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Twelve studies fulfilled the inclusion criteria: Four were uncontrolled studies while eight studies were randomized controlled clinical trials (RCT), including two multicentre studies. Five researchers used intranasal amphotericin B lavage while four used the spray or inhalation methods. Improvement of symptoms outcome was demonstrated in 1/7 (14%) of the included manuscripts. Reduction in CT inflammatory mucosal thickening was achieved in 1/4 (25%) of the studies. Endoscopic outcome improvement was obtained in 3/9 (33%) of the checked articles. Post treatment fungal eradication was not observed in any study 3/3 (100%). Topical amphotericin B had no significant effect on activation markers of nasal inflammatory cells except for IL5 in 1/3 (33%) of the reviewed articles.
Evidence did not support benefit of local nasal antifungal amphotricin B in treating CRS, and their routine use is not justified. Larger and better-designed double-blind placebos RCTs are required.
Chronic rhinosinusitis (CRS) is an inflammatory disease of the nose and paranasal sinuses for at least 12 weeks with distinctive symptoms (e.g. nasal blockage, nasal discharge, facial pain and/or reduced sense of smell) and either endoscopic signs of polyps, mucopurulent secretions, or edema and/or mucosal thickening in computed tomography (CT) 1-2. Although the pathogenesis of CRS and nasal polyposis is not well understood, there are several distinctive characteristics. The histological hallmark of this disease is marked increase of tissue inflammatory cells especially eosinophils and lymphocytes leading to amplification of the related inflammatory cytokine expression. Ponikau et al hypothesized that such eosinoplilic inflammation observed in CRS patients is triggered by an enhanced (but not classical allergic IgE-type) immune response against fungis in the nasal mucus.
So an empiric treatment with local antifungal drugs e.g. amphotricin B, which are directly administered to the sinonasal mucus, could reduce the antigenic stimulus arising from these non-invasive fungal organisms. Subsequently it will reduce the eosinophilic reaction directed towards the fungi and improve the course of the disease. Following endoscopic sinus surgery using this medication for adequate time and concentration should be advantageous for these patients, and might even reduce risk of recurrence. Also, amphotricin B was observed to have anti-inflammatory effects with potentiality to reduce eosinophil and mast cell activation markers. With this striking treatment researchers are faced with peculiar challenges associated with application of new CRS treatment. One of these difficulties is failure to spot a united definition for CRS together with limited recognition of the pathogenesis of the disease and deficiency of worldwide approved clinical and laboratory markers to assess treatment responses 3.
Behind this attractive track multiple researchers hurried up using intranasal lavage or spray containing amphotericin B for treatment of CRS without observing the previous three challenges and without following the road map of the best level of evidence. Even some centers have been using this medication without evidence based proves of efficiency in treatment of such disease. During the last 10 years 199 studies were published about this topic until delivery of our review. The results are so far controversial. Therefore, our aim was to find the best available evidence from the currently available researches about the effectiveness of intranasal amphotericin B in treatment of CRS.
Literature Search and Selection of Cases:
The design of the study was focused on studies that primarily used intranasal antifungal for the treatment of CRS with and CRS without NP, with the overall primary outcome being the response to treatment.
The following databases were used in the search: PUBMED, MEDLINE, EMBASE,COCHRANE,SCIENCEDIRECT, HINARI and OVID MEDLINE databases were done in 27/7/2010. All articles published in peer-reviewed journals in English language were eligible for review. Medical subject headings and main key words used in the database searches were topical, nasal, antifungal, Amphotericin B, rhinosinusitis and chronic sinusitis.
The following inclusion criteria were used in the research protocol for the study: 1) Studies using local antifungal (Amphotericin B) in the treatment of CRS with and without NP 2) Sample size was mentioned 3) Studies done with or without a control group for comparison to the treatment group (randomized controlled trials [RCT] were preferred) 4) Definition and diagnosis of CRS included in the design of the study 5) The duration of treatment was reported 6) Preparations of local antifungal (Amphotericin B) mentioned 7) subjective or objective outcomes were present. Articles which were missed one or more of the inclusion criteria were excluded.
Initial screening computerized search of articles obtained from the literature. Search was performed by reviewers based on the research protocol criteria. Flow chart can be seen in figure 1. We found 199 articles after discussion between the reviewers, there were, 34 articles identified as potentially relevant.
These articles then underwent a second-stage review. The articles were read in detail and discussed by the reviewers before making a final decision regarding inclusion or exclusion from the current study. Only 12 were found fulfilling the inclusion criteria of the study and were considered eligible.
