In reference to The Effect of Topical Amphotericin B on Inflammatory Markers in Patients with Chronic Rhinosinusitis: A Multicenter Randomized Controlled Study

We read with great interest the article by Ebbens et al. ‘‘The Effect of Topical Amphotericin B on Inflammatory Markers in Patients with Chronic Rhinosinusitis: A Multicenter Randomized Controlled Study’’ in the February 2009 issue of Laryngoscope. The paper does not support the effectiveness of an intranasal amphotericin B lavage in chronic rhinosinusitis (CRS) with nasal polyposis after endoscopic sinus surgery. It is somewhat disturbing that the concentration of amphotericin B applied (100 mg/mL) seems rather extreme; it is at least 10 times higher than any other published in the literature. This concentration is particularly confusing since the earlier article from the Ebbens group (part I of the current multicenter study) mentioned a concentration of only 0.1 mg/mL. In this earlier clinical study, the amphotericin B was administered before endoscopic sinus surgery. Further, from the aspects of pharmacology and microbiology, it is not immediately obvious why sugar was added to the placebo nasal lavage solution. During the past 7 years, seven clinical trials have been reported in which experience with local antifungal treatment regimes in CRS was discussed. The controversial characteristics of these studies are summarized in Table I. Only three of the papers were based on double-blind, placebo-controlled investigations, and only one of these three was a multicentric study, which hampers interpretation of the results. In one case, patients with allergic fungal rhinosinusitis were excluded completely, and in some the numbers of recruited patients were extremely low. The duration of treatment ranged between 4 and 80 weeks, and the mode of drug/placebo application also varied: nasal lavage, nasal spray, or nasal inhalation. The concentration and the recommended daily dose of amphotericin B likewise varied in these studies. In one case, the nasal spray even contained sugar, which could facilitate the growth of fungi. The conditions of drug storage and checks on the stability of the amphotericin B solutions were totally ignored in most of these studies. As the patient compliance was considered in only one investigation, it is difficult to draw conclusions concerning the effectiveness or ineffectiveness of amphotericin B treatment. Certain clinical observations which cannot be ignored, and which point to the possible etiological role of fungi in CRS are: 1) Gosepath et al. recently identified the presence of DNA fragments of Alternaria in the sinonasal mucous membranes of patients with CRS, and concluded that the fungal antigen is transported from the eosinophilic mucin (EM) to the small vessels of the nasal mucous membranes by the antigen-presenting cells (macrophages), triggering eosinophil infiltration. 2) Shin et al. demonstrated that the levels of serum IgG to Alternaria and Cladosporium were higher in patients with CRS than in healthy individuals. 3) The presence of specific IgG antibodies correlated with increased IL-5 and IL-13 concentrations during exposure to Alternaria in vitro, but this did not hold for the controls. 4) Ponikau et al. reported that regular application of a nasal lavage containing amphotericin B for 6 months resulted in decreased concentrations of both neurotoxin and IL-5 originating from eosinophilic cells. In contrast, the levels of both mediators increased in the placebo group, though the changes were not significant. The observations of other researchers on the inflammatory mediators did not confirm these results. Despite such reports, there seem to be at least three reasons why some investigators doubt the relevance of fungi in CRS. First, the incidence of fungal colonization in patients with CRS is similar to that in healthy individuals. Moreover, the presence of EM is not always associated with a positive fungal culture, and the group of CRS patients with EM includes subgroups based on the presence of fungi in the EM and on IgE-mediated fungal hypersensitivity that share clinical characteristics. The third important fact is that bacteria too have been isolated from the sinus cavities of patients with positive fungal cultures; it therefore remains unclear whether intranasal fungal antigens do exacerbate the chronic inflammatory response or are simply present coincidentally in patients with CRS. It appears that further research and better study design are essential before final conclusions regarding this issue can be drawn.