A meta-analysis of topical amphotericin B for the treatment of chronic rhinosinusitis

Abstract

Background

Fungal species have been implicated in the pathophysiology of chronic rhinosinusitis (CRS). Based on this observation, some clinicians have employed topical antifungal therapy with amphotericin B (AMB); however, its efficacy has not been consistently supported by the literature.

Methods

A comprehensive review of the English-language literature on the role of topical AMB therapy in CRS treatment was performed. Search criteria included placebo-controlled trials between the years of 2000 and 2009. Studies that reported outcomes based on computed tomography (CT), nasal endoscopy (NE), and symptom scores (SS) were included.

Results

Three published studies reported CT outcomes. After pooling patients from these 3 studies, meta-analysis revealed no significant difference between AMB-treated and control groups (p = 0.07). Four studies reported NE outcomes, in which central tendency (mean or median) and variance were identified. Among these 4 studies, combining AMB-treated patients did not reveal any significant effect when compared to the small control group (p = 0.53). Only 2 studies reported SS; no significant differences in symptoms were noted (p = 0.33).

Conclusion

A systematic review of the literature does not support the use of topical AMB for the treatment of CRS. © 2011 ARS-AAOA, LLC.

Isaacs S, Fakhri S, Luong A, Citardi MJ. A meta-analysis of topical amphotericin B for the treatment of chronic rhinosinusitis. Int Forum Allergy Rhinol. 2011;1:250–254

Chronic rhinosinusitis (CRS) is an inflammatory disorder affecting the mucosal lining of the nose and paranasal sinuses. The role of fungus in sinonasal inflammatory diseases has been well documented. Traditionally, fungal sinus disease has been classified as invasive fungal sinusitis, fungus ball (mycetoma), and allergic fungal rhinosinusitis (AFRS). In the 1990s Bent and Kuhn1 defined AFRS as an eosinophilic inflammatory process associated with the presence of fungal antigens. Wei et al.2 and Ponikau et al.3 attempted to identify the prevalence of fungus in all patients with CRS. Using novel methods of collecting and handling fungi in nasal secretions, fungal cultures were positive in 96% of 210 consecutive CRS patients. Eosinophilic mucin was identified in 96% of 101 consecutive surgical cases of CRS. They concluded that fungal pathogens may be the inciting event in all patients with CRS with and without polyps. Interestingly, positive fungal cultures were identified in 100% of the 31 control patients.

On the basis of these observations, several authors have proposed the use of topical antifungal medications for the treatment of patients with CRS. Several studies have evaluated the use of intranasal amphotericin B (AMB) with conflicting results. The purpose of this meta-analysis is to evaluate the efficacy of intranasal AMB in patients with CRS.

Materials and methods

A comprehensive review of the literature on the use of topical intranasal AMB for the treatment of CRS was conducted using Medline and PubMed databases. The keywords “intranasal amphotericin B,” “topical amphotericin B,” and “chronic rhinosinusitis” were used. All English language reports with series of patients since 1999 were selected. Specific inclusion criteria included studies with CRS patients (polypoid and nonpolypoid), reported concentrations of topical AMB, and follow-up with measurable outcomes. Two independent investigators (A.L. and S.I.) reviewed the studies for inclusion in this analysis.

The first outcome measure was radiologic improvement based on computed tomography (CT). Patients were characterized into 3 groups (improved, no change, and worse). Only studies listing numbers of patients who improved, and those containing both a treatment and control group (saline irrigation), were included. Proportions of positive and negative outcomes were compared between control and AMB-treated patients using a Fisher's exact test. Outcomes based on endoscope scores were also reviewed. Studies that reported a measure of central tendency (mean or median), a measure of variance, and a sample size were reviewed. The mean change in endoscopic scores (posttreatment score to pretreatment score) between control and AMB-treated patients were assessed.

The final outcome measured was improvement based on symptom score. Patients were characterized into 2 groups (improved, or no change/worse). Only studies listing numbers of patients who improved, and those containing both a treatment and control group were included. Proportions of positive and negative outcomes were compared between control and AMB-treated patients using a Fisher's exact test.

