Management of rhinosinusitis: an evidence based approach

Transcription

1 REVIEW C URRENT OPINION Management of rhinosinusitis: an evidence based approach Andrew J. Para a, Elisabeth Clayton b, and Anju T. Peters b Purpose of review The most recent recommendations for the management of both acute (ARS) and chronic rhinosinusitis (CRS) based on the strongest data available for each treatment modality are summarized in this review. The clinical relationships between CRS and its comorbidities are also discussed. Recent findings The most promising advances in rhinosinusitis management involve the use of mabs (anti-ige, anti-il-5, anti-il-4ra) in trials of CRS with nasal polyposis. Otherwise, the mainstays of treatment for both ARS and CRS have largely remained the same over the past several years. Summary The treatment of ARS primarily involves symptomatic control with intranasal corticosteroids and nasal saline irrigation; antibiotics should be reserved for the patients who are believed to have bacterial rhinosinusitis. Treating CRS effectively involves using intranasal corticosteroids and irrigation, systemic corticosteroids, and potentially systemic antibiotics. Biologics (mabs) have shown benefit in clinical studies. Providers should also be aware of concomitant disease processes that may afflict patients with CRS. Keywords acute rhinosinusitis, biologic therapy, chronic rhinosinusitis with nasal polyps, chronic rhinosinusitis without nasal polyps, immunotherapy, intranasal corticosteroids, monoclonal antibody INTRODUCTION Rhinosinusitis is characterized by symptomatic inflammation of the nasal cavity and paranasal sinuses that both decreases quality of life and poses a large economic cost on affected patients and society. The burden of rhinosinusitis from a population perspective is extensive; approximately 11% of US adults have received a diagnosis of sinusitis in their lifetime [1]. Recent estimates suggest that chronic rhinosinusitis (CRS) alone cost over $60 billion in 2011, and patients with acute rhinosinusitis (ARS) often seek medical attention despite the likelihood that the vast majority of cases will resolve without intervention [2]. Unfortunately, the misprescription of therapy especially antimicrobials continues to plague most healthcare encounters for rhinosinusitis. A recent analysis of ambulatory care data from 2006 to 2010 in the United States nationally showed that 85.5% of office visits for ARS and 69.3% for CRS resulted in antibiotic prescriptions despite historical estimates that no more than 0.5 2% of cases of ARS involve a bacterial cause [3,4]. The following review highlights the indications for antibiotic prescription and clarifies which, and to what extent, management strategies for ARS and CRS are corroborated by objective evidence in the literature. Particular attention is paid to new data that have been published in the past year. PRIMARY GUIDELINES Two guidelines have been published recently for the management of rhinosinusitis. A practice parameter on the diagnosis and management of rhinosinusitis was developed by the Joint Council of Allergy, Asthma and Immunology; the American Academy of Allergy, Asthma and Immunology; and the American College of Allergy, Asthma and Immunology (denoted as the AAAAI/ACAAI guidelines in a Department of Medicine and b Division of Allergy/Immunology, Department of Medicine, Northwestern University, Chicago, Illinois, USA Correspondence to Anju T. Peters, MD, 211 E. Ontario, #1000, Chicago, IL 60611, USA. Tel: ; fax: ; anjupeters@northwestern.edu Curr Opin Allergy Clin Immunol 2016, 16: DOI: /ACI Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved.

