Chronic rhinosinusitis without nasal polyposis: Management and prognosis

INTRODUCTION — Chronic rhinosinusitis without nasal polyposis (CRSsNP) is characterized by 12 weeks or more of at least two of four cardinal symptoms: nasal obstruction, anterior or posterior nasal discharge, reduction or loss of smell, and facial pain/pressure/fullness. In addition, there must be objective evidence of mucosal inflammation, either by direct visualization or on an imaging study (usually sinus computed tomography [CT] scan). The diagnosis of CRS is discussed separately. (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis".)

Chronic rhinosinusitis without nasal polyposis is abbreviated in the medical literature as CRSsNP ("s" for "sans" [French], meaning "without"). CRSsNP is the most common subtype of CRS, representing approximately 70 percent of all CRS patients. Other subtypes include chronic rhinosinusitis with nasal polyposis (CRSwNP) and allergic fungal rhinosinusitis (AFRS). It is important to distinguish these subtypes when considering management options. Information on how to manage the other subtypes is provided separately. (See "Chronic rhinosinusitis with nasal polyposis: Management and prognosis" and "Allergic fungal rhinosinusitis".)

GOALS OF THERAPY — People with CRSsNP experience a significant negative impact on quality of life (QoL). The primary goal of therapy is to improve disease-related QoL by controlling symptoms. Modern trial designs generally attempt to capture both subjective symptom control and objective measures of mucosal disease (eg, nasal endoscopy or imaging scores), although symptom control is the most important outcome to patients [1]. Most patients with CRSsNP cannot be cured but can achieve varying degrees of control of symptoms with long-term management.

It is also helpful to individualize goals with each patient, as some may value specific outcomes over others. As an example, one patient may have a strong preference for restoring a sense of smell if olfaction is important for their occupation, whereas another may wish to avoid use of antibiotics or oral glucocorticoids. However, educating the patient of the chronic nature of the disease and setting realistic expectations are important.

In patients with comorbid lower airway diseases such as asthma, chronic obstructive pulmonary disease (COPD), or bronchiectasis, another goal of medical therapy for CRSsNP is improved control of lower respiratory disease. (See "Relationships between rhinosinusitis and asthma".)

The approach outlined in this topic is consistent with published guidelines, particularly the 2021 International Consensus on Allergy and Rhinology-Rhinosinusitis (ICAR-RS) and the European Position Paper on Rhinosinusitis and Nasal Polyps 2020 (EPOS2020) [2,3]. (See 'Society guideline links' below.)

REFERRAL — Initial diagnosis and management of CRSsNP can begin with the generalist. However, when the diagnosis or subtype of CRS is uncertain, or if a patient does not benefit from initial therapy, referral to a specialist is appropriate.

●Otolaryngology specialists can help clarify a CRS diagnosis with nasal endoscopy and distinguish CRS subtypes (CRSsNP, chronic rhinosinusitis with nasal polyposis [CRSwNP], allergic fungal rhinosinusitis [AFRS]). They can obtain and interpret sinus images to identify complicating features. This includes addressing rare complications of sinusitis. Otolaryngology specialists can also obtain cultures from purulent material to guide treatment decisions and can perform sinus surgery. (See 'Functional endoscopic sinus surgery' below.)

●Allergy/immunology specialists can help identify and manage contributing factors including environmental factors (allergens, environmental tobacco smoke), comorbid airway diseases (asthma, chronic obstructive pulmonary disease [COPD], bronchiectasis), and immunodeficiency disorders (such as common variable immune deficiency or specific antibody deficiency).

INITIAL INTERVENTIONS FOR ALL PATIENTS — In all patients, we initially ensure that there are no danger signs to suggest complications or other conditions that can mimic aspects of CRSsNP. We then begin treatment with an intranasal saline spray or irrigation, an intranasal corticosteroid (INCS), or both for at least two months, as improvement is often gradual [4]. When saline and an INCS are used together, the saline should be used first to clear mucous and optimize mucosal absorption of the INCS. Once the saline has drained completely, patients can apply the INCS.

Assess for danger signs — A small minority of patients may develop complications of rhinosinusitis, such as expansion of infection/inflammation to involve the orbit or other structures. Specific complications include orbital involvement, mucocele formation, cavernous vein thrombosis, and frontal sinus erosion (Pott's puffy tumor) [5-7]. The following symptoms and signs require immediate evaluation:

●High fever

●Severe headache or meningeal signs

●Significant or recurrent epistaxis

●Orbital signs and symptoms (preseptal or orbital cellulitis, enophthalmos, epiphora, diplopia, proptosis, visual loss, or optic neuropathy)

If any of these signs or symptoms are present, urgent involvement of an otolaryngologist/head and neck surgeon, ophthalmologist, and/or neurosurgeon is indicated.

Saline — Saline irrigations thin and flush out mucus and inflammatory debris, reduce nasal irritants and allergens, and improve mucociliary function. Patients can perform irrigations as needed, which is usually one to three times daily. Saline can be delivered as a spray or high-volume rinse (60 to 240 mL) [2]. Larger-volume irrigations are more effective than nasal sprays [8,9]. Therefore, we favor a high-volume (240 mL) isotonic (0.9%) saline rinse as the first choice for most patients. To make the saline solution, which also contains baking soda to normalize pH [8], patients can buy commercially prepared packets or make their own solutions, and a patient handout is available (table 1). (See "Patient education: How to rinse out your nose with salt water (The Basics)".)

