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Topical Therapies for Refractory Chronic Rhinosinusitis
Top i c a l Th e r a p i e s f o r R e f r a c t o r y C h ro n i c Rhinosinusitis Akshay Sanan, MD, Mindy Rabinowitz, Gurston Nyquist, MD*
MD,
Marc Rosen,
MD,
KEYWORDS Topical therapy Chronic rhinosinusitis Anti-inflammatory Antimicrobial Surfactant Stents KEY POINTS Chronic rhinosinusitis (CRS) is a common disease that has a substantive impact on quality of life. CRS treatments are aimed at reducing sinonasal inflammation, infection, and reestablishing mucociliary clearance. Sinus surgery is an effective adjunct for topical sinonasal drug delivery for patients with CRS. With a 5% to 10% failure rate from surgery, there is an additional subset of patients who are recalcitrant to conventional medical and surgical therapies, leading to alternative therapies centered on anti-infective and anti-inflammatory nasal irrigations. Topical therapies have become an integral component in the management plan for CRS. Although topical therapy is not a panacea, it can, because of its safety profile, be repeated and/or sustained over extended periods, thus avoiding the risks of prolonged oral corticosteroids, intravenous antibiotics, and/or repeat surgery.
OVERVIEW
Chronic rhinosinusitis (CRS) is a multifactorial disorder that is heterogeneous in presentation and clinical course. Treatment of CRS is based on several factors including the type of rhinosinusitis (acute, chronic, or fungal), presence of nasal polyposis, concurrent medical comorbidities, symptom severity, and response to previous medical treatments.1 Medical treatment should be considered the cornerstone of disease treatment of CRS, with sinus surgery reserved for medical failures or patients’ complications. However, with a 5% to 10% failure rate from surgery, there is an additional
Department of Otolaryngology – Head & Neck Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA * Corresponding author. Division of Endoscopic Sinus & Skull Base Surgery, Department of Otolaryngology – Head & Neck Surgery, 925 Chestnut Street, 7th Floor, Philadelphia, PA 19107. E-mail address: [email protected] Otolaryngol Clin N Am 50 (2017) 129–141 http://dx.doi.org/10.1016/j.otc.2016.08.011 0030-6665/17/ª 2016 Elsevier Inc. All rights reserved.
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subset of patients who are refractory to conventional medical and surgical therapies.2 The focus of this article is on therapies centered on topical delivery and application for refractory CRS. CRS has been simplified to two subgroups: CRS with nasal polyps (NP) and CRS without NP.3 In the past, these two entities were considered to be a spectrum of one disease where CRS with NP was thought to be the end point of CRS. However, it has been shown that these two diseases have distinct differences and patients can respond differently to medical treatment.3,4 This article mentions specific recommendations based on the CRS subgroup when possible. Generally, the treatment of CRS is intended to reduce symptoms, improve quality of life, and prevent disease progression or recurrence. More specifically, topical therapies are aimed at reducing mucosal inflammation, reducing pathogenic bacterial burden and improving mucociliary clearance and sinonasal function. Clinicians often try to minimize systemic medical therapies and favor the use of topical therapies to focus drug delivery locally. Major factors that impact topical therapy success include the patient’s anatomy and the dynamics of the delivery device. Advantages of topical medical therapy include direct delivery onto diseased tissue, potential for delivering higher local drug concentrations, and minimizing systemic absorption. Disadvantages of topical medical therapy include challenges with application technique; local adverse effects, such as epistaxis or patient discomfort; and variable sinus penetration. Because of the accessible nature of the sinonasal cavity, it is amenable to topical medical therapy and this has become an integral strategy in the management of refractory CRS. Effective drug delivery to the involved tissue is a challenge that all topical drug therapies must overcome during the management of CRS. Endoscopic sinus surgery (ESS) is an important component in the management of medically refractory CRS, clinically and economically.5,6 One major advantage of ESS is creating an open and accessible cavity. This has been demonstrated to optimize sinonasal penetration of topical medical therapy.7 Potential topical sinonasal therapy strategies include topical saline irrigations, topical corticosteroids, topical antibiotics, topical antifungals, topical stents, and topical alternative medications. METHODS OF DELIVERY
The main factors associated with particle penetration include the size of the sinus ostia, the size of the particle, and the flow rate (liters per minute) of the aerosol. Particles greater than 10 mm in size typically do not make it past the nasal cavity, and particles less than 5 mm enter the lungs.8 Early studies estimated that the ideal particle size for maxillary sinus penetration is between 3 mm and 10 mm. Further studies concluded that smaller particle size, 45-degree insertion angle of the topical therapy, and higher flow rate (5 L/min compared with 1 L/min as demonstrated by Saijo and colleagues9) improved maxillary sinus penetration.8 Nasal sprays are a popular option for topical drug delivery because of their ease of use and diverse available formulations. Typical nasal sprays generate droplets of 50 mm to 100 mm in diameter and deliver 70 mL to 150 mL of drug per puff, at velocities of 7.5 L/ min to 20 L/min.10 However, a large fraction of the spray is deposited in the anterior nasal cavity without any paranasal sinus penetration. Also, half of the spray is cleared within 15 minutes from the nasal cavity, with minimal activity occurring at 6 hours.10 Nebulizers deliver medications in mist form and are commonly used for treating disease of the lower airway. Multiple nebulizers exist for topical sinonasal topical delivery. Some studies on pulsating aerosol nebulizers demonstrated increased deposition in
Topical Therapies for Refractory Chronic Rhinosinusitis
the maxillary ostia, increased deposition in the posterior nasal cavity, and slower clearance time compared with the nasal pump sprays.11 Although nebulizers represent a technologic advance compared with nasal pump sprays, the literature to support their efficacy is not definitive.12 TOPICAL SINONASAL SALINE
Use high-volume, low-pressure sinonasal saline irrigations in addition to other topical therapies for CRS. Saline irrigation is well-tolerated without significant adverse effects. It is recommended as a beneficial treatment of CRS. Saline irrigations and sprays are the most commonly used intervention for rhinitis and rhinosinusitis. Saline nasal irrigation has been recommended in the most recent clinical guidelines for CRS.13 It is a common treatment adjunct in the management of CRS. Saline irrigation mechanically removes mucus, crusts, debris, and allergens from the sinonasal cavity, and potentially has the additional benefit of improving mucociliary clearance, ciliary beat frequency, and protecting the sinonasal mucosa.14 The mechanical clearance of mucus by saline is thought to be the most important factor. Both hypertonic and isotonic saline have been shown to have a positive impact on mucociliary clearance time. There is substantial variability in the volume (low or high), pressure (low or high), and frequency (once daily to four times daily) of saline irrigation protocols. Large-volume, low-pressure nasal irrigation is more effective than saline sprays or nebulizers in penetrating the sinus ostia.15 In multiple randomized trials, saline irrigation for CRS improved symptoms, quality of life, endoscopic examination findings, and was tolerated without any significant harmful effects.9 The favorable safety profile, lack of systemic absorption risk, and good patient acceptance make it an appealing long-term topical therapy strategy.16 Daily hypertonic saline irrigation improved disease-specific symptom and healthrelated quality of life after 6 months.17–21 Bachmann and colleagues18 evaluated the effects of isotonic and hypertonic saline irrigations and demonstrated that both solutions improve sinonasal symptoms, with no significant differences between groups. Hypertonic preparations have been shown to elicit some pain and discomfort greater than 2.7%. At concentrations greater than 5.4%, patients experience nasal obstruction secondary to vasodilation and there is reduced airspace as measured by acoustic rhinomanometry.22 Rabago and colleagues17 randomized patients into two groups (hypertonic saline irrigations and no treatment) and demonstrated that daily hypertonic nasal saline irrigations significantly improved CRS health-related quality of life, symptoms scores, and decreased CRS medication usage. Pynnonen and colleagues23 compared high-volume (240 mL), low-pressure isotonic saline irrigation with lowvolume nasal saline spray and evaluated 20-item Sino-Nasal Outcomes Test (SNOT-20) and symptom scores at 2, 4, and 8 weeks posttreatment. Their study demonstrated that both groups had improvement in health-related quality of life at 8 weeks, but there was statistically significant long-term health-related quality of life and symptoms in patients using high-volume saline irrigations. This study focused on a community population of patients with sinonasal complaints and excluded patients with recent sinus surgery. With adherence to therapy, side effects were minimal and included local irritation, nosebleeds, nasal burning, nausea, and headaches. In a follow-up study, patients reported reduced sinusitis symptoms and sinusitis-related medication use for an additional 12 months.24 Another study found Dead Sea salt saline more beneficial compared with hypertonic saline for CRS symptoms.25 There is substantial evidence to support the use of sinonasal saline irrigations in the
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management of CRS.17–21 Because of the excellent safety profile of sinonasal saline irrigations, it is a great topical therapy option for patients with refractory CRS. Isotonic and hypertonic saline irrigations seem to provide similar outcomes, and high-volume, low-pressure saline irrigations are superior to low-volume nasal saline spray.
