The interleukin-4/interleukin-13 pathway in type 2 inflammation in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is predominantly a type 2 inflammatory disease associated with type 2 (T2) cell responses and epithelial barrier, mucociliary, and olfactory dysfunction. The inflammatory cytokines interleukin (IL)-4, IL-13, and IL-5 are key mediators driving and perpetuating type 2 inflammation. The inflammatory responses driven by these cytokines include the recruitment and activation of eosinophils, basophils, mast cells, goblet cells, M2 macrophages, and B cells. The activation of these immune cells results in a range of pathologic effects including immunoglobulin E production, an increase in the number of smooth muscle cells within the nasal mucosa and a reduction in their contractility, increased deposition of fibrinogen, mucus hyperproduction, and local edema. The cytokine-driven structural changes include nasal polyp formation and nasal epithelial tissue remodeling, which perpetuate barrier dysfunction. Type 2 inflammation may also alter the availability or function of olfactory sensory neurons contributing to loss of sense of smell. Targeting these key cytokine pathways has emerged as an effective approach for the treatment of type 2 inflammatory airway diseases, and a number of biologic agents are now available or in development for CRSwNP. In this review, we provide an overview of the inflammatory pathways involved in CRSwNP and describe how targeting key drivers of type 2 inflammation is an effective therapeutic option for patients.

Assessment of chronic rhinosinusitis with nasal polyps: Development of the Nasal Polyp Patient Assessment Scoring Sheet tool.

Background: Chronic rhinosinusitis (CRS) is a heterogeneous disorder with a wide range of validated subjective and objective assessment tools to assess disease severity. However, a comprehensive and easy-to-use tool that integrates these measures for determining disease severity and response to treatment is still obscure. The objective of this study was to develop a standardized assessment tool that facilitates diagnosis, uniform patient monitoring, and comparison of treatment outcomes between different centers both in routine clinical practice and in research. Methods: To develop this tool, published literature on assessment tools was searched on various databases. A panel of 12 steering committee members conducted an advisory board meeting to review the findings. Specific outcome measures to be included in a comprehensive assessment tool and follow-up sheet were then collated following consensus approval from the panel. The tool was further validated for content and revised with expert recommendations to arrive at the finalized Nasal Polyp Patient Assessment Scoring Sheet (N-PASS) tool. Results: The N-PASS tool was developed by integrating the subjective and objective measures for CRS assessment. Based on expert opinions, N-PASS was revised to be used as an easy-to-use guidance tool that captures patient-reported and physician-assessed components for comprehensively assessing disease status and response to treatment. Conclusion: The N-PASS tool can be used to aid in the diagnosis and management of CRS cases with nasal polyps. The tool would also aid in improved monitoring of patients and pave the way for an international disease registry. Level of evidence: Oxford Level 3.

Rhinitis Control and Medication Use in a Real-World Sample of Patients With Persistent Rhinitis or Rhinosinusitis: A Community Pharmacy Study.

BACKGROUND: Little is known about rhinitis control in real-life, nor about the contribution of treatment-related and patient-related factors. OBJECTIVE: This study aimed to examine the level of rhinitis control and rhinitis medication utilization in patients with persistent rhinitis and to identify predictors of rhinitis control. METHODS: A cross-sectional observational study was conducted in patients with persistent rhinitis recruited in community pharmacies. Participants completed the Rhinitis Control Assessment Test, a questionnaire on patient/rhinitis characteristics, and rhinitis medication use. A visual analog scale for nasal symptoms was also completed. Pharmacy dispensing data were used to calculate adherence to intranasal glucocorticoids. Nasal spray technique was evaluated using a standardized checklist. Predictors of rhinitis control were explored using a linear regression model. RESULTS: A total of 1,514 patients, recruited in 215 pharmacies, participated in the study (mean age 48.7 y, 62% female). Almost 60% exhibited suboptimal rhinitis control (Rhinitis Control Assessment Test ≤ 21 of 30). A 50-mm cut-off on the visual analog scale yielded 78.1% sensitivity to identify suboptimal rhinitis control. Participants most frequently used intranasal glucocorticoids (55.6%) and intranasal decongestants (47.4%). Only 10.3% of current nasal spray users demonstrated perfect technique. More than half (54.8%) of glucocorticoid users were identified as underadherent. Female sex, self-reported nasal hyperreactivity, active asthma, and use of oral/intranasal decongestants or nasal saline were identified as predictors of worse rhinitis control. CONCLUSIONS: Suboptimal rhinitis control was common in this real-life sample of persistent rhinitis patients. Improving use of rhinitis medication may be key to increase disease control.

