Management of Rhinosinusitis: An Evidence Based Approach

Andrew J. Para; Elisabeth Clayton; Anju T. Peters


Curr Opin Allergy Clin Immunol. 2016;16(4):383-389. 

In This Article

Chronic Rhinosinusitis

CRS is defined as rhinosinusitis that lasts longer than 12 weeks and is suggested as a diagnosis based on 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 placebo-controlled 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 14–20 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 [alpha] subunit of the IL-4 receptor (IL-4R[alpha]) 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) 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-4R[alpha] 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 11 555 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.

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 15 807 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 (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]