TOPICAL SINONASAL STEROIDS
Topical sinonasal steroid therapy can achieve local steroid effects while minimizing potential adverse effects associated with systemic steroid therapy (Box 1). Corticosteroids are potent medications that target the proinflammatory pathway. Because of the localized effects and excellent safety profile, topical sinonasal steroid therapy has become a common treatment option for CRS with and without nasal polyposis. Nasal corticosteroids have been shown to inhibit immediate and late-phase reactions to antigenic stimulation in patients with allergic rhinitis.26 Generally, sinonasal steroids with low systemic bioavailability, such as mometasone furoate or fluticasone furoate, have not been associated with reduced bone growth or adrenal suppression, which was first noted with more systemically available sinonasal steroids, such as beclomethasone dipropionate.27 However, high-dose dexamethasone nasal spray (0.132% aqueous nasal spray) given for at least 6 weeks does seem to have the potential to cause a decrease in serum cortisol levels.28 There is also no clear evidence that the use of sinonasal corticosteroids correlates with systemic changes in bone mineral biology, cataracts, or glaucoma. In fact, Martino and colleagues28 showed that a 6-week course of high-dose dexamethasone nasal spray (0.132% aqueous nasal spray) was not associated with ocular hypertension. Adverse effects of topical sinonasal steroids include epistaxis, headache, cough, nasal irritation, and nasal crusting. These happen in less than 5% of patients.29,30 Rarely, septal perforations have been reported with sinonasal steroid use. Because of this, patients are instructed to direct the nasal spray toward the lateral nasal cavity wall instead of toward the septum. There are several potential topical steroid solutions that are categorized into Food and Drug Administration (FDA)-approved and off-label use for sinonasal topical therapy. FDA-approved therapies apply to metered-dose topical steroid solutions and include mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, beclomethasone diproprionate, cicleosnide, flunisolide, and triamcinolone acetonide.
Box 1 Topical corticosteroids Food and Drug Administration–Approved Topical Corticosteroids Topical corticosteroids are effective in CRS with and without polyps. They decrease polyp size in CRS with polyps. They help control symptoms in CRS without polyps. Topical corticosteroids are well-tolerated without significant adverse effects. It is recommended as a beneficial treatment of CRS. “Off-Label” Use Topical Corticosteroids “Off-label” topical corticosteroids include the following: (1) budesonide nasal saline irrigations, (2) intranasal dexamethasone ophthalmic drops, (3) intranasal prednisolone ophthalmic drops, and (4) intranasal ciprofloxacin/dexamethasone otic drops. Further research is needed before making a definitive recommendation.
Topical Therapies for Refractory Chronic Rhinosinusitis
Off-label topical steroids lack FDA approval for nasal therapy. Although ample evidence exists on FDA-approved topical therapies, there is a growing body of literature for the off-label use of sinonasal steroid solutions. Advantages of off-label steroid solutions include delivery of the higher volume and higher concentrations of topical steroid to the sinonasal mucosa. However, the unknown risk of off-label topical sinonasal steroid use is the potential systemic absorption resulting in short- and long-term sequelae, which is yet to be determined. Several studies have demonstrated the efficacy of intranasal steroids in the management of CRS with and without NP. These sprays are used most commonly in the management of symptoms associated with seasonal and perennial allergic rhinitis.31 Guidelines recommend topical steroids as the first-line medication based on the results of several randomized controlled trials with fluticasone propionate, beclomethasone dipropionate, budesonide, or mometasone furoate.32 Topical nasal steroids are effective for the treatment of CRS with polyposis and are often considered the first-line treatment option.33 Nasal corticosteroids have also been shown to delay the recurrence of NP after surgery.34 Recent studies have demonstrated the efficacy of using budesonide respules for eosinophilic CRS or CRS with nasal polyposis. Budesonide respules are considered off-label use, because they are not FDA approved for nasal use. The respules are directly applied as nasal drops or as an addition to nasal irrigation. As described by the study authors, there is theoretically a higher concentration of steroids applied to the sinonasal mucosa with budesonide respules compared with traditional steroid sprays.35 The intranasal clinical improvement in patients with nasal polyposis using budesonide rinses seems significant, especially in patients with eosinophilic chronic sinusitis with NP.36 There is fear of systemic steroid side effects with off-label use of steroid solutions, but many studies have shown there is a lack of systemic effects. Bhalla and colleagues37 studied the effect of off-label topical budesonide irrigations and demonstrated no significant adrenal suppression. Lastly, Welch and colleagues38 demonstrated that twice-daily budesonide nasal irrigation following ESS did not alter the serum cortisol or 24-hour urine cortisol levels and concluded that high-volume delivery techniques, such as Neti pot, result in less than 5% of the solution remaining in the sinuses, and that the actual concentration of steroid the patient is exposed to is low and may be lower than traditional steroid nasal sprays. Other off-label solutions include intranasal dexamethasone ophthalmic drops, prednisolone ophthalmic drops, and ciprofloxacin/dexamethasone otic drops. In contrast to the low systemic side-effect profile of budesonide rinses, studies demonstrate a decrease in serum cortisol levels after 6 weeks of intranasal dexamethasone spray.28 DelGaudio and Wise39 studied intranasal dexamethasone ophthalmic drops, prednisolone ophthalmic drops, and ciprofloxacin/dexamethasone otic drops and only 1 of 36 patients required medication discontinuation because of a decrease in morning cortisol level. Although there can be significant clinical improvement with the use of dexamethasone and prednisolone intranasal sprays for the treatment of nasal polyposis, these medications have a higher systemic side effect profile and impact the hypothalamic-pituitary-adrenal axis. Nasal pump sprays, the most common delivery method of topical nasal corticosteroids, have almost no sinus penetration in nonoperated patients. Studies are needed to assess the long-term safety of off-label used nasal steroids. Finally, to optimize treatment with intranasal steroid sprays, patients should be educated on the delivery technique to maximize application to the sinonasal mucosa instead of simple nasal application.
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TOPICAL SINONASAL ANTIBIOTICS
Topical antibiotics are not first-line therapy for CRS. Stronger evidence exists for its use in patients with cystic fibrosis. It is recommended against use of topical antibiotics (spray and nebulizer) for CRS. Topical antibiotics have emerged as adjunctive treatment of CRS because they offer the potential for high local concentration at the desired target site with minimization of systemic side effects.40 The extent to which bacterial colonization, infection, and biofilms contribute to the pathophysiology of CRS is controversial. Systemic antibiotics are typically reserved for treatment of acute exacerbations of CRS. However, some evidence exists that long-term systemic macrolide therapy and doxycycline can improve subjective and objective outcomes while providing anti-inflammatory and prociliary benefits in addition to antimicrobial effects.41,42 Systemic antibiotics do have potential side effects including cramping, diarrhea, increasing bacterial resistance, allergic reactions, and potential for organ toxicity. Sykes and colleagues43 evaluated dexamethasone/tramazoline and neomycin/ dexamethasone compared with a placebo and used a four-times-daily spray technique. They demonstrated that both groups had symptomatic improvement compared with placebo. Desrosiers and Salas-Prato44 evaluated a topical tobramycin-saline solution using a large-particle nebulizer compared with saline alone. Aerosolized forms of tobramycin were initially used in the treatment of pseudomonal pulmonary infections in patients with cystic fibrosis. After a 4-week treatment course, they demonstrated that both groups received clinical improvement, with no additional benefit derived from the topical tobramycin. Tobramycin nasal irrigations in patients with cystic fibrosis yielded reduction in revision sinus surgery and improved outcome scores.44 Videler and colleagues45 evaluated a Rhinoflow (Respironics, Inc., Cedar Grove, NJ) nebulizer of bacitracin/colimycin compared with placebo and they demonstrated clinical improvement in both groups with no additional benefit perceived by the topical antibiotic group. Topical high-volume mupirocin-saline irrigation has been studied as a potential therapeutic option for patients with Staphylococcus aureus, including methicillin-resistant S aureus culture-positive refractory CRS. Uren and colleagues46 evaluated the effects of a twice-daily mupirocin saline irrigation for 3 weeks in patients with S aureus–positive refractory CRS. Their group demonstrated improved endoscopic and overall symptom scores with minimal adverse effects. Even though high-volume mupirocin saline irrigations have demonstrated promising results in S aureus–positive refractory CRS, reinfection is common. A growing concern is the development of mupirocin resistance, and mupirocin-resistant strains of methicillinresistant S aureus may make the topical use of mupirocin obsolete in the future. The current literature on topical antibiotics in the management of CRS is heterogeneous and limited by lack of prospective and randomized controlled trials. Thus, it is difficult to definitively support the use of topical antibiotics. More research is needed to evaluate the safety of topical antibiotic therapies and the potential risks of bacterial resistance and local and systemic adverse effects. Interestingly, Desroriers and SalasPrato44 noted a paradoxic increase in nasal congestion with nebulized tobramycin. The risk of bacterial resistance is a serious concern and needs to be thoroughly vetted before recommending topical antimicrobial therapy. Given the low-level evidence, topical antibiotics should not be first-line management but may be attempted in patients refractory to the traditional topical steroids and oral antibiotics. Larger and better-designed randomized, double-blinded, placebo-controlled trials are required to more fully evaluate this modality of treatment. If the clinician uses topical antibiotic therapy, therapy should be guided by cultures and sensitivities.