Nonallergic Rhinopathy: A Comprehensive Review of Classification, Diagnosis, and Treatment.

Chronic nonallergic rhinitis syndromes encompass various conditions, of which vasomotor rhinitis is the most common form, representing approximately 80% of patients, also referred to as nonallergic rhinopathy (NAR), nasal hyperreactivity, neurogenic rhinitis, or idiopathic rhinitis. Expert panels have recommended replacing vasomotor rhinitis terminology because it is more descriptive of this condition that is characterized by symptoms triggered by chemical irritants and weather changes through chemosensors, mechanosensors, thermosensors, and/or osmosensors activated through different transient receptor potential calcium ion channels. Elucidating the specific role of transient receptor potential vanilloid 1, triggered by capsaicin, has been an important advancement in better understanding the pathophysiology of NAR because it has now been shown that downregulation of transient receptor potential vanilloid 1 receptors by several therapeutic compounds provides symptomatic relief for this condition. The classification of NAR is further complicated by its association with allergic rhinitis referred to as mixed rhinitis, which involves both immunoglobulin E-mediated and neurogenic mechanistic pathways. Comorbidities associated with NAR, including rhinosinusitis, headaches, asthma, chronic cough, and sleep disturbances, underscore the need for comprehensive management. Treatment options for NAR include environmental interventions, pharmacotherapy, and in refractory cases, surgical options, emphasizing the need for a tailored approach for each patient. Thus, it is extremely important to accurately diagnose NAR because inappropriate therapies lead to poor clinical outcomes and unnecessary health care and economic burdens for these patients. This review provides a comprehensive overview of NAR subtypes, focusing on classification, diagnosis, and treatment approaches for NAR.

Omalizumab improves sleep and health status for patients with chronic rhinosinusitis with nasal polyps: An analysis of randomized clinical trials.

BACKGROUND: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have high incidence of sleep impairment. We evaluated the impact of omalizumab treatment on sleep characteristics and associated health status in patients with CRSwNP. METHODS: Prespecified exploratory analysis assessed outcomes from patients included in the POLYP 1 and POLYP 2 phase 3 clinical trials and the open-label extension. Sleep was assessed by the sleep domain of the Sino-Nasal Outcome Test-22 (SNOT-22; MCID > 4 in patients with CRS) and the Medical Outcomes Study Sleep Scale (MOS-Sleep). Health status was assessed by Healthy Days Core Module (HDCM) and sinonasal-specific Patient Global Impression of Change (PGIC). RESULTS: Omalizumab improved sleep as assessed by the SNOT-22 sleep domain. At week 24, adjusted mean (95%CI) SNOT-22 sleep scores had reduced from baseline by -8.5 (-9.9 to -7.1) with omalizumab versus -2.7 (-4.1 to -1.3) with placebo. At week 52 (all patents on OMA), adjusted mean (95%CI) SNOT-22 sleep scores had reduced from baseline by -10.1 (-11.4 to -8.7) with omalizumab. Improvements were observed in all eight items of the SNOT-22 sleep domain: difficulty falling asleep, fatigue, frustration/restlessness/irritability, lack good night's sleep, reduced concentration, reduced productivity, wake up tired, and wake up at night. In addition, omalizumab improved six of eight sleep outcomes on the MOS-Sleep scale. There were concurrent improvements in HDCM and PGIC. CONCLUSION: Omalizumab improved sleep and self-reported health status in patients with CRSwNP. This contributes to evidence that omalizumab provides value for patients beyond the reduction of sinonasal symptoms.

Clinical benefits with 300 IR HDM SLIT tablet in Europeans with house dust mite allergic rhinitis: Post hoc analysis of a large phase 3 trial.

