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The Cochrane Corner

Topical Steroid for Chronic Rhinosinusitis without Polyps Martin J. Burton, DM, FRCS1, Matthew W. Ryan, MD2, and Richard M. Rosenfeld, MD, MPH3 Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Abstract The “Cochrane Corner” is a quarterly section in the Journal that highlights systematic reviews relevant to otolaryngology– head and neck surgery, with invited commentary to aid clinical decision making. This installment features a Cochrane Review, titled “Topical Steroid for Chronic Rhinosinusitis without Polyps,” that finds good evidence to support therapeutic benefits with no increase in adverse events compared with placebo controls. Keywords chronic rhinosinusitis, systematic review, topical corticosteroid therapy Received December 4, 2011; accepted December 6, 2011.

C

hronic rhinosinusitis (CRS) affects 14% to 16% of people in the United States and is diagnosed when symptoms last 12 weeks or longer and are accompanied by signs of inflammation (Table 1).1 Topical steroids are often used to manage CRS, but the impact of therapy on symptoms is unclear. This review quantifies the impact of topical steroids on CRS outcomes for patients without nasal polyps, which comprise at least two-thirds of all patients diagnosed with CRS.

Topical Steroid for Chronic Rhinosinusitis without Polyps, by Snidvongs K, Kalish L, Sacks R, Craig JC, and Harvey RJ2 Disclaimer This is an abstract of a Cochrane Review published in the Cochrane Library 2010 Issue 5 (see www.thecochranelibrary. com for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and the Cochrane Library should be consulted for the most recent version of the review.

Otolaryngology– Head and Neck Surgery 146(2) 175­–179 © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2012 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0194599811434064 http://otojournal.org

Background Topical corticosteroid is used as part of a comprehensive medical treatment for chronic rhinosinusitis (CRS) without polyps. Nevertheless, there is insufficient evidence to show a clear overall benefit. Trials studying the efficacy of topical corticosteroid use various delivery methods in patients who have or have not had sinus surgery, which directly impacts on topical delivery and distribution.

Objectives To assess the effects of topical steroid in patients with CRS without nasal polyps and perform a meta-analysis of symptom improvement data, including subgroup analysis by sinus surgery status and topical delivery methods.

Search Methods We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ISRCTN and additional sources for published and unpublished trials. The date of the most recent search was July 9, 2010.

Selection Criteria All randomized trials in which a topically administered corticosteroid was compared with either a placebo, no treatment or alternative topically administered corticosteroid for the treatment of CRS without polyps in patients of any age.

1

Department of Otolaryngology, University of Oxford and the Radcliffe Infirmary, Oxford, UK 2 University of Texas Southwestern Medical Center, Dallas, Texas, USA 3 Department of Otolaryngology, State University of New York, Downstate Medical Center, Brooklyn, New York, USA Corresponding Author: Richard M. Rosenfeld, MD, MPH, Department of Otolaryngology, State University of New York, Downstate Medical Center, 339 Hicks St, Brooklyn, NY 11201, USA Email: [email protected]

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Table 1. Diagnostic Criteria for Chronic Rhinosinusitis Criteria

Definition

Twelve weeks or longer of 2 or more signs or symptoms:

AND inflammation documented by at least 1 clinical or radiographic finding:

•  Mucopurulent drainage (anterior, posterior, or both), • Nasal obstruction (congestion), •  Facial pain/pressure/fullness AND/OR •  Decreased sense of smell • Purulent (not clear) mucus or edema in the middle meatus or ethmoid region by nasal endoscopy or anterior rhinoscopy, •  Polyps in the nasal cavity or the middle meatus, AND/OR • Computed tomographic imaging showing inflammation of the paranasal sinuses

Based on Rosenfeld et al.1

Data Collection and Analysis Two authors reviewed the search results and selected trials meeting the eligibility criteria, obtaining full texts and contacting authors where necessary. We documented our justification for the exclusion of studies. Two authors extracted data using a predetermined standardized data form.