2 Pharmacotherapy and evidence based medicine KEY POINTS In patients with ARS, consider antibiotics only when patients have symptoms longer than 10 days or experience the double-worsening phenomenon. Misuse of antibiotics is a fairly predominant issue in patients with viral rhinosinusitis. There are very strong data to support the use of INCS in both ARS and CRS. They pose minimal risk to patients and their use should be highly encouraged. Despite the lack of Food and Drug Administration approval for use in CRS alone, there are promising data to support the use of anti-il-4ra, anti-il-5, and anti-ige mabs in patients with CRSwNP. There have been several recent studies commenting on how CRS is connected to allergic rhinitis, asthma, and GERD; however, further data are needed to fully explain these relationships and the implications of management strategies for allergic rhinitis, asthma, and GERD in the context of CRS. the remainder of this review) [5]. The American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF) independently published their own guidelines in Otolaryngology: Head and Neck Surgery in 2015 [6]. Both make recommendations of varying strength depending on the quality of supporting data in the literature. ACUTE RHINOSINUSITIS ARS is defined as rhinosinusitis that lasts less than 4 weeks. Diagnosis should be made clinically in patients reporting symptoms of purulent nasal discharge, nasal obstruction, facial pain/pressure/ fullness, and/or headache; however, the time course of the above symptoms delineates the likely causative pathogen. Viral rhinosinusitis typically lasts less than 10 days with no acute symptomatic worsening after disease onset. Acute bacterial rhinosinusitis (ABRS) should be considered when symptoms persist for longer than 10 days or when patients experience symptomatic improvement followed by reexacerbation, termed double-worsening. When providers are concerned for ABRS based on the historical findings noted above, the AAAAI/ ACAAI and AAO-HNSF guidelines differ in their recommendations. The AAAAI/ACAAI guidelines recommend (grade B recommendation) treating episodes of ABRS with antibiotics, but the AAO-HNSF guidelines recommend (grade B/C recommendation) either watchful waiting or prescribing antibiotics. Under the AAO-HNSF treatment algorithm, if a provider initially chooses watchful waiting, patients should be started on antibiotics if symptoms persist longer than 7 days after diagnosis or if they experience the double-worsening phenomenon. Both guidelines suggest amoxicillin clavulanic acid as a first-line antibiotic regimen with respiratory fluoroquinolones or doxycycline as alternatives in cases of documented penicillin allergy. Despite the above recommendations, a recent Cochrane review of 63 studies showed only moderate evidence to support the use of antibiotics in patients with uncomplicated ABRS [7]. The authors also noted that approximately 80% of patients experience symptom resolution without antibiotics and warned of the individual and population level consequences of antibiotic use. Regardless, providers should at least consider prescribing antibiotics in patients with symptoms to suggest ABRS. Both viral rhinosinusitis and ABRS warrant symptomatic management and intranasal corticosteroids (INCS) and nasal saline irrigation are the only strategies supported by objective data. The AAAAI/ACAAI guidelines recommend (grade B recommendation) using INCS in all cases of ARS. No comment is made regarding the use of irrigation for ARS. However, the AAO-HNSF lists INCS and saline irrigation as management options that providers can consider to aid in symptomatic relief. A 2013 Cochrane review that used four studies with 1943 patients with ARS showed that INCS contributed to symptomatic improvement and resolution compared with placebo [8]. Another meta-analysis of six studies with 2495 patients with ARS treated with antibiotics or antibiotics with INCS showed a small therapeutic benefit with INCS [9]. The data to support the use of nasal irrigation exist but are weak. A Cochrane review published in 2015 endorsed a possible benefit with nasal irrigation in the symptomatic treatment of ARS but acknowledges the need for further study to improve confidence in the recommendation [10 & ]. Fortunately, both INCS and nasal irrigation pose little risk and should be encouraged to patients even in instances where only minimal relief may be provided. Unfortunately, little to no evidence exists to support the use of analgesics such as acetaminophen or NSAIDs, antihistamines, topical decongestants, or systemic decongestants. These medications can be prescribed but providers should be aware of each medication s side-effect profile in the context of the every individual patient. There are some cases of ARS that may warrant surgical evaluation but the specifics are not detailed here. CHRONIC RHINOSINUSITIS CRS is defined as rhinosinusitis that lasts longer than 12 weeks and is suggested as a diagnosis based on Volume 16 Number 4 August 2016