Background: House dust mite (HDM)-induced allergic rhinitis (AR) is a major cause of allergic respiratory disease. The efficacy and safety of the 300 IR HDM sublingual immunotherapy (SLIT) tablet in patients with moderate-to-severe HDM-AR was confirmed in a large, international, phase 3 randomized controlled trials (RCTs). Here, we analyzed the results in the European population. Methods: Data from 91 European centers that participated in the international, double-blind, RCT (EudraCT 2014-004223-46, NCT02443805) with the 300 IR HDM SLIT tablet versus placebo over 12 months were analyzed post hoc. The treatment effect in European adults and adolescents was notably assessed through the European Academy of Allergy and Clinical Immunology (EAACI)-recommended combined symptom and medication score (CSMS0-6, pre-defined endpoint) and the total combined rhinitis score (TCRS0-24, post hoc endpoint, also balanced) during the primary evaluation period (4 weeks at the end of treatment period) using analysis of covariance (ANCOVA). Results: There were 818 patients who comprised the modified full analysis set in Europe. Over the primary period, the differences in CSMS0-6 and TCRS0-24 between the 300 IR and placebo groups were statistically significant (p < 0.0001): -0.32 (95%CI [-0.46; -0.17]) and -1.28 (95%CI [-1.63; -0.94]), respectively, with relative differences of -20.9% and -21.2%. All post hoc and the rhinoconjunctivitis quality of life endpoints were significantly improved with 300 IR versus placebo. The 300 IR HDM tablet was generally well tolerated. Conclusion: This RCT sub-analysis confirmed the 300 IR HDM SLIT tablet is an effective and safe treatment for European adults and adolescents with HDM-AR with clinically meaningful benefits from the patients' perspective. Trial registration: NCT02443805. Registered on April 29, 2015./EudraCT 2014-004223-46. Registered on September 16, 2015.

Sustained efficacy of mepolizumab in patients with severe chronic rhinosinusitis with nasal polyps: SYNAPSE 24-week treatment-free follow-up.

BACKGROUND: In the 52-week Phase III SYNAPSE study, mepolizumab given every 4 weeks (100 mg subcutaneously) reduced nasal polyp (NP) size, improved symptoms and quality of life (QoL), and reduced corticosteroid use and number of sinus surgeries in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP), versus placebo. Because the durability of mepolizumab's efficacy after discontinuation is poorly understood in CRSwNP, the efficacy of mepolizumab after discontinuation was analyzed in severe CRSwNP, over a 24-week follow-up. METHODS: Changes from SYNAPSE baseline to end of treatment (week 52) and end of follow-up (week 76) were assessed for total endoscopic NP score, nasal obstruction and overall symptoms visual analog scale scores, and 22-item Sino-Nasal Outcome Test score. Time to first sinus surgery, time to first corticosteroid use, and geometric mean blood eosinophil counts (BECs) were also assessed. RESULTS: Among 134 follow-up patients, clinical improvements observed with mepolizumab versus placebo were partially evident 24 weeks after discontinuation despite BEC returning to baseline. The mean (95% confidence interval [CI]) change from baseline in NP score (week 52: -1.3 [1.8 to -0.9] vs. -0.3 [-0.6 to 0.1]; week 76: -1.2 [-1.6 to -0.7] vs. -0.1 [-0.5 to 0.3]) and the proportion of patients having sinus surgery (week 52: 4% vs. 25%; week 76: 9% vs. 31%) remained substantially improved with mepolizumab versus placebo. Mepolizumab-associated improvements in overall symptoms, quality of life, and corticosteroid use versus placebo were partially sustained at week 76. CONCLUSION: Fifty-two weeks of mepolizumab treatment is associated with sustained clinical benefits up to 24 weeks after discontinuation in patients with severe CRSwNP, which should be considered by physicians when making treatment decisions.

Omalizumab improves sinonasal outcomes in patients with chronic rhinosinusitis with nasal polyps regardless of allergic status.