Topical Therapies for Refractory Chronic Rhinosinusitis
TOPICAL SINONASAL ANTIFUNGALS
There is no evidence to promote the use of topical antifungals for CRS. It is recommended against the use of topical antifungal therapy. The significance of fungal infection on CRS has long been debated.47 Two studies have demonstrated the low occurrence rate (1.6%–2.4%) of fungal organisms among patients with CRS.48,49 In classically defined allergic fungal sinusitis, fungal elements are believed to underlie an IgE-mediated hypersensitivity that drives the eosinophilic inflammatory process. Antifungals have been suggested as systemic or topical preparations when fungus-related sinus inflammation is suspected. Because systemic antifungals have significant side effects that involve the liver and kidney, topical antifungals are more often advocated as a treatment modality for CRS. Ponikau and colleagues50 performed a double-blinded, randomized control trial and showed that topical amphotericin B was associated with lower reoccurrence of NP, improvement in symptoms and computed tomography scans, and endoscopic scores. However, the results of Ponikau and colleagues50 were limited to objective measures of endoscopy and computed tomography scan scores, with no significant difference in patient CRS health-related quality of life outcome scores. One study demonstrated when amphotericin B was included in the solution used for nasal irrigation, 39% of patients with CRS resolved their NP at the end of treatment.51 Given the preliminary data, future subsequent studies included a large number of randomized control trials evaluating topical antifungal therapy. These groups were not able to replicate Ponikau and colleagues’ results and found no significant improvement or benefit in symptoms with topical antifungal therapy. For example, topical amphotericin B had no effect on inflammatory markers. Rather, the placebo group had higher levels of wound recovery.52 One double-blinded, randomized control trial showed that antifungal therapy had no benefit over the control group and had higher adverse effects than the control trial.53 Another double-blinded, randomized multicenter study demonstrated no significant differences in symptom scores between the patients with CRS who used topical amphotericin B and the placebo. Two meta-analyses also agreed that although topical antifungal therapy did show improvements in radiographic measurements, they did not significantly impact patient symptoms. Furthermore, patients had a higher rate of adverse effects compared with the placebo group.54,55 The authors concluded there is no evidence to support the use of topical antifungal therapy for CRS and that antifungals not only lack evidence but have a preponderance of harm and are not recommended for topical therapy use. Side effects of topical antifungal therapy include nasal burning, skin irritation, epistaxis, and acute flare-ups of CRS.56
TOPICAL SINONASAL STENTS
Topical stents are used in adjunct to other topical therapies for CRS. They are well tolerated without significant adverse effects. It is recommended as a beneficial adjunct for CRS. Newer drug delivery devices via topical stents are addressing the shortcomings of nasal aerosol delivery. Stents allow for the slow release of topical drugs at targeted sites and have been used in the paranasal sinuses over the past decade. Early studies in animal models showed that drug-eluting stents have decreased granulation tissue without any epithelial damage, decreased postoperative stromal proliferation, and have negligible systemic absorption.57,58 Most studies have focused on
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topical steroid stent use but some studies have also examined the role of antibiotic stents.59,60 The Relieva Stratus MicroFlow Spacer (Acclarent, Menlo Park, CA) is a drugeluting stent that is temporarily implanted in the frontal or ethmoid sinus. It was introduced in 2009 and it provides local and targeted delivery of triamcinolone acetonide.61,62 However, the Relieva Stratus was recently pulled off the market after a lawsuit was filed against Acclarent for promoting off-label use of the stent.63 PROPEL sinus implant (Intersect ENT, Palo Alto, CA) was approved by the FDA in 2011 for topical steroid delivery in the paranasal sinus cavity (Fig. 1). The implant is a bioabsorbable implant that self-expands and releases mometasone furoate over 4 weeks.64 Murr and colleagues64 did a prospective double-blinded trial on the Propel sinus implant and noted significantly reduced inflammation and prevention of significant adhesions compared with the control implant in patients with CRS with polyposis. The Advance II trial by Marple and colleagues65 was a prospective, randomized, controlled, double-blinded study that concluded the Propel sinus implant yielded decreased adhesions, decreased nasal polyposis, and decreased postoperative interventions with no observable ocular safety risk when compared with a nondrug releasing implant. Lastly, Rudmik and colleagues66 demonstrated that an off-label drug-eluting middle meatal spacer of dexamethasone and Sinu-Foam (Arthrocare, Sunnyvale, CA) did not improve endoscopic outcomes in the early postoperative period when combined with postoperative saline irrigations and a shortcourse systemic steroids for patients with CRS without nasal polyposis. Drugeluting stents are a promising new technology in the otolaryngologist’s armamentarium for CRS. Future stent design should focus on larger steroid dose and/or longer duration of drug elution along with use of additional anti-inflammatory medications, such as antivascular endothelial growth factor. OTHER TOPICAL SINONASAL THERAPIES
Alternative topical therapies exist for CRS. However, data are sparse and not definitive. No recommendation is made for alternative topical therapy for CRS.
Fig. 1. The PROPEL mini implant is spring loaded and conforms to the patient’s sinus anatomy on implantation. It is impregnated with mometasone furoate, which slowly releases over the course of 30 days.