3 Management of rhinosinusitis Para et al. patient complaints of nasal obstruction, facial congestion/pressure/fullness, discolored nasal discharge, and hyposmia. In contrast to ARS, which is generally only a clinical diagnosis, CRS requires objective evidence of disease by anterior rhinoscopy, nasal endoscopy, and/or radiographic imaging [typically computed tomography (CT)] for definitive diagnosis. CRS has been classically differentiated into CRS with (CRSwNP) and without nasal polyps (CRSsNP), based on the presence of nasal polyps. INCS are the mainstay of treatment for CRSwNP and CRSsNP and are recommended by both the AAAAI/ACAAI (grade A recommendation) and AAO-HNSF (grade B/C recommendation) guidelines. A Cochrane review from 2011 utilizing 10 studies with a total of 590 patients with CRSsNP showed symptomatic improvement with minimal adverse events with the use of INCS [11]. Similarly, a 2012 Cochrane review of 40 studies with 3624 patients with CRSwNP verified that INCS generated symptomatic improvement, reduced polyp size and polyp score, and prevented recurrence of nasal polyps after sinus surgery [12]. INCS have historically been delivered as a nasal spray but a recent randomized controlled trial (RCT) of 60 patients with CRSwNP in China showed that transnasal nebulization of corticosteroids improved symptoms and reduced polyp size [13 ]. These findings highlight the utility and efficacy of alternative delivery methods of INCS to the nasal and paranasal sinus mucosae. The AAAAI/ACAAI and AAO-HNSF guidelines also recommend (grade A, grade B/C recommendations, respectively) the use of saline nasal irrigation in both CRSwNP and CRSsNP. Evidence supporting this treatment method stems from a 2007 Cochrane review that assessed eight studies and showed symptomatic improvement above placebo and as an adjunct to INCS [14]. The AAAAI/ACAAI guidelines recommend antibiotics for acute exacerbations of CRS, particularly for patients with purulent nasal drainage (grade C recommendation). However, the duration of treatment and selection of antibiotic have not been well studied. A Cochrane review from 2011 found only one study of antibiotic use in CRS that met inclusion criteria [15]. This placebo-controlled trial of patients with CRSsNP found that 12 weeks of treatment with roxithromycin decreased nasal endoscopy score and improved symptoms. However, these results were not sustained 3 months after treatment, and there was high risk of bias in the study. The authors concluded that there is limited evidence for use of antibiotics in CRS. A subsequent placebo-controlled study [16] of 12 weeks of low-dose azithromycin treatment in patients with moderate-to-severe CRS with and without polyps found no improvement in symptoms, olfaction or nasal endoscopy score compared to placebo. A few randomized studies without placebo have compared shorter antibiotic courses for the treatment of CRSsNP. Namyslowski et al. [17] found that treatment of CRS exacerbations with 14 days of cefuroxime or amoxicillin/clavulanate achieved clinical response in 88 and 98% of patients, respectively. Another study [18] comparing ciprofloxacin with amoxicillin/clavulanate found that 9 days of treatment resulted in clinical cure in 58 and 51% of patients, respectively. A third trial compared amoxicillin/clavulanate and placebo with amoxicillin/clavulanate and methylprednisolone in a pediatric population. After 15 days of oral steroids and 30 days of antibiotics, both groups experienced symptomatic improvement compared with baseline. However, the steroid-treated group had a greater reduction in symptom scores [19]. This limited evidence supports a role for antibiotic treatment in CRS, with additional benefit from combining steroids and antibiotics, although the optimal duration of antibiotic treatment remains poorly defined. A study of CRSwNP