BACKGROUND: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) often have atopic comorbidities, including elevated IgE levels and comorbid asthma. Omalizumab, an IgE monoclonal antibody, is an effective treatment for CRSwNP, but the impact of allergy or asthma status on response to omalizumab in patients with CRSwNP has not been well studied. OBJECTIVE: To evaluate the impact of allergy and asthma status on omalizumab treatment in patients with CRSwNP, this posthoc exploratory analysis assessed sinonasal outcomes from subgroups of patients included in POLYP 1 and POLYP 2 and the open-label extension (OLE) trials. METHODS: Patients (N = 249) were grouped by the presence/absence of comorbid allergy (≥ 1 physician-reported allergic rhinitis, allergic sinusitis, food allergy, or atopic dermatitis), presence/absence of comorbid asthma, baseline serum total IgE (≥ 150 or <150 IU/mL), and baseline blood eosinophil levels (>300 or ≤ 300 cells/µL). Sinonasal outcomes were the nasal polyps score, nasal congestion score, and sino-nasal outcome test-22. RESULTS: During POLYP 1 and POLYP 2 and the OLE, omalizumab treatment improved the nasal polyps score, nasal congestion score, and sino-nasal outcome test-22 score in patients with/without physician-reported allergic comorbidities, with/without asthma, with higher/lower total IgE levels, and with higher/lower blood eosinophil counts. In the OLE, the pattern of improvement was similar in patients who continued or switched to omalizumab. CONCLUSION: In patients with CRSwNP, omalizumab improved sinonasal outcomes independent of allergic status, which suggests that a wide range of patients with different endotypes and phenotypes of CRSwNP may benefit from omalizumab treatment. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03280550, NCT03280537, NCT03478930.

EUFOREA/EPOS2020 statement on the clinical considerations for chronic rhinosinusitis with nasal polyps care.

Following the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) treatment algorithm for chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), patients suffering from severe uncontrolled CRSwNP are recommended to receive oral corticosteroids, (revision) sinus surgery, systemic biologicals and/or aspirin treatment after desensitization (ATAD). Given the major differences in indications, outcomes, practical considerations, risks and costs of these key pillars of treatment, there is a growing need to define criteria for each treatment option and list the clinically relevant and major considerations for them. This EUFOREA document therefore provides an expert panel overview of the expected outcomes, specific considerations and (contra)indications of the five major treatment arms of severe uncontrolled CRSwNP: oral corticosteroids, primary and revision sinus surgery, biological treatment and ATAD. This overview of treatment considerations is needed to allow physicians and patients to consider the different options in the context of providing optimal and personalized care for severe uncontrolled CRSwNP. In conclusion, the five major treatment options for severe uncontrolled CRSwNP have intrinsic advantages, specific indications and considerations that are of importance to the patient, the physician and the society. This EUFOREA statement supports the unmet need to define criteria for the indication of every treatment pillar of CRSwNP.

The Unified Airway Hypothesis: Evidence From Specific Intervention With Anti-IL-5 Biologic Therapy.

The unified airway hypothesis proposes that upper and lower airway diseases reflect a single pathological process manifesting in different locations within the airway. Functional, epidemiological, and pathological evidence has supported this well-established hypothesis for some time. However, literature on the pathobiologic roles/therapeutic targeting of eosinophils and IL-5 in upper and lower airway diseases (including asthma, chronic rhinosinusitis with nasal polyps [CRSwNP], and nonsteroidal anti-inflammatory drug-exacerbated respiratory disease) has recently emerged. This narrative review revisits the unified airway hypothesis by searching the scientific literature for recent learnings and clinical trial/real-world data that provide a novel perspective on its relevance for clinicians. According to the available literature, eosinophils and IL-5 have important pathophysiological roles in both the upper and lower airways, although the impact of eosinophils and IL-5 may vary in asthma and CRSwNP. Some differential effects of anti-IL-5 and anti-IL-5-receptor therapies in CRSwNP have been observed, requiring further investigation. However, pharmaceutical targeting of eosinophils and IL-5 in patients with upper, lower, and comorbid upper and lower airway inflammation has led to clinical benefit, supporting the hypothesis that these are linked conditions manifesting in different locations. Consideration of this approach may improve patient care and aid clinical decision making.

Dupilumab provides early and durable improvement of symptoms in patients with chronic rhinosinusitis with nasal polyps.