Topical Therapies for Refractory Chronic Rhinosinusitis
Refractory CRS is a medically and surgically challenging subset of patients. Hence, creative alternatives have been explored. Topics to be discussed include surfactants, topical manuka, honey and topical xylitol. A small prospective noncontrolled, nonblinded study of patients treated with twicedaily sinus irrigations with 1% baby shampoo in saline resulted in subjective improvement in SNOT-22 scores in 47% of heavily pretreated patients with CRS.67 Baby shampoo is thought to act as a surfactant with the ability to thin mucus, disrupt microbial cell membranes, and potentially reduce biofilm formation. Surfactants are compounds that lower the surface tension of liquids and are thought to improve mucociliary clearance by reducing the adherence of mucus to the epithelial layer. Chiu and colleagues68 followed up with a study that demonstrated baby shampoo irrigation resulted in a transient increase in ciliary beat frequency in murine nasal explants with no evidence of ciliary or epithelial toxicity. Isaacs and colleagues69 studied mucociliary clearance time in patients using topical baby shampoo in saline compared with saline alone and found statistically significant increased mucociliary clearance time in the surfactant group. Surfactants were also thought to help decrease biofilm formation. Citric acid zwitterionic surfactant was noted to be highly effective in killing bacterial biofilms in animal studies.70 However, because of its ciliotoxic properties, the reduction of cilia allowed biofilms to proliferate approximately 7 days after initial treatment in a rabbit model.71 Clinically, patients have complained of foul taste, nasal burning, epistaxis, and headache. Future research with randomized, doubleblinded, controlled trials is needed to determine the true impact of topical surfactants in CRS. Manuka (Leptospermum scoparium) honey and the active component, methylglyoxal (MGO), have been described as a natural, inexpensive, and nontoxic topical therapy for CRS. These have been shown to possess antistaphylococcus and antipseudomonas biofilm properties in vitro.72 Jervis-Bardy and coworkers72 evaluated the antibiofilm properties of manuka honey and MGO-only solutions. MGO, a derivative from the manuka flower, is considered to be the main antimicrobial agent, with honey potentiating its effects through an unknown mechanism. They demonstrated that antibiofilm properties existed with both topical solutions. However, this study was limited by the fact it was an in vitro analysis. Future in vivo studies are required to determine the effects of manuka honey and MGO in patients with CRS. Xylitol is a sugar alcohol that has gained prominence as a naturally occurring antibacterial agent. Weissman and colleagues73 performed a randomized, doubleblinded controlled trial to study if topical xylitol saline irrigations yielded significant improvement in patients with CRS compared with saline irrigations. Their study demonstrated a statistically significant improvement in SNOT-22 scores in the xylitol group. There was no difference in adverse effects between the two groups. The most common adverse effects were sweet taste of the xylitol solution. This study was limited by its small sample size of 20 patients. Future studies with larger patient populations are needed to examine this topical treatment. SUMMARY
Topical therapy has become an important tool in the otolaryngologist’s armamentarium for refractory CRS. Daily high-volume sinonasal saline irrigation and FDAapproved standard metered-dose topical nasal steroid therapy are supported by the most evidence. Nonstandard (off-label) topical sinonasal steroid therapies are a potential option for refractory CRS. Current evidence recommends against the use of topical antifungal therapy and topical antibiotic therapy delivered using spray and
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nebulized techniques in routine cases of CRS. There is insufficient evidence to provide clinical recommendations for alternative therapies, such as topical surfactant, manuka honey, or xylitol. Stents are a new modality with preliminary data showing they are an option when traditional treatment (oral antibiotics, saline, and steroid sprays) has failed. Further research with long-term effects and outcomes studies for refractory CRS are needed. REFERENCES
1. Kennedy DW, Gwaltney JM, Jones JG. Medical management of sinusitis: educational goals and management guidelines. The International Conference on Sinus Disease. Ann Otol Rhinol Laryngol Suppl 1995;167:22–30. 2. Senior BA, Kennedy DW, Tanabodee J, et al. Long-term results of functional endoscopic sinus surgery. Laryngoscope 1998;108(2):151–7. 3. Meltzer EO, Hamilos DL, Hadley JA. Rhinosinusitis: establishing definitions for clinical research and patient care. Otolaryngol Head Neck Surg 2004;131(6 Suppl):S1–62. 4. Eloy P, Poirrier AL, De Dorlodot C, et al. Actual concepts in rhinosinusitis: a review of clinical presentations, inflammatory pathways, cytokine profiles, remodeling, and management. Curr Allergy Asthma Rep 2011;11(2):146–62. 5. Soler ZM, Wittenberg E, Schlosser RJ, et al. Health state utility values in patients undergoing endoscopic sinus surgery. Laryngoscope 2011;121:2672–8. 6. Bhattacharyya N, Orlandi RR, Grebner J, et al. Cost burden of chronic rhinosinusitis: a claims-based study. Otolaryngol Head Neck Surg 2011;144:440–5. 7. Harvey RJ, Goddard JC, Wise SK, et al. Effects of endoscopic sinus surgery and delivery device on cadaver sinus irrigation. Otolaryngol Head Neck Surg 2008; 139:137–42. 8. Laube BL. Devices for aerosol delivery to treat sinusitis. J Aerosol Med 2007; 20(Suppl 1):S5–17 [discussion: S17–8]. 9. Saijo R, Majima Y, Hyo N, et al. Particle deposition of therapeutic aerosols in the nose and paranasal sinuses after transnasal sinus surgery: a cast model study. Am J Rhinol 2004;18(1):1–7. 10. Moller W, Lubbers C, Munzing W, et al. Pulsating airflow and drug delivery to paranasal sinuses. Curr Opin Otolaryngol Head Neck Surg 2011;19(1):48–53. 11. Moller W, Schuschnig U, Meyer G, et al. Ventilation and drug delivery to the paranasal sinuses: studies in a nasal cast using pulsating airflow. Rhinology 2008; 46(3):213–20. 12. Hwang PH, Woo RJ, Fong KJ. Intranasal deposition of nebulized saline: a radionuclide distribution study. Am J Rhinol 2006;20(3):255–61. 13. Rosenfeld RM, Andes D, Bhattacharyya N, et al. Clinical practice guideline: adult sinusitis 1. Otolaryngol Head Neck Surg 2007;137(Suppl 3):S1–3. 14. Harvey R, Hannan SA, Badia L, et al. Nasal saline irrigations for the symptoms of chronic rhinosinusitis. Cochrane Database Syst Rev 2007;(3):CD006394. 15. Wormald PK, Cain T, Oates L, et al. A comparative study of three methods of nasal irrigation. Laryngoscope 2004;114:2224–7. 16. Rabago D, Barrett B, Marchand L, et al. Qualitative aspects of nasal irrigation use by patients with chronic sinus disease in a multimethod study. Ann Fam Med 2006;4:295–301. 17. Rabago D, Zgierska A, Mundt M, et al. Efficacy of daily hypertonic saline nasal irrigation among patients with sinusitis: a randomized controlled trial. J Fam Pract 2002;51:1049–55.
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18. Bachmann G, Hommel G, Michel O. Effect of irrigation of the nose with isotonic salt solution on adult patients with chronic paranasal sinus disease. Eur Arch Otorhinolaryngol 2000;257:537–41. 19. Heatley DG, McConnell KE, Kille TL, et al. Nasal irrigation for the alleviation of sinonasal symptoms. Otolaryngol Head Neck Surg 2001;125:44–8. 20. Pinto JM, Elwany S, Baroody FM, et al. Effects of saline sprays on symptoms after endoscopic sinus surgery. Am J Rhinol 2006;20:191–6. 21. Freeman SR, Sivayoham ES, Jepson K, et al. A preliminary randomised controlled trial evaluating the efficacy of saline douching following endoscopic sinus surgery. Clin Otolaryngol 2008;33:462–5. 22. Baraniuk JN, Ali M, Naranch K. Hypertonic saline nasal provocation and acoustic rhinometry. Clin Exp Allergy 2002;32(4):543–50. 23. Pynnonen MA, Mukerji SS, Kim HM, et al. Nasal saline for chronic sinonasal symptoms: a randomized controlled trial. Arch Otolaryngol Head Neck Surg 2007;133:1115–20. 24. Rabago D, Pasic T, Azierska A, et al. The efficacy of hypertonic saline nasal irrigation for chronic sinonasal symptoms. Otolaryngol Head Neck Surg 2005; 133:3–8. 25. Friedman M, Vidyasagar R, Joseph N. A randomized, prospective, doubleblinded study on the efficacy of dead sea salt nasal irrigations. Laryngoscope 2006;116:878–82. 26. Mabry RL. Pharmacotherapy of allergic rhinitis: corticosteroids. Otolaryngol Head Neck Surg 1995;113(1):120–5. 27. Holm AF, Fokkens WJ, Godthelp T, et al. A 1 year placebo-controlled study of intranasal fluticasone propionate aqueous nasal spray in patients with perennial allergic rhinitis: a safety and biopsy study. Clin Otolaryngol 1998;23(1):69–73. 28. Martino B, Church C, Seiberling K. Effect of intranasal dexamethasone on endogenous cortisol level and intraocular pressure. Int Forum Allergy Rhinol 2015;5(7): 605–9. 29. Corren J. Intranasal corticosteroids for allergic rhinitis: how do different agents compare? J Allergy Clin Immunol 1999;104:S144–9. 30. Nasonex. Prod Inf. 2010. Available at: http://www.merck.com/product/usa/pi_ circulars/n/nasonex/nasonex_pi.pdf. Accessed January 8, 2016. 31. Melvin TA, Patel AA. Pharmacotherapy for allergic rhinitis. Otolaryngol Clin North Am 2011;44(3):727–39. 32. Fokkens W, Lund V, Mullol J. On behalf of the European position paper on rhinosinusitis and nasal polyps group. Rhinol Suppl 2007;20:1–136. 33. Badia L, Lund V. Topical corticosteroids in nasal polyposis. Drugs 2001;51:573–8. 34. Stajme P, Olsson P, Alenius M. Use of mometasone furoate to prevent polyp relapse after endoscopic sinus surgery. Arch Otolaryngol Head Neck Surg 2009;135(3):296–302. 35. Steinke JW, Payne SC, Tessier ME, et al. Pilot study of budesonide inhalant suspension for chronic eosinophilic sinusitis. J Allergy Clin Immunol 2009;123: 1352–4. 36. Jang DW, Lachanas VA, Segel J, et al. Budesonide nasal irrigations in the postoperative management of chronic rhinosinusitis. Int Forum Allergy Rhinol 2013; 3(9):708–11. 37. Bhalla RK, Payton K, Wright ED. Safety of budesonide in saline sinonasal irrigations in the management of chronic rhinosinusitis with polyposis: lack of significant adrenal suppression. J Otolaryngol Head Neck Surg 2008;37:821–5.