SPSS 16.0 was used for all statistical analyses. The critical alpha level was set at p = 0.05 for all tests, and all p values quoted are 2-tailed.

Results

The comprehensive literature review yielded 10 articles published between 1999 and 2009, of which 6 met the inclusion criteria (Table 1). All studies were prospective. Three studies were uncontrolled whereas the other 3 were randomized control trials (RCTs). In those studies with a control group, the control was saline.

Table 1. Literature review

Author	Publication year	Type of study	Number of patients	Amphotericin B patients	Length of treatment (weeks)	Delivery	Concentration (mg/mL)	Outcome
RCT = randomized control trial.
Ricchetti et al.9	2002	Open	74	74	4	Lavage	0.1	Effective
Ponikau et al.8	2002	Open	51	51	12	Lavage	0.1	Effective
Weschta et al.5	2004	Double-blind RCT	78	28	8	Spray	3.0	Ineffective
Ponikau et al.4	2005	Double-blind RCT	30	10	24	Lavage	0.25	Effective
Helbling et al.7	2006	Open	21	21	12	Spray	10.0	Ineffective
Gerlinger et al.6	2009	RCT	30	14	52	Spray	5.0	Ineffective

Two of the published studies assessed outcomes based upon CT scores: Ponikau et al.4 and Wescheta et al.5 The inclusion criteria for these 2 studies were different. The Ponikau et al.4 study included all patients with CRS and at least 5 mm of mucosal thickening in 2 or more sinuses on CT. Patients with CRS and a minimum pretreatment Lund-Mackay CT score of 19 were included in the Wescheta et al.5 study. In addition, Wescheta et al.5 excluded suspected AFRS cases. Both studies also excluded patients who were recently treated with systemic corticosteroids. The measurement of disease severity on CT differed between these studies. Ponikau et al.4 measured the percentage of airspace occluded by inflammatory disease. Wescheta et al.5 characterized a positive outcome by a 50% improvement in the Lund-Mackay score.

Pooling patients from these studies revealed no significant difference between AMB-treated and control groups (p = 0.77; Table 2), when CT scores were characterized into positive or unchanged/worse categories. Comparisons of the method of drug delivery (irrigation vs spray) suggested that spray resulted in a higher proportion of patients who improved compared with irrigation, in both AMB-treated (p = 0.01) and control (p = 0.03) groups.

Table 2. Summary of studies reporting CT scores^*

	Treatment group		Control group
Study	Improved	No change or deteriorated	Improved	No change or deteriorated	p
^*Numbers of patients in each study who showed improvement, no change or deterioration on CT analysis at the end of the study period. Only studies containing both treatment and control groups are included. Values of p are given for 2-tailed Fisher's exact tests for each study individually, and for a total of all patients. CT = computed tomography.
Ponikau et al., 20054	7	63	5	21	0.55
Wescheta et al., 20045	2	26	0	22	0.50
Total	9	89	5	43	0.77

Four studies met the inclusion criteria for comparisons based upon endoscopic assessments: Gerlinger et al.,6 Helbling et al.,7 Ponikau et al.,8 and Richetti et al.,9 although only 1 (Gerlinger et al.6) was a double-blind study containing a control group. Combining AMB-treated patients from 4 studies did not reveal any significant effect when compared to the small control group (p = 0.53; Fig. 1). Control patients (n = 16) showed marginally better, although nonsignificant, improvement compared with patients in the AMB-treated group (n = 157). In addition, no significant difference in outcomes between the patients who received AMB via spray (n = 35) and those using irrigation (n = 122) was noted (p = 0.11, Mann-Whitney U test) (Fig. 2).

Figure 1. Mean changes in endoscopic score of AMB-treated patients (n = 157, gray bar) and control-treated patients (n = 16, white bar). Bars show mean ± SEM. There was no significant difference between the 2 groups (p = 0.53, Mann-Whitney U test). SEM = standard error of the mean.