Objectives: To evaluate within-patient symptom improvement in the dupilumab SINUS-24/-52 studies in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) (NCT02912468/NCT02898454). Methods: Patients received dupilumab 300 mg or placebo every 2 weeks for 24 (SINUS-24) or 52 weeks (SINUS-52) on background intranasal corticosteroids. Patients daily reported symptoms of nasal congestion (NC), loss of smell (LoS) and rhinorrhoea on a scale of 0-3 (0 - no symptoms, 1 - mild, 2 - moderate, 3 - severe symptoms). The proportions of patients with moderate-to-severe symptoms (score ≥ 2) at baseline who improved to no-to-mild symptoms (score ≤ 1) were determined at Weeks 2, 24 (pooled studies) and 52 (SINUS-52). Subgroups with prior sinonasal surgery and coexisting asthma were analysed. Results: At baseline in the pooled intention-to-treat population (n = 724), the proportions of patients with scores ≥ 2 for NC, LoS and rhinorrhoea were 87, 94 and 64%, respectively. Significantly, more patients achieved scores ≤ 1 (no/mild symptoms) with dupilumab vs placebo for each symptom at each time point {Week 2 NC 12% vs 2% [odds ratio 8.9 (95% CI 3.0-26.3)], LoS 5% vs 1% [4.6 (1.3-16.8)], rhinorrhoea 9% vs 2% [4.8 (1.5-15.4)], all P < 0.05; Week 24 NC 54% vs 14% [8.7 (5.6-13.5)], LoS 43% vs 6% [14.4 (7.9-26.0)], rhinorrhoea 53% vs 16% [6.6 (4.1-10.9)], all P < 0.0001}. Results were similar in subgroups with prior surgery and coexisting asthma. Conclusion: Significantly, more patients achieved improvement from moderate-to-severe symptoms to no-to-mild symptoms with dupilumab than placebo, regardless of prior surgery or coexisting asthma. Improvement was observed as early as Week 2 and continued through to Week 52.

European Academy of Allergy and Clinical Immunology position paper on endoscopic scoring of nasal polyposis.

Nasal endoscopy is not only used for the diagnosis of chronic rhinosinusitis with nasal polyps (CRSwNP), but also for monitoring the response to therapy playing an important role in both daily practice and research. In contrast to patient-reported outcomes, endoscopic nasal polyp scoring by independent blinded readers is an objective measurement, not influenced by the placebo effect. It is safer and cheaper compared with computed tomography imaging and therefore, better suited for regular assessments of the extent of the disease. Since the early 90s, a variety of endoscopic staging methods have been proposed and used in clinical research, making it hard to compare results from different studies. This paper resulted from a task force with experts in the field of CRSwNP, originated by the Ear, Nose and Throat section of the European Academy of Allergy and Clinical Immunology and aims to provide a unified endoscopic NP scoring system that can serve as a reference standard for researchers, but also as a useful tool for practitioners involved in the management of CRSwNP.

The Indispensable Nasal Decongestant: Patients' Views and Perspectives on Nasal Decongestant Overuse.

BACKGROUND: Rhinitis medicamentosa (RM) is a type of nonallergic rhinitis caused by prolonged use of nasal decongestants (NDs). Although it is a preventable phenotype of rhinitis, little is known about patients dealing with this condition. OBJECTIVE: To gain a better understanding of patients' views and experiences of ND overuse, and potential facilitators and barriers to discontinue the overuse. METHODS: We performed a qualitative study using in-depth semistructured interviews with 22 patients who have been using an ND on an almost daily basis for at least 6 months. The interviews were conducted face-to-face, audio-recorded, and transcribed verbatim. Data analysis followed the grounded theory approach. RESULTS: Interviewees described the large impact of nasal congestion on their daily lives. Despite efforts to try other treatment options, the ND was considered the only effective aid to resolve the troublesome symptom. Most participants were aware that the prolonged use was problematic, sometimes leading to hiding behavior in order to avoid criticism by others including their health professionals. Many participants expressed a strong will to discontinue. However, multiple barriers to withdrawal were identified including fear of surgery or the impact of withdrawal on sleep, lack of good alternatives, and negative experiences with past withdrawal attempts. Patients thus face a dilemma in which the barriers to withdrawal currently outweigh the possible benefits. CONCLUSION: The use of NDs is considered indispensable by many chronic users. The facilitators and barriers identified in this study provide opportunities to reduce the use of NDs and the prevalence of RM in the future.

Chronic Rhinosinusitis Outcome Registry (CHRINOSOR): Establishment of an International Outcome Registry Driven by mHealth Technology.

BACKGROUND: Real-world evidence (RWE) is a valuable instrument to better understand the patient journey and effectiveness of therapies. RWE on the prevalence of uncontrolled chronic rhinosinusitis (CRS) and CRS natural course