Current Medical Management of Chronic Rhinosinusitis in Adults (2024)

Rhinosinusitis is a prevalent disorder that places a heavy financial strain on society in terms of medical expenses and lost productivity. It is characterized by discomfort and pressure in the face, sinus and nasal lining irritation, nasal obstruction, rhinorrhea, and loss of smell. It occurs with or without nasal polyps. This chapter aims to evaluate and review each medical intervention for chronic rhinosinusitis to provide analysis and medical management recommendations. It is known that medical management of chronic sinusitis is a complex subject with many options available with different advantages and disadvantages, and so during our literature review, we focused on reaching to recommendations based on the latest and most accurate available studies from double-blinded randomized controlled clinical trial and meta-analyses using Ovid Medline, CINAHL, Scopus, and Cochrane. We focused on studies that compared the different types of medical management options to a placebo and in some instances to other drugs regarding how the patient’s quality of life and disease burden improved. Based on our literature review, medications that showed benefit and improved patient quality of life were intranasal/systemic steroids, saline irrigation, biologics Anti-IL-5 and Anti-IL4/IL13, antihistamine, and montelukast. Other mentioned medical interventions need larger and higher-quality studies.

Author Information

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• Moath Abdulrahman Alfaleh*

  • Department of Otolaryngology-Head and Neck Surgery, King Fahad Specialist Hospital, Dammam, SaudiArabia

*Address all correspondence to: moathalfaleh@hotmail.com

1. Introduction

In much of the world, rhinosinusitis is a prevalent disorder that places a heavy financial strain on society in terms of medical expenses and lost productivity. It is characterized by discomfort and pressure in the face, sinus and nasal lining irritation, nasal obstruction, rhinorrhea, and loss of smell. It can occur with or without nasal polyps. This chapter aims to evaluate and review each medical intervention for chronic rhinosinusitis to provide analysis and medical management recommendations. As it is known that medical management of chronic sinusitis is a complex subject with many options available with different advantages and disadvantages, and so, during our literature review we focused on reaching to our recommendations based on the latest and most accurate available studies from double-blinded randomized controlled clinical trial and meta-analyses through using Ovid Medline, CINAHL, Scopus, and Cochrane, in which we focused on studies that compared the different types of medical management options to a placebo and in some instances to other drugs in regard to how the patient’s quality of life disease burden improved. Based on our literature review, medications that showed benefit and improved patient quality of life were intranasal/systemic steroid, saline irrigation, biologics Anti-IL-5 and Anti-IL4/IL13, antihistamine, and montelukast. Other mentioned medical interventions need larger and higher-quality studies.

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2. Short-term oral antibiotics for chronic rhinosinusitis (CRS)

In basic and secondary care settings, individuals with chronic rhinosinusitis (CRS) are frequently offered short-term regimens of antibiotics [1]. More proof is required to fully understand the function of antibiotics in the treatment of CRS. For this evaluation, 4 weeks or less is considered a short treatment period for antibiotics. Two published randomized clinical studies with a placebo control have examined the impact of short-term antibiotics in CRS [2, 3]. Thirty-two individuals with acute on chronic CRS exacerbations participated in a single-center, placebo-controlled trial [2]. In this study, an immediate worsening of sinonasal symptoms in the previous 4 weeks (nasal secretion, nasal obstruction/congestion, sense of smell, and/or face discomfort) in patients with underlying CRS was considered as an acute aggravation of the CRS condition. For 2 weeks, patients were randomly assigned to receive either a placebo or amoxicillin/clavulanate. Despite the fact that both groups’ nasal secretions and nasal blockage significantly improved from baseline, on the Visual Analog Scale-Severity Scoring Assessment, there were no statistically significant changes between the groups [nasal secretion: mean difference (MD) -2 (−16.1, 12.1), p=0.44; nasal obstruction: MD – 6.6(−10.6, 24), p=0.78]. Nose endoscopic scores at day 14 did not differ between the groups (overall endoscopy score, p=0.88; nasal polyps, p=0.58; oedema, p=0.36; nasal secretion, p=0.42). After 3 months, the groups’ improvements in quality of life (Sino-nasal Outcome Test, SNOT-22) were comparable [MD -2.7 (−20.36, 14), p=0.75]. There was a notable observation of bacterial eradication in 29% of the amoxicillin/clavulanate group and 9% of the placebo group; nevertheless, there was no statistically significant difference seen between the groups (p=0.37).

A double-blinded, placebo-controlled randomized controlled study (RCT) was carried out by Van Zele et al. [3] to evaluate the efficacy of doxycycline in the treatment of CRS with nasal polyps (CRSwNP) in 28 patients. After starting doxycycline therapy, there was a significant reduction in postnasal drip symptom ratings at week 2 (p=0.044) and a tendency toward a decrease in rhinorrhea at week 8 (p=0.058) (no adjustments were made for multiple testing). During the trial period, doxycycline did not significantly affect rhinorrhea, postnasal drip, or nasal congestion. It also did not significantly affect loss of smell. For 3 months, the doxycycline group showed a little but significant decrease in nasal polyp size (0,5 on an 8-point scale) in comparison to the placebo group (p=0.015).

Ninety patients were included in the analysis of a single-blind, randomized, controlled trial that took place between 2018 and 2019 [4]. For 4 weeks, the patients in the clarithromycin group were given 500mg pills twice a day. For 4 weeks, the second group took 500mg pills of azithromycin every day. The group treated with azithromycin saw a considerably greater rate of complete symptom remission (71.1 vs. 24.4%, P<0.001) than that treated with clarithromycin. There was no significant difference (P=0.120) in the baseline Lund Mackay ratings between the groups. Nevertheless, both groups saw a substantial decrease in Lund Mackay scores following the intervention; however, the azithromycin group experienced a significantly larger improvement (P<0.001).

