Chronic Rhinosinusitis: Evidence-Based Medical Treatment

Key Points

Strongly Recommended Therapies

High volume saline irrigations and topical intranasal corticosteroids are supported by a strong recommendation for the treatment of chronic rhinosinusitis with and without nasal polyps (CRSwNP and CRSsNP).

Recommended Therapies

Nonstandard delivery of topical intranasal steroids in irrigations (budesonide irrigation) is supported for use in CRS (CRSwNP and CRSsNP) by moderate evidence as a recommendation.
Aspirin desensitization is recommended in CRS with nasal polyps (CRSwNP).

Optional Therapies

Oral corticosteroids may be considered an option for the treatment of CRSwNP. There is no recommendation possible for their use in CRSsNP.
Oral macrolide antibiotics may be considered as an option for patients with CRS and may be more beneficial in CRSsNP.
Leukotriene inhibitors may be considered in CRSwNP.
Immunotherapy: Identification and treatment of inflammatory triggers are theoretically beneficial and may be considered as an option.

Therapies With Recommendations Against

The routine use of non-macrolide oral antibiotics, intravenous antibiotics, and topical antibiotics is recommended against.
The routine use of antifungals (oral or topical) is recommended against.
The use of colloid silver is recommended against.

Therapies With No Recommendation

No recommendation can be made regarding the use of alternative therapies, including topical surfactants, Manuka honey, xylitol, or photodynamic therapy.
No recommendations can be made regarding the use of biologic therapies in CRS, as these drugs are currently under investigation, pending the results of Phase 3 clinical trials.

Introduction

There are many options available for the medical management of chronic rhinosinusitis (CRS). These can vary greatly in cost, benefit, and potential harm. This variety presents clinicians with the ongoing challenge of trying to determine which therapies to use. As the body of literature on CRS continues to grow, identifying the most effective and up-to-date methods to optimize the treatment of CRS has become increasingly difficult. This phenomenon is not unique to CRS, or even otolaryngology. For the average family physician to remain current on medical literature, they would need to read 17 to 19 papers per day, every day of the year. This is an impossible task, and in the wake of this, systematic reviews of the literature using the principles of evidence-based medicine (EBM) have proliferated.

EBM is a concept that has existed for many decades, but was formalized and popularized in the nineties as medical literature began to grow exponentially. EBM is described as the “conscientious, explicit, and judicious use of current best evidence” in clinical decision making. It is a careful integration of evidence and individual clinical expertise, while also considering patient values and preferences ( Fig. 42.1 ). Emphasis on each of these components allows physicians to retain their autonomy while optimizing patient care. Clinical decision making based on EBM has been shown to improve quality of care and clinical outcome and, subsequently, the value of care.

Fig. 42.1, A description of the components of evidence-based medicine (EBM).

EBM relies on identifying the best evidence, which depends on the reader having an understanding of what characterizes high-quality and low-quality research. Individual studies can be described by their level of evidence, defined by the Oxford Centre for Evidence-Based Medicine ( Fig. 42.2 ). Subsequently, aggregate grades of evidence have been created to describe strength of all available literature on a topic ( Fig. 42.3 ). In recent years, methodology for Evidence-Based Reviews with Recommendations (EBRR) and International Consensus Statements has been developed, and these serve as essential EBM resources. These documents involve an extensive review of all literature on a topic and, where possible, provide a recommendation and a value judgment based on the level of evidence, balance of benefit versus harm, and cost. The International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR:RS) provides the most up-to-date and inclusive review of all literature on rhinosinusitis, and serves as the scaffold for this chapter. The objective of this chapter is to provide a summary of the available medical therapies for CRS, as well as the supporting evidence for each therapy (up to date as of March 2018). Hopefully, this will serve as a useful reference for physicians treating CRS.

Fig. 42.2, Levels of evidence for studies on disease therapy, prevention, etiology, and harm.

Fig. 42.3, Description of Aggregate Grades of Evidence and Recommendations.

