,000 in women. Approximately 1–4% of patients with sarcoidosis have sinonasal manifestations. The disease is more common in women and in African American and Latin populations, with a peak incidence between the ages of 20 and 40 years and a second peak in women greater than 50.

Sarcoidosis is a chronic granulomatous disease with predominantly pulmonary manifestations, although almost any organ system may become involved. Classic head and neck manifestations include xerostomia and salivary gland enlargement, xerophthalmia, and supraglottic laryngeal lesions causing hoarseness. Other manifestations include lupus pernio (cutaneous sarcoid), neurosarcoidosis, and uveoparotid fever (Heerfordt's disease), which is the association of uveitis, parotitis, and facial nerve paralysis with sarcoidosis.

Pathogenesis

The etiology of sarcoidosis is unknown. The histopathology reveals noncaseating granulomas without necrosis or vasculitis (Figures 13–2A and 13–2B).

Clinical Findings

The clinical symptoms associated with sinonasal sarcoidosis are usually nonspecific and include nasal obstruction, chronic crusting, anosmia, epistaxis, postnasal drainage, headache, and recurrent sinus infections. In patients with sinonasal symptoms and coexisting lung disease, sarcoidosis should be in the differential diagnosis. Classic intranasal findings include hypertrophied mucosa and submucosal granulomatous nodules. Other intranasal features suggestive of sarcoidosis include severe nasal obstruction and crusting with friable mucosa, nasal polyps, turbinoseptal synechiae, septal perforation, and external nasal deformity such as saddle nose. A thorough history and head and neck examination may reveal other manifestations. Ultimately, directed intranasal biopsy may be needed to definitively establish the diagnosis. Positive laboratory studies, including elevated ACE and calcium levels, and a chest X-ray, showing bilateral hilar adenopathy are highly suggestive.

Treatment

Depending on the severity of sinonasal disease, patients may be managed with topical steroids, intralesional steroid injections, or systemic steroids. Nasal irrigation may allow for the mechanical debridement of crusting and thick mucus. Surgical intervention should be avoided when possible but may be necessary for refractory cases of nasal obstruction and chronic sinusitis. For systemic sarcoidosis, oral corticosteroids are the mainstay of therapy. Treatment regimens may also include cytotoxic agents (methotrexate, azathioprine, cyclophosphamide, chlorambucil), anti-malarial drugs (chloroquine and hydroxychloroquine), thalidomide, and TNF-alpha inhibitors (infliximab, adalimumab, etanercept). Overall, therapy should be designed to minimize the use of long-term systemic steroids if the patient's systemic disease is well controlled.

Churg–Strauss Syndrome

Essentials of Diagnosis

• Criteria based on definitions of the American College of Rheumatology in 1990:

  1. Asthma.

  2. Peripheral blood eosinophilia > 10%.

  3. Neuropathy.

  4. Migratory pulmonary infiltrates.

  5. Paranasal sinus abnormalities.

  6. Tissue eosinophils.

• The presence of four of the above six findings results in a diagnostic sensitivity of 85%, with a specificity of 99%.

General Considerations

Churg–Strauss syndrome is a rare granulomatous vasculitis involving small to medium sized vessels and is characterized by asthma, hypereosinophilia, and extravascular eosinophilic granulomas. The cause of the disease is unknown, but factors implicated include vaccinations, desensitization, and various medications such as leukotriene-receptor antagonists. Approximately 50% of patients have a positive ANCA, which is usually perinuclear (p-ANCA) on immunofluorescence with myeloperoxidase (MPO-ANCA) specificity on enzyme immunoassay.

Clinical Findings

The symptoms and signs of Churg–Strauss syndrome generally occur in three phases, and shorter transition intervals to progressive stages are associated with more severe disease:

1. The prodromal stage may last for years and is characterized by adult-onset asthma and allergic rhinitis with nasal polyposis (70%) and recurrent sinusitis. Septal perforation is rare.

2. The second stage consists of peripheral blood and tissue eosinophilia, primarily in the lungs (Löffler's syndrome) and gastrointestinal system.

3. The third stage consists of the development of systemic vasculitis, which may involve the peripheral nervous system, integument, heart, gastrointestinal system, and kidneys, although renal dysfunction is usually not as severe as in Wegener's granulomatosis.