In a randomized controlled trial, the authors measured the levels of two frequently given antibiotics, roxithromycin and doxycycline, in the sinonasal mucus, serum, and sinonasal tissues of patients with CRS after a one-week treatment [5]. Two groups were randomly assigned to twenty patients after they undergone functional endoscopic sinus surgery (FESS) for chronic rhinosis (CRS): (1) 100mg of doxycycline every day for 7 days and 2) 300mg of roxithromycin per day for 7 days. Liquid chromatography-tandem mass spectrometry was used to detect drug levels in steady state in blood, sinonasal tissues, and mucus. The amounts of doxycycline in the mucus were found to be substantially lower than those in the tissue (mean mucus/tissue ratio 1/4 0.18, p<0.0001) and serum (mean mucus/serum ratio 1/4 0.16, p<0.001). The concentration of roxithromycin in the mucus was likewise considerably lower than that in the tissue (mean mucus/tissue ratio 1/4 0.60, p<0.001) and serum (mean mucus/serum ratio 1/4 0.37, p 1/4 0.002).

Because of the complexity of bacterial biofilm antimicrobial tolerance, the effectiveness of doxycycline and roxithromycin in sinonasal mucus in vivo cannot be predicted solely from reported minimum inhibitory concentrations. However, these results suggest that low mucosal penetration of antibiotics may be one of the factors contributing to the limited efficacy of these agents in the treatment of CRS.

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3. Long-term oral antibiotics for chronic rhinosinusitis (CRS)

Long-term antibiotic therapy was defined for the purposes of this systematic review as any course of treatment lasting more than 4 weeks. A few placebo-controlled trials have examined the effects of treating acute rhinosinusitis with antibiotics, despite the fact that this approach is often used. Two such studies assess the results of prolonged administration of macrolide antibiotics. The effects of long-term macrolide treatment on signs, symptoms, and patient-reported quality of life outcomes have been examined in two completed placebo-controlled trials [6, 7]. Both trials assessed a 12-week course of therapy; however, Wallwork et al. assessed roxithromycin at 150mg daily, while Videler et al. assessed azithromycin (AZM) at 500mg per week. In terms of nasal endoscopy, saccharin transit time, and SNOT-20 scores, Wallwork and colleagues demonstrated a notable improvement. In Wallwork and colleagues, groups were separated into low and high IgE levels (less than 200μg/L against more than 200μg/L); the low IgE group showed a substantial improvement in endoscopy, saccharin transit time, and nasal lavage of IL-8. Nevertheless, Videler et al.’s results did not improve, and since IgE was not assessed, a subgroup analysis was not feasible. By the time the study came to a close, Videler and colleagues had seen a nonsignificant improvement in 35% of the placebo group and 51% of patients on Azithromycin. Remarkably, 50% of the Azithromycin group claimed “improvement/cure” when the groups were reassessed by phone 12weeks after the antibiotics ended, compared to 9% in the placebo group. This was statistically significant (p=0.017). The response rate for Wallwork and colleagues was 67% in the roxithromycin group and 22% in the placebo group. Despite having comparable study numbers (60 vs. 64), the inclusion criteria of these research differed. Videler included individuals with and without nasal polyps, but Wallwork et al. exclusively included patients without nasal polyps. In the Wallwork et al. paper, patients were sub-analyzed according to their IgE levels, as previously mentioned. The majority of nonresponders were in the high IgE group. Another important difference was the dosing regimen, which in the study done by Videler etal. it was a once-weekly dosing compared to Wallwork et al.’s low-dose daily dosage.

A double-blind, randomized, placebo-controlled trial was conducted by de Oliveira et al. [8]. For 12weeks, patients were given 500mg of azithromycin orally three times a week. Sino-Nasal Outcome Test (SNOT-22), and nasal polyp biopsies were used to assess improvement. Data gathered 3 months after therapy and before treatment were compared. Evaluation of quality of life took place at the 1-year follow-up. For a duration of 12weeks, treatment with 500mg azithromycin three times a week resulted in a reduction in the amount of eosinophils in polyp biopsies, polyp staging, and a substantial clinical improvement based on subjective improvement as assessed by a quality-of-life questionnaire (the SNOT-22). On the other hand, the placebo group did not exhibit any noteworthy changes before or during the intervention. Furthermore, after the 1-year follow-up after therapy, the azithromycin group’s improved quality of life persisted. Even though the current literature suggests that azithromycin therapy should be administered only to CRS patients with low polyposis and IgE, the outcomes that were seen in this particular patient group were unexpected.

Metanalysis conducted by Do Hyun Kim et al. to assess the efficacy of doxycycline (DOX) versus traditional therapy for individuals suffering from nasal polyps and refractory chronic rhinosinusitis (CRSwNP) [9, 10]. Up until September 2023, six databases were checked. Studies comparing improvements in refractory chronic sinusitis-related symptoms in groups treated with DOX and control groups were obtained. Lund-Kennedy (LK) score [−0.3670 (range - 0.6173; −0.1166); I2=92.8%], nasal polyposis score [−0.9484 (−1.2287; −0.6680); I2=92.5%], patient-reported sinonasal outcome test (SNOT) score [−0.3141 (−0.4622; −0.1660); I2=91.2%], and nasal obstruction score [−0.1813 (−0.3382; −0.0243); I2=86.2%] were all significantly decreased by DOX. The DOX group had considerably less nasal polyposis at the beginning of therapy, the completion of treatment, and 4 and 8 weeks later, according to subgroup analyses based on the measurement timepoints. Additionally, improvements were shown by the LK scores both during and after therapy. Over time,the therapy group’s SNOT score tended to drop. The symptoms of nasal blockage improved both during and 4 weeks after therapy. In conclusion, by decreasing inflammation and recurring polyposis, DOX improves the postoperative endoscopic results for patients with CRSwNP who are resistant.