Medical Therapies

Each medical therapy is described individually as follows, including assessment of benefit and risks as well as other important considerations. Where possible, or relevant, CRS with polyps (CRSwNP) and CRS without polyps (CRSsNP) are discussed separately. A recommendation with aggregate grade evidence is made where possible. Table 42.1 provides a summary of the available evidence for medical therapies in CRS.

TABLE 42.1

Summary of Medical Therapy for Chronic Rhinosinusitis

Medication	Benefits	Risks	Evidence ^a	Recommendation	Comments
Saline irrigations	Improved QOL, symptoms, endoscopic and radiologic outcomes	Local irritation, nasal burning, headaches, and ear pain/congestion	A	Strong recommendation	High volume (>200 mL) saline irritations are strongly recommended as an adjunctive therapy
C orticosteroids
INCS: standard delivery	Improved symptoms, endoscopic scores, and reduction in polyp burden and recurrence	Epistaxis, headaches	A	Strong recommendation	Standard metered dose INCS should be used in treatment of CRSsNP
INCS: nonstandard delivery	Improved symptoms and endoscopic scores	Nasal irritation, possible systemic absorption, possible ocular effects, epistaxis, and infection	Irrigations: B	Recommendation	Budesonide is the corticosteroid used in irrigation studies
			YAMIK: Insufficient	Recommend against
			MAST: B	Option
			MAD: B	Option
Oral corticosteroids	Improved symptoms, endoscopic scores, and reduced polyp burden	Adrenal suppression, psychiatric disturbances, GI distress, and bone abnormalities ^b	CRSwNP: A	Option
Oral corticosteroids			CRSsNP: D	No recommendation
A ntibiotics
Oral macrolides	Improved symptoms, endoscopic scores, and reduced polyp burden	GI upset, ototoxicity, drug interactions, and cardiotoxicity	B	Option	Greater benefits seen in CRSsNP and patients without allergy/IgE elevation
Oral non-macrolides	Subjective improvement in symptoms in heterogeneous studies	Bacterial resistance, anaphylaxis, rash, GI upset, elevated LFTs, and Clostridium difficile colitis	B	Recommend against	Should be considered for ABRS Doxycycline may have anti-inflammatory benefits in CRSwNP
Intravenous	Unclear	Neutropenia, sepsis, elevated LFTs, rash, bleeding, thrombophlebitis, and DVT	C	Recommend against	Essential for the management of extranasal complications of ABRS
Topical	None, avoidance of systemic side effects	Nasal irritation	B	Recommend against	Further study needed, may be beneficial in select cases
A ntifungals
Oral	None		B	Recommend against
Topical	None	Nasal irritation	C	Recommend against
A lternative T herapies
Topical surfactants	Biofilm treatment, clearance of thick secretions, and possible improvement in subjective and objective measures	Nasal irrigation and possible reduction in mucociliary clearance	B	No recommendation	Baby shampoo 1% is the suggested concentration for clinical use
Manuka honey	Biofilm treatment and possible improvement in subjective and objective measures	Nasal irrigation, ciliary damage	C	No recommendation	MGO concentration affects toxicity and benefits
Xylitol	Reduced crusting and possible improvement in subjective and objective measures	Nasal irrigation	Insufficient	No recommendation
Colloid silver	None	Nasal irrigation	Insufficient	Recommend against	FDA rules unsafe and nonefficacious
Photodynamic therapy	Reduced biofilm burden	Unknown	Insufficient	No recommendation	No human trials exist
Leukotriene inhibitors	Improvements comparable to INCS	Elevated LFTs, rare neuropsychiatric effects	A	Option	Evidence available for CRSwNP only
ASA desensitization	Reduced polyp burden, improved symptoms, and reduced revision rate	Anaphylaxis, pulmonary exacerbations, GI bleeding, worsening kidney disease, and coagulopathy	B	Recommended	Recommended post-ESS in AERD patients
Immunotherapy	Unclear, theoretic benefit	Minimal, treatment dependent	C	Option	Identification and treatment of inflammatory triggers is theoretically beneficial
Biologic therapies	Improved symptoms, endoscopic scores, and reduced polyp burden	Cost Otherwise drug dependent	D	No recommendation	Reslizumab, mepolizumab, benralizumab, dupilumab, and omalizumab are biologics under investigation for CRSwNP

ABRS , Acute bacterial rhinosinusitis; AERD , aspirin exacerbated respiratory disease; ASA , aspirin; CRSsNP , chronic rhinosinusitis without nasal polyps; CRSwNP , chronic rhinosinusitis without nasal polyps; DVT , deep vein thrombosis; ESS , endoscopic sinus surgery; FDA , Food and Drug Administration; GI , gastrointestinal; IgE , immunoglobulin E; INCS , intranasal corticosteroids; LFT , liver function test; MAD , mucosalized atom device; MAST , maxillary antrostomy sinus tube; MGO , methylglyoxal; QOL , quality of life.

a Aggregate grade of evidence.

b Overview of complications; others may exist.

Saline Irrigations

Saline irrigations are one of the essential components of medical management for CRS. While the exact mechanism of action of saline irrigations is unclear, they are thought to improve nasal mucosa function by direct cleansing, removal of inflammatory mediators, and improved mucociliary function. There have been multiple studies investigating the efficacy of saline irrigations in CRS, which show a reduction in symptoms and improvements in disease-specific quality of life. In addition, their use is associated with improved objective measures of CRS, such as endoscopy scores and radiologic imaging scores. Saline irrigations are associated with an excellent safety profile and are generally well tolerated. There are few associated risks, which include local irritation, nasal burning, headaches, and ear pain/congestion. Bacterial contamination of rinse bottles is reported, but is not associated with an increased risk of sinus infections. However, the regular replacement of bottles and use of clean water are suggested.

Within the realm of saline irrigations, significant variation exists. The volume of saline can be high or low (greater or less than 50 mL), the solution used may be isotonic or hypertonic, and the recommended frequency varies as well. Evidence suggests high volume irrigations are superior to low volume devices, such as saline sprays. Isotonic and hypotonic solutions result in similar symptomatic outcomes, while hypertonic may improve radiographic scores. The ideal frequency of irrigations has not been defined. Of note, saline irrigations are typically used as an adjunctive therapy with other topical intranasal therapies, such as corticosteroids, and are not advocated as monotherapy for CRS.

Given the efficacy and minimal risks associated with saline irrigations, a strong recommendation has been made for their use as an adjunctive medical therapy in CRS, supported by an A aggregate grade of evidence.

Corticosteroids

Intranasal Corticosteroids—Standard Delivery

Standard delivery (drops and sprays) intranasal corticosteroids (INCS) are the mainstay of medical management for CRS and have been well studied. They are associated with improvements in both objective and subjective CRS measures and are well tolerated, with the most common side effects being minor epistaxis and headaches. They are also safe for long-term use with minimal systemic absorption, though this varies from less than 1% to up to 50%, depending on the specific formulation used. Utilizing those with lower systemic absorption is generally preferred, as no differences in efficacy have been found between formulations. The effects of INCS in CRSwNP have been studied extensively, with more than 30 randomized controlled trials with a minimum duration of treatment of 4 weeks. In these patients, INCS use is associated with improvements in symptom scores, endoscopic appearance, polyp scores, olfactory function, nasal airway, and a reduction in polyp recurrences. Delivery by sprays or drops is equally efficacious in CRSwNP. CRSsNP has been studied to a lesser degree with several randomized controlled trials. These studies also found improvements in symptom scores and endoscopic appearance. Of note, no studies have evaluated the use of drops in CRSsNP. Given the preponderance of evidence available, as well as the significant benefit over harm, evidence-based recommendations are made as follows.

Recommendations:

INCS—Standard Delivery (CRSwNP): Strong Recommendation for drops or sprays (Grade A evidence)
INCS—Standard Delivery (CRSsNP): Strong Recommendation for sprays (Grade A evidence)

Intranasal Corticosteroids—Nonstandard Delivery

One of the challenges that INCS sprays and drops face is limited distribution to the sinonasal cavity, especially in patients who have not had endoscopic sinus surgery (ESS). To address this deficiency, multiple nonstandard delivery methods have been investigated for the delivery of INCS. One method of delivery is corticosteroid irrigations, which most commonly involves the off-label use of budesonide. Liquid or powder budesonide is added to saline irrigations, taking advantage of the increased penetration of irrigations compared to nasal sprays. The studies examining the efficacy and safety of these irrigations have mixed populations of CRSwNP and CRSsNP, with or without a history of ESS. The results of the studies available at the time of the ICAR:RS publication were mixed, with some showing improvement and others showing no benefit. As such, corticosteroid irrigations were recommended as an option. Since this time, there have been three randomized controlled trials, two prospective trials, and a systematic review with meta-analysis examining the effects of corticosteroid irrigations in patients who had previously received ESS. The majority of these studies found significant improvements in symptom scores, quality of life, and endoscopic scores. Harvey et al. compared corticosteroid irrigations to corticosteroid nasal sprays in postoperative CRS patients (with and without polyps), with a follow-up duration of 12 months, and found a significant benefit of irrigations over sprays in quality of life and symptoms scores. Recent literature on budesonide irrigations has also found the risks of systemic complications to be very low. There is a growing body of literature showing a preponderance of benefit over harm with corticosteroid irrigations. As such, the recommendation for their use has been updated as follows.

There are three other nonstandard delivery devices that have been investigated in CRS. The YAMIK sinus catheter device, when used with corticosteroids, provided no additional benefits and was associated with device-related discomfort and epistaxis. Its use is not recommended. Maxillary antrostomy sinus tubes (MAST) have been evaluated in two studies, both of which noted improvements in symptom scores. In the single randomized controlled trial, 35% of patients experienced complications (epistaxis, tube migration, and infection). There is a balance of benefit and harm in these limited studies. Mucosal atomized devices (MAD) have been evaluated in three trials. These studies all show improvements in symptom scores, and more recent studies have found improvements in endoscopic scores as well. Interestingly, one small study limited to CRSwNP found MAD delivery of corticosteroids resulted in a superior improvement compared with budesonide irrigations. It is worth noting that two studies have now found evidence of cortisol suppression (but not adrenal suppression), and one found a 6% incidence of elevated intraocular pressure associated with MAD use. The benefits of MAD appear to be similar to the risk of harm. Considering the limited evidence available for these nonstandard delivery devices, a summary of recommendations is as follows.

Recommendations:

Corticosteroids irrigations: Recommendation especially post-ESS (Grade B evidence)
YAMIK device: Recommendation Against (Insufficient, single 1b study)
MAST: Option (Grade B evidence) in CRSw/sNP
MAD: Option (Grade B evidence) in CRSw/sNP

Oral Corticosteroids

Oral corticosteroids are a potent anti-inflammatory treatment with many well-established side effects. Corticosteroids are associated with adrenal suppression and insufficiency, psychiatric disturbances, disruption in bone metabolism, and gastrointestinal distress. Notwithstanding these negative effects, they also play an important role in the control of many inflammatory disorders, including CRS. A significant amount of research has been done on the effects of oral corticosteroids in CRSwNP. These studies have shown a significant reduction in CRS symptoms, as well as improvements in objective measures such as polyp burden. These effects also persist up to 12 weeks following a short course (up to 14 days) of oral corticosteroids. The evidence suggests that the benefits of infrequent and short courses of oral corticosteroids outweigh the risks in CRSwNP. The literature regarding the effect of oral corticosteroids on CRSsNP is limited, and these studies lack adequate control groups to assess the effects attributable to oral corticosteroids. Given the balance of benefit versus harm, the following recommendations for CRSwNP and CRSsNP are listed as follows.

Recommendations:

Oral corticosteroids (CRSwNP): Option (Grade A evidence)
Oral corticosteroids (CRSsNP): No recommendation (Grade D evidence)

Antibiotics

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