Either isotonic saline or hypertonic saline (usually 3%) can be used. Hypertonic saline, which theoretically draws fluid out of the nasal mucosa, may provide slightly better symptom improvement [9-11] but often causes more nasal irritation [2,12]. Similarly, water or hypotonic saline should be avoided because they can be irritating. Nasal saline irrigation is well tolerated by most adults, although children may not be able to perform it properly. Most complaints regarding use are related to nasal drainage after irrigation and Eustachian tube obstruction or irritation. Eustachian tube complaints can be reduced by instructing patients to relax the mouth and throat and allow irrigation to pass out through the other nostril, as well as into the oropharynx and out the mouth. In addition, avoiding nose blowing for approximately 15 minutes after irrigation will decrease the potential for auto-insufflating the Eustachian tubes with the saline solution. We advise patients to wait until the saline has completely drained before using the INCS so that the medication is not diluted.

Several devices for high-volume saline rinses are commercially available. The most common are squeeze bottles and neti pots. Patients should clean the device they are using for the rinse to avoid risk of bacterial contamination [13]. In our experience, patients are often unaware of this recommendation. Periodic microwaving and device replacement, along with use of distilled or boiled water to prepare the rinse, are ways to reduce contamination risk. Transmission of life-threatening infections through nonsterilized tap water has occurred, as discussed in more detail separately. (See "Pharmacotherapy of allergic rhinitis", section on 'Nasal saline'.)

Saline nasal sprays can be used instead of irrigations for patients who do not want to perform irrigations or find them uncomfortable.

Efficacy — Using saline is likely to improve symptoms and quality of life (QoL) with a small-to-moderate effect size, based on systematic reviews [2,8]. Studies allowing for a definitive recommendation of spray versus high-volume saline rinse specifically for CRSsNP are lacking. In the International Consensus on Allergy and Rhinology-Rhinosinusitis (ICAR-RS) guideline, high-volume (>60 mL) rinses are favored, whereas, in the European guideline on Rhinosinusitis and Nasal Polyps 2020 (EPOS2020), sprays and rinses are considered together [2,3].

Additives — Adding substances to saline rinse solutions, such as xylitol (proposed natural antimicrobial properties), alkalol (contains herbal antiseptics), or baby shampoo [14], may benefit some individuals but is not clearly supported by studies. The risks of their use should be weighed against the limited evidence for efficacy.

Intranasal corticosteroids — In keeping with guidelines and consensus statements, we recommend topical INCS as first-line pharmacotherapy for CRSsNP [2,3,15]. We typically start with an INCS delivered via a nasal spray, many of which are available without a prescription (table 2). Other delivery systems including addition of INCS to saline irrigations [16], drops that are applied directly into the nares, exhalation delivery systems [17,18], and nebulizations [19]. A detailed discussion of the other delivery systems for INCS is found separately. (See "Chronic rhinosinusitis with nasal polyposis: Management and prognosis", section on 'Intranasal corticosteroids'.)

The ability of different delivery systems to introduce medications into the paranasal sinuses is dependent on several factors, including whether the patient has had previous sinus surgery, the degree of mucosal edema, and the volume and pressure generated by the delivery system [20]. If patients have not had previous sinus surgery, INCS delivered by nasal sprays are unlikely to actually penetrate the sinus cavities, but they are still beneficial by reducing intranasal mucus production and mucosal edema at the outflow tracts of the various sinuses, thus improving drainage. In patients who have had surgery, solutions from sprays, but more likely irrigations, are sometimes able to enter the sinus cavities.

Our approach to using INCS is described here as definitive studies comparing different delivery systems in patients with CRSsNP are lacking:

●For patients who have not had prior sinus surgery, we suggest nasal sprays as the first option. We ensure that the patient understands proper technique and the importance of using the sprays every day to achieve the best treatment outcome.

To use an INCS spray properly, patients should tilt the head slightly forward, aim away from the septum, and avoid taking vigorous sniffs as the medicine is dispensed (so that it stays in the nasal passages and is not pulled down the throat) (figure 1).

●For patients who had previous sinus surgery or have not responded to INCS sprays used properly and consistently, we suggest a different delivery option. One option is to use glucocorticoid solutions designed for asthma nebulizers (eg, budesonide ampules, 0.5 mg/2 mL) mixed into a high-volume (60 to 240 mL) saline rinse, one or two times per day. There is less information about rinsing with glucocorticoids other than budesonide, but other formulations could be considered using dose-equivalent ranges, and several preparations of glucocorticoid "nasal drops" are available worldwide [21]. If an exhalation delivery system or nasal nebulizer is chosen, patients should follow manufacturers' instructions.