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4. Topical antibiotics for chronic rhinosinusitis (CRS)

The possible existence of bacterial biofilm in sinuses provides justification for using local antibiotics to treat patients with resistant, hard-to-treat rhinosinusitis. The sinus mucosa in these individuals stays inflamed even after washing with saline, anti-inflammatory corticosteroid therapy, and/or systemic antibiotics. These patients usually have undergone sinus surgery and so have wide open sinuses that are easily accessible for local treatment.

Pseudomonas aeruginosa or Staphylococcus aureus are frequently grown from these sinuses (producing biofilms) [11].

Nebulization of a solution of 150mg tobramycin every day for 7 days resulted in the elimination of bacteria based on posttreatment culture, which was considerably better than placebo; all of this according to research conducted by Bonfils et al. in which they recruited 59 patients with CRSwNP who still had symptoms following sinus surgery [12] Day 0 and Day 10 of the bacteriological examination were conducted in accordance with Day et al.’s [13] investigation of the existence of pathogenic strains in culture and their sensitivity to antibiotics, together with a cytological analysis of the quantity and presence of leukocytes (at Day 0 and Day 10). The bacterial isolates from day 10 posttreatment and pretreatment were compared.

Leukocyte counts and antibiotic sensitivity tests were also conducted. But there was no discernible difference in the symptoms [12].

Victoria et al. conducted a prospective randomized controlled trial that is single-blinded (doctors only). Acute exacerbations of chronic rhinosinusitis and gram-positive bacteria on culture were seen in the postsurgical subjects. Subjects were divided into 3 groups (saline group, povidoen-iodine group, and mupirocin group), and for 30 days, they had twice-daily sinus irrigations [14]. The Mupirocin (14/20, 70%) group of the 62 participants under analysis had a greater posttreatment culture-negative povidone-iodine rate than the povidone-idodine (9/21, 43%) and Saline (9/19, 47%) groups, although this difference was not statistically significant (p=0.28). The Lund-Kennedy endoscopic score (povidone-iodine −3.5 [−7, −0.5] vs. mupirocin −2 [−4, 2] vs. saline −3 [−5, 0]; p=0.35) and the Sinonasal Outcome Test-20 score (povidone-iodine −0.3 [−0.6, 0.05] vs. mupirocin −0.3 [−0.7, 0.05] vs. saline −0.4 [−0.8, 0.05]; p=0.74) did not differ significantly. When compared to saline and povidone-iodine, mupirocin sinus irrigations produced a greater posttreatment culture “control” rate in patients who had previously had sinus surgery and had acute exacerbations of CRS and gram-positive bacteria on culture.

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5. Intranasal corticosteroid for chronic rhinosinusitis (CRS)

In a double-blinded placebo-controlled trial conducted by Leopold et al. [15], 323 patients with CRSwNP 27% of whom previously had sinus surgery were randomized to receive either an exhalation delivery system (EDS)–placebo or twice-daily EDS-FLU (93, 186, or 372mg) for a total of 24weeks (16 double-blind plus 8 open-label when all got 372mg). The coprimary end goals were the total bilateral polyp grade at 16weeks and the change in nasal congestion/obstruction at 4weeks. Functioning, polyp removal, and symptoms were secondary end goals. On both coprimary end points, EDS-FLU outperformed EDS-placebo (P<.001 across all dosages). The average polyp grade steadily increased through week 24 (P<.009, all comparisons), and at that point, 25% of patients had at least one side of the polyp removed, compared to 8.7% with the EDS-placebo (P<.014, all comparisons). Additionally, patients’ SNOT scores increased considerably (P<.05 for all dosages) from those in patients receiving EDS-placebo (221.1 to 221.4 vs. 211.7 at week 16). All four of the defining illness symptoms were considerably improved by EDS-FLU (all dosages) at the end of the double-blind phase. 69% of the patients who received EDS-FLU experienced “much” or “very much” improvement. The percentage of patients who could have surgery dropped by 62–67%. The safety profile matched the information from earlier trials. In this study, they concluded that in individuals with chronic rhinosinusitis with nasal polyps, EDS-FLU results in a clinically and statistically significant improvement in all four diagnostically defined illness symptoms, polyp grade, and quality of life.

Japanese patients with chronic rhinosinusitis with nasal polyps have among them a common variant known as eosinophilic chronic rhinosinusitis (ECRS). Refractory eosinophilic airway inflammation, ECRS is strongly linked to asthma and necessitates comprehensive management as part of the unified airway concept [16, 17]. Kobayashi et al. in a double-blinded placebo-controlled trial reported a series of ECRS patients with asthma treated with fine-particle inhaled corticosteroid (ICS) exhalation through the nose (ETN). A double-blind randomization process was used to assign 23 patients with severe ECRS who were not responding to intranasal corticosteroid therapy to either the HFA-134a-beclomethasone dipropionate (HFA-BDP) metered-dose inhaler (MDI) ETN (n=11) or the placebo MDI ETN (n=12) over a 4-week period. Assessments were made of changes from the baseline in the nasal polyp score, smell test, computed tomographic (CT) score, and quality of life (QOL) score. Measurements of fractionated exhaled nitric oxide (FENO), a sign of eosinophilic airway inflammation, were made. Evaluation of the corticosteroid response was done both before and after therapy. Furthermore, a particle deposition model was used to illustrate the deposition of small particles. Purified eosinophils were co-incubated with BEAS-2B human bronchial epithelial cells to assess corticosteroid sensitivity and investigate the function of eosinophils on airway inflammation. Treatment with HFA-BDP MDI ETN increased corticosteroid sensitivity, and all evaluated clinical endpoints without impairing pulmonary function. HFA-BDP MDI ETN therapy decreased FENO and blood eosinophil count. According to the visualization investigation, fine particle deposition in the middle meatus, including the sinus ostia, was caused by ETN at expiratory flow rates of 10–30L/min. Corticosteroid resistance was produced when BEAS-2B cells and eosinophils were co-incubated.