Results Ten studies (590 patients) met the inclusion criteria. The trials were of low (6 trials) and medium (4 trials) risk of bias. The primary outcome was sinonasal symptoms. When compared with placebo, topical steroid improved symptom scores (standardized mean difference –0.37; 95% confidence interval (CI) –0.60 to –0.13, P = .002; 5 trials, n = 286) and had a greater proportion of responders (risk ratio 1.69; 95% CI 1.21 to 2.37, P = .002; 4 trials, n = 263). With a limited number of studies, the subgroup analyses of patients who had received sinus surgery versus those who had not was not significant (P = .35). Subgroup analyses by topical delivery method revealed more benefit when steroid was administered directly to the sinuses than with simple nasal delivery (P = .04). There were no differences between groups for quality of life and adverse events.

Authors’ Conclusions Topical steroid is a beneficial treatment for CRS without polyps and the adverse effects are minor. It may be included in a comprehensive treatment of CRS without polyps. Direct delivery of steroid to the sinuses may bring more beneficial effect. Further studies comparing different topical drug delivery methods to the sinuses, with appropriate treatment duration (longer than 12 weeks), are required.

Comments on Cochrane Review Comments by Ryan Despite significant advances in our understanding of CRS— advances that began with the dawn of the endoscopic era—the evidence supporting treatment approaches remains woefully limited. To date, 6 Cochrane reviews have examined the evidence for medical treatment approaches in CRS, and these reviews include the findings from just 29 randomized controlled trials (RCTs). These numbers are quite small for a

chronic disease process that affects up to 16% of the US population and costs billions of dollars per year in health care expenditures and lost worker productivity. A number of factors explain the current lag in CRS treatment research. The modern era for the diagnosis and treatment of CRS did not begin until the introduction of nasal endoscopy and the widespread availability of computed tomography (CT) imaging in the 1980s. Creating an operational definition for the disease that is both clinically useful and applicable in the research setting remains a challenge. Over the past 30 years, CRS definitions have changed in tandem with our rapidly evolving conceptualizations of the disease. We now recognize that CRS is a group of disorders (rather than one disease) characterized by prolonged symptomatic paranasal sinus inflammation (typically lasting 12 weeks or more), but further categorization of this “group of disorders” is elusive. Our understanding of the underlying etiology of CRS is also evolving. Older explanations for the development of CRS invoked sinus ostial obstruction, mucus stasis, changes in pH or luminal gas concentrations, and subsequent chronic bacterial infection with irreversible pathologic tissue changes in the sinus mucosa.3 Current theories to explain the development of CRS focus on additional intrinsic and extrinsic factors that promote sinus mucosal inflammation. These include staphylococcal colonization with superantigen elaboration, fungal hypersensitivity, atopy and deregulated IgE-mediated immunity, biofilms with persistent bacterial organisms, mucociliary clearance defects, defective innate immunity, and so on. Although CRS may be a common phenotypic expression of a variety of pathophysiologic processes, it is first and foremost an inflammatory disease. The medical treatment approaches that have been applied in CRS are derived from assumptions about the causes of the disease as well as expert opinion, rather than from experimental approaches. The traditional use of antibiotics for CRS is the most obvious example. The rationale for antibiotic treatment can be traced back to the theory that CRS develops from an unresolved acute bacterial sinusitis, and antibiotics have long been used for the treatment of CRS in the absence of RCTs showing efficacy.4 The role of antibiotics as a part of the treatment approach for CRS should depend on the results of RCTs, not expert opinion or first principles. The pitfalls of a “rational” treatment approach are illustrated by the recent history of antifungal treatments for CRS.

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Figure 1. Forest plot of randomized controlled trials comparing topical steroids with placebo for rhinosinusitis symptom scores. Individual study results are expressed as the standard difference (Std diff) in means, with a horizontal line showing the 95% confidence limits and a black box for the point estimate.The overall fixed effects estimate (black diamond at bottom) of –0.38 is consistent with a small to moderate effect size, with steroids reducing symptom scores by about one-third of a standard deviation over placebo.The associated I2 of 12% indicates low heterogeneity. CI, confidence interval. Data adapted from Snidvongs and colleagues2 and reanalyzed using Comprehensive Meta-Analysis Version 2.6