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38. Welch KC, Thaler ER, Doghramji LL, et al. The effects of serum and urinary cortisol levels of topical intranasal irrigations with budesonide added to saline in patients with recurrent polyposis after endoscopic sinus surgery. Am J Rhinol Allergy 2010;24:26–8. 39. DelGaudio JM, Wise SK. Topical steroid drops for the treatment of sinus ostia stenosis in the postoperative period. Am J Rhinol 2006;20:563–7. 40. Lim M, Citardi MJ, Leong JL. Topical antimicrobials in the management of chronic rhinosinusitis: a systematic review. Am J Rhinol 2008;22:381–9. 41. Soler ZM, Smith TL. What is the role of long-term macrolide therapy in the treatment of recalcitrant chronic rhinosinusitis? Laryngoscope 2009;119:2083–4. 42. Van Zele T, Gevaert P, Hotapples G, et al. Oral steroids and doxycycline: two different approaches to treat nasal polyps. J Allergy Clin Immunol 2010;125(5): 1069–76. 43. Sykes DA, Wilson R, Chan KL, et al. Relative importance of antibiotic and improved clearance in topical treatment of chronic mucopurulent rhinosinusitis. A controlled study. Lancet 1986;2:359–60. 44. Desrosiers MY, Salas-Prato M. Treatment of chronic 866. rhinosinusitis refractory to other treatments with topical antibiotic therapy delivered by means of a largeparticle nebulizer: results of a controlled trial. Otolaryngol Head Neck Surg 2001; 125:265–9. 45. Videler WJ, van Drunen CM, Reitsma JB, et al. Nebulized bacitracin/colimycin: a treatment option in recalcitrant chronic rhinosinusitis with Staphylococcus aureus? A double-blind, randomized, placebo-controlled, cross-over pilot study. Rhinology 2008;46:92–8. 46. Uren B, Psaltis A, Wormald PJ. Nasal lavage with mupirocin for the treatment of surgically recalcitrant chronic rhinosinusitis. Laryngoscope 2008;118:1677–80. 47. Ebbens FA, Scadding GK, Badia L, et al. Amphotericin B nasal lavages: not a solution for patients with chronic rhinosinusitis. J Allergy Clin Immunol 2006;118: 1149–56. 48. Jennings BH, Andersson KE, Johansson SA. Assessment of systemic effects of inhaled glucocorticoids, the influence of the frequency of blood sampling technique on plasma cortisol and leucocytes. Eur J Clin Pharmacol 1990;39:127–31. 49. Mantovani K, Bisanha AA, Demarco RC, et al. Maxillary sinuses microbiology from patients with chronic rhinosinusitis. Braz J Otorhinolaryngol 2010;76:548–51. 50. Ponikau JU, Sherris DA, Kita H, et al. Intranasal antifungal treatment in 51 patients with chronic rhinosinusitis. J Allergy Clin Immunol 2002;110:862–6. 51. Ricchetti A, Landis BN, Maffioli A, et al. Effect of antifungal nasal lavage with amphotericin B on nasal polyposis. J Laryngol Otol 2002;116:261–3. 52. Ebbens FA, Georgalas C, Luiten S, et al. The effect of topical amphotericin B on inflammatory markers in patients with chronic rhinosinusitis: a multicenter randomized controlled study. Laryngoscope 2009;119:401–8. 53. Weschta M, Rimek D, Formanek M, et al. Topical antifungal treatment of chronic rhinosinusitis with nasal polyps: a randomized, double-blind clinical trial. J Allergy Clin Immunol 2004;113:1122–8. 54. Stankiewicz JA, Musgrave BK, Scianna JM. Nasal amphotericin irrigation in chronic rhinosinusitis. Curr Opin Otolaryngol Head Neck Surg 2008;16:44–6. 55. Isaacs S, Fakhri S, Luong A, et al. A meta-analysis of topical amphotericin B for the treatment of chronic rhinosinusitis. Int Forum Allergy Rhinol 2011;1:250–4. 56. Sacks PL, Harvey RJ, Rimmer J, et al. Topical and systemic antifungal therapy for the symptomatic treatment of chronic rhinosinusitis. Cochrane Database Syst Rev 2011;(8):CD008263.
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57. Beule AG, Scharf C, Biebler KE, et al. Effects of topically applied dexamethasone on mucosal wound healing using a drug-releasing stent. Laryngoscope 2008; 118(11):2073–7. 58. Beule AG, Steinmeier E, Kaftan H, et al. Effects of a dexamethasone-releasing stent on osteoneogenesis in a rabbit model. Am J Rhinol Allergy 2009;23(4): 433–6. 59. Bleier BS, Kofonow JM, Hashmi N, et al. Antibiotic eluting chitosan glycerophosphate implant in the setting of acute bacterial sinusitis: a rabbit model. Am J Rhinol Allergy 2010;24(2):129–32. 60. Huvenne W, Zhang N, Tijsma E, et al. Pilot study using doxycycline-releasing stents to ameliorate postoperative healing quality after sinus surgery. Wound Repair Regen 2008;16(6):757–67. 61. Catalano PJ, Thong M, Weiss R, et al. The MicroFlow spacer: a drug-eluting stent for the ethmoid sinus. Indian J Otolaryngol Head Neck Surg 2011;63(3):279–84. 62. Taulu R, Numminen J, Bizaki A, et al. Image-guided, navigation-assisted Relieva Stratus MicroFlow Spacer insertion into the ethmoid sinus. Eur Arch Otorhinolaryngol 2015;272(9):2335–40. 63. J&J Hit with New Multimillion-Dollar Fraud Suit. 2016. Available at: http:// www.qmed.com/mpmn/medtechpulse/jj-hit-new-multimillion-dollar-fraud-suit. Accessed January 31, 2016. 64. Murr AH, Smith TL, Hwang PH, et al. Safety and efficacy of a novel bioabsorbable, steroid- eluting sinus stent. Int Forum Allergy Rhinol 2011;1(1): 23–32. 65. Marple BF, Smith TL, Han JK, et al. Advance II: a prospective, randomized study assessing safety and efficacy of bioabsorbable steroid-releasing sinus implants. Otolaryngol Head Neck Surg 2012;146(6):1004–11. 66. Rudmik L, Mace J, Mechor B. Effect of a dexamethasone Sinu-Foam middle meatal spacer on endoscopic sinus surgery outcomes: a randomized, doubleblind, placebo-controlled trial. Int Forum Allergy Rhinol 2012;2(3):248–51. 67. Chiu AG, Palmer JN, Woodworth BA, et al. Baby shampoo nasal irrigations for the symptomatic post-functional endoscopic sinus surgery patient. Am J Rhinol 2008;22(1):34–7. 68. Chiu AG, Chen B, Palmer JN, et al. Safety evaluation of sinus surfactant solution on respiratory cilia function. Int Forum Allergy Rhinol 2011;1(4):280–3. 69. Isaacs S, Fakhri S, Luong A, et al. The effect of dilute baby shampoo on nasal mucociliary clearance in healthy subjects. Am J Rhinol Allergy 2011;25:e27–9. 70. Desrosiers M, Myntti M, James G. Methods for removing bacterial biofilms: in vitro study using clinical chronic rhinosinusitis specimens. Am J Rhinol 2007;21(5): 527–32. 71. Tamashiro E, Banks CA, Chen B, et al. In vivo effects of citric acid/zwitterionic surfactant cleansing solution on rabbit sinus mucosa. Am J Rhinol Allergy 2009; 23(6):597–601. 72. Jervis-Bardy J, Foreman A, Bray S, et al. Methylglyoxal-infused honey mimics the anti-Staphylococcus aureus biofilm activity of manuka honey: potential implication in chronic rhinosinusitis. Laryngoscope 2011;121:1104–7. 73. Weissman JD, Fernandez F, Hwang PH. Xylitol nasal irrigation in the management of chronic rhinosinusitis: a pilot study. Laryngoscope 2011;121:2468–72.
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Marc Rosen,
MD,
KEYWORDS Topical therapy Chronic rhinosinusitis Anti-inflammatory Antimicrobial Surfactant Stents KEY POINTS Chronic rhinosinusitis (CRS) is a common disease that has a substantive impact on quality of life. CRS treatments are aimed at reducing sinonasal inflammation, infection, and reestablishing mucociliary clearance. Sinus surgery is an effective adjunct for topical sinonasal drug delivery for patients with CRS. With a 5% to 10% failure rate from surgery, there is an additional subset of patients who are recalcitrant to conventional medical and surgical therapies, leading to alternative therapies centered on anti-infective and anti-inflammatory nasal irrigations. Topical therapies have become an integral component in the management plan for CRS. Although topical therapy is not a panacea, it can, because of its safety profile, be repeated and/or sustained over extended periods, thus avoiding the risks of prolonged oral corticosteroids, intravenous antibiotics, and/or repeat surgery.
