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common airborne fungi with the production of IL-13 and IL-5, which are crucial for eosinophilic inflammation (60). Another study by the Mayo Clinic reported that Alternaria alternata induced eosinophil degranulation in vitro (61). The authors concluded that certain environmental fungi may be important in the exacerbation of inflammation in asthma and allergic diseases. The potential association between fungal elements and inflammation in CRS has generated interest in the use of topical or systemic antifungal agents. Topical and Systemic Antifungal Therapy Despite initial enthusiasm for the use of topical antifungal agents, subsequent studies have not confirmed benefit over that provided by saline irrigation (62, 63). Similarly, a multicenter high-dose double-blind study of terbinafine (Lamisil) in the treatment of CRS performed by Kennedy and colleagues (64) failed to demonstrate any significant benefit either in terms of symptomatic or radiographic resolution. On the other hand, oral itraconazole has been used as an adjunctive treatment of allergic bronchopulmonary aspergillosis (ABPA), and there is significant anecdotal evidence that this may also be helpful in some patients with CRS and nasal polyposis. In patients with APBA, itraconazole has been shown to lower the need for oral steroids, decrease IgE levels, and improve pulmonary function, exercise tolerance, and symptoms. Oral antifungals have been proposed as a treatment option for select patients with allergic fungal sinusitis (65–67) (AFS) and nonallergic eosinophilic fungal sinusitis (66), diseases considered to be similar to ABPA (Figure 2). There are also anecdotal reports of efficacy in patients with Samter triad, a condition associated with severe nasal polyposis, asthma, and aspirin sensitivity. Patients with AFS are characterized by severe nasal polyposis and thick allergic mucin. Aggressive surgery is usually necessary to remove the bulk of sinus disease; however, in some patients the mucosa remains inflamed unless patients are treated with prolonged courses of oral steroids postoperatively. Clinically, itraconazole has been used for select patients as a steroid-sparing agent, either reducing the dose of oral steroids necessary to control sinus inflammation and polyps or replacing them completely (68). Similar to ABPA (69), it is hypothesized that the response to itraconazole in the sinuses is due to a decrease in the overall fungal load and possibly due to the drug’s antiinflammatory effects (65, 66, 68). Seiberling and Wormald (66) recently reviewed a series of 23 patients with AFS and nonallergic rhinitis with eosinophilia syndrome (NARES) treated with a 6-month course of itraconazole 100 mg twice daily. Nineteen patients (83%) responded to treatment with improvements in symptoms and endoscopic examinations. Eleven patients (48%) had complete response to treatment at a mean follow-up of 15.7 months. Three patients (13%) developed transient elevation of liver function tests (LFTs) that returned to baseline after ceasing therapy. In another study, Rains and Mineck (67) looked at the use of high-dose itraconazole (400 mg/d for 1 mo, 300 mg/d for 1 mo, 200 mg/d for 1 mo, or until clear by endoscopy) started after sinus surgery in 137 patients with AFS. Aspergillus was the most common fungus isolated in this study. After treatment, 69 patients (50.3%) had recurrence at an average of 10.8 months and 17 patients (20.5%) required revision sinus surgery. The authors concluded that itraconazole was safe and reduced the need for oral steroids and further revision surgery. Side effects included edema (7.9%), nausea (5.8%), elevated LFTs (4.3%), fatigue (2.2%), rash (2.2%), headache (0.7%), and malaise (0.7%). Patients started on itraconazole therapy should be monitored closely for side effects, and LFTs should be checked every
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