Clinical Consultation: Intranasal antifungals for sinusitis

Is there a role for intranasal antifungals for chronic sinusitis?

In what circumstances, if any, would you consider using an intranasal antifungal agent to treat a patient with chronic rhinosinusitis (CRS)?

CRS is the most common chronic disease in the United States, affecting 17.4% of adults, with an estimated direct cost of $5.6 billion yearly.^1,2 There frequently is no definitive or quick cure. The clinical diagnosis of CRS is based on the presence and persistence of certain symptoms. The finding of mucosal thickening on coronal CT scan of the paranasal sinuses strengthens the clinical diagnosis.

CRS is a multifactorial disease, with genetic, infectious, allergic, and immunodeficiency factors playing roles of variable proportion from patient to patient. The percentage of CRS cases that are caused or complicated by fungi is not known. The hypothesis that fungi cause CRS has not been proved. Nevertheless, some persons apparently believe there is a pandemic of fungal CRS, and intranasal antifungal therapy is used in some patients.

Open trials and anecdotal reports suggesting benefit from intranasal antifungal therapy have been overstated to the general public in the press.³ This publicity coincides with the "craze" over increased morbidity from fungi in the home and work environments. Increasing numbers of patients with CRS who have not responded to conventional therapies ask their physicians for antifungal therapy.

As physicians, we should clearly explain to our patients what is fact versus conjecture. It is not easy to establish that CRS is caused or complicated by fungi. Intranasal antifungal therapy for CRS is expensive ($500 to $2000 yearly), may have side effects and, if effective, may have to be continued indefinitely to prevent recurrence. A well-designed, double-blind, placebo-controlled study of this therapy for CRS is long overdue.

Do fungi cause CRS?

In l983, Katzenstein and associates⁴ described a new form of CRS caused by Aspergillus species. The histologic characteristics were pronounced eosinophilia of the nasal mucosa and nasal secretions, with clumps of eosinophils--allergic mucin--and noninvasive fungal hyphae of Aspergillus species.⁴ The allergic mucin is a by-product of degradation of eosinophils (Charcot-Leyden crystals). A few years later, a number of other species of fungi were associated with this new form of CRS, and Robson and associates⁵ created the term "allergic fungal sinusitis," because some patients have atopy and specific IgE to certain airborne fungi.^4-8

Exposure and colonization of the nasal mucosa to airborne fungi is universal. In one study, 96% of the patients with CRS had cultures positive for fungi.⁹ Fungal elements were identified in 81% of the surgical specimens of nasal and sinus mucosa.However, cultures of nasal secretions were positive for fungi in the control group as well, and the types of organisms were similar to those found in the patients with CRS.⁹ Therefore, the fundamental questions remain unanswered. In susceptible persons, do airborne fungi cause CRS? If so, what is the incidence and pathogenesis, and what is the appropriate therapy?

In an open trial of 51 patients with CRS, intranasal irrigation using 20 mL of a solution of 100 µg/mL of amphotericin B in sterile water was reported to be safe and effective.¹⁰ Conversely, a recent double-blind, placebo-controlled study found no benefit with amphotericin B, 3 mg/mL, administered in a nasal spray, 2 puffs per nostril 4 times daily.¹¹

Shin and associates¹² found that peripheral blood mononuclear cells from patients with CRS (but not those of persons without CRS) produced both interleukin (IL)-5 and IL-13 when exposed to fungal antigens of Alternaria (one of the most common airborne fungi worldwide) in vitro. Furthermore, levels of IgG antibodies to Alternaria and Cladosporium were significantly higher in the sera from patients with CRS than from persons without CRS.

What to look for

A fungal role in the pathogenesis of CRS is likely when rhinoscopy reveals abundant jelly-like mucus and there is evidence of striking eosinophilia in sputum, in nasal or sinus secretions, or on histology of surgical specimens from nasal or sinus mucosa. A history of atopy, positive allergy skin test reactions to airborne fungi, nasal polyps, failure to benefit from corticosteroid and/or antibiotic therapy, and identification of fungi by culture or histology suggest the possibility of a fungal role in the inflammatory process of CRS.

There are no specific findings on coronal CT scanning of the paranasal sinuses that suggest the presence of fungi. All specimens from patients undergoing sinus surgery should be submitted for fungal stain and culture, in addition to the usual histologic examination. Soon, we should be able to determine whether measurements of serum IgG to common airborne fungi or the identification and quantitation of molecular by-products of airborne fungi in nasal or sinus secretions are of any additional help in this search for a fungal role in a patient's CRS.

The approach to therapy

When a fungal comorbidity is suspected based on the rationale described above, a therapeutic trial of an intranasal antifungal may be considered in a patient with CRS (with or without polyps). In 2001 and 2003, the Mayo Clinic obtained 3 US patents covering the use of intranasal antifungal agents in the treatment of CRS.^13-15 In 2004, the Mayo Clinic licensed the use of intranasal amphotericin B for CRS.¹⁶

The Table lists the 3 antifungal formulations for intranasal therapy as prepared by the pharmacy at the Mayo Clinic. Other preparations of antifungals for intranasal therapy are also available in the United States and Europe. At present, there is no evidence that any one of these preparations is better than the others.

To document effectiveness of therapy, it is advisable that the patient first undergo a therapeutic trial with nasal irrigation or spray using a saline solution for 3 months, while the rest of the patient's medications for CRS are optimized. The patient should be instructed to keep a symptom diary.¹⁷ If symptoms are still present after this baseline period, a therapeutic trial of an intranasal antifungal for 4 to 6 months may be considered.

Patients should be monitored monthly for symptom control and possible side effects from the intranasal therapy. If this therapy is found to be safe and effective, it may become part of the patient's maintenance therapy for CRS, since discontinuation may result in recurrence of symptoms within weeks or months.¹⁰

Patients with nasal polyps that are large enough to interfere with an adequate delivery of the intranasal therapy by irrigation or spray often require shrinkage of the polyps with systemic corticosteroids or surgery. Patients who have undergone sinus surgery for removal of polyps and creation of nasoantral windows may be considered for a 4- to 6-month therapeutic trial with an intranasal antifungal if there is histologic evidence of eosinophilia with or without identification of fungi by culture or histology.

References:

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