OVERVIEW
Chronic rhinosinusitis (CRS) is a multifactorial disorder that is heterogeneous in presentation and clinical course. Treatment of CRS is based on several factors including the type of rhinosinusitis (acute, chronic, or fungal), presence of nasal polyposis, concurrent medical comorbidities, symptom severity, and response to previous medical treatments.1 Medical treatment should be considered the cornerstone of disease treatment of CRS, with sinus surgery reserved for medical failures or patients’ complications. However, with a 5% to 10% failure rate from surgery, there is an additional
Department of Otolaryngology – Head & Neck Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA * Corresponding author. Division of Endoscopic Sinus & Skull Base Surgery, Department of Otolaryngology – Head & Neck Surgery, 925 Chestnut Street, 7th Floor, Philadelphia, PA 19107. E-mail address: [email protected] Otolaryngol Clin N Am 50 (2017) 129–141 http://dx.doi.org/10.1016/j.otc.2016.08.011 0030-6665/17/ª 2016 Elsevier Inc. All rights reserved.
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subset of patients who are refractory to conventional medical and surgical therapies.2 The focus of this article is on therapies centered on topical delivery and application for refractory CRS. CRS has been simplified to two subgroups: CRS with nasal polyps (NP) and CRS without NP.3 In the past, these two entities were considered to be a spectrum of one disease where CRS with NP was thought to be the end point of CRS. However, it has been shown that these two diseases have distinct differences and patients can respond differently to medical treatment.3,4 This article mentions specific recommendations based on the CRS subgroup when possible. Generally, the treatment of CRS is intended to reduce symptoms, improve quality of life, and prevent disease progression or recurrence. More specifically, topical therapies are aimed at reducing mucosal inflammation, reducing pathogenic bacterial burden and improving mucociliary clearance and sinonasal function. Clinicians often try to minimize systemic medical therapies and favor the use of topical therapies to focus drug delivery locally. Major factors that impact topical therapy success include the patient’s anatomy and the dynamics of the delivery device. Advantages of topical medical therapy include direct delivery onto diseased tissue, potential for delivering higher local drug concentrations, and minimizing systemic absorption. Disadvantages of topical medical therapy include challenges with application technique; local adverse effects, such as epistaxis or patient discomfort; and variable sinus penetration. Because of the accessible nature of the sinonasal cavity, it is amenable to topical medical therapy and this has become an integral strategy in the management of refractory CRS. Effective drug delivery to the involved tissue is a challenge that all topical drug therapies must overcome during the management of CRS. Endoscopic sinus surgery (ESS) is an important component in the management of medically refractory CRS, clinically and economically.5,6 One major advantage of ESS is creating an open and accessible cavity. This has been demonstrated to optimize sinonasal penetration of topical medical therapy.7 Potential topical sinonasal therapy strategies include topical saline irrigations, topical corticosteroids, topical antibiotics, topical antifungals, topical stents, and topical alternative medications. METHODS OF DELIVERY
The main factors associated with particle penetration include the size of the sinus ostia, the size of the particle, and the flow rate (liters per minute) of the aerosol. Particles greater than 10 mm in size typically do not make it past the nasal cavity, and particles less than 5 mm enter the lungs.8 Early studies estimated that the ideal particle size for maxillary sinus penetration is between 3 mm and 10 mm. Further studies concluded that smaller particle size, 45-degree insertion angle of the topical therapy, and higher flow rate (5 L/min compared with 1 L/min as demonstrated by Saijo and colleagues9) improved maxillary sinus penetration.8 Nasal sprays are a popular option for topical drug delivery because of their ease of use and diverse available formulations. Typical nasal sprays generate droplets of 50 mm to 100 mm in diameter and deliver 70 mL to 150 mL of drug per puff, at velocities of 7.5 L/ min to 20 L/min.10 However, a large fraction of the spray is deposited in the anterior nasal cavity without any paranasal sinus penetration. Also, half of the spray is cleared within 15 minutes from the nasal cavity, with minimal activity occurring at 6 hours.10 Nebulizers deliver medications in mist form and are commonly used for treating disease of the lower airway. Multiple nebulizers exist for topical sinonasal topical delivery. Some studies on pulsating aerosol nebulizers demonstrated increased deposition in
Topical Therapies for Refractory Chronic Rhinosinusitis
the maxillary ostia, increased deposition in the posterior nasal cavity, and slower clearance time compared with the nasal pump sprays.11 Although nebulizers represent a technologic advance compared with nasal pump sprays, the literature to support their efficacy is not definitive.12 TOPICAL SINONASAL SALINE
Use high-volume, low-pressure sinonasal saline irrigations in addition to other topical therapies for CRS. Saline irrigation is well-tolerated without significant adverse effects. It is recommended as a beneficial treatment of CRS. Saline irrigations and sprays are the most commonly used intervention for rhinitis and rhinosinusitis. Saline nasal irrigation has been recommended in the most recent clinical guidelines for CRS.13 It is a common treatment adjunct in the management of CRS. Saline irrigation mechanically removes mucus, crusts, debris, and allergens from the sinonasal cavity, and potentially has the additional benefit of improving mucociliary clearance, ciliary beat frequency, and protecting the sinonasal mucosa.14 The mechanical clearance of mucus by saline is thought to be the most important factor. Both hypertonic and isotonic saline have been shown to have a positive impact on mucociliary clearance time. There is substantial variability in the volume (low or high), pressure (low or high), and frequency (once daily to four times daily) of saline irrigation protocols. Large-volume, low-pressure nasal irrigation is more effective than saline sprays or nebulizers in penetrating the sinus ostia.15 In multiple randomized trials, saline irrigation for CRS improved symptoms, quality of life, endoscopic examination findings, and was tolerated without any significant harmful effects.9 The favorable safety profile, lack of systemic absorption risk, and good patient acceptance make it an appealing long-term topical therapy strategy.16 Daily hypertonic saline irrigation improved disease-specific symptom and healthrelated quality of life after 6 months.17–21 Bachmann and colleagues18 evaluated the effects of isotonic and hypertonic saline irrigations and demonstrated that both solutions improve sinonasal symptoms, with no significant differences between groups. Hypertonic preparations have been shown to elicit some pain and discomfort greater than 2.7%. At concentrations greater than 5.4%, patients experience nasal obstruction secondary to vasodilation and there is reduced airspace as measured by acoustic rhinomanometry.22 Rabago and colleagues17 randomized patients into two groups (hypertonic saline irrigations and no treatment) and demonstrated that daily hypertonic nasal saline irrigations significantly improved CRS health-related quality of life, symptoms scores, and decreased CRS medication usage. Pynnonen and colleagues23 compared high-volume (240 mL), low-pressure isotonic saline irrigation with lowvolume nasal saline spray and evaluated 20-item Sino-Nasal Outcomes Test (SNOT-20) and symptom scores at 2, 4, and 8 weeks posttreatment. Their study demonstrated that both groups had improvement in health-related quality of life at 8 weeks, but there was statistically significant long-term health-related quality of life and symptoms in patients using high-volume saline irrigations. This study focused on a community population of patients with sinonasal complaints and excluded patients with recent sinus surgery. With adherence to therapy, side effects were minimal and included local irritation, nosebleeds, nasal burning, nausea, and headaches. In a follow-up study, patients reported reduced sinusitis symptoms and sinusitis-related medication use for an additional 12 months.24 Another study found Dead Sea salt saline more beneficial compared with hypertonic saline for CRS symptoms.25 There is substantial evidence to support the use of sinonasal saline irrigations in the
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management of CRS.17–21 Because of the excellent safety profile of sinonasal saline irrigations, it is a great topical therapy option for patients with refractory CRS. Isotonic and hypertonic saline irrigations seem to provide similar outcomes, and high-volume, low-pressure saline irrigations are superior to low-volume nasal saline spray.