compared treatment with doxycycline, methylprednisolone, and placebo. After 20 days of treatment, doxycycline and methylprednisolone both reduced polyp size compared with placebo [20]. This is the only placebocontrolled study in the literature that addresses the use of antibiotics in patients with CRSwNP alone. Systemic steroids are often prescribed to reduce inflammation in CRS and improve delivery of topical steroids to the sinuses. The AAAAI/ACAAI guidelines recommend short courses of steroids for treatment of CRSwNP (grade A recommendation). This recommendation is supported by a Cochrane review of three studies including 166 patients treated with oral steroids for days. The review found that steroids improved symptoms and decreased polyp size during short-term follow-up, although the quality of evidence was poor to moderate [21]. More recently, it was shown that prednisolone 25 mg daily for 2 weeks plus intranasal steroid improved olfaction and reduced polyp size compared with placebo and intranasal steroid. These results were sustained after 6 months [22]. Prospective data on treatment of CRSsNP with oral steroids alone are lacking, but the AAAAI/ACAAI guidelines do recommend short courses of steroids for this group as well (grade C recommendation). The recent introduction of (mab) targeting IgE, IL-5, and the a subunit of the IL-4 receptor (IL-4Ra) has expanded possible treatment options for CRSwNP, although none of these is Food and Drug Administration approved for CRS alone. The AAAAI/ ACAAI guidelines recommend considering anti-ige therapy with omalizumab (grade C recommendation) Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved

4 Pharmacotherapy and evidence based medicine or anti-il-5 therapy with mepolizumab (grade B recommendation). Gevaert et al. [23] conducted a randomized, double-blind, placebo-controlled trial of omalizumab in patients with CRSwNP and asthma. In this study, omalizumab decreased nasal polyp size, decreased symptoms, and improved quality of life after 16 weeks of treatment. However, Pinto et al. found that omalizumab did not improve symptoms or polyp scores compared to placebo. A subsequent systematic review evaluating these two studies determined that there is limited evidence for the use of omalizumab in the treatment of CRSwNP [24 ]. Gevaert et al. [25] also studied mepolizumab in a randomized, placebo-controlled trial of patients with CRSwNP. This study found that mepolizumab decreased nasal polyp score and improved CT scores after 8 weeks of treatment. There was also a nonsignificant trend towards improvement in symptoms. Another IL-5 called reslizumab was shown to decrease nasal polyp scores in half of the patients in the treatment arm of another randomized, placebo-controlled trial of 24 patients with CRSwNP [26]. The newest mab for treatment of allergic diseases is dupilumab, an anti-il-4ra antibody. Dupilumab was recently compared with placebo for treatment of CRSwNP refractory to intranasal steroids [27 ]. The investigators found that dupilumab and intranasal mometasone decreased nasal polyp score and improved quality of life compared with placebo and intranasal mometasone after 16 weeks of treatment. A subgroup analysis found greater benefit for patients with asthma than for those without asthma. There are no formal recommendations for the use of dupilumab in the treatment of CRS, but these data indicate that dupilumab may be beneficial for patients with disease refractory to first-line treatment. See Table 1 for a summary of the mabs discussed in this study. It has been previously documented that CRS is associated with several other conditions, including allergic rhinitis, asthma, and gastroesophageal reflux disease (GERD) [28]. In theory, allergic rhinitis predisposes patients to CRS via mucosal inflammation and increased mucus production that impairs physiologic paranasal sinus drainage; however, there is no direct evidence of causality between allergic rhinitis and CRS. A 2014 systematic review of the literature available on immunotherapy assessed seven studies (of which none was an RCT) and concluded there is weak evidence to support using immunotherapy as an adjunctive management option for CRS in patients with concomitant allergic rhinitis [29]. The AAAAI/ ACAAI guidelines recommend (grade B recommendation) testing for aeroallergen hypersensitivity in patients with CRS; however, the AAO-HNSF guidelines only offer this as a management