Safety and efficacy — INCS are unlikely to be associated with systemic adverse effects and are generally well tolerated and accepted by most patients [22]. They are likely to result in small-to-moderate improvements in symptoms and QoL, although studies of INCS delivered by simple nasal spray are mixed [2]. If the patient has not experienced benefit with a spray, therapy can be changed to glucocorticoid irrigations in a high-volume saline rinse [22].

Address contributing factors — Other initial considerations include potential management of allergic and irritant triggers, including:

●Allergic rhinitis should be suspected in patients with prominent sneezing or nasal or ocular pruritus. Additional therapies that may be helpful in patients with allergic rhinitis include nonsedating antihistamines, intranasal antihistamines, and allergen immunotherapy. (See "Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis" and "Allergen avoidance in the treatment of asthma and allergic rhinitis" and "Subcutaneous immunotherapy (SCIT) for allergic rhinoconjunctivitis and asthma: Indications and efficacy".)

●Tobacco smoking or secondhand exposure can worsen the symptoms of CRS [23]. Smoking cessation should be addressed. (see "Overview of smoking cessation management in adults" and "Pharmacotherapy for smoking cessation in adults")

●Primary or secondary immunodeficiency should be considered in patients with a history of pneumonia (one or more) and recurrent episodes of sinusitis requiring antibiotics. The most common type of immunodeficiency associated with CRSsNP are antibody defects, including specific antibody deficiency and common variable immunodeficiency. (See "Primary humoral immunodeficiencies: An overview", section on 'Presentation of humoral immunodeficiency'.)

●Gastroesophageal reflux disease or laryngopharyngeal reflux disease may contribute to refractory CRS. Reflux therapy may be considered in those with reflux and CRS, but use of proton pump inhibitors (PPIs) is not recommended specifically for the treatment of CRS [24]. (See "Medical management of gastroesophageal reflux disease in adults" and "Laryngopharyngeal reflux in adults: Evaluation, diagnosis, and management".)

MONITORING — Upon initiation of treatment, patients should be monitored at regular intervals. We usually ask patients to return three months after initiation of therapy and then every three to six months thereafter until symptoms are adequately managed. At each visit, we assess sinonasal symptoms and quality of life (QoL), perform a nasal exam (endoscopic if available), and review any use of oral glucocorticoids or antibiotics for exacerbations. We use validated symptom questionnaires such as the Sino-Nasal Outcomes Test (SNOT-22) to assess symptom severity of CRS-related QoL.

REFRACTORY SYMPTOMS

Reasons for inadequate response — If a patient has not had improvement in their symptoms and quality of life (QoL) after using saline and an intranasal corticosteroid (INCS) for at least two months, we confirm that the patient used these therapies consistently during the treatment period and with proper technique.

If there was good adherence and technique, we reconsider the diagnosis by considering the following questions:

●Was there convincing objective evidence on endoscopic exam or imaging to support a diagnosis of CRSsNP? (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis", section on 'Demonstration of mucosal disease'.)

●Is CRSsNP the correct subtype? (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis", section on 'Determining the subtype of disease'.)

●Is odontogenic sinusitis a possibility [25]? In one review, it was estimated that nearly 30 percent of unilateral maxillary sinusitis cases may arise from underlying dental pathology [26]. A complicated dental history or concerning examination can further increase clinical suspicion. Imaging of the teeth and collaboration with dental/oral surgeons are indicated. (See "Epidemiology, pathogenesis, and clinical manifestations of odontogenic infections" and "Complications, diagnosis, and treatment of odontogenic infections".)

●Could some of the symptoms be attributable to conditions other than CRSsNP? Common mimics include various forms of rhinitis (without sinusitis), headache and facial pain syndromes, and laryngopharyngeal reflux. (See "An overview of rhinitis" and "Evaluation of headache in adults" and "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis", section on 'Differential diagnosis'.)

If an otolaryngologist has not been consulted yet, it is helpful to pursue referral at this point. (See 'Referral' above.)

Choice of next intervention — Even with optimal use of INCS and intranasal saline, many patients experience only modest improvement. There are several options for next steps, with few comparative studies to support one therapy over another. The following is the authors' approach (algorithm 1). Two common next steps are either short courses of oral glucocorticoids and/or antibiotics or referral to an otolaryngologist for sinus surgery.

Short course of oral glucocorticoids and/or antibiotics — For most patients with inadequate relief after several months of saline and INCS, we favor the combination of an oral glucocorticoid and oral antibiotics for 10 to 14 days. This is common practice, although supporting data are sparse. The International Consensus on Allergy and Rhinology-Rhinosinusitis (ICAR-RS) lists both oral glucocorticoids and antibiotics as treatment options but does not specifically recommend either or the combination for patients with CRSsNP, due to lack of data [2]. If clearly purulent discharge is visible, we may prescribe an antibiotic alone, without oral glucocorticoids. However, it can be difficult even to appreciate if the mucus is purulent. Some patients with CRSsNP will have clearly mucopurulent drainage on exam, but most have only thickened secretions that are not clearly purulent, making the differentiation between infection and inflammation difficult without culture information. If there is no purulence but notable mucosal edema, we may prescribe glucocorticoids alone. If both purulent secretions and mucosal edema are present, we usually give combined therapy.

