Topical and systemic antifungal therapy for the symptomatic treatment of chronic rhinosinusitis and allergic fungal sinusitis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
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To assess the effectiveness of systemic antifungal agents in the symptomatic management of chronic rhinosinusitis and allergic fungal sinusitis.
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To assess the effectiveness of topical antifungal agents in the symptomatic management of chronic rhinosinusitis and allergic fungal sinusitis.
Background
Description of the condition
Chronic rhinosinusitis is an inflammatory disorder of the nose and sinuses which is clinically defined as persistence of symptoms of nasal blockage or discharge for at least 12 weeks combined with endoscopic abnormalities (polyps, mucopurulent discharge, mucosal swelling) or abnormal sinus CT scan. Other symptoms may include facial pain or reduced sense of smell (Fokkens 2007a). While allergy and bacterial infection play a role in the aetiology of this condition it is best considered to be a multifactorial chronic inflammatory disorder. It is distinguished from allergic rhinitis by the involvement of both the nose and the sinuses. The lower respiratory tract is also frequently affected, supporting the concept of united airways disease (Rimmer 2006). Chronic rhinosinusitis affects an increasing proportion of the adult population until the sixth decade of life then declines (Chen 2003).
Chronic rhinosinusitis is thought to affect between 5% and 15% of the population (Melen 1994). It is a diagnosis that is made by a wide variety of practitioners, including primary care physicians, otolaryngologists, immunologists, allergists and respiratory physicians. It is the principal diagnosis in nearly 2% of all patient visits to primary care (Schappert 1992). Medical therapy has been the basis for treating chronic rhinosinusitis. Short and long‐term antibiotic therapy, topical and systemic steroids, topical and oral decongestants, oral antihistamines, mast cell stabilisers, anti‐leukotriene agents, mucolytics, topical antibiotics, topical and systemic antimycotics, proton pump inhibitors, bacterial lysates, immunotherapy, phytotherapy and avoidance of environmental factors have all played a role in the management of chronic rhinosinusitis (Fokkens 2007a).
Fungal related sinus disease is not uncommon (Sasama 2005). Fungus disease can affect both immunocompetent and immunosuppressed patients. In the immunosuppressed patient group, the fungus is typically invasive and can manifest in an acute invasive or a more chronic invasive form. The treatment of this is well‐documented and consists of combination of surgical and medical therapy, including systemic antifungal therapy. Invasive fungal disease is a unique entity and represents angioinvasive fungal propagation in the immunocompromised host setting. This is not the common chronic rhinosinusitis experienced by the vast majority of chronic sinus patients. In immunocompetent patients, fungus may be involved in several forms. Fungal ball is well‐documented and was previously termed mycetoma. This is a slow‐growing fungal collection in an abnormal sinus. Surgical evacuation is a definitive treatment for this condition.
However, there are a large number of patients with chronic rhinosinusitis in which fungus has been associated (Lanza 2006; Ponikau 2002). Allergic fungal sinusitis (AFS) is a well‐recognised subgroup of chronic rhinosinusitis, in which a strong IgE mediated hypersensitivity to fungal elements drives the inflammatory process. Unfortunately, our current classification system for chronic inflammatory rhinosinusitis is very rudimentary with only polyps and eosinophilic inflammation as the main subgroups. Allergic fungal sinusitis, with its IgE dominated aetiology, is the only currently accepted additional category (Meltzer 2006). Ponikau et al from the Mayo Clinic documented fungus as a potential cause of chronic rhinosinusitis and advocated the use of topical antifungals (Ponikau 1999). Since then there has been increasing controversy and contrasting papers have advocated the use of both topical and systemic antifungal agents in the management of these patients (Ebbens 2007).
Description of the intervention
Antifungal agents can be used as systemic medications or as topical preparations and delivered directly to the sinuses. Systemic antifungals are given orally or intravenously. Topical treatments can be given using different delivery systems and in different paranasal sinus states. Topical therapy may be administered by douching, nebulisation, atomisation, inhalations, irrigation, spray, drops or powder insufflations. There is a significant difference in the distribution of medication to the paranasal sinuses before and after sinus surgery (Harvey 2008).
We will evaluate all antifungals utilised in the management of inflammatory disease of the paranasal sinuses, both systemically and topically. Examples include amphotericin B, fluconazole, itraconazole, voriconazole and ketoconazole. These agents may be fungistatic or fungicidal depending on the drug concentration and the susceptibility of the fungus.