Treatment

The administration of corticosteroids (prednisone 1 mg/kg/d) usually results in a rapid regression of symptoms. Although a steroid taper can be initiated after approximately 1 month, long-term low-dose corticosteroid treatment is often necessary due to persistent asthma. Cyclophosphamide is indicated for first-line therapy when poor prognostic indicators are present or as second-line treatment with failure of corticosteroid therapy.

T-Cell Lymphoma

Essentials of Diagnosis

• Nasal obstruction and epistaxis.
• Rapidly progressive with aggressive local destruction.
• May have systemic symptoms such as fever, chills, night sweats, and weight loss.
• Tissue biopsy with immunophenotyping and Epstein–Barr virus (EBV) studies for diagnosis.
• Multiple biopsy specimens required due to friable tissue with large areas of secondary necrosis.

General Considerations

Extranodal nasal natural killer (NK)/T-cell lymphoma, previously described as lethal midline granuloma or polymorphic reticulosis, is rare in the United States and Europe but is common in East Asia and Central America. In China, it is the second most common type of extranodal non-Hodgkin lymphoma. The ratio of male to female patients who present with T-cell lymphoma is approximately three to one, with a median age of presentation in the fifth decade. Overall, patients with T-cell lymphoma tend to be younger than patients with conventional lymphomas. These tumors tend to resist traditional non-Hodgkin regimens, resulting in poor outcomes.

Pathogenesis

Histologically, nasal extranodal NK/T-cell lymphoma is characterized by mixed cellular infiltrates with angiocentric lymphoid invasion and occlusion of blood vessels, resulting in ischemic necrosis of normal and neoplastic tissues (Figures 13–3A and 13–3B).

Extranodal NK/T-cell lymphoma has a strong association with EBV irrespective of ethnic origin, strongly suggesting that the virus plays a pathogenic role. The lymphoma cells characteristically express CD2, CD45RO, CD7, CD43, CD3 epsilon, and the NK-cell marker CD56, which is usually not present in inflammatory mucosa. However, other T-cell antigens, such as CD3 and CD5, are often absent. Lymphoma cells also express cytotoxic molecules, including perforin and TIA-1.

Clinical Findings

A high index of suspicion is required for early diagnosis of extranodal NK/T-cell lymphoma, as patients typically present initially with nasal obstruction and epistaxis. Patients may also have facial or orbital swelling, sore throat, or hoarseness, depending on the extent of tumor involvement. Systemic symptoms of fever or weight loss are also present in some cases. Clinical findings include ulceration and necrotic granulomatous tissue with a friable surface. Exam often demonstrates septal perforation, and eventual palatal destruction may occur.

The tumor is highly invasive locally and often involves surrounding tissues, including the paranasal sinuses, orbit, and skin, resulting in an extensive destructive midline process. The oropharynx, hypopharynx, and larynx may also be involved. If disseminated, the tumor may be found in the gastrointestinal tract or genital organs. Cocaine abuse may present similarly as an impressive midline nasal destructive process, and its use should be ascertained in the patient's history. Table 13–1 lists the complete differential diagnosis of midline nasal destructive lesions.

Treatment

If untreated, the complications can range from local tissue destruction to death. In most cases a combination of chemotherapy and radiation therapy appears to be more effective than either modality alone. Radiation therapy alone may be sufficient in localized nasal disease. However, a 50% rate of relapse exists despite high initial efficacy with radiation. Surgical management is limited to reconstruction of bony and soft tissue defects after treatment, particularly in cases of hard palate or orbital floor destruction.

Rhinoscleroma

Essentials of Diagnosis

• High index of suspicion in individuals from endemic regions.
• Extensive nasal polyposis adherent to nasal septum, with minimal sinus involvement.
• Cultures with Klebsiella pneumoniae rhinoscleromatis (typically not normal nasal flora).
• Nonenhancing, well-defined borders on CT scans; bone and cartilage rarely involved.
• Biopsies of actively involved areas (septum or inferior turbinates) diagnostic.