option. Further data analysis is necessary to clarify the extent of benefit from immunotherapy in the context of CRS, but providers should at least consider aeroallergen testing and subsequent IT in the appropriate clinical scenario. Although CRS and asthma are closely associated, the exact pathophysiologic mechanism of the relationship between CRS and asthma has remained elusive. A recent study [30 & ] of respondents for the Canadian National Population Health Survey between 1998/1999 and 2010/2011 with known CRS were shown to have an increased risk of developing asthma (odds ratio 2.7) during the follow-up period. However, new data from a US multicenter RCT using 237 adults with CRS surprisingly showed no improvement of asthma control with treatment of CRS with INCS [31 ]. In 2014, the AAAAI/ACAAI guidelines recommended (grade C) aggressively treating rhinosinusitis in patients with asthma to augment asthma control but observational studies were used to draw this conclusion, as evidenced by the relatively weak recommendation. Given the new data presented above from a recent RCT, providers should be encouraged to treat CRS while knowing improved asthma control will likely require separate uptitration of asthma-specific medications. Table 1. Monoclonal antibody immunotherapies studied in patients with chronic rhinosinusitis with nasal polyps Pharmacologic agent Molecular target Strength of supporting data Omalizumab Anti-IgE mab One double-blind placebo-controlled RCT of 24 patients with CRSwNP and asthma with data to support [23], but subsequent systematic review of 2 studies deems more data necessarily [24 ] Mepolizumab Anti-IL-5 mab One double-blind placebo-controlled RCT of 30 patients with CRSwNP showing statistically significant benefit of anti-il-5 therapy [25] Reslizumab Anti-IL-5 mab One double-blind placebo-controlled RCT of 24 patients with CRSwNP showed half of patients receiving anti-il-5 therapy had reduced polyp scores [26] Dupilumab Anti-IL-4Ra mab One double-blind placebo-controlled parallel group RCT of 51 patients with CRSwNP showed decreased nasal polyp burden with anti-il-4ra therapy [27 ] CRSsNP chronic rhinosinusitis without nasal polyps; CRSwNP, chronic rhinosinusitis with nasal polyps; IL-4Ra, IL-4 receptor a subunit; mab, monoclonal antibody; RCT, randomized controlled trial Volume 16 Number 4 August 2016

5 Management of rhinosinusitis Para et al. Table 2. Summary of referenced literature from the Cochrane Review Database Treatment modality Condition being treated Strength of evidence via Cochrane review Antibiotics ABRS Total 63 studies, 1915 patients in RCT þ 54 antibiotic comparison trials, moderate supporting evidence [7] CRS One study, 64 patients, high risk of bias, more data needed [15] Intranasal corticosteroids ARS Four studies, 1943 patients, therapeutic benefit of INCS in ARS [8] CRSwNP Total 40 studies, 3624 patients, evidence supports symptomatic improvement with INCS [12] CRSsNP Total 10 studies, 590 patients, evidence supports symptomatic improvement with INCS [11] Systemic corticosteroids CRS Three studies, 166 patients, poor-moderate evidence supporting use in CRS [21] Nasal saline irrigation ARS Five studies 749 patients, possible therapeutic benefit [10 & ] CRS Eight studies, symptomatic improvement as adjunct to INCS [14] Endoscopic sinus surgery CRSwNP Four studies, 231 patients, moderate-high risk of bias, more data needed [36] ABRS, acute bacterial rhinosinusitis; CRS, chronic rhinosinusitis; CRSsNP, chronic rhinosinusitis without nasal polyps; CRSwNP, chronic rhinosinusitis with nasal polyps; INCS, intranasal corticosteroids; RCT, randomized controlled trial. Similarly, CRS and GERD are known to be associated but their causative relationship is unclear. Reflux of gastrointestinal particles into the upper airway theoretically increases nasal mucosal inflammation, predisposing patients to impaired paranasal sinus drainage, but this mechanism has yet to be proven clinically. A recent observational cohort study [32 & ] published in 2015 followed patients with GERD for roughly 2 years and found that these individuals had an increased risk of developing CRS (odds ratio 2.36). CRSsNP interestingly occurred more frequently than CRSwNP in the study population, which correlates with the hypothesis that reflux drives mucosal inflammation without an associated polyposis. A different case-control study [33 & ] from 2015 compared patients with