The reviewers were not blinded to the authors, institutions, journals of publication, or outcomes of the studies. Methodological quality was evaluated to determine the strength of each study. Level of evidence for these articles was made according the North American Spine Society January 2005.
Data were extracted from included trials. All studies were evaluated for their inclusion and exclusion criteria of study subjects, type of the article, sample size, drug and formulations used the conditions of drug storage and checking the stability of the amphotericin B solutions, trial length, patient compliance and outcomes.
Nine studies were correlated together according to both subjective and objective outcome measures e.g. assessment of symptom and quality-of-life scores and/or radiological and/or sinoscopic and/or fungal assessment outcome. Other studies were correlated together according to the effect of local antifungal (Amphotericin B) on nasal inflammatory markers.
The controversial characteristics and outcomes of all included studies were reviewed systematically. Studies were categorized by outcome measures (Table 1,5).
Study characteristics, including sample size, trial length, drug and formulations used, the conditions of drug storage and checking the stability of the amphotericin B solutions, patient compliance, patient selection criteria, fungal allergy, concomitant treatment, previous sinoscopic surgery and outcomes were tabulated and compared across all studies (1-7). Outcome measures of each study were summarized and tabulated.
Data were scored as numeric or categorical variables. We first calculated summary statistics and then performed several post hoc comparisons of treatment and placebo.
In the present review, analysis of the various studies and direct comparisons cannot strictly be made because the studies under review differ in various aspects, including study designs, patient characteristics, outcome measures, and quality of the studies. With standing these difficulties, many of the studies used different outcomes. Twelve studies that fulfilled the inclusion criteria were identified (Tables 1-7).
There were 9 studies in the review that measured the effectiveness of intranasal amphotericin B lavage or spray according to both subjective and objective outcome measures. There were three uncontrolled studies 7-8,10. Six studies were RCT 6,9,11,12,14. (Table 1). There were studies excluded patients with AFRS completely 9, 12, 14. Four studies in the review measured the effectiveness of intranasal amphotericin B lavage or spray based on changes of nasal inflammatory markers in CRS with or without NP. One was controlled clinical trial 15, while three were double-blind RCT 6, 16-17. Levels of evidence are summarized in Table 1, 5.
In the present review, there was a big difference in Ricchetti et al 8 , Ponikau et al 7, Weschta et al 9, Corradini et al 11, Ebbens et al 12, Liang et al 13 and Gerlinger et al 14 studies in terms of the concentration and the daily amount of amphotericin B , total dose, the form of drug/placebo application also varied: nasal lavage 6-8,12-13, nasal spray 9-10,14 or nasal inhalation 19, method of delivery (20 ml nasal lavage in each nostril, twice a day vs 20 mL nasal lavage in each nostril twice daily with a bulb syringe vs nasal sprays 2 puffs per nostril 4 times daily vs 20 mL nasal lavage in each nostril twice a day by using a bulb syringe using a bulb syringe vs nasal sprays one puff in each nostril three times a day vs inhalation vs 25 mL nasal lavage in each nostril twice daily using an Emcur (also named Rhinicur) nasal douching device vs 250 mL nasal irrigation by using a Sanvic SH903 pulsatile irrigator in each nostril vs 100 μl two doses twice daily into each nostril using dosing spray caps, respectively), and duration which ranged between 4 and 80 weeks.
In some of the studies, the number of recruited patients was extremely low 6,9-10,14. Patient compliance was examined in only two studies 9,12. In some studies the nasal spray even contained sugar, which could facilitate the growths of fungi 9,12. The conditions of drug storage and checking the stability of the amphotericin B solutions was completely ignored in most of these studies. Variables subjective and objective outcome were measured although all must be used.
The effectiveness of intranasal amphotericin B lavage in treatment of CRS (table 3)
Symptoms outcome was shown in four studies 6-7, 12-13 used amphotericin B nasal irrigations 6-8,12-13. Only in Ponikau et al 7 (uncontrolled study) significant improvements was observed in symptoms outcome. The remaining studies 6, 12-13 did not detect any significant overall difference in symptoms with treatment and no significant difference was observed between treated and placebo group.
CT imaging outcome was demonstrated in two studies 6-7 significant reduction in the percentage of mucosal thickening on CT scans compared with placebo. Ponikau et al 6 showed that there was radiological benefit without symptomatic improvement in patients with CRS with or without nasal polyps.