General Considerations

Rhinoscleroma is a rare, chronic progressive granulomatous disease of the upper respiratory tract caused by Klebsiella rhinoscleromatis. Nasal disease presents with three typical stages: (1) catarrhal (atrophic), with nonspecific rhinitis; (2) proliferative (granulomatous), characterized by granulomatous reaction and the presence of Mikulicz cells; and (3) cicatricial (sclerotic), in which mucosal fibrosis is seen. The rise in the incidence of rhinoscleroma in the United States may be due to the increased number of immigrants from endemic regions such as Eastern and Central Europe, Central and South America, East Africa, and the Indian subcontinent. Rhinoscleroma may be found in all age groups, but most frequently affects adolescents and young adults. Poor hygiene, crowded living conditions, and poor nutrition contribute to its spread via airborne transmission.

Pathogenesis

The chronicity of this disease is believed to be a result of the ability of the bacteria to evade the host defenses during the proliferative stage. During the catarrhal phase, the organism gains access to the subepithelial layer via ulcerations that allow deep colonization. The bacteria then spread to other areas through the subepithelium and are phagocytosed by histiocytes, forming Mikulicz cells. The organism continues to multiply intracellularly until the Mikulicz cells rupture and deliver viable bacteria interstitially. This cycle continues and eventually leads to clinically evident granuloma formation and pseudoepitheliomatous hyperplasia.

Clinical Findings

Rhinoscleroma manifests primarily in the nose, but it can affect any part of the upper respiratory tract, including the eustachian tube, maxillary antrum, oral cavity, larynx, orbit, trachea, and bronchi. In advanced disease, nasal obstruction (94%), nasal deformity (32%), epistaxis (11%), and crusting (94%) are the main symptoms. Laryngeal involvement may present as hoarseness with associated findings of interarytenoid hyperemia, exudates, and vocal cord edema. Late laryngeal fibrosis typically involves the glottis and subglottis, with subsequent stridor and potential airway obstruction.

Treatment

A combination of conservative surgical debridement and long-term antibiotic coverage is the mainstay of therapy for rhinoscleroma. Tetracycline has been shown to be effective and inexpensive for patients unless contraindicated. Fluoroquinolones may be used as an alternative, given their excellent gram-negative activity, intracellular efficacy, and low toxicity. The organism is often difficult to eradicate, and relapse can occur even with aggressive therapy due to the organism's ability to remain dormant in its spore form.

Rhinosporidiosis

Essentials of Diagnosis

• High index of suspicion in individuals from endemic regions.
• Nasal obstruction and epistaxis, frequent ocular involvement
• Friable, polypoid, vascular nasal mass with red “strawberry” appearance.
• Histopathology showing thick-walled sporangium filled with endospores, pseudoepitheliomatous hyperplasia.

General Considerations

Rhinosporidiosis is a chronic granulomatous inflammatory disease caused by Rhinosporidium seebri. It is endemic in India and Sri Lanka and has been reported sporadically in multiple other locations, including South America and Africa. The organism is found in stagnant water and soil and is thought to be spread by contaminated water and inoculation of spores into traumatized epithelium.

The disease follows an indolent course and typically involves the nose and nasopharynx (70–85%) and the eye, particularly the conjunctiva or lacrimal sac (15%), but it can also involve other sites, including the skin, paranasal sinuses, palate, tonsil, larynx, tracheobronchial tree, parotid gland, and genitalia. The rare disseminated form is fatal and involves skin, bone, and brain.

Pathogenesis

Rhinosporidium seebri is difficult to isolate in cultures and some aspects of its epidemiology and life cycle remain controversial. After a period of growth, the early spore begins a series of mitotic divisions. With each division the number of nuclei and spores increases, and the spore wall thickens. The mature sporangium discharges its contents, releasing copious spores into the nasal secretions. Staining with hematoxylin–eosin stain reveals pseudoepitheliomatous hyperplasia, thick-walled fungal sporangia containing numerous endospores, and fibrous stroma with chronic inflammatory cells. The organism is present in all stages of development.

Clinical Findings

Patients typically present with symptoms of progressive nasal obstruction, chronic epistaxis, and watery rhinorrhea that becomes purulent during infection. Clinical exam reveals a polypoid, friable nasal mass with a red surface that bleeds easily due to its underlying vascularity. The mass grows slowly and is usually painless. The surface of the lesions contains pin-sized yellow spots bulging through attenuated epithelium that represent the mature sporangia and give the mass its classic “strawberry” appearance.

Treatment

Treatment is surgical excision with cauterization of the base. Antifungals, steroids, dapsone, and radiotherapy have been used with limited efficacy.