A metanalysis conducted by Bognanni et al. looked for randomized controlled trials comparing INCS administered in any way to placebo or other INCS administration types in studies stored in Medline, Embase, and Central between September 1, 2021 and the creation of the database [18]. Sixty-one randomized controlled trials with 7176 individuals and 8 treatments were examined. In comparison to a placebo, the quality of life linked to sinusitis may be enhanced by INCS rinse (mean difference [MD] −6.83, 95% confidence interval [CI] −11.94 to −1.71) and exhalation delivery system (EDS) (MD −7.86, 95% CI −14.64 to −1.08). In comparison to placebo, nasal obstruction symptoms are probably lessened after receiving INCS by stent/dressing (MD −0.31, 95% CI −0.54 to −0.08), spray (MD −0.51, 95% CI −0.61 to −0.41), and EDS (MD −0.35, 95% CI −0.51 to −0.18). The unfavorable effects of the various therapies did not significantly differ from one another (moderate certainty for INCS spray, extremely low to medium certainty for others). For CRSwNP, there are several effective INCS delivery methods that can enhance patient important results. The broadest possible range of evaluated outcomes seems to benefit from INCS using stent, spray, and EDS.

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6. Systemic corticosteroid for chronic rhinosinusitis (CRS)

For chronic rhinosinusitis with nasal polyps, short doses of systemic corticosteroids (7–21days) are commonly administered in conjunction with local corticosteroids. In addition to lowering inflammation, systemic corticosteroids may also shrink nasal polyps. It is interesting to note that, in particular, olfactory mucosal inflammation is frequently decreased, leading to a quick improvement in olfaction (days) without any discernible change in polyp volume.

Shen et al. conducted a double-blind, placebo-controlled, randomized clinical study in which patient who underwent ESS with bilateral CRSwNP were randomly assigned to take oral prednisolone (30mg/day) or a placebo for 2 weeks following operation. As the subjective outcomes, the visual analog scale (VAS) and Sino-Nasal Outcome Test 22 (SNOT-22) scores were selected and assessed at preoperative baseline, as well as 1, 3, and 6months after surgery. The objective result was measured using Lund-Kennedy Endoscopic Scores (LKESs), which were assessed preoperatively, at 2weeks, 2, 3, and 6months after surgery [19, 20]. Out of the 100 patients that were included, only 82 with bilateral CRSwNP finished the 6-month follow-up. At every follow-up point, there was no discernible variation in the subjective results. Six months after surgery, the corticosteroid group reported an improvement in LKESs (p=0.05) among the objective results. Only patients with NECRSwNP (<10 eosinophils/HPF) showed a significant improvement in LKESs at 3months postoperatively (p=0.03), after classification by tissue eosinophils. In conclusion, oral corticosteroids administered after surgery did not result in further improvements in VAS or SNOT-22 scores; however, at 6 months after surgery, there was a tendency of improving LKES. At the three-month follow-up, this impact was significant only among NECRSwNP patients after stratification by tissue eosinophils.

In a meta-analysis conducted by Zhang et al. [21], 7 RCTs with a total of 414 participants were included in the meta-analysis out of the 337 pertinent papers that were found. In contrast to nonsteroid treatments or placebos, systemic corticosteroids significantly increased peak nasal inspiratory flow (PNIF) (SMD 42.39; 95% CI, 28.95 to 55.84; P<.00001), decreased the size of nasal polyps (SMD ~4.76; 95% CI, ~6.99 to ~2.52; P<.0001), and improved nasal obstruction scores (standardized mean difference; SMD ~2.81; 95% confidence interval [CI], ~4.68 to ~0.95; P 1/4 .003). The low-dose subgroup (less than 50mg/day prednisone) and high-dose (greater than or equal to 50mg/day prednisone) had comparable advantages. But individuals receiving large dosages of prednisone reported experiencing sleeplessness and gastrointestinal problems more frequently. No discernible variation was seen in the frequency of any adverse events among the groupings. In conclusion for individuals with CRSwNP, systemic corticosteroids significantly reduce the amount of nasal polyps and significantly improve PNIF and nasal symptoms. In CRSwNP, prednisone dosages under 50mg/day were advised when the benefits of oral corticosteroids were weighed against possible side effects.

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7. Saline

In order to effectively manage CRS, nasal saline irrigation is thought to be crucial. By disrupting and eliminating antigens, biofilms, and inflammatory mediators as well as improving mucus clearance and ciliary beat activity, saline nasal irrigation may improve the function of the nasal mucosa through a number of physiological effects. It may also increase the hydration of the sol layer. Saline may also act as a carrier to provide the necessary volume to deliver medication into the sinuses. That being said, there is not much agreement on the optimal irrigation technique, the tonicity (concentration) of the saline solution, or the appropriateness of the devices, head position, volume, pressure, and frequency of washing.