Figure 2. Mean changes in endoscopic score of AMB-treated patients receiving the drug by either spray (n = 35, light gray bar), or by irrigation (n = 122, dark gray bar). Bars show mean ± SEM. There was no significant difference between the 2 groups (p = 0.11, Mann-Whitney U test). SEM = standard error of the mean.

Two of the published studies were included in the analysis of the affect of topical AMB on symptom scores: Ponikau et al.4 and Ponikau et al.8 Both included data on the number of patients who improved or were unaffected by this treatment. The Sinus Nasal Outcome Test-20 (SNOT-20) was measured at baseline and after treatment. Comparison of the AMB-treated patients from these 2 studies did not demonstrate any significant difference from the control group (p = 0.33) (Table 3).

Table 3. Summary of studies reporting symptom scores^*

	Treatment group		Control group
Study	Improved	No change or deteriorated	Improved	No change or deteriorated	p
^*Numbers of patients in each study who showed improvement, no change or deterioration in symptom score at the end of the study period. Values of p are given for 2-tailed Fisher's exact tests for each study individually, and for a total of all patients.
Ponikau et al., 20028	38	13
Ponikau et al., 20054	9	1	9	5	0.34
Total	47	14	9	5	0.33

The data from the 3 controlled trials were pooled and analyzed. Patients were characterized as improved or unchanged/worse based on 1 of the 3 outcomes measured (CT, endoscopy, or symptom score). There was no significant difference between those treated with intranasal AMB and the saline controls (p = 0.34) (Table 4).

Table 4. Summary of objective outcome measures in studies with treatment and control groups^*

	Treatment group		Control group
Study	Improved	No change or deteriorated	Improved	No change or deteriorated	p
^*Numbers of patients in each study who showed improvement, no change or deterioration in objective outcome (CT, endoscopy, or symptom score) at the end of the study period. Only studies containing both treatment and control groups are included. Values of p are given for 2-tailed Fisher's exact tests for each study individually, and for a total of all patients. CT = computed tomography.
Ponikau et al., 20028; CT	7	63	5	21	0.55
Wescheta et al., 20045; CT	2	26	0	22	0.50
Gerlinger et al., 20096; endoscopy	13	1	11	6	0.05
Ponikau et al., 20054; symptom score	9	1	9	5	0.34
Total	31	91	25	54	0.34

Discussion

In 1999, Ponikau et al.3 proposed the notion that CRS may be due to fungal pathogens. If fungi are indeed the prime driver in CRS pathophysiology, efforts to eradicate fungi from the sinonasal spaces in CRS patients seem reasonable. In this view, eradication of the inciting fungal pathogen would prevent the inflammatory response and subsequent clinical course of CRS. Nonetheless, the role of topical antifungal agents (most commonly AMB) has been controversial. The earliest studies demonstrated an improvement in symptoms, endoscopy scores, and CT in patients using AMB lavages8,9; however, these studies were uncontrolled and thus allowed for observer bias. Furthermore, patients in these studies were permitted to continue topical or systemic corticosteroids. Ponikau followed his initial study with an RCT comparing AMB lavage (20 mL of 250 µg/mL solution twice a day) with saline controls4; they reported only a trend for improvement in symptoms, endoscopy scores, and mucosal thickening seen on CT in the treatment group as compared to placebo.

Weschta et al.5 performed an RCT comparing AMB sprays (200 μL of 3 mg/mL solution 4 times per day) with saline. This method of application was selected to remove the beneficial effect of a lavage as confounding variable. In this study, AMB demonstrated no efficacy in terms of CT score as compared to the saline controls. In fact, the median posttreatment symptoms scores were significantly worse in the AMB group. At the same time, Helbling et al.7 looked at a prospective series of patients treated with Amphotericin nasal sprays (0.2 mL of 1% solution 3 times a day). In this uncontrolled study, 76% of the patients had unchanged posttreatment endoscopy scores. An important aspect of this study was that corticosteroids had to be discontinued prior to enrollment. AMB was the only nasal medication during the course of the study. Gerlinger et al.6 studied the efficacy of AMB nasal sprays (4 mg per day) for postoperative treatment. Compared to the saline control, the AMB group did not demonstrate a difference in CT scores, symptoms, or quality of life up to 12 months after surgery. There was a trend toward improvement in endoscopy scores in those patients treated with AMB; however, this did not correlate with symptomatic improvement.6 Accentia Pharmaceuticals (Tampa, FL), a company that was developing a topical AMB irrigation solution (based upon Ponikau's data) and conducted formal trials as part of an effort to secure the U.S. Food and Drug Administration (FDA) indication for CRS, reported in its 2010 U.S. Securities and Exchange Commission Form 10-K, “the clinical trial did not indicate statistically significant clinical benefit and the trial was not considered to be successful.”10