Figure 2. Forest plot of randomized controlled trials comparing topical steroids with placebo for percentage of individuals with improved symptoms. Individual study results are expressed as success rate, with a horizontal line showing the 95% confidence limits and a black box for the point estimate. The overall fixed effects estimate (black diamond at bottom) of –1.69 shows a 69% increase in the incidence of symptom improvement (success) with steroids. The associated I2 of 24% indicates relatively low heterogeneity. CI, confidence interval. Data adapted from Snidvongs and colleagues2 and reanalyzed using Comprehensive Meta-Analysis Version 2.6

In the 2000s, fungal hypersensitivity was postulated to be Based on the meta-analysis, it appears that topical steroids do the predominant trigger for CRS inflammation, and topical have a beneficial effect on symptoms in patients with nonpolantifungal treatments were subsequently promoted as the ypoid CRS (Figures 1 and 2). “answer” in the treatment of CRS. Perhaps because this theory A number of variables may influence this beneficial effect. was so controversial, several well-designed RCTs were perIntranasal steroid treatment may be more effective in patients formed. Almost without exception, these studies demonstrated who have undergone prior endoscopic surgery as this allows a lack of efficacy for topical amphotericin.5 better access for topical medications to reach the sinus mucosa. If CRS is an inflammatory disease, then certainly antiThe method of delivery also may be an important factor in inflammatory medications such as corticosteroids should be treatment success: irrigation seems to provide better distribution helpful. But recent history teaches us that such an assumption of topical medication, especially in the previously operated is not appropriate. Randomized controlled trials (and systempatient. In this review,2 irrigation or direct sinus cannulation atic reviews of these trials) are required to determine the benappeared to provide a greater benefit than nasal delivery methefit of steroids in CRS. Refinement of our treatment approaches ods (drops, sprays, nebulizer). Given the small number of depends on well-designed randomized trials rather than constudies, however, the analysis did not show a significant diftinued pursuit of a rational etiopathogenic treatment approach. ference in treatment effect in patients who had undergone preTo determine the effectiveness of topical steroids in nonvious sinus surgery. polypoid CRS, Snidvongs and colleagues2 have examined Future studies should be performed to determine the effithe symptom improvement seen in randomized, placebocacy of low-volume vs large-volume intranasal application controlled trials. These trials have significant variability in and the effect of endoscopic sinus surgery and other CRS variterms of CRS definition, steroid molecule, dosing, delivery ables on the outcomes of topical steroid treatment. However, method, primary and secondary outcomes measures, and coinamong medication options for CRS, corticosteroids now have terventions (eg, surgery, antibiotics, and systemic steroids). the strongest evidence to support their use. Downloaded from oto.sagepub.com at UNIVERSIDAD DE SEVILLA on March 26, 2015

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Figure 3. Risk of bias graph with each item presented as percentages across all studies included in the meta-analyses. With permission from Snidvongs and colleagues.2

Comments by Burton

Comments by Rosenfeld

The use of topical nasal steroids has transformed the management of patients with CRS. Their use is widespread. As a consequence, the results and conclusions in this Cochrane review are unsurprising. The reader may ask, what is the merit in a systematic review if the conclusions are self-evident? I have always seen the process of undertaking a systematic review as the first step in planning high-quality research. If not a “hypothesis-generating” episode per se, at the very least it a hypothesis-modifying one. A good review will point us in the right direction for further research. Careful analysis of the results may indicate fruitful avenues for further investigation. In his critique, Dr Ryan elucidates some of these in relation to the management of CRS—for example, the efficacy of a low vs high volume of intranasal steroid applications and the effect of treatment when combined with endoscopic sinus surgery. For the researcher planning his or her next research project, there are several advantages to perusing the Cochrane review. The authors will have carefully considered the type of outcome measures that they believe are most important to patients and will have looked at the various ways of measuring those outcomes. They will have identified issues with the original trials related to conduct and analysis that were problematic, hopefully allowing the next generation of researchers to avoid these. The review should provide clear indications of how not to do a trial in this area as well as how to do one successfully. It will provide pilot data for the power calculations necessary to undertake a trial that can reasonably be expected to detect a clinically significant treatment difference. At the Annual Meeting of the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) in September 2011, I had the privilege of talking about systematic reviews in general—and Cochrane reviews in particular— with many members and guests of the Academy. Any reader who is interested in participating in the work of the Cochrane ENT Disorders Group is warmly welcome to contact our team by e-mailing [email protected]. We would be delighted to involve you in preparing a review or assisting with our peer review process.