How the intervention might work
There are specific subtypes of chronic rhinosinusitis in which fungus has been associated (Lanza 2006; Ponikau 2002). Allergic fungal sinusitis is one such example and the pathway of fungal‐mediated antigen‐specific IgE immune hypersensitivity is well‐recognised. However, recent research suggests that a much broader group of chronic rhinosinusitis, with an eosinophilic inflammation, may be mediated by fungal elements and a subsequent cascade of immune effects through non‐classical pathways (Sok 2007). Although good research demonstrates an interaction of the immune system with fungus in chronic rhinosinusitis (Ponikau 2007), this does not necessarily imply that antifungals will be effective in managing chronic rhinosinusitis. In analogy, there is little plausibility in using anti‐dust mite agents in managing house dust mite allergic rhinitis. It is well‐established that parts of common live and dead dust mite along with dust mite faecal matter can still stimulate the same response in these patients. Similarly, in chronic rhinosinusitis the inappropriate immune activation may be the driving pathologic mechanism and fungal elements only the innocent target of the process. Fungus is ubiquitous in both our environment and sinuses (Lackner 2005)
Why it is important to do this review
Chronic rhinosinusitis has a significant impact on the quality of life and health burden within the adult population (Gliklich 1995). The impact of the disease on quality of life, as measured by SF‐36 scores, is comparable to or worse than that of other chronic conditions such as chronic obstructive pulmonary disease, congestive heart failure and back pain (Metson 2000).
Systemic antifungals have significant side effects, particularly with regard to the hepatic and renal toxicity. Topical amphotericin is expensive and also associated with potential adverse events (Ebbens 2006). With the potential for fungus to be a common mediator of chronic rhinosinusitis, and a patient population of over 60 million in the USA and European Union, it is essential that the need for, and reported benefit and adverse effects of antifungals are well‐documented prior to broadly applying this form of therapy (Meltzer 2004).
The aim of the review is to assess the potential advantage of either topical or systemic antifungal therapy in the treatment of chronic rhinosinusitis. This will be performed by reviewing all papers concerned with the use of both systemic and topical antifungal agents in the treatment of fungal related chronic rhinosinusitis, including both chronic rhinosinusitis and allergic fungal sinusitis, as this distinction is often ambiguous in some trials. A systematic review of the evidence available in the literature will be presented, in order to aid prescribers in making informed decisions about treating patients with chronic rhinosinusitis.
Objectives
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To assess the effectiveness of systemic antifungal agents in the symptomatic management of chronic rhinosinusitis and allergic fungal sinusitis.
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To assess the effectiveness of topical antifungal agents in the symptomatic management of chronic rhinosinusitis and allergic fungal sinusitis.
Methods
Criteria for considering studies for this review
Types of studies
Placebo‐controlled randomised trials and controlled trials. We will also seek controlled studies to define adverse events.
Types of participants
We will include both adults and children with chronic rhinosinusitis as defined by either the EPOS criteria (Fokkens 2007a; Fokkens 2007b) or by the AAO‐HNS (Benninger 2003; Meltzer 2004). Fungus can be demonstrated in almost all diseased and normal sinuses (Lackner 2005), thus associated fungus confirmed either histologically or on culture will not be used as an inclusion criteria. The immunological role of the fungus and the host is still an area of ongoing research. Patients with classic allergic fungal rhinosinusitis satisfying the Bent‐Kuhn criteria (Morpeth 1996) for the diagnosis of AFS will be used for subset analysis. We will also define patients receiving their topical therapy both before and after endoscopic sinus surgery as a subgroup.
Types of interventions
We will consider studies involving both systemic and topical antifungal therapies. Systemic antifungals can be given orally or intravenously. Topical therapy may be administered by douching, nebulisation, atomisation, inhalations, irrigation, spray, drops or powder insufflations.
Types of outcome measures
Primary outcomes
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Symptoms improvement as defined by:
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collated symptom scores (visual analogue scales or Likert severity categories);
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validated disease‐specific quality of life questionnaires, such as the RSOM 31, SNOT‐20 (Piccirillo 2002), RSDI or CSS.
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Secondary outcomes
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Adverse events associated with treatment.
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Surrogate outcomes:
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endoscopic scores;
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radiographic scores (i.e. Lund‐Mackay);
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biochemical markers (i.e. IL5, IL8, eosinophilia).
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Search methods for identification of studies
We will conduct systematic searches for randomised controlled trials. There will be no language; publication year; or publication status restrictions. We may contact original authors for clarification and further data if trial reports are unclear; and we will arrange translations of papers where necessary.
Electronic searches
Published, unpublished and ongoing studies will be identified by searching the following databases from their inception: the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, current issue); PubMed; EMBASE; CINAHL; LILACS; KoreaMed; IndMed; PakMediNet; CAB Abstracts; Web of Science; BIOSIS Previews; CNKI; mRCT (Current Controlled Trials); ClinicalTrials.gov; ICTRP (International Clinical Trials Registry Platform); and Google.