CRS with and without GERD and showed that patients with comorbid CRS and GERD had worse subjective quality of life scores as measured by the sinonasal outcome test-22 (SNOT-22) survey. The AAAAI/ACAAI guideline acknowledges the GERD-CRS association but recommends evaluating patients with CRS for concomitant GERD as an option (grade C recommendation). The weak recommendation stems from the lack of data showing that treatment of GERD improves CRS symptoms or objective scores. Immunodeficiencies should be considered in patients with CRS, especially those with recurrent or refractory disease. A systematic review and meta-analysis published in 2015 reported an increased prevalence of humoral immunodeficiencies in patients with recurrent and refractory CRS (13 and 23%, respectively) [34 & ]. The AAAAI/ACAAI guidelines recommend (grade B recommendation) evaluating patients with CRS for immunodeficiency, but the AAO-HNSF guidelines only offer it as a management option. With what we know from the above meta-analysis and because CRS refractory to medical therapy often warrants surgical evaluation, it is reasonable that patients should be evaluated for a predisposing immunodeficiency prior to pursuit of more aggressive treatment modalities. Aspirin-exacerbated respiratory disease (AERD) classically presents as a triad of aspirin/nsaid sensitivity, asthma, and CRSwNP. Treating AERD patients with aspirin desensitization was documented as an effective treatment modality that improves nasal polyp scores and reduces CRS symptoms decades ago [35]. No major advances have been made recently in the management of AERD from a CRS perspective. The AAAAI/ACAAI guidelines recommend (grade C recommendation) evaluating patients with CRSwNP for possible AERD and treating them accordingly (i.e. with aspirin desensitization). There are no detailed comments on AERD within the AAO-HNSF guidelines. Endoscopic sinus surgery (ESS) should be considered by providers for patients with CRS refractory to medical therapy alone. A 2014 Cochrane review looked at four prospective randomized controlled trials from the 1990s 2000s (all four of which had medium-to-high risk of bias) with a total of 231 patients with CRSwNP comparing surgical with medical management alone and determined that no conclusion regarding the benefit of ESS could be made given the poor available data [36]. However, a more recent prospective nonrandomized cohort study [37] that compared ESS with medical management alone for patients with CRS found an improvement in quality of life measures in the 1-year follow-up period. Two other recent studies [38,39] endorsed economic and subjective quality of life benefits from ESS in patients with refractory disease as well. The AAAAI/ACAAI guidelines recommend Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved

6 Pharmacotherapy and evidence based medicine (grade C) considering ESS for refractory CRS with subsequent medical management postoperatively. Recent literature has also supported the use of steroid-releasing sinus implants to improve postoperative outcomes and decrease the need for further therapy [40]. CONCLUSION Both the AAAAI/ACAAI and AAO-HNSF guidelines outline the current treatment recommendations for ARS and CRS. Given the data available since the guidelines releases, we anticipate only a few changes to the recommendations provided. In summary, ARS management is primarily dictated by symptomatic management with INCS and nasal saline irrigation, with antibiotics reserved for cases highly suspicious for a bacterial cause. CRS management can be more complex given the plethora of associated conditions, but the mainstays of treatment for both CRSwNP and CRSsNP are INCS, nasal saline irrigation, and oral corticosteroids. Recent data proving the efficacy of mabs in CRS are promising and these therapies will likely become increasingly utilized in the near future. Antibiotics may be useful for CRS but further data are needed to clarify the optimal antibiotic choice and therapy duration. The Cochrane Review Database has generated several systematic reviews and meta-analyses of the literature available on many of the above treatment modalities; these are referenced throughout this review and summarized in Table 2. Lastly, treating underlying or comorbid conditions in patients with CRS is appropriate in the right clinical setting. Acknowledgements None. Financial support and sponsorship This study was