Key points

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. 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 subset of patients who are refractory to conventional medical and surgical therapies. 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. 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. 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. One major advantage of ESS is creating an open and accessible cavity. This has been demonstrated to optimize sinonasal penetration of topical medical therapy. Potential topical sinonasal therapy strategies include topical saline irrigations, topical corticosteroids, topical antibiotics, topical antifungals, topical stents, and topical alternative medications.

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. 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 subset of patients who are refractory to conventional medical and surgical therapies. 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. 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. 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. One major advantage of ESS is creating an open and accessible cavity. This has been demonstrated to optimize sinonasal penetration of topical medical therapy. 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 μm in size typically do not make it past the nasal cavity, and particles less than 5 μm enter the lungs. Early studies estimated that the ideal particle size for maxillary sinus penetration is between 3 μm and 10 μm. 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 colleagues ) improved maxillary sinus penetration.

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 μm to 100 μm in diameter and deliver 70 μL to 150 μL of drug per puff, at velocities of 7.5 L/min to 20 L/min. 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.

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 the maxillary ostia, increased deposition in the posterior nasal cavity, and slower clearance time compared with the nasal pump sprays. Although nebulizers represent a technologic advance compared with nasal pump sprays, the literature to support their efficacy is not definitive.

Topical sinonasal saline

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  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. 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. 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. In multiple randomized trials, saline irrigation for CRS improved symptoms, quality of life, endoscopic examination findings, and was tolerated without any significant harmful effects. The favorable safety profile, lack of systemic absorption risk, and good patient acceptance make it an appealing long-term topical therapy strategy.

Daily hypertonic saline irrigation improved disease-specific symptom and health-related quality of life after 6 months. Bachmann and colleagues 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. Rabago and colleagues 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 colleagues compared high-volume (240 mL), low-pressure isotonic saline irrigation with low-volume 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. Another study found Dead Sea salt saline more beneficial compared with hypertonic saline for CRS symptoms. There is substantial evidence to support the use of sinonasal saline irrigations in the management of CRS. 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. 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. 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. 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 colleagues 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. 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. 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. 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. Topical nasal steroids are effective for the treatment of CRS with polyposis and are often considered the first-line treatment option. Nasal corticosteroids have also been shown to delay the recurrence of NP after surgery.

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. The intranasal clinical improvement in patients with nasal polyposis using budesonide rinses seems significant, especially in patients with eosinophilic chronic sinusitis with NP. 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 colleagues studied the effect of off-label topical budesonide irrigations and demonstrated no significant adrenal suppression. Lastly, Welch and colleagues 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. DelGaudio and Wise 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.