These published studies included a heterogeneous group of patients and reflect ongoing controversies in the operational definitions of CRS and its mechanisms. In particular, these patients differed in terms of disease severity, concomitant corticosteroid use, and operative history. In addition, the AMB delivery methods, concentration and duration of treatment differed in all of the studies.

The purpose of the analysis described in the current report was to combine the results of all of these studies and determine if topical AMB is indeed efficacious in the treatment of CRS. The results of this study showed that there was no significant difference between topical AMB and saline when evaluating posttreatment CT, endoscopy, and symptom scores. It should be noted that the patients in the control arm showed a marginal but insignificant improvement in posttreatment endoscopy scores as compared to topical AMB. Thus, clinicians who incorporate topical AMB in treatment regimens for CRS may wish to reconsider that therapeutic model.

Ebbens et al.11 has performed the largest double-blinded, RCT evaluating intranasal AMB to date. In this report, 116 patients with CRS were randomized to receive either AMB irrigations (25 mL of 100 µg/mL) twice daily or saline irrigations. Nasal endoscopy and symptom scores (Rhinosinusitis Outcome Measure-31) were the primary outcomes measured and revealed no difference between the 2 groups after 13 weeks of treatment. This study was not included in the present analysis because it only reported the mean change in endoscopy score for each treatment arm as a group. No individual participant data was included.

The central premise for the use topical AMB in CRS treatment is the eradication of fungus. The current data do not provide consistent evidence that AMB can eradicate fungus—at least as currently formulated and delivered for the sinonasal spaces. Ponikau et al.4 found that the concentration of Alternaria protein within the nasal mucus did not change after treatment with Amphotericin. In 2009, Liang et al.12 performed an RCT comparing AMB (4 mL of 5 mg/mL solution daily) and saline lavages; in this report, endoscopy and symptoms scores did not differ between treatment and control groups, and cultures of nasal secretions revealed a similar proportion of patients with identifiable fungus and no reduction in the intranasal fungal burden after treatment in both groups.

Of course, any systematic review of the type presented here is subject to criticism. Such systematic reviews are only a function of the underlying data, and in the published reports for topical AMB for CRS, the studies have not been very strong. Only 3 of the 6 studies were RCTs. Furthermore, each study included unique definitions for CRS and clinical outcomes and each study relied upon unique AMB formulations. Nonetheless, when these studies are taken together into a single review, it becomes clear that topical AMB does not appear to be more efficacious than saline when used as a treatment for all clinical CRS subsets. It should be noted what this data analysis does not say. Based on these data, it would be inappropriate to state that CRS does not have fungal etiology and it would be incorrect that to assume that efforts to eradicate fungus are not useful. The apparent failure of the studies to achieve their primary outcome measures may reflect other factors, including incorrect selection of the antifungal agent and poor drug delivery. It is possible that another agent delivered to the target sinuses may indeed be efficacious. At this point, additional efforts to characterize the role of fungus in CRS, including subsets of CRS, like AFRS, seem appropriate. In addition, exploration of drug delivery systems seems warranted.

Conclusion

Data from published trials of topical AMB for the treatment of CRS were systematically reviewed. This analysis strongly suggests that topical AMB does not seem to improve CT and endoscopy scores when used in all CRS patients. In the clinical realm, the exact incremental benefit from topical AMB is questionable. The role for fungus in the mechanisms for CRS and its subtypes remains controversial, and additional investigations are warranted.