Subject strategies for databases will be modelled on the search strategy designed for CENTRAL (Appendix 1). Where appropriate, we will combine subject strategies with adaptations of the highly sensitive search strategy designed by the Cochrane Collaboration for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1, Box 6.4.b. (Handbook 2008).
Searching other resources
We will scan reference lists of identified publications for additional trials and contact authors if necessary. We will search PubMed, TRIPdatabase, NHS Evidence ‐ ENT & Audiology and Google to retrieve existing systematic reviews possibly relevant to this systematic review, so that we can scan their reference lists for additional trials. We will seek abstracts from conference proceedings via the Cochrane Ear, Nose and Throat Disorders Group Trials Register.
Data collection and analysis
Selection of studies
One review author (PS) will review and select trials found in the searches and evaluate them against the inclusion criteria. In cases where PS is unsure as to whether the trial is relevant, a second review author (RJH) will be consulted.
Data extraction and management
We will use a structured data collection form. The review authors (PS and RJH) will conduct the data extraction and assess the quality of the method used in each included trial. If necessary, we will contact authors of studies for clarification.
We will consider:
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number of participants;
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age of participants;
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characteristics of trial such e.g. duration of trial;
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method of randomisation;
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method of blinding;
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whether an intention‐to‐treat analysis was conducted;
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exclusion criteria;
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diagnostic criteria;
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duration of treatment;
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outcomes;
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duration of illness;
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severity of illness;
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adverse effects; and
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other medicines being used.
Assessment of risk of bias in included studies
We will conduct assessment of risk of bias in accordance with the Cochrane Collaboration tool for assessing risk of bias (Handbook 2008). This tool deals with sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, incomplete outcome data, selective outcome reporting and other sources of bias.
Two review authors (PS and RJH) will assess the risk of bias. Should disagreements arise, a third author (JFR) will be consulted. In trials lacking details of randomisation and other characteristics, we will contact authors of the studies to obtain further information.
Measures of treatment effect
We will obtain standardised mean differences (SMD) from the reported results in order to compare trials using different scales as outcome tools. Multiple symptom scores and disease‐specific quality of life questionnaires are likely to be utilised. We will extract raw data from graphs and tables. We will also derive standard deviation (SD) results for the mean changes or impute these from the confidence intervals (CI) or from SDs from individual patient groups. If available, we will collect total number of patients either improved or worse from the intervention as dichotomous data. For dichotomous data we will calculate the risk ratio (RR). We will collect dichotomous data for adverse events.
Dealing with missing data
We will analyse all data on an intention‐to‐treat basis and in original group allocations. Where data are missing, we will collect the reasons for loss to follow up from the manuscript or by communication with the author.
Assessment of heterogeneity
1. Clinical heterogeneity
We will consider all included studies and, if issues appear that may add to clinical heterogeneity, we will note and consider these in the analysis.
2. Statistical
We will visually inspect graphs to investigate statistical heterogeneity. We will investigate heterogeneity between studies using the I² statistic (Handbook 2008), which provides an estimate of the percentage of variation observed in results that is unlikely to be due to chance. A value of 50% or greater will be taken to indicate heterogeneity.
Assessment of reporting biases
Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results, as described in section 10.1 of the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2008).
Data synthesis
We will attempt to analyse data by intention‐to‐treat. If data are comparable and of sufficient quality, we will attempt to combine these to give a summary measure of effect, using a random‐effects model.
Subgroup analysis and investigation of heterogeneity
We will use the classification of chronic rhinosinusitis to investigate subgroups and heterogeneity. We will use allergic fungal sinusitis and chronic rhinosinusitis, with and without polyps, as the categories. We will categorise eosinophilic chronic rhinosinusitis as chronic rhinosinusitis with polyps. If possible, the device used to delivery topical antifungals may be used for subgroup assessment, as these devices have different fluid dynamics. Finally, topical treatments that have been used in patients before and after sinus surgery will have different efficacy of distribution and we will use the surgical state of patients for subgroup analysis.
Sensitivity analysis
We will produce a sensitivity table during the review process. The concurrent use of oral steroids during the treatment course may be excluded as itraconazole has been known to cause a steroid potentiating effect and this may distort the effect attributable to the antifungal agent. We will note the concentration of amphotericin on the data sheet for topical therapy. This may be used for sensitivity analysis as topical nasal amphotericin B irrigation may be ineffective in killing fungi in vitro at the FDA approved concentration of 100 ug/ml and concentrations of 200 ug/ml or higher might be required for effective fungicidal activity. We are likely to use the eligibility of participant criteria for allergic fungal sinusitis for sensitivity analysis. We will use those studies in which patients are diagnosed with allergic fungal sinusitis without fulfilling the strict Bent‐Kuhn criteria (Morpeth 1996) for a sensitivity check.