In a non-blinded randomized controlled trial Glotakis et al. evaluated 174 patients with CRSwNP (whom 154 were posteopratively), they were divided to 3 groups [22]. The first group used 250ml of 1175% Emser Salt solution (EmsSalt) (n=59) twice daily for 1 year, the second group used 250ml of isosmotic mineral salt mixture (IsoMix) (n=58) twice daily for 1 year, and in the third group they were on no irrigation (n=57) for one year. Outcomes were measured at 3, 6, 9, and 12months including nasal symptoms, RQLQ , missed work days and postoperative condition of the mucosa. Results were significantly improved outcomes when comparing irrigation to no irrigation in terms of nasal symptoms and RQLQ. There is no discernible difference between mucosa and missed work days. There are no appreciable variations between the isosmotic mineral salt mixture and Emser Salt.

In a meta-analysis conducted by Lei Liu et al. [23, 24], in an effort to offer a guide for clinical nasal irrigation for the treatment of chronic rhinosinusitis, the authors compared the efficaciousness of hypertonic and isotonic saline in the management of rhinosinusitis. There were seven investigations in all. In four groupings, the effects of hypertonic saline on nasal symptoms were stronger. The patients with nasal secretion (SMD=1.52; 95% CI: 1.04, 2.00; p<0.01), congestion (SMD=1.52; 95% CI: 1.04, 2.00; p<0.01), headache (SMD=0.82; 95% CI: 0.38, 1.26; p<0.01), and overall symptomatic relief (SMD=1.63; 95% CI: 0.83, 2.44; p<0.01) were the first group of patients classified as (1). On the other hand, there was no difference in the improvement of radiologic scores (SMD=2.44; 95% CI: −3.14, 8.02; p<0.01) or scent (SMD=0.47; 95% CI: −0.65, 1.59; p=0.41). Furthermore, compared to the isotonic saline group, the hypertonic saline group had a higher improvement in mucociliary clearance time scores (SMD=1.19; 95% CI: 0.78, 1.60; p<0.01). Greater mild negative effects were observed with hypertonic saline. In conclusion, when treating chronic rhinosinusitis, hypertonic saline nasal irrigation is far more successful than isotonic saline and has less side effects. It also improves ciliary movement and nasal symptoms, but there is no discernible change in imaging results or improvement in smell.

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8. Anti-IgE

A substantial local IgE production that may contribute to chronic inflammation by persistently activating mast cells is a pathophysiological feature of CRSwNP [25]. Omalizumab is a recombinant humanized monoclonal antibody that has been studied for its potential use in the treatment of CRS in a randomized clinical study by Gevaert et al. [25]. Omalizumab works by selectively attaching to free circulating IgE, which inhibits the activation of effector cells such as mast cells, basophils, and dendritic cells and reduces the expression of IgE receptors on them. A subcutaneous dose of omalizumab (four to eight doses) or a placebo was administered to 24 individuals with CRSwNP with concomitant asthma for a period of more than 2 years. There were 20–700 kU/mL of total serum IgE. There was no discernible decrease in RSOM-31 or SF-36 following the subcutaneous delivery of four to eight doses of omalizumab. On the other hand, the omalizumab group showed a substantial improvement in the physical domain of the SF-36 and the Asthma Quality of Life Questionnaire (AQLQ), while the placebo group showed no meaningful changes. Comparing anti-IgE to baseline, there was a substantial reduction in the symptoms ratings for nasal congestion (p=0.003), anterior rhinorrhoea (p=0.003), loss of smell (p=0.004), wheeze (p=0.02), and dyspnea (p=0.02). Anti-IgE medication did not help the patient’s cough or spirometric findings. Over the course of the trial, a linear mixed model showed that the omalizumab group had a lower total nasal polyp score (NPS) than the placebo group (p=0.2). The omalizumab group showed significantly higher Lund-MacKay scores on radiologic imaging (p=0.04) when compared to the placebo group. Anti-IgE therapy was used, and the improvements in radiography and clinical outcomes were observed regardless of serum IgE levels. Patients who were allergic (−2.57; p=0.03) and nonallergic (−2.75; p=0.06) showed a decrease in total NPS after 16weeks. Compared to nonallergic patients (20.66, p=0.75), allergic patients showed an improvement in their Lund-Mackay CT scan scores (22.61, p=0.04). On the other hand, the nonallergic group’s total AQLQ score showed improvement (259.4, p=0.03), but the allergic group’s score (212.3, p=0.12) did not. Among the patients covered, 22 out of 23 (95.7%) had at least one adverse event. In the omalizumab group, the most often reported adverse event was a common cold, which happened more frequently in the treatment group than in the control group (p=0.02). In the omalizumab group, one patient died of lymphoblastic lymphoma a year after the research began. It is noteworthy that the analysis did not include four out of eight patients (or 50%) in the control group.

A randomized, double-blind, placebo-controlled study of anti-IgE for CRS was carried out by Pinto et al. [26] in 14 patients (12 of 14 with CRSwNP) who were not responding to conventional therapy. It was necessary for participants to have serum total IgE levels between 30 and 700IU/ml. For 6 months, all patients received subcutaneous injections of either placebo or omalizumab at a rate of 0.016mg/kg per IU every 2 to 4 weeks. The SNOT- 20 scores did not significantly differ between the treatments (median omalizumab −5.5, placebo −2.3, p<0.60). Over the course of the study, the omalizumab group showed a clinically significant improvement (defined as at least 0.8) in their median change in SNOT-20 scores, while the placebo group showed no clinically significant change (−1.05 vs. -0.20, p<0.78). All domains showed no significant differences between treatments, with the exception of vitality (p<0.05; omalizumab 9.4, placebo 12.5). Comparing the omalizumab and placebo groups, there were no statistically significant differences in the sinus opacity in the CT scan, the median change in the percentage of eosinophils in nasal lavage, the median PNIF, the total nasal symptom scores, or the results of nasal endoscopy. Omalizumab-using patients utilized less antibiotics (0 vs. 1, p<0.32) and fewer doses of steroids (median 0 vs. 1, p<0.043) during the trial than placebo-using patients. During the trial, no negative outcomes or side effects happened [26].