Endoscopic outcome was displayed with significant improvement in two uncontrolled studies 7-8 and one double-blind, randomized, placebo-controlled study 6. In other two double-blind, randomized, placebo-controlled studies12,13 no difference was observed between treated and placebo groups.
Fungal assessment after treatment was exhibited in two studies 6,13 without significant differences between the amphotricin B and placebo groups.
The effectiveness of intranasal amphotericin B spray or inhalation in treatment of CRS (Table 4).
Four studies used amphotericin B nasal spray 9-10,14 or nasal inhalation. 19 Symptoms outcome was demonstrated in three studies 9-10, 14. No significant differences were observed between the amphotricin B and placebo treated groups. Weschta et al 9 revealed that the symptom scores were distinctly worse after amphotericin B therapy than in the control group.
CT imaging outcome was shown in two studies 9,14 the comparison between treated and untreated groups did not indicate a significant change.
Endoscopic outcome was demonstrated in four studies 9-11,14 without remarkable changes after treatment.
Fungal assessment after treatment was displayed in Weschta et al 9 with fungal eradication only in 11 patients but without effect on the CT sores, the symptom scores, the RQL scores, or the endoscopy scores.
The effect of topical amphotericin B either nasal lavage or spray on activation markers of nasal inflammatory cells in CRS with or without NP (Table 7).
There was a difference in Shin and Yu 15, Ponikau et al 6, Weschta et al 16, and Ebbens et al 17 studies in terms of the concentration of amphotericin B used, total dose, and method of delivery, duration ranged between 4 and 24 weeks.
Topical amphotericin B either nasal lavage or spray have no significant effect on activation markers of nasal inflammatory cells in chronic rhinosinusitis with or without nasal polyps 15-17. Whether dosage, treatment time and route of administration have an impact on treatment outcomes need further studies.
Ponikau et al 6 demonstrated that detectable Alternaria protein levels in all mucus specimens from patients with CRS confirming the presence of fungi; however, the intranasal fungal burden (estimated only by total Alternaria protein) was not reduced after treatment. Also, Weschta et al 16 detected absent correlation between nasal cell activation markers and fungus detection before treatment. Successful fungi eradication, defined as fungus detection before but not after treatment, did not influence nasal cell activation markers in CRS.
In 1999, Ponikau et al 18 proposed a new hypothesis for the pathophysiology of chronic rhinosinusitis (CRS). Since this study, several other studies also have confirmed that nasal cavities in the healthy patients as well as patients with CRS have a high prevalence of fungi 19-21. Other studies demonstrated its presence but without relation to the disease subjective or objective parameters. These contradictory results in pathogenesis studies were reflected also in the revised treatment researches.
Amphotericin B has remained the treatment of choice for systemic fungal disease since the 1950s . Despite its clinical effectiveness, use of amphotericin B is limited by adverse systemic reactions, infusion-related reactions, electrolyte wasting and nephrotoxicity, renal, liver, and cardiac toxicity 14-15. Therefore, direct intranasal administrations of antifungal drugs by irrigation and sprays employed by researchers to bypass the systemic toxicity. Amphotericin B seemed an appropriate drug because it is highly effective (90%) against the majority of fungi cultured from the sinonasal tract, such as Aspergillus spp. and Penicillium spp. 31. In recent years, several hypotheses have been put forward regarding topical amphotericin's mechanism of action. Working as an antifungal agent (if the fungal theory is the true etiopathologic assumption of CRS), using amphotricin b is expected to improve the course of the disease. Reviewing different subjective and objective parameters of the disease, improvement was not seen except in less than 40% of the studies. As we are inhaling more than 100,000 fungal spore per day its use will be useless. It has been suggested that amphotericin B may reduce inflammation via a direct cytotoxic effect on nasal polyp epithelial cells 32-33 or that it may have anti-inflammatory properties 15-16. These mechanisms of action can explain the improvement obtained in some studies in benefit of topical amphotericin B irrigations in two uncontrolled trials 7-8 and one RCT. Although we must realize that nasal irrigation by itself promotes an improvement in nasal symptoms by decreasing mucosal edema and inflammatory mediators and by mechanical clearing of mucus inspissations 34. To counteract the irrigation effects, amphotricin B was applied as a nasal spray or inhalation in 5 studies. The authors of such 5 researches claimed using these methods for more than one reason. Various studies using nasal corticosteroids have shown that nasal sprays may effectively alter the course of nasal polyposis and decrease the levels of cell activation markers in nasal secretions 35-36. Also, it is much more convenient to apply nasal spray than to perform nasal lavage, and patients' compliance was considered more consistent and easier to assess with nasal sprays. Although nasal sprays distribute well within the nasal cavity, their penetration into the paranasal sinuses of healthy subjects or in patients after sinus surgery is inferior to nasal lavage 38. Also, because patients had advanced polyps, it was assumed that their sinus ostia were blocked and that fluid would not be able to enter the sinus lumen. Thus, the advantages of nasal spray application appeared to out-weigh the possible benefits of nasal saline irrigation. However, neither nasal sprays nor nasal lavages are supposed to access the sinus lumen in substantial amounts. By passing the effects of irrigations most of the studies using nasal sprays failed to show benefits for local amphotricin B.