Whereas I agree with Drs Ryan and Burton that the results of this meta-analysis do support using topical steroids in patients with CRS, the issue that has not been raised, but merits further consideration, is how confident should we be in these results? To answer this question, let us look at the quality of the source articles, consistency of the results, and magnitude of benefits achieved. The risk of bias for the RCTs in the review is relatively low (Figure 3), the main concerns being a lack of clarity in most trials as to how the randomization was performed and whether the allocation was truly concealed from the investigators. Selective reporting was a problem for about 50% of studies, for which some prespecified outcomes were incompletely reported. A glance at the forest plots in Figures 1 and 2 suggests relatively consistent results among RCTs, which is supported by a formal test for heterogeneity (I2 of 12% and 24%, respectively). We can therefore conclude that quality and combinability are reasonable. My concern with the results, however, lies in the modest magnitude of effect and the broad 95% confidence intervals (CIs) that limit generalizability. Symptom scores decrease, on average, only about a one-third standard deviation (SD) with steroid use (Figure 1), with the lower limit of the 95% CI unable to exclude a trivial benefit of only 0.13 SD. The chance of symptom improvement (Figure 2) increases by 69%, on average, with steroids, but again the lower limit of the 95% CI is less impressive and cannot exclude an effect as small as 21%. Generalizability of these results is further limited by having nearly 60% of the total 286 patients contributed from a single trial, with the other trials of very small sample size. The largest trial administered steroids for 20 weeks before assessing outcomes. In summary, offering topical steroids to patient with CRS is a reasonable option for clinicians, with the anticipation of mild symptom relief in many patients without polyps after several months of use. The cost and mild adverse effects of topical steroids may lead some patients to conclude that this level of benefit is simply not worth the effort, a decision that should be respected by clinicians. Additional large trials are

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needed to increase our confidence in the benefits of therapy and the magnitude of benefits that patients can expect. Author Contributions Martin J. Burton, writer; Matthew W. Ryan, writer; Richard M. Rosenfeld, concept, writer, critical revision.

Disclosures Competing interests: Matthew W. Ryan is on the speakers bureau for Alcon and Merck, Inc, SRx Advisors, and the advisory panel for Teva. Sponsorships: None. Funding source: None.

References 1. Rosenfeld RM, Andes D, Bhattacharyya N, et al. Clinical practice guideline: adult sinusitis. Otolaryngol Head Neck Surg. 2007;137:S1-S31.

2. Snidvongs K, Kalish L, Sacks R, Craig JC, Harvey RJ. Topical steroid for chronic rhinosinusitis without polyps. Cochrane Database Syst Rev. 2011;(8):CD009274. DOI: 10.1002/14651858. CD009274. 3. Rybak LP. Medical treatment of chronic sinusitis in the immunocompetent and immunosuppressed patient: a review. Otolarynol Head Neck Surg. 1982;90:534-539. 4. Piromchai P, Thanaviratananich S, Laopaiboon M. Systemic antibiotics for chronic rhinosinusitis without nasal polyps in adults. Cochrane Database Syst Rev. 2011;(5):CD008233. DOI: 10.1002/14651858.CD008233.pub2. 5. Sacks PL, Harvey RJ, Rimmer J, Gallagher RM, Sacks R. Topical and systemic antifungal therapy for the symptomatic treatment of chronic rhinosinusitis. Cochrane Database Syst Rev. 2011;(8):CD008263. DOI:10.1002/14651858.CD008263.pub2. 6. Borenstein M, Rothstein H. Comprehensive Meta-Analysis, Version 2: A Computer Program for Research Synthesis. Englewood, NJ: Biostat; 2005.

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Topical steroid for chronic rhinosinusitis without polyps.

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