In a meta-analysis study conducted by Qingwu Wu et al. [27, 28], randomized controlled studies comparing placebo and omalizumab in adult patients with CRSwNP, administered for a minimum of 16weeks. Four randomized controlled trials with a total of 303 participants were found. Nasal Polyps Score (MD=−1.20; 95% CI −1.48 to −0.92), Nasal Congestion Score (MD=−0.67; 95% CI −0.86 to −0.48), Sino-Nasal Outcome Test-22 (MD=−15.62; 95% CI −19.79 to −11.45), Total Nasal Symptom Score (MD=−1.84; 95% CI −2.43 to −1.25), and decreased surgical requirement (risk ratio (RR)=5.61; 95% CI 1.99 to 15.81) were among the significantly different outcomes when omalizumab was compared to placebo. The probability of adverse events (RR=0.83; 95% CI 0.60 to 1.15), significant adverse events (RR=1.40; 95% CI 0.29 to 6.80), and rescue systemic corticosteroid (RR=0.52; 95% CI 0.17 to 1.61) did not vary either. In conclusion, omalizumab was shown to be safe and well-tolerated, and it improved endoscopic, clinical, and patient-reported outcomes in people with moderate to severe CRSwNP. Regarding adverse effects, current research on anti-immunoglobulin-E (IgE) therapy indicates a very low risk of anaphylaxis [27]; however, there is some evidence linking the drug to venous and arterial thromboembolic events that result in cardiovascular and cerebrovascular accidents [29].

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9. Anti-IL5

In the past, systemic and topical corticosteroids, long-term antibiotics, and surgery have all been used to treat CRS. Even with the application of optimal practices, some patients continue to have recalcitrant disease. Final development into an eosinophil requires interleukin 5 (IL-5), which also increases the mature cell’s survival time within the tissue [30]. The care of patients with nonallergic asthma and CRSwNP may involve IL-5 as a target due to its observed elevation in nasal polyp tissue [31].

Bachert et al. conducted a double-blind, randomized, placebo-controlled experiment; patients with recurrent nasal polyposis who needed surgery were enrolled if they were between the ages of 18 and 70. In addition to daily topical corticosteroid treatment, patients received 750mg intravenous mepolizumab or placebo every 4 weeks for a total of six treatments [26]. The number of patients who were no longer in need of surgery at Week 25 was the main outcome, which was determined by combining the endoscopic nasal polyp score with the visual analogue scale (VAS) score for nasal polyposis severity. Patient-reported outcomes (PRO), safety, improvement in individual VAS symptoms (rhinorrhea, mucus in the throat, nasal blockage, and sense of smell), and change in the nasal polyposis severity VAS score were among the secondary objectives. Mepolizumab (n=54) or a placebo (n=51) was administered to 105 patients. When compared to the placebo group, a considerably higher percentage of patients in the mepolizumab group (16[30%] vs. 5[10%], respectively, P=0.006) no longer needed surgery. The nasal polyposis severity VAS score, endoscopic nasal polyp score, individual VAS symptom ratings, and SNOT-22 PRO score significantly improved in the mepolizumab group as compared to the placebo group. In terms of safety, mepolizumab was similar to a placebo. In conclusion, mepolizumab medication resulted in a higher improvement in symptoms and a reduction in the need for surgery compared to placebo in individuals with recurrent nasal polyposis on topical corticosteroids.

Gevaert et al. conducted a double-blind study conducted on thirty patients who had severe nasal polyposis (grade 3 or 4, or recurring after surgery) and were not responding to corticosteroid therapy. The patients were randomly assigned to receive either a placebo (n510) or two single intravenous injections of 750mg of mepolizumab (n520) spaced 28days apart [32]. Monthly assessments of the change from baseline in NPscore were conducted until week 8, 1 month following the last dose. At week eight, computed tomographic scans were also carried out. At week 8 relative to baseline, 12 out of 20 patients on mepolizumab had a substantially better NP score and computed tomographic scan score than 1 out of 10 patients on placebo. In conclusion, in 12 out of 20 individuals, mepolizumab produced a statistically significant decrease in NP size for at least 1 month following dosage. A possible new treatment strategy for those with severe eosinophilic nasal polyposis is IL-5 inhibition.

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10. Anti-IL4/IL13

Strong type 2 immune mediators, IL-4 and IL-13, have different and overlapping roles. Both IL-13 and IL-4 play a significant role in IgE synthesis, eosinophil activation, mucus secretion, and airway remodeling. They also partially share receptors and signaling pathways. By starting T cell development toward the TH2 subtype, IL-4 is a key differentiating agent that drives a TH2 type response. Moreover, type 2-related chemokines and cytokines as TARC, fotaxin, IL-5, IL-9, and IL-13 are produced in response to IL-4. Additionally, the primary factors that cause B cells to flip their isotype class and generate Ig are IL-4 and IL-13. Dupilumab is a subcutaneous injection-based completely human monoclonal antibody targeting the IL-4 receptor subunit that blocks IL-4 and IL-13 signaling [28].