Human Immundeficiency Virus (HIV)

Essentials of Diagnosis

• HIV serology is diagnostic.
• CD4 cell counts and viral titers are indicative; lower CD4 counts and higher viral titers correlate with symptomatic immunodeficiency.
• Opportunistic pathogens can be seen with CD4 <50 cells/mm3. Empirically treat for Pseudomonas aeruginosa in HIV patients with sinusitis when CD4 <200 cells/mm3.
• Endoscopic cultures should be used to guide antibiotic coverage.
• Biopsy nasal masses and suspicious skin lesions to rule out malignant neoplasms.

General Considerations

Rhinosinusitis may affect up to 68% of patients infected with the human immunodeficiency virus (HIV), with an incidence and severity that correlate with the stage of HIV infection. As immune function deteriorates, the incidence of opportunistic infections increases, especially with CD4 counts below 50 cells/mm3.

Pathogenesis

HIV infection results in a gradual depression of humoral and cellular immunity, primarily due to the depletion of helper T lymphocytes. The result is an increased susceptibility to infection. With respect to sinonasal disease, HIV-infected patients have been found to have increased mucociliary transport time, resulting in stasis and thick, tenacious nasal secretions that increase the risk of sinonasal infection. Some studies have suggested that polyclonal B-cell activation with increased immunoglobulin production may result in increased atopy in HIV-positive patients and thus a higher incidence of allergic symptoms. However, the relationship between HIV infection and increased atopy is unclear at this time.

Clinical Findings

The typical presentation of rhinosinusitis in these patients is no different from that in seronegative patients; common findings consist of fever, facial pain or pressure, headache, postnasal drip, purulent nasal discharge, periorbital swelling, and nasal congestion. As the HIV infection progresses, the inflammatory response is reduced, resulting in less mucosal edema and rhinorrhea. The microbiology is usually the same as in seronegative patients when the CD4 count is > 50 cells/mm3, with Streptococcus pneumoniae, Haemophilusinfluenzae, and Moraxella catarrhalis being common for acute infection and Staphylococcus aureus,Pseudomonas aeruginosa, and anaerobes being common for chronic infection. When the CD4 count falls below 50 cells/mm3, the risk of infection by opportunistic bacterial, fungal, protozoal, and viral organisms increases. Although extrasinus complications of sinusitis are not known to have a greater incidence in these patients, a high index of suspicion is required with progressive immunodeficiency. These patients are also at risk for life-threatening invasive fungal sinusitis, particularly if the absolute neutrophil count is less than 600/mm3. Skin lesions such as Kaposi's sarcoma, herpetic ulcerations, and seborrhea-like dermatitis are common cutaneous processes that affect the nose and surrounding facial skin. These lesions may herald progression from asymptomatic HIV infection to AIDS. Nasopharyngeal lymphoid hypertrophy affects 56–88% of patients early in the disease course, causing nasal obstruction and serous otitis media, and may warrant biopsy to rule out lymphoma.

Treatment

The level of immunodeficiency should guide initial antibiotic therapy, and endoscopically obtained cultures should be performed to further tailor therapy. When the CD4 count is greater than 200 cells/mm3, therapy should include coverage for Streptococcus, Staphylococcus, and Haemophilus influenzae. First-line choices include amoxicillin, amoxicillin/clavulanate, cefuroxime, trimethoprim/sulfamethoxazole, or a macrolide. With incomplete response to initial antibiotic therapy, the development of chronicity, or a CD4 count below 200 cells/mm3, coverage should expand to include Pseudomonas aeruginosa and anaerobes. Clindamycin and metronidazole may improve response in these cases. Antibiotic therapy should be continued for a minimum of 3 weeks, along with systemic decongestants, mucolytics, and nasal saline irrigation. In chronic disease, topical nasal steroids may reduce inflammation and rhinorrhea. Prophylactic treatment with trimethoprim/sulfamethoxazole has been shown to decrease the risk of sinusitis and otitis media. When medical measures fail or in the case of extrasinus complications, functional endoscopic sinus surgery has been shown to be safe and effective. A low CD4 count is not a contraindication for surgical management.

We would like to acknowledge Ashish R. Shah, MD, John M. Ryzenman, MD, and Thomas A. Tami, MD for their contribution to this chapter in the previous editions of CDT.