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

Abstract

In Reply: Few will be unaware of the intriguing proposition from Dr. Ponikau and colleagues that most, if not all, chronic inflammation in the nose and sinuses is a response to inhaled fungal material.1 Predicated on this, impressive claims were made for the effects of topical intranasal amphotericin, provoking much media interest and the widespread use of this treatment in the US despite the lack of well-powered level 1 evidence. It was against this background that our double-blind, placebo-controlled, multicenter trial was conceived and undertaken.2 As part of this trial, nasal lavage samples of patients suffering from chronic rhinosinusitis (CRS) with or without nasal polyposis were analyzed before and after the start of topical amphotericin B treatment. Unfortunately, as is correctly observed by Gerlinger et al., a typographic error has occurred in the Laryngoscope publication on the dose of amphotericin B that was used.3 The correct dose of amphotericin B that was used in both studies is 100 μg/mL. Other comments made by Gerlinger et al. are, however, less correct or incomplete. To guarantee adequate access to sinonasal mucosa upon irrigation with amphotericin B, previous endoscopic surgery was obligatory for inclusion in our clinical trial.2 The statement of Gerlinger et al. that amphotericin B was administered before endoscopic sinus surgery is thus incorrect. In addition, Gerlinger et al. suggest that it is not clear why sugar was added to the placebo nasal lavage solution. We clearly state in our first manuscript that glucose 2.5% was used as a diluent because amphotericin B for injection forms precipitants when dissolved in saline. Glucose, on the other hand, was shown to be compatible with amphotericin B by the manufacturer. Glucose has no effect on drug bioavailability and reduces nasal irritation due to low osmolarity. As no differences in appearance, taste, smell, and osmolarity were allowed, a similar diluent was used in our placebo nasal lavage solution.2 Although Gerlinger et al. suggest that current data on topical antifungal effectiveness or ineffectiveness are too heterogeneous to draw any conclusions, we feel that based on data from one uncontrolled prospective trial4 and four double-blind, placebo controlled studies2, 5-7 (including our double-blind, placebo-controlled study),2 we are able to conclude that topical antifungals are ineffective in the treatment of CRS patients with and without nasal polyposis. And, although Gerlinger et al. suggest that the double-blind, placebo-controlled trial by Ponikau et al. is in support of a positive effect of topical amphotericin B in CRS patients, we question whether modest, nonrelevant, radiological improvements without symptomatic benefit are clinically significant.5 Despite the negative findings of all randomized controlled trials, one could still argue that dosage, treatment time, and route of administration may have influenced treatment outcome. As recent in vitro data suggest that amphotericin B nasal lavages are ineffective in killing fungi at concentrations of 100 μg/mL when used for 6 consecutive weeks8 (dosages used by both Ponikau et al. in their non–placebo-controlled study9 and our group2), one may conclude that the lack of effect of topical amphotericin B may be explained by inadequate dosing. However, treatment with topical amphotericin B in a concentration of 250 μg/mL, a dosage demonstrated to be effective in killing fungi within 6 weeks, was recently shown to be equally ineffective clinically.5 This, in combination with the observation by Weschta et al.7 that fungal eradication does not alleviate CRS signs and symptoms, questions the role of fungal eradication in disease resolution. Although several intriguing studies on the role of fungi in CRS pathogenesis have been published in recent years, some of which are mentioned by Gerlinger et al. in the remainder of their letter to the editor, currently there are more questions than answers concerning the role of fungi in the pathophysiology of CRS.10, 11 We agree that further studies are necessary to clarify the exact role of fungi in CRS pathogenesis, to assess which fungal organisms, if any, are pathogenic, and what exactly characterizes the immunological response to fungi that may potentially result in the development of disease. Presently, in the absence of convincing microbiological and immunological data or evidence of effectiveness of both topical and oral antifungals, we feel that the case against the fungus remains unproven. Fenna A. Ebbens MD, PhD*, Christos Georgalas MD, PhD*, Wytske J. Fokkens MD, PhD*, * Department of Otorhinolaryngology–Head and Neck Surgery, Academic Medical Center, Amsterdam, The Netherlands.