Although safe to use and despite initial evidence of benefit of topical amphotericin B irrigations in two uncontrolled trials 7-8, one subsequent uncontrolled prospective trial 10 and subsequent double-blind placebo-controlled studies investigating the effect of topical amphotericin B irrigations and nasal spray either failed to show benefit 9-10, 12-17. The pharmacodynamics and distribution of antifungals in the sinus cavities needs further study.
The question arises what could led to the ineffectiveness of amphotericin B treatment in more than 60% of the previously published clinical studies. There are a number of possibilities: (1) The fungal theory can not act as CRS is a multi-factorial disease with variable pathogenesis e.g immune deficiency, genetic factors, bacterial biofilms, bacterial superantigen, anatomic variations, atopy, environmental factors 1, (2) The compliance may not be satisfactory during the course of long-lasting examination protocols, which is usually not taken into consideration in clinical studies 39 , (3) Differences in sensitivity of the various fungi to amphotericin B 40 , (4) Differences in effectiveness of the mechanisms repairing the direct membrane damage and the consequences of oxidative stress 41, (5) In patients with advanced CRS with nasal polyposis, the amount of drug that penetrates to the depth of sinuses filled with eosinophilic mucin and polyps may be insufficient. (6) Treatment did not extend to the frontal, posterior ethmoid or sphenoid sinuses because delivery of the treatment to these areas is limited (7) In topical therapy application can pose several obstacles such as obstructive disease as obstructive polypoid disease, which impedes drug delivery, and decreased mucociliary clearance can result in reduced drug distribution in patients with CRS .
Rules for evidence-based medicine (EBM) provide a vigorous methodology for the evaluation of previous studies, which individually carry little impact, but, collectively, show clinically meaningful results. Unfortunately, systematic reviews of the literature are limited by the quality of previous publications. For instance, studies that point to a small but statistically significant impact of an intervention probably should carry less weight than studies that show a larger therapeutic effect. Similarly, it is problematic to compare outcomes from treatment groups from different studies, because patient characteristics and other parameters are not uniform across different studies. Thus, one can only assess the quality of conclusions reached in individual studies. This approach relies on the application of EBM principles that provide a robust and reproducible methodology for the assessment of clinical research conclusions from numerous individual trials. EBM is not a perfect solution but is a practical and widely accepted solution for clinical dilemmas with no other easy answer.
Evidence did not support benefit of local nasal antifungal amphotricin B in treating CRS, and their routine use is not justified based on the conflicting data in the literature and the efficacy of topical antifungal agents remains controversial.
Larger and better-designed randomized double-blind placebo-controlled trials are required to more fully evaluate this emerging modality of treatment. Consideration must be given for conditions of drug storage, the stability of the amphotericin B solutions, patient compliance and to determine if changes in dosage, treatment time or route of administration could improve results.
Legends to figures:
-Figure 1: Flow diagram of article selection for inclusion in study
Legends to tables:
-Table 1: Characteristic of included clinical studies dealing with antifungal treatment
• An Introduction outlining the explicit clinical problem,
rationale for the intervention (if applicable), and the rationale
for conducting the review.
• A Methods section that specifies the information sources,
search strategy, inclusion and exclusion criteria for articles,
criteria and process used for validity assessment (if none, so
state), process for data abstraction, and statistical methods for
• A Results section that describes study selection, study
characteristics, and, when applicable, uses statistical methods to
summarize data and to assess heterogeneity.
• A Discussion section that summarizes key findings, makes
clinical inferences based on validity, interprets results in light of
the total available evidence, and lists potential biases in the
• Manuscript length of no more than 4,500 words (exclusive
of the title page and abstract), with up to 100 references and a
total of 15 images (figures and/or tables).
• Adherence to the PRISMA statement (www.prisma-statement.
org/), including a flow chart of article selection.