TOPICAL SINONASAL STEROIDS
Topical sinonasal steroid therapy can achieve local steroid effects while minimizing potential adverse effects associated with systemic steroid therapy (Box 1). Corticosteroids are potent medications that target the proinflammatory pathway. Because of the localized effects and excellent safety profile, topical sinonasal steroid therapy has become a common treatment option for CRS with and without nasal polyposis. Nasal corticosteroids have been shown to inhibit immediate and late-phase reactions to antigenic stimulation in patients with allergic rhinitis.26 Generally, sinonasal steroids with low systemic bioavailability, such as mometasone furoate or fluticasone furoate, have not been associated with reduced bone growth or adrenal suppression, which was first noted with more systemically available sinonasal steroids, such as beclomethasone dipropionate.27 However, high-dose dexamethasone nasal spray (0.132% aqueous nasal spray) given for at least 6 weeks does seem to have the potential to cause a decrease in serum cortisol levels.28 There is also no clear evidence that the use of sinonasal corticosteroids correlates with systemic changes in bone mineral biology, cataracts, or glaucoma. In fact, Martino and colleagues28 showed that a 6-week course of high-dose dexamethasone nasal spray (0.132% aqueous nasal spray) was not associated with ocular hypertension. Adverse effects of topical sinonasal steroids include epistaxis, headache, cough, nasal irritation, and nasal crusting. These happen in less than 5% of patients.29,30 Rarely, septal perforations have been reported with sinonasal steroid use. Because of this, patients are instructed to direct the nasal spray toward the lateral nasal cavity wall instead of toward the septum. There are several potential topical steroid solutions that are categorized into Food and Drug Administration (FDA)-approved and off-label use for sinonasal topical therapy. FDA-approved therapies apply to metered-dose topical steroid solutions and include mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, beclomethasone diproprionate, cicleosnide, flunisolide, and triamcinolone acetonide.
Box 1 Topical corticosteroids Food and Drug Administration–Approved Topical Corticosteroids Topical corticosteroids are effective in CRS with and without polyps. They decrease polyp size in CRS with polyps. They help control symptoms in CRS without polyps. Topical corticosteroids are well-tolerated without significant adverse effects. It is recommended as a beneficial treatment of CRS. “Off-Label” Use Topical Corticosteroids “Off-label” topical corticosteroids include the following: (1) budesonide nasal saline irrigations, (2) intranasal dexamethasone ophthalmic drops, (3) intranasal prednisolone ophthalmic drops, and (4) intranasal ciprofloxacin/dexamethasone otic drops. Further research is needed before making a definitive recommendation.
Topical Therapies for Refractory Chronic Rhinosinusitis
Off-label topical steroids lack FDA approval for nasal therapy. Although ample evidence exists on FDA-approved topical therapies, there is a growing body of literature for the off-label use of sinonasal steroid solutions. Advantages of off-label steroid solutions include delivery of the higher volume and higher concentrations of topical steroid to the sinonasal mucosa. However, the unknown risk of off-label topical sinonasal steroid use is the potential systemic absorption resulting in short- and long-term sequelae, which is yet to be determined. Several studies have demonstrated the efficacy of intranasal steroids in the management of CRS with and without NP. These sprays are used most commonly in the management of symptoms associated with seasonal and perennial allergic rhinitis.31 Guidelines recommend topical steroids as the first-line medication based on the results of several randomized controlled trials with fluticasone propionate, beclomethasone dipropionate, budesonide, or mometasone furoate.32 Topical nasal steroids are effective for the treatment of CRS with polyposis and are often considered the first-line treatment option.33 Nasal corticosteroids have also been shown to delay the recurrence of NP after surgery.34 Recent studies have demonstrated the efficacy of using budesonide respules for eosinophilic CRS or CRS with nasal polyposis. Budesonide respules are considered off-label use, because they are not FDA approved for nasal use. The respules are directly applied as nasal drops or as an addition to nasal irrigation. As described by the study authors, there is theoretically a higher concentration of steroids applied to the sinonasal mucosa with budesonide respules compared with traditional steroid sprays.35 The intranasal clinical improvement in patients with nasal polyposis using budesonide rinses seems significant, especially in patients with eosinophilic chronic sinusitis with NP.36 There is fear of systemic steroid side effects with off-label use of steroid solutions, but many studies have shown there is a lack of systemic effects. Bhalla and colleagues37 studied the effect of off-label topical budesonide irrigations and demonstrated no significant adrenal suppression. Lastly, Welch and colleagues38 demonstrated that twice-daily budesonide nasal irrigation following ESS did not alter the serum cortisol or 24-hour urine cortisol levels and concluded that high-volume delivery techniques, such as Neti pot, result in less than 5% of the solution remaining in the sinuses, and that the actual concentration of steroid the patient is exposed to is low and may be lower than traditional steroid nasal sprays. Other off-label solutions include intranasal dexamethasone ophthalmic drops, prednisolone ophthalmic drops, and ciprofloxacin/dexamethasone otic drops. In contrast to the low systemic side-effect profile of budesonide rinses, studies demonstrate a decrease in serum cortisol levels after 6 weeks of intranasal dexamethasone spray.28 DelGaudio and Wise39 studied intranasal dexamethasone ophthalmic drops, prednisolone ophthalmic drops, and ciprofloxacin/dexamethasone otic drops and only 1 of 36 patients required medication discontinuation because of a decrease in morning cortisol level. Although there can be significant clinical improvement with the use of dexamethasone and prednisolone intranasal sprays for the treatment of nasal polyposis, these medications have a higher systemic side effect profile and impact the hypothalamic-pituitary-adrenal axis. Nasal pump sprays, the most common delivery method of topical nasal corticosteroids, have almost no sinus penetration in nonoperated patients. Studies are needed to assess the long-term safety of off-label used nasal steroids. Finally, to optimize treatment with intranasal steroid sprays, patients should be educated on the delivery technique to maximize application to the sinonasal mucosa instead of simple nasal application.
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TOPICAL SINONASAL ANTIBIOTICS
Topical antibiotics are not first-line therapy for CRS. Stronger evidence exists for its use in patients with cystic fibrosis. It is recommended against use of topical antibiotics (spray and nebulizer) for CRS. Topical antibiotics have emerged as adjunctive treatment of CRS because they offer the potential for high local concentration at the desired target site with minimization of systemic side effects.40 The extent to which bacterial colonization, infection, and biofilms contribute to the pathophysiology of CRS is controversial. Systemic antibiotics are typically reserved for treatment of acute exacerbations of CRS. However, some evidence exists that long-term systemic macrolide therapy and doxycycline can improve subjective and objective outcomes while providing anti-inflammatory and prociliary benefits in addition to antimicrobial effects.41,42 Systemic antibiotics do have potential side effects including cramping, diarrhea, increasing bacterial resistance, allergic reactions, and potential for organ toxicity. Sykes and colleagues43 evaluated dexamethasone/tramazoline and neomycin/ dexamethasone compared with a placebo and used a four-times-daily spray technique. They demonstrated that both groups had symptomatic improvement compared with placebo. Desrosiers and Salas-Prato44 evaluated a topical tobramycin-saline solution using a large-particle nebulizer compared with saline alone. Aerosolized forms of tobramycin were initially used in the treatment of pseudomonal pulmonary infections in patients with cystic fibrosis. After a 4-week treatment course, they demonstrated that both groups received clinical improvement, with no additional benefit derived from the topical tobramycin. Tobramycin nasal irrigations in patients with cystic fibrosis yielded reduction in revision sinus surgery and improved outcome scores.44 Videler and colleagues45 evaluated a Rhinoflow (Respironics, Inc., Cedar Grove, NJ) nebulizer of bacitracin/colimycin compared with placebo and they demonstrated clinical improvement in both groups with no additional benefit perceived by the topical antibiotic group. Topical high-volume mupirocin-saline irrigation has been studied as a potential therapeutic option for patients with Staphylococcus aureus, including methicillin-resistant S aureus culture-positive refractory CRS. Uren and colleagues46 evaluated the effects of a twice-daily mupirocin saline irrigation for 3 weeks in patients with S aureus–positive refractory CRS. Their group demonstrated improved endoscopic and overall symptom scores with minimal adverse effects. Even though high-volume mupirocin saline irrigations have demonstrated promising results in S aureus–positive refractory CRS, reinfection is common. A growing concern is the development of mupirocin resistance, and mupirocin-resistant strains of methicillinresistant S aureus may make the topical use of mupirocin obsolete in the future. The current literature on topical antibiotics in the management of CRS is heterogeneous and limited by lack of prospective and randomized controlled trials. Thus, it is difficult to definitively support the use of topical antibiotics. More research is needed to evaluate the safety of topical antibiotic therapies and the potential risks of bacterial resistance and local and systemic adverse effects. Interestingly, Desroriers and SalasPrato44 noted a paradoxic increase in nasal congestion with nebulized tobramycin. The risk of bacterial resistance is a serious concern and needs to be thoroughly vetted before recommending topical antimicrobial therapy. Given the low-level evidence, topical antibiotics should not be first-line management but may be attempted in patients refractory to the traditional topical steroids and oral antibiotics. Larger and better-designed randomized, double-blinded, placebo-controlled trials are required to more fully evaluate this modality of treatment. If the clinician uses topical antibiotic therapy, therapy should be guided by cultures and sensitivities.