Bachert et al. conducted a 16-week follow-up randomized, double-blind, placebo-controlled parallel-group trial that involved 60 adults with chronic sinusitis and nasal polyposis who were not responding to intranasal corticosteroids. The study was carried out at 13 sites in the US and Europe between August 2013 and August 2014 [29]. Subcutaneous dupilumab (a 600mg loading dose followed by 300mg weekly; n=30) or placebo (n=30) plus mometasone furoate nasal spray for 16weeks. Any changes in the primary end point were recorded, including endoscopic nasal polyp score at 16 weeks (range, 0–8; larger scores indicate worse condition). The 22-item SinoNasal Outcome Test score (range, 0–110; higher scores indicating worse quality of life; minimal clinically important difference=8.90), the Lund-Mackay computed tomography (CT) score (range, 0–24; higher scores indicate worse status), the sense of smell as measured by the University of Pennsylvania Smell Identification Test (UPSIT) score (range, 0–40; higher scores indicate better status), symptoms, and safety were among the secondary end points. Fifty patients (mean [SD] age, 48.4years [9.4years], 34 men [56.7%], and 35 with concomitant asthma) who were randomly assigned were all enrolled in the trial; fifty-one of them finished it. The nasal polyp score exhibited a least squares (LS) mean change of −0.3 (95%CI, −1.0 to 0.4) when administered placebo and−1.9 (95%CI, −2.5 to −1.2) when administered dupilumab (LS mean difference, −1.6 [95%CI, −2.4 to −0.7]; P<.001). For the Lund-Mackay CT total score, the LS mean difference between the two groups was −8.8 (95%CI, −11.1 to −6.6; P<.001). The 22-item SNOT showed significant improvements with dupilumab (LS mean difference between groups, −18.1 [95%CI, −25.6 to −10.6]; P<.001), as did the UPSIT, which measured sense of smell (LS mean difference, 14.8 [95%CI, 10.9 to 18.7]; P<.001). Nasopharyngitis (33% in the placebo group vs. 47% in the dupilumab group), injection site responses (7 vs. 40%, respectively), and headache (17 vs. 20%) were the most frequent side effects. In conclusion after 16weeks, the endoscopic nasal polyp load in persons with symptomatic chronic sinusitis and nasal polyposis unresponsive to intranasal corticosteroids was lower when subcutaneous dupilumab was added to mometasone furoate nasal spray as opposed to mometasone alone [29].

Bachert et al. conducted a two international, multicenter, parallel-group, randomized, double-blind, and placebo-controlled trials evaluated the addition of dupilumab to the standard of therapy for people with severe CRSwNP. SINUS-52 was conducted in 117 centers across 14 nations, while SINUS-24 was conducted in 67 centers across 13 countries. Patients must have been 18years of age or older, have bilateral CRSwNP, and still be experiencing symptoms even after using intranasal corticosteroids, getting systemic corticosteroids within the last 2 years, or having undergone sinonasal surgery [30]. For a duration of 24weeks, patients in SINUS-24 were randomized (1:1) to receive subcutaneous dupilumab 300mg or a placebo every 2 weeks. In SINUS-52, patients were randomized (1:1:1) to receive placebo every 2 weeks for 52weeks, dupilumab 300mg every 2 weeks for 24 weeks and then every 4 weeks for the final 28 weeks. Using a permuted block randomization schedule, all patients were assigned at random centrally. Randomization was stratified by nation, prior surgery at screening, and status of respiratory disease aggravated by nonsteroidal anti-inflammatory drugs or asthma at screening. Included were patients with and without co-occurring asthma. In an intention-to-treat population, coprimary outcomes included changes in nasal polyp score (NPS) from baseline to week 24, nasal congestion or obstruction, and sinus Lund-Mackay CT scores (a coprimary endpoint in Japan). A pooled population comprising the dupilumab group in SINUS-52 up to week 24, the dupilumab group in SINUS-24, and the placebo groups in both studies up to week 24 was used to evaluate safety. The results showed a significant and clinically meaningful decrease in MD was observed in the SNOT-22 score (scale 0–110) after 4–6months (784 individuals; two studies; I2=0%). At 4–6months, the rhinosinusitis disease severity (VAS) demonstrated a substantial and clinically meaningful decline of MD – 2.54 (95% CI −2.84–−2.23); two studies; 784 participants; I2=40%). A noteworthy and clinically meaningful decrease of MD – 0.86 (95% CI −0.98–−0.75); 784 individuals; two studies; I2=0%) was observed in the nasal congestion/obstruction score at 4–6months. The UPSIT was utilized to assess smell. A significant and clinically meaningful drop of MD 10.83 (95% CI 9.59–12.08); 784 individuals; two studies; I2=0%) was observed in the UPSIT score at 4–6months. In these investigations, the primary endpoint was the nasal polyp score. In these trials, the average nasal polyp score was approximately 6, which denotes a serious polyp illness. In two investigations with 784 patients, the nasal polyp score at 4–6months shown a significant decrease of MD −1.79 (95% CI −2.01–−1.56); I2=65%. At 4–6months, the Lund-Mackay score (scale 0-48) revealed a significant decrease in SMD −1.50 (95% CI −1.84–−1.16); there were 784 individuals in two investigations, with an I2 of 71%. Lastly, there was a notable effect on FEV1 and ACQ. Both studies demonstrated a significant improvement over placebo; however, the data could not be merged into a meta-analysis because ACQ5 and ACQ6 were employed. A meta-analysis of the FEV1 data revealed a substantial improvement in FEV1 (l) at 4–6months of MD 0.21 (95% CI 0.20 – 0.22); there were 488 participants in two investigations, with an I2 of 0%. The most frequent side effects with placebo included headache, epistaxis, injection-site erythema, worsened nasal polyps and asthma, and rhinopharyngitis [30].