supported in part by Grant U19AI [Chronic Rhinosinusitis Integrative Studies Program (CRISP)] from the NIH, and by the Ernest S. Bazley Foundation. Conflicts of interest Anju Peters is a consultant for Greer. The authors have no other conflicts of interest. REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest of outstanding interest 1. Blackwell DL, Lucas JW, Clarke TC. Summary health statistics for U.S. adults: national health interview survey, Vital Health Stat ; Caulley L, Thavorn K, Rudmik L, et al. Direct costs of adult chronic rhinosinusitis by using 4 methods of estimation: Results of the US Medical Expenditure Panel Survey. J Allergy Clin Immunol 2015; 136: Smith SS, Evans CT, Tan BK, et al. National burden of antibiotic use for adult rhinosinusitis. J Allergy Clin Immunol 2013; 132: Gwaltney JM Jr. Acute community-acquired sinusitis. Clin Infec Dis 1996; 23: Peters AT, Spector S, Hsu J, et al. Diagnosis and managementofrhinosinusitis: a practice parameter update. Ann Allergy Asthma Immunol 2014; 113: Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, et al. Clinical practice guideline (update): adult sinusitis. Otolaryngol Head Neck Surg 2015; 152 (2 Suppl):S1 S Ahovuo-Saloranta A, Rautakorpi UM, Borisenko OV, et al. Antibiotics for acute maxillary sinusitis in adults. Cochrane Database Syst Rev 2014; 2:CD Zalmanovici Trestioreanu A, Yaphe J. Intranasal steroids for acute sinusitis. Cochrane Database Syst Rev 2013; 12:CD Hayward G, Heneghan C, Perera R, Thompson M. Intranasal corticosteroids in management of acute sinusitis: a systematic review and meta-analysis. Ann Fam Med 2012; 10: & King D, Mitchell B, Williams CP, Spurling GK. Saline nasal irrigation for acute upper respiratory tract infections. Cochrane Database Syst Rev 2015; 4:CD A systematic review of the available literature on the efficacy of saline irrigation for ARS. The data are weak but they do suggest that patients can experience symptomatic improvement from saline rinses. 11. Snidvongs K, Kalish L, Sacks R, et al. Topical steroid for chronic rhinosinusitis without polyps. Cochrane Database Syst Rev 2011; 8:CD Kalish L, Snidvongs K, Sivasubramaniam R, et al. Topical steroids for nasal polyps. Cochrane Database Syst Rev 2012; 12:CD Wang C, Lou H, Wang X, et al. Effect of budesonide transnasal nebulization in patients with eosinophilic chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol 2015; 135: In this RCT, 60 patients with CRSwNP were given either nebulized budesonide or placebo transnasally. The nebulized INCS effectively reduced polyp size and symptom scores, highlighting a delivery method for INCS outside of nasal sprays. 14. Harvey R, Hannan SA, Badia L, Scadding G. Nasal saline irrigations for the symptoms of chronic rhinosinusitis. Cochrane Database Syst Rev 2007; 3:CD Piromchai P, Thanaviratananich S, Laopaiboon M. Systemic antibiotics for chronic rhinosinusitis without nasal polyps in adults. Cochrane Database Syst Rev 2011; 5:CD Videler WJ, Badia L, Harvey RJ, et al. Lack of efficacy of long-term, low-dose azithromycin in chronic rhinosinusitis: a randomized controlled trial. Allergy 2011; 66: Namyslowski G, Misiolek M, Czecior E, et al. Comparison of the efficacy and tolerability of amoxycillin/clavulanic acid 875 mg b.i.d. with cefuroxime 500 mg b.i.d. in the treatment of chronic and acute exacerbation of chronic sinusitis in adults. J Chemother 2002; 14: Legent F, Bordure P, Beauvillain C, Berche P. A double-blind comparison of ciprofloxacin and amoxycillin/clavulanic acid in the treatment of chronic sinusitis. Chemotherapy 1994; 40 (Suppl 1): Ozturk F, Bakirtas A, Ileri F, Turktas I. Efficacy and tolerability of systemic methylprednisolone in children and adolescents with chronic rhinosinusitis: a double-blind, placebo-controlled randomized trial. J Allergy Clin Immunol 2011; 128: Van zele T, Gevaert P, Holtappels G, et al. Oral steroids and doxycycline: two different approaches to treat nasal polyps. J Allergy Clin Immunol 2010; 125: Martinez-devesa P, Patiar S. Oral steroids for nasal polyps. Cochrane Database Syst Rev 2011; 7:CD Vaidyanathan S, Barnes M, Williamson P, et al. Treatment of chronic rhinosinusitis with nasal polyposis with oral steroids followed by topical steroids: a randomized trial. Ann Intern Med 2011; 154: Gevaert P, Calus L, Van zele T, et al. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol 2013; 131: Hong CJ, Tsang AC, Quinn JG, et al. Anti-IgEmonoclonalantibodytherapyforthe treatment of chronic rhinosinusitis: a systematic review. Syst Rev 2015; 4:166. The systematic review of two studies on anti-ige therapy versus placebo in patients with CRSwNP determined that more data are needed to comment on its efficacy in this context. 25. Gevaert P, Van bruaene N, Cattaert T, et al. Mepolizumab, a humanized anti-il- 5 mab, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol 2011; 128: Gavaert P, Lang-Loidolt D, Lackner A, et al. Nasal IL-5 levels determine the response to anti-il-5 treatment in patients with nasal polyps. J Allergy Clin Immunol 2006; 118: Bachert C, Mannent L, Naclerio RM, et al. Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial. JAMA 2016; 315: The double-blinded RCT compared dupilumab (an anti-il-4ra mab) to placebo in patients with CRSwNP refractory to INCS therapy and showed an improvement in endoscopic nasal polyp, computed tomography imaging, and symptom severity and quality of life scores Volume 16 Number 4 August 2016

7 Management of rhinosinusitis Para et al. 28. Tan BK, Chandra RK, Pollak J, et al. Incidence and associated premorbid diagnoses of patients with chronic rhinosinusitis. J Allergy Clin Immunol 2013; 131: DeYoung K, Wentzel JL, Schlosser RJ, et al. Systematic review of immunotherapy for chronic rhinosinusitis. Am J Rhinol Allergy 2014; 28: & Habib AR, Javer AR, Buxton JA. A population-based study investigating chronic rhinosinusitis and the incidence of asthma. Laryngoscope 2015; doi: /lary [Epub ahead of print] The retrospective cohort analysis used data from a Canadian survey to show that patients with CRS had a much greater chance of developing asthma compared with patients without CRS. 31. American Lung Association-Asthma Clinical Research Centers Writing C. Dixon AE, Castro M, et al. Efficacy of nasal mometasone for the treatment of chronic sinonasal disease in patients with inadequately controlled asthma. J Allergy Clin Immunol 2015; 135: The multicenter double-blinded RCT showed that treating CRS with INCS compared to placebo had no effect on asthma control in patients with both conditions. 32. & Lin YH, Chang TS, Yao YC, Li YC. Increased risk of chronic sinusitis in adults with gastroesophgeal reflux disease: a nationwide population-based cohort study. Medicine (Baltimore) 2015; 94: e1642. The retrospective cohort study using data from Taiwanese health insurance research surveys showed an association between preexisting GERD and the development of CRS. These patients more commonly developed CRSsNP than CRSwNP. 33. Bohnhorst I, Jawad S, Lange B, et al. Prevalence of chronic rhinosinusitis in a & population of patients with gastroesophageal reflux disease. Am J Rhinol Allergy 2015; 29:e70 e74. The case-control study highlighted the known association between GERD and CRS and showed that GERD decreases quality of life and symptom severity scores from a CRS standpoint. 34. Schwitzguebel AJ, Jandus P, Lacroix JS, et al. Immunoglobulin deficiency in & patients with chronic rhinosinusitis: systematic review of the literature and meta-analysis. J Allergy Clin Immunol 2015; 136: The systematic review and meta-analysis showed that patients with CRS are more likely to have underlying humoral immunodeficiencies compared with those without CRS. Patients with refractory CRS are at even higher risk. 35. Stevenson DD, Hankammer MA, Mathison DA, et al. Aspirin desensitization treatment of aspirin-sensitive patients with rhinosinusitis-asthma: long-term outcomes. J Allergy Clin Immunol 1996; 98: Rimmer J, Fokkens W, Chong LY, Hopkins C. Surgical versus medical interventions for chronic rhinosinusitis with nasal polyps. Cochrane Database Syst Rev 2014; 12:CD Smith TL, Kern R, Palmer JN, et al. Medical therapy vs surgery for chronic rhinosinusitis: a prospective, multiinstitutional study with 1-year follow-up. Int Forum Allergy Rhinol 2013; 3: Rudmik L, Mace J, Soler ZM, Smith TL. Long-term utility outcomes in patients undergoing endoscopic sinus surgery. Laryngoscope 2014; 124: Rudmik L, Soler ZM, Mace JC, et al. Economic evaluation of endoscopic sinus surgery versus continued medical therapy for refractory chronic rhinosinusitis. Laryngoscope 2015; 125: Han JK, Marple BF, Smith TL, et al. Effect of steroid-releasing sinus implants on postoperative medical and surgical interventions: an efficacy meta-analysis. Int Forum Allergy Rhinol 2012; 2: Copyright ß 2016 Wolters Kluwer Health, Inc. All rights reserved