Topical Therapies for Refractory Chronic Rhinosinusitis
TOPICAL SINONASAL ANTIFUNGALS
There is no evidence to promote the use of topical antifungals for CRS. It is recommended against the use of topical antifungal therapy. The significance of fungal infection on CRS has long been debated.47 Two studies have demonstrated the low occurrence rate (1.6%–2.4%) of fungal organisms among patients with CRS.48,49 In classically defined allergic fungal sinusitis, fungal elements are believed to underlie an IgE-mediated hypersensitivity that drives the eosinophilic inflammatory process. Antifungals have been suggested as systemic or topical preparations when fungus-related sinus inflammation is suspected. Because systemic antifungals have significant side effects that involve the liver and kidney, topical antifungals are more often advocated as a treatment modality for CRS. Ponikau and colleagues50 performed a double-blinded, randomized control trial and showed that topical amphotericin B was associated with lower reoccurrence of NP, improvement in symptoms and computed tomography scans, and endoscopic scores. However, the results of Ponikau and colleagues50 were limited to objective measures of endoscopy and computed tomography scan scores, with no significant difference in patient CRS health-related quality of life outcome scores. One study demonstrated when amphotericin B was included in the solution used for nasal irrigation, 39% of patients with CRS resolved their NP at the end of treatment.51 Given the preliminary data, future subsequent studies included a large number of randomized control trials evaluating topical antifungal therapy. These groups were not able to replicate Ponikau and colleagues’ results and found no significant improvement or benefit in symptoms with topical antifungal therapy. For example, topical amphotericin B had no effect on inflammatory markers. Rather, the placebo group had higher levels of wound recovery.52 One double-blinded, randomized control trial showed that antifungal therapy had no benefit over the control group and had higher adverse effects than the control trial.53 Another double-blinded, randomized multicenter study demonstrated no significant differences in symptom scores between the patients with CRS who used topical amphotericin B and the placebo. Two meta-analyses also agreed that although topical antifungal therapy did show improvements in radiographic measurements, they did not significantly impact patient symptoms. Furthermore, patients had a higher rate of adverse effects compared with the placebo group.54,55 The authors concluded there is no evidence to support the use of topical antifungal therapy for CRS and that antifungals not only lack evidence but have a preponderance of harm and are not recommended for topical therapy use. Side effects of topical antifungal therapy include nasal burning, skin irritation, epistaxis, and acute flare-ups of CRS.56
TOPICAL SINONASAL STENTS
Topical stents are used in adjunct to other topical therapies for CRS. They are well tolerated without significant adverse effects. It is recommended as a beneficial adjunct for CRS. Newer drug delivery devices via topical stents are addressing the shortcomings of nasal aerosol delivery. Stents allow for the slow release of topical drugs at targeted sites and have been used in the paranasal sinuses over the past decade. Early studies in animal models showed that drug-eluting stents have decreased granulation tissue without any epithelial damage, decreased postoperative stromal proliferation, and have negligible systemic absorption.57,58 Most studies have focused on
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topical steroid stent use but some studies have also examined the role of antibiotic stents.59,60 The Relieva Stratus MicroFlow Spacer (Acclarent, Menlo Park, CA) is a drugeluting stent that is temporarily implanted in the frontal or ethmoid sinus. It was introduced in 2009 and it provides local and targeted delivery of triamcinolone acetonide.61,62 However, the Relieva Stratus was recently pulled off the market after a lawsuit was filed against Acclarent for promoting off-label use of the stent.63 PROPEL sinus implant (Intersect ENT, Palo Alto, CA) was approved by the FDA in 2011 for topical steroid delivery in the paranasal sinus cavity (Fig. 1). The implant is a bioabsorbable implant that self-expands and releases mometasone furoate over 4 weeks.64 Murr and colleagues64 did a prospective double-blinded trial on the Propel sinus implant and noted significantly reduced inflammation and prevention of significant adhesions compared with the control implant in patients with CRS with polyposis. The Advance II trial by Marple and colleagues65 was a prospective, randomized, controlled, double-blinded study that concluded the Propel sinus implant yielded decreased adhesions, decreased nasal polyposis, and decreased postoperative interventions with no observable ocular safety risk when compared with a nondrug releasing implant. Lastly, Rudmik and colleagues66 demonstrated that an off-label drug-eluting middle meatal spacer of dexamethasone and Sinu-Foam (Arthrocare, Sunnyvale, CA) did not improve endoscopic outcomes in the early postoperative period when combined with postoperative saline irrigations and a shortcourse systemic steroids for patients with CRS without nasal polyposis. Drugeluting stents are a promising new technology in the otolaryngologist’s armamentarium for CRS. Future stent design should focus on larger steroid dose and/or longer duration of drug elution along with use of additional anti-inflammatory medications, such as antivascular endothelial growth factor. OTHER TOPICAL SINONASAL THERAPIES
Alternative topical therapies exist for CRS. However, data are sparse and not definitive. No recommendation is made for alternative topical therapy for CRS.
Fig. 1. The PROPEL mini implant is spring loaded and conforms to the patient’s sinus anatomy on implantation. It is impregnated with mometasone furoate, which slowly releases over the course of 30 days.
Topical Therapies for Refractory Chronic Rhinosinusitis
Refractory CRS is a medically and surgically challenging subset of patients. Hence, creative alternatives have been explored. Topics to be discussed include surfactants, topical manuka, honey and topical xylitol. A small prospective noncontrolled, nonblinded study of patients treated with twicedaily sinus irrigations with 1% baby shampoo in saline resulted in subjective improvement in SNOT-22 scores in 47% of heavily pretreated patients with CRS.67 Baby shampoo is thought to act as a surfactant with the ability to thin mucus, disrupt microbial cell membranes, and potentially reduce biofilm formation. Surfactants are compounds that lower the surface tension of liquids and are thought to improve mucociliary clearance by reducing the adherence of mucus to the epithelial layer. Chiu and colleagues68 followed up with a study that demonstrated baby shampoo irrigation resulted in a transient increase in ciliary beat frequency in murine nasal explants with no evidence of ciliary or epithelial toxicity. Isaacs and colleagues69 studied mucociliary clearance time in patients using topical baby shampoo in saline compared with saline alone and found statistically significant increased mucociliary clearance time in the surfactant group. Surfactants were also thought to help decrease biofilm formation. Citric acid zwitterionic surfactant was noted to be highly effective in killing bacterial biofilms in animal studies.70 However, because of its ciliotoxic properties, the reduction of cilia allowed biofilms to proliferate approximately 7 days after initial treatment in a rabbit model.71 Clinically, patients have complained of foul taste, nasal burning, epistaxis, and headache. Future research with randomized, doubleblinded, controlled trials is needed to determine the true impact of topical surfactants in CRS. Manuka (Leptospermum scoparium) honey and the active component, methylglyoxal (MGO), have been described as a natural, inexpensive, and nontoxic topical therapy for CRS. These have been shown to possess antistaphylococcus and antipseudomonas biofilm properties in vitro.72 Jervis-Bardy and coworkers72 evaluated the antibiofilm properties of manuka honey and MGO-only solutions. MGO, a derivative from the manuka flower, is considered to be the main antimicrobial agent, with honey potentiating its effects through an unknown mechanism. They demonstrated that antibiofilm properties existed with both topical solutions. However, this study was limited by the fact it was an in vitro analysis. Future in vivo studies are required to determine the effects of manuka honey and MGO in patients with CRS. Xylitol is a sugar alcohol that has gained prominence as a naturally occurring antibacterial agent. Weissman and colleagues73 performed a randomized, doubleblinded controlled trial to study if topical xylitol saline irrigations yielded significant improvement in patients with CRS compared with saline irrigations. Their study demonstrated a statistically significant improvement in SNOT-22 scores in the xylitol group. There was no difference in adverse effects between the two groups. The most common adverse effects were sweet taste of the xylitol solution. This study was limited by its small sample size of 20 patients. Future studies with larger patient populations are needed to examine this topical treatment. SUMMARY
Topical therapy has become an important tool in the otolaryngologist’s armamentarium for refractory CRS. Daily high-volume sinonasal saline irrigation and FDAapproved standard metered-dose topical nasal steroid therapy are supported by the most evidence. Nonstandard (off-label) topical sinonasal steroid therapies are a potential option for refractory CRS. Current evidence recommends against the use of topical antifungal therapy and topical antibiotic therapy delivered using spray and
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nebulized techniques in routine cases of CRS. There is insufficient evidence to provide clinical recommendations for alternative therapies, such as topical surfactant, manuka honey, or xylitol. Stents are a new modality with preliminary data showing they are an option when traditional treatment (oral antibiotics, saline, and steroid sprays) has failed. Further research with long-term effects and outcomes studies for refractory CRS are needed. REFERENCES
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