In a phase III trial study done by Anju etal. individuals with severe CRSwNP with or without concurrent AR were studied for the safety and effectiveness of dupilumab using this post hoc approach. This study used SINUS-24 weeks or SINUS-52 weeks protocol for dupilumab injections [33]. The analysis involved patients who were randomized every 2 weeks for 24 (SINUS-24) or 52weeks (SINUS-52) to receive subcutaneous dupilumab 300mg (n=438) or placebo (n=286). The first 24weeks of treatment’s pooled data are shown. The patient’s self-reported history of allergic rhinitis (AR) status was used to examine changes from baseline in illness outcome measures and biomarker levels. In all, 46.7% (338 out of 724 patients) had AR. Patients with and without AR had largely comparable baseline characteristics. There was no discernible treatment difference between patients with and without AR at week 24, and dupilumab dramatically improved objective and patient-reported markers of CRSwNP, including loss of smell. It also lowered systemic and nasal biomarker levels compared placebo. Regardless of AR status, there was a substantial decrease in the use of systemic corticosteroids and/or sinonasal surgery with dupilumab compared to placebo (p<0.0029). Dupilumab’s safety profile was comparable in those with and without AR. In patients with severe CRSwNP, dupilumab showed statistically significant improvements in both clinical end goals and symptom scores when compared to placebo, regardless of concomitant AR status—a common patient subgroup that is frequently linked to worse CRSwNP outcomes [33].

In a meta-analysis conducted by Qingwu Wu [34], the included nine RCTs involved 1190 patients comparing three distinct biologics (omalizumab, mepolizumab, and dupilumab) with the placebo. Dupilumab demonstrated the highest level of efficacy for surface under the cumulative ranking curve (SUCRA) values of 0.900, 0.916, 1.000, and 0.807, respectively, for nasal polyp score (NPS), SNOT-22 score, University of Pennsylvania Smell Identification Test (UPSIT) score, and nasal congestion score (NCS). When it came to SUCRA values of 0.606, 0.500, and 0.693, omalizumab was the most effective drug in terms of SNOT-22, UPSIT, and NCS. For SUCRA values of 0.563, mepolizumab placed second in terms of NPS effectiveness, while for SUCRA values of 0.746, mepolizumab had the greatest risk of adverse events (AEs). In conclusion Omalizumab is the second-best option for CRSwNP, whereas dupilumab is the best option based on safety (AEs) and effectiveness (NPS). Mepolizumab had the highest risk of adverse events (AEs) while having the second-best effectiveness rating.

11. Antihistamine

It is unknown how sensitization functions in CRSsNP. One may be tempted to hypothesize that an atopic person is more susceptible to developing CRS if they have allergic irritation in their nose. Nevertheless, there are contradictory studies assessing atopy as a risk factor for CRS. In a DBPCT, Haye et al. [35] randomly assigned 45 CRSwNP patients (16 of whom had allergies) to receive a placebo or 20mg of cetirizine for a duration of 3 months. Cetirizine, according to the authors, decreased the number of days with a score for nasal sneeze and rhinorrhea that was less than one. At all time periods, the cetirizine-treated group experienced a score of 90–100% compared to the placebo group’s 70–80% for rhinorrhea and 80–90% for sneezing. Nevertheless, information about individuals with and without allergies was not provided individually. The cetirizine had no influence on the size of nasal polyps.

12. Anti-leukotrienes

Eosinophils and mast cells produce a family of inflammatory mediators called cysteineyl leukotrienes (CysLT) by breaking down arachidonic acid. CysLT are known to promote bronchoconstriction, mucus formation, edema, and neutrophil and eosinophil chemotaxis, and they may also have a role in the pathogenesis of asthma, rhinitis, and maybe CRSwNP.

Asthma, allergic rhinitis, and CRS with nasal polyposis (CRSwNP) have all been linked to the overproduction of CysLTs and overexpression of the receptor.

In a systemic review conducted by Wentzel et al. [36], studies evaluating the impact of leukotriene antagonists (LTAs) on clinical outcome markers of CRSwNP were included in a systematic review. Trials evaluating LTAs in CRS without nasal polyps or asthma symptoms alone met the exclusion criteria. The aim of this study is to evaluate the effects of LTA therapy on immunological markers, objective clinical outcomes, and nasal symptoms in CRSwNP, both alone and in combination with intranasal corticosteroids (INCSs). Twelve studies met the qualifying requirements: seven case series and five randomized control trials. Compared to placebo, LTAs significantly reduced CRSwNP symptoms; however, a meta-analysis of these randomized studies was not possible. The two studies that were included in the meta-analysis revealed that there was no difference in the treatment modalities, with a standardized mean difference of pooled total symptom scores between the LTA and INCS study arms of 0.02 (95% confidence range, −0.39-0.44). All trials reported improvements in immunological markers, clinical outcomes, and/or symptoms following LTA therapy; larger improvements were noted in a subset of symptoms compared to those seen with INCSs. Atopy, aspirin-exacerbated respiratory disorders, and concurrent asthma did not consistently or substantially alter these findings.

In a randomized controlled trial that evaluated adding montelukast to intransal spry therapy for chronic rhinosinusitis patients. In this study conducted by Suri et al. [37], 40 adult CRSwNP patients were randomly assigned to two groups. The subjects received budesonide nasal spray for 8 weeks, either with or without additional oral montelukast, and oral prednisolone for 14days. After 8 weeks of therapy, subjects receiving supplemental oral montelukast reported a statistically significant improvement in their overall symptom score, sense of smell, and sneezing, which persisted for 4 weeks after the medication was stopped.

13. Conclusion

The data comparing placebo and montelukast was of extremely poor quality. The limited number of research and patients in the studies resulted in a downgrading of the evidence. The literature does not advise its usage unless a patient is unable to take nasal corticosteroids, based on the data currently available. Furthermore, the data contrasting montelukast with nasal corticosteroids is of low quality. The literature does not advise combining montelukast with nasal corticosteroids based on the available data. No meta-analysis is found.