●In adults, the authors prefer prednisone 40 mg per day for five days, then 20 mg per day for five days, taken with food in the morning. However, the optimal regimen has not been determined, and other shorter or longer systemic glucocorticoid courses, depending on patient preference and comorbidities, are suitable. For example, longer courses of an oral glucocorticoid, such as 20 days, have also been suggested [27].

●We select an antibiotic based on culture of material obtained endoscopically from a sinus cavity whenever possible. (Note that cultures obtained by swabbing the nasal cavities generally reflect skin flora and are not useful.) If culture is not possible, then the choice of antibiotics is empiric and guided by additional factors such as local resistance patterns and potential for adverse effects. Empiric choices of antibiotics for CRS are reviewed in more detail elsewhere (see "Microbiology and antibiotic management of chronic rhinosinusitis", section on 'Empiric regimen selection'). We usually give a 10- to 14-day course, occasionally extending it if the patient is not fully improved or purulence persists at the end of 14 days.

Efficacy — High-quality evidence is lacking for oral glucocorticoids, oral antibiotics, or the combination specifically for CRSsNP [2]. In one retrospective study, 100 patients with CRSsNP were treated either with oral (nonmacrolide) antibiotics, oral glucocorticoids (variable regimens), or both for 10 to 21 days [27]. All three groups showed similar improvement in objective Lung-MacKay scores, and there was no difference in the percentage of each group that eventually required surgery. Use of glucocorticoids is also based on studies showing that approximately 55 percent of CRSsNP have type 2 inflammation, which could reasonably be expected to improve with oral glucocorticoids [2]. Note that the repeated use of systemic glucocorticoids and antibiotics, even if helpful over the short term, is not an effective long-term management plan due to the long-term adverse effects (table 3).

Functional endoscopic sinus surgery — In patients in whom medical treatment does not result in sufficient improvement in symptoms, the next logical step is sinus surgery. Functional endoscopic sinus surgery (FESS) involves removing tissue around the natural drainage pathways (the ostia) of the paranasal sinuses to widen the outflow tracts. Restoring physiologic sinus ventilation and drainage can facilitate the gradual resolution of mucosal disease. The mucosal lining is disturbed as minimally as possible. CRSsNP can involve some or all of the four sinuses (frontal, ethmoid, maxillary, and sphenoid), and sinus surgery can similarly involve just some or all of the sinuses at the discretion of the surgeon (figure 2).

FESS typically requires general anesthesia and is most often performed through an endoscope, such that there is no external visible incisions. Patients will experience some discomfort and congestion for several days after the surgery. The major risk is bleeding, but absolute complication rates are low (eg, <5 percent for all complications and <1 percent for serious complications) [2].

Indications for sinus surgery — FESS does not directly treat the underlying inflammation that causes CRSsNP, and thus sinus surgery is not typically considered the first intervention for CRSsNP. Instead, FESS is performed in conjunction with medical management to control inflammatory processes. Without ongoing medical management, symptoms will usually return.

Indications for surgical intervention in patients with CRSsNP include the following:

●Failure of medical treatments (ie, those discussed above)

●Inability of topical therapies to penetrate the nasal passages despite medical therapy

●Bony erosion or extension of disease beyond the sinus cavities

CRS is an inflammatory disorder of the sinonasal mucosa, and underlying structural abnormalities, such as septal deviation and enlarged sinus structures (eg, turbinates, concha bullosa, large Haller cells), are not known to occur at a higher frequency in patients with CRS compared with controls [2].

Approaches for severe or recurrent sinus disease — In some cases of severe and/or recurrent inflammation despite maximal medical management and previous surgery, extended approaches are used. The most common is maximal widening of the openings of the sinuses. Examples include maxillary sinus mega-antrostomies to extend the opening to the floor of the nasal cavity and frontal sinus drill-out procedures (Modified Lothrop or Draf III) that remove the entire floor of the frontal sinus while connecting the right and left sinuses together. These procedures are beyond the scope of this topic but are employed in cases of severe CRSsNP.

Efficacy — In a 2017 systematic review and meta-analysis, FESS was compared with continued medical treatment in patients who had already received appropriate medical therapy, defined in this analysis as usually consisting of eight weeks of INCS and three weeks of antibiotics. Approximately one-half of the studies also included one to two weeks of oral glucocorticoids [28]. Patients chose their treatment using shared decision making. Over the subsequent year, patients who underwent surgery attained relatively greater improvement compared with those who continued medical therapy. However, it was not possible to make a direct comparison because patients with lower QoL scores tended to choose FESS, while those with higher scores chose continued medical management.

Several studies have shown durable improvement in patient symptoms with surgery over 5 and 10 years [29,30]. In addition, in patients with both asthma and CRS, there is some evidence that FESS combined with ongoing medical therapy results in better long-term asthma control than medical management alone [31,32]. A systematic review and meta-analysis of 22 studies examining the impact of FESS on asthma in patients with CRS demonstrated reduction in asthma exacerbations, decrease in systemic and inhaled corticosteroids, and overall improvement in asthma control; however, there was no improvement in lung function [33].

Adjuncts to sinus surgery — Adjuncts to sinus surgery include steroid-eluting stents and dressings.

●Steroid-eluting stents and dressings:

•Implants – Bioabsorbable sinus implants that elute mometasone are approved by the US Food and Drug Administration (FDA) specifically for maintaining the patency of the frontal or ethmoid sinus openings after FESS [34,35]. The implants deliver 370 mcg of mometasone furoate over 30 days. Data from two randomized trials including 143 patients demonstrated that the drug-eluting ethmoid implants reduced the need for postoperative interventions and oral glucocorticoids [36].

•Nasal packing materials – At the end of surgery, surgeons can mix glucocorticoid with bioabsorbable packing material. Although this technique is presumably safer than repeated or sustained oral glucocorticoids, the safety of direct application and systemic uptake of this non-US FDA-approved method is not definitively known, and supporting evidence is limited [37,38].

●Balloon ostial dilation — Balloon ostial dilation (BOD) is a procedure in which the frontal, sphenoid, or maxillary sinus ostium is dilated using a balloon catheter. This procedure also goes by other names, including "sinus ostial dilation" and "balloon catheter sinusotomy," but "balloon ostial dilation" is the terminology recommended by the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS). Note that BOD cannot be used to widen the ethmoid sinuses given the multiple air cells involved and convoluted drainage pathway. The ethmoid sinuses are typically an area of significant inflammation in CRS, and FESS is still needed when the ethmoid sinuses are involved.

BOD does not involve surgical removal of tissue and can be performed in the office setting under local anesthesia in adolescent and adults. Because no tissue is removed, BOD is less effective compared with FESS in patients with significant inflammation, and there is concern that allowing diseased tissue to remain in place inhibits resolution of the inflammation. However, it may be an adequate alternative to FESS in those with mild disease. Uptake of this technique is variable. Often, it is performed in the same setting as traditional FESS as an adjunct technique to facilitate widening of the drainage pathway of more difficult sinuses (ie, frontal). Although durable improvement in CRS symptoms have been demonstrated with this technique, data comparing BOD and FESS for the management of CRS are limited and mostly sponsored by manufacturers of the balloon catheters [39-44].

A 2018 consensus statement suggested that BOD may be beneficial as an adjunct procedure to FESS in patients with CRSsNP and in widening stenosed sinus openings in patients with previous sinus surgery [45].

Need for revision sinus surgery — In most studies evaluating long-term outcomes (eg, 5 to 10 years) after FESS, between 15 and 20 percent of patients with all types of CRS require repeat surgery, although most of these patients have CRSwNP. In one study that included data specifically on outcomes in patients with CRSsNP, only 3 percent of 59 patients required repeat surgery over the course of a decade of follow-up [30].

Common reasons for patients to not improve after FESS or to require repeat sinus surgery include:

●Inconsistent adherence to maintenance therapies (usually intranasal saline and INCS).

●Incomplete or improper sinus surgery. One possible complication of FESS is mucus recirculation syndrome, a condition in which mucus draining through a sinus ostium reenters the sinus through a different ostium rather than draining down the nasopharynx [46-52]. The vast majority of cases involve the maxillary sinus [46]. In most cases, the problematic ostium was surgically created, although mucus recirculation can also arise from an accessory sinus ostia (which can be congenital or form spontaneously). Patients suspected of having this disorder should be evaluated by an otolaryngology specialist [48]. Irrigation may sometimes resolve this problem. However, surgery to remove the tissue separating the two ostia and create a single ostium has been reported to be curative [46,53].

●Unrecognized and untreated comorbid conditions, such as allergic rhinitis or immunodeficiency.

●An unrecognized odontogenic source of infection [25]. (See 'Reasons for inadequate response' above.)

OTHER MEDICAL THERAPIES

Extended course of a macrolide antibiotic — In patients with CRSsNP, macrolides are used primarily for their antiinflammatory and immunomodulatory effects, rather than their antimicrobial effects, similar to their use in asthma [54]. Administration of an oral macrolide antibiotic for 4 to 12 weeks is a treatment option for CRSsNP that has not responded to other measures [2]. This approach is sometimes chosen for patients with non-type 2, noneosinophilic inflammation, although there are no definite biomarkers to identify patients who will respond. (See 'The role of endotypes' below.)

If we select this option as a result of shared decision making with the patient, we usually administer a 12-week course of azithromycin (either 250 or 500 mg three times per week) after reviewing the small risk of adverse effects and assessing for possible drug interactions. However, the best macrolide antibiotic to choose, the dose of drug, and the duration of treatment have not been studied adequately. We favor azithromycin because it is generally well tolerated and has fewer drug interactions and adverse effects than other macrolides. We avoid clarithromycin in particular in patients with cardiovascular disease. (See "Azithromycin and clarithromycin", section on 'Adverse reactions'.)

Evidence of the benefit of macrolides in CRS is limited, and the available studies do not clearly show that macrolides are superior to other treatments.

●In a 2017 systematic review that included patients with all types of CRS, the quality of the evidence for use of macrolides in CRS was low in general but looked most promising for patients with NP who had already undergone surgery [55]. Only three trials included in the systematic review were limited to patients with CRSsNP. In one, 12 weeks of a daily macrolide provided some benefit over placebo; however, the benefit was not sustained after cessation of therapy [56]. In the other two studies, macrolides were compared with other treatments (mometasone nasal spray or Chinese herbal medicine) without placebo controls and appeared to have similar efficacy [57,58].

●A subsequent randomized trial compared four weeks of amoxicillin-clavulanate plus a short course of oral glucocorticoid (ie, the approach mentioned previously) with eight weeks of clarithromycin in 57 patients with CRSsNP [59]. Thirty-seven patients completed the study, and Sino-Nasal Outcome Test (SNOT-20) and imaging scores improved to similar degrees, although the group receiving amoxicillin-clavulanate had significantly more adverse reactions. After treatment, functional endoscopic sinus surgery (FESS) was required for uncontrolled symptoms in 35 and 41 percent of patients who received amoxicillin-clavulanate plus glucocorticoids or clarithromycin, respectively.

In an effort to clarify the role of long-term macrolides, the Defining best Management for Adults with Chronic RhinOsinusitis (MACRO) trial, a multicenter, randomized clinical trial designed to compare long-term macrolide therapy with endoscopic sinus surgery in patients in whom initial therapy with saline and INCS failed, has been initiated in the United Kingdom [60-62]. Results are pending.

Biologics for patients with coexistent conditions — No biologic agent is specifically approved for the treatment of CRSsNP, and data demonstrating efficacy for CRSsNP are very preliminary [63,64]. However, biologic therapies can be given to patients with concomitant conditions for which there are established biologic treatments, most commonly asthma. In patients with both CRSsNP and moderate-to-severe asthma that is not adequately controlled with inhaled glucocorticoids and long-acting beta agonists, we sometimes offer one of the biologics for asthma: dupilumab, omalizumab, mepolizumab, reslizumab, benralizumab, or tezepelumab, with the choice based on the characteristics of the patient's asthma (table 4) (see "Treatment of severe asthma in adolescents and adults"). The same approach can apply to patients with other coexisting conditions that are treated with biologics (eg, severe atopic dermatitis, urticaria refractory to antihistamines, etc).

The role of endotypes — Endotypes refer to classifications of CRS based on pathophysiology and profiles of underlying inflammation, as determined by biomarkers and gene expression [65]. In patients with asthma, endotyping may help direct therapy as patients with type 2 inflammation may respond better to glucocorticoids and certain biologic therapies (ie, dupilumab and omalizumab). CRSsNP can be categorized into three different endotypes, independent of the presence of polyps: type 1 (21 percent), type 2 (55 percent), and type 3 (27 percent), at least in European and North American patient populations [2,66,67]. However, the prevalence of the various endotypes differs around the world, and some patients do not appear to have any of these endotypes [68].

The subset of patients with both CRSsNP and asthma with evidence of type 2 inflammation could be expected to respond to some degree to biologics that target immunoglobulin E (IgE; omalizumab) or interleukin (IL) 4/13 (dupilumab). Patients with prominent eosinophilia in the peripheral blood or respiratory tract tissues could be expected to respond to biologics that target IL-5 (mepolizumab and reslizumab) or its receptor (benralizumab).

Although the definition of type 2 inflammation is not standardized, the following criteria are used most often to identify the presence of type 2 inflammation:

●Elevated blood eosinophils (>150/microL)

●Elevated total IgE >100 international units/mL

●Sensitivity to environmental allergens on skin testing or in vitro allergen-specific IgE immunoassays

●Sinus tissue eosinophilia (when this information is available as a result of sinus surgery)

●Fractional exhaled nitric oxide (FeNO) ≥25 ppb (in patients with concomitant asthma)

Although there is some preliminary evidence of benefit of biologics in CRSsNP [63,64], more study is needed.

Other therapies without strong supporting evidence — Additional therapies that lack adequate supporting evidence include traditional Chinese medicines [69], topical or systemic antifungals [70], probiotics [71], acupuncture [72], Ayurvedic medicine [73], crenotherapy [74], Manuka Honey, mucoactive drugs, decongestants, herbal treatments, and homeopathy. In agreement with guidelines, we do not advocate use of these therapies [2].

MAINTENANCE THERAPY — For patients whose symptoms become adequately controlled as a result of medical or surgical treatment, maintenance with saline (rinse or spray) and intranasal corticosteroids (INCS) is usually continued long term. If symptoms are completely controlled, we gradually lower therapy, first reducing the INCS dosing (including conversion of a rinse or exhalation delivery system to a spray) over months to years. A trial off INCS could be considered after being stable for several months or longer on the lowest dose. Saline spray or rinse is sometimes maintained indefinitely, although some patients may be able to successfully stop them as well.

TREATING EXACERBATIONS — Acute exacerbations of CRS have been defined as transient worsening of symptoms that returns to baseline either without intervention or after intervention with antibiotics and/or glucocorticoids [2]. The cause of acute exacerbations is likely multifactorial and includes viral infections (likely the most frequent cause), bacterial infections, medication nonadherence, and allergen or irritant exposure. The evidence for treatment of CRSsNP exacerbations is extremely limited.

Ideally, patients with CRSsNP who experience worsening symptoms should be evaluated with nasal endoscopy because the information obtained may be able to clarify whether a bacterial infection is likely or not. When a bacterial infection is suspected (symptoms lasting more than seven days with purulent nasal drainage), we suggest an endoscopically obtained sinus culture to guide antibiotic therapy. Debridement of purulent secretions may also be helpful. The addition of an oral glucocorticoid can be considered when severe edema is present on examination, when patients have had previous favorable responses to glucocorticoids, or for a coexisting asthma exacerbation.

●Oral antibiotics are often given to treat exacerbations of CRS with purulent secretions. Patients with CRSsNP with uncomplicated bacterial infections can be treated similarly to an acute uncomplicated bacterial sinusitis (algorithm 2). (See "Uncomplicated acute sinusitis and rhinosinusitis in adults: Treatment".)

●A brief escalation of topical corticosteroid therapy can be sufficient to alleviate symptoms of an acute exacerbation in some patients. Examples include changing from a corticosteroid nasal spray to undiluted budesonide respules or to a 10- to 14-day tapering course of oral glucocorticoids (see 'Intranasal corticosteroids' above). Following resolution of the acute exacerbation, the patient should return to their usual intranasal corticosteroid (INCS) delivery mode to minimize potential adverse effects of the concentrated budesonide. Oral glucocorticoids are sometimes indicated for concomitant asthma exacerbations.

●Irrigations with antibiotic solutions are also used both for exacerbations and as an adjunctive therapy, typically in patients who have undergone previous sinus surgery but continue to produce mucopurulent secretions [75]. If we offer this treatment, we base the choice of antibiotic on culture data and typically treat for two to four weeks, performing a follow-up examination near the conclusion of treatment. Studies of efficacy in all types of CRS are reviewed separately. (See "Microbiology and antibiotic management of chronic rhinosinusitis", section on 'Limited role for other antibiotic routes'.)

SPECIAL POPULATIONS

Children — Medical management of CRSsNP in children includes the use of saline and intranasal corticosteroids (INCS) as in adults [2]. Children vary in the age at which they can perform irrigations themselves. Monitoring growth and other signs of systemic glucocorticoid adverse effects, especially in children who have other topical corticosteroid exposure (eg, skin, lungs, gastrointestinal tract), helps with management choices. For acute exacerbations, we use treatment algorithms developed for acute bacterial rhinosinusitis (algorithm 3 and algorithm 4) (see "Acute bacterial rhinosinusitis in children: Microbiology and management"). Systemic antibiotics with or without systemic glucocorticoids can be considered [76].

Important differences in the management of CRSsNP in children and adults are the following [77]:

●The role of adenoidal hypertrophy is more important in children, and, in children with enlarged adenoids, adenoidectomy should be performed before functional endoscopic sinus surgery (FESS) is considered.

●The use of long-term antibiotics (macrolides or other) has not been shown to be effective.

●The impact of biologics on pediatric CRSsNP has not been studied.

Surgical interventions in children — Surgical procedures should be considered in children only after medical therapy has failed, and decisions should be individualized.

●Adenoidectomy – In children with CRS and adenoidal hypertrophy who have not improved sufficiently with medical therapy, adenoidectomy appears beneficial in observational studies, although controlled trials are lacking [78,79]. Adenoidectomy is suggested before FESS in young children with CRS and adenoidal hypertrophy [78,80]. The available literature regarding adenoidectomy in children with CRS is reviewed in more detail separately. (See "Tonsillectomy and/or adenoidectomy in children: Indications and contraindications", section on 'Chronic sinusitis'.)

●Functional endoscopic sinus surgery – FESS in children appears to be safe, but efficacy compared with other surgical interventions, biologics, or ongoing medical therapies is unclear. FESS in children is usually performed only on the maxillary sinuses, which are lavaged during the same procedure. A 2013 systematic review of the literature evaluating FESS for the treatment of refractory CRS in children included 11 studies [81]. Among those, there were three prospective studies but no randomized, controlled trials and no uniformity in outcomes assessed. There were 6 complications in 440 surgeries (1.4 percent). Most studies reported subjective measures of improvement with success rates between 82 and 100 percent, but the quality of the evidence was low.

●Pediatric balloon ostial dilation — Balloon ostial dilation (BOD) is an option for children with CRSsNP, which can be performed at the discretion of the otolaryngologist, but its role in the management of CRSsNP requires further study. It may be difficult for children to tolerate as an office procedure. Most studies have involved widening the drainage pathways of the maxillary sinuses only. Earlier prospective pediatric cohort studies of BOD, with or without ethmoidectomy or adenoidectomy, suggested benefit beyond that of adenoidectomy alone [82-84]. A 2020 meta-analysis of BOD in children with CRS identified 10 studies, of which three compared BOD with adenoidectomy, saline irrigation, or maxillary antrostomy (ie, surgical widening of drainage pathways) [85]. Two of these studies found BOD to be inferior to standard techniques. In a subsequent study, BOD appeared similarly effective to adenoidectomy plus lavage of the maxillary sinuses [86].

Pregnancy — INCS sprays used at the lowest effective dose and saline irrigations are considered safe during pregnancy [87]. High-quality evidence for management options for CRSsNP specifically during pregnancy is lacking. Studies of the use of INCS in pregnancy for other allergic disorders are discussed separately. (See "Recognition and management of allergic disease during pregnancy".)

For acute exacerbations during pregnancy, decisions on management should account for pregnancy safety data for antibiotics and oral glucocorticoids.

PROGNOSIS — Long-term outcomes in patients with CRSsNP are poorly studied. An international registry has been established to collect data on the natural history of the disorder and treatment outcomes [88].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic rhinosinusitis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Chronic sinusitis (The Basics)" and "Patient education: How to rinse out your nose with salt water (The Basics)")

●Beyond the Basics topic (see "Patient education: Chronic rhinosinusitis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definitions – Chronic rhinosinusitis without nasal polyposis (CRSsNP) is a complex inflammatory condition involving the paranasal sinuses and linings of the nasal passages, which lasts 12 weeks or longer. Symptoms include nasal obstruction or blockage, thick nasal drainage, facial pressure, and reduction in sense of smell. Nasal polyps are not present in CRSsNP. (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis".)

●Initial therapies – Our treatment approach is depicted in the algorithm and is consistent with multiple guidelines (algorithm 1). In patients with CRSsNP, we suggest a combination of intranasal corticosteroids (INCS) and intranasal saline as initial therapy, rather than either therapy alone or treatment with oral glucocorticoids or antibiotics (Grade 2C). Treatment should be continued for at least two months as improvement may be gradual. It is important to teach patients the proper techniques for using nasal sprays and nasal irrigations (figure 1). (See 'Initial interventions for all patients' above.)

•Intranasal corticosteroids – We begin with commercially available nasal sprays (table 2). If patients have insufficient benefit from nasal sprays, we try other delivery systems, such as adding corticosteroid solutions to saline irrigation, nasal drops, nasal nebulizations, or exhalation delivery systems. (See 'Intranasal corticosteroids' above.)

•Intranasal saline – We suggest high-volume (60 to 240 mL) saline irrigations rather than low-volume saline sprays (Grade 2C). Isotonic saline is better tolerated than hypertonic saline. (See 'Saline' above.)

Even with optimal and consistent use, many patients experience only modest improvement with these initial interventions. (See 'Reasons for inadequate response' above.)

●Patients with persistent symptoms – For patients with persistent symptoms, there are several options for additional treatments but very few studies to define their relative efficacy. We suggest a short course of both oral glucocorticoids and antibiotics (Grade 2C); however, treating with either glucocorticoids or antibiotics as monotherapy or referral for sinus surgery are reasonable alternatives in these patients (algorithm 1). (See 'Choice of next intervention' above and 'Short course of oral glucocorticoids and/or antibiotics' above and 'Referral' above.)

●Sinus surgery – For patients with persistent symptoms despite the nonsurgical interventions mentioned above, we suggest sinus surgery (Grade 2C). Functional endoscopic sinus surgery (FESS) involves removing tissue around the natural drainage pathways (the ostia) of the paranasal sinuses to widen the outflow tracts (figure 2). Restoring physiologic sinus ventilation and drainage can facilitate the gradual resolution of mucosal disease, but surgery must be followed by ongoing medical therapy to address mucosal inflammation. (See 'Functional endoscopic sinus surgery' above.)

The surgical approach differs in children. Many children with CRSsNP will have enlarged adenoids, and, in such patients, adenoidectomy should be performed before FESS is considered. (See 'Children' above.)

●Other medical therapies – Other medical therapies include an extended course of macrolide antibiotics and one of several respiratory biologic therapies if there is an indication for a biologic (usually moderate-to-severe asthma). These treatments can be prescribed in patients who have contraindications to sinus surgery or have recurrent symptoms following surgery. (See 'Other medical therapies' above.)

There are no approved biologic therapies for CRSsNP, but if the patient has a coexisting condition that can be treated with a respiratory biologic (ie, dupilumab, omalizumab, mepolizumab, reslizumab, benralizumab, or tezepelumab), the CRSsNP symptoms may also improve. (See 'Biologics for patients with coexistent conditions' above.)

●Maintenance therapy – For patients whose symptoms become adequately controlled as a result of medical or surgical treatment, maintenance with saline (rinse or spray) and INCS is usually continued long term. We have the patient continue with the delivery method that worked best for them, at the lowest dose that maintains symptom control. (See 'Maintenance therapy' above.)

●Managing acute exacerbations – CRSsNP can worsen periodically due to viral or bacterial infections, medication nonadherence, and allergen or irritant exposure. Symptoms sometime spontaneously return to baseline, but, if not, the choice of treatment (oral or topical antibiotics, a temporary change to a more intense form of INCS, or a brief course of oral glucocorticoids) depends on the suspected cause. (See 'Treating exacerbations' above.)

●Prognosis – Long-term outcomes in patients with CRSsNP are poorly studied, although many patients require indefinite treatment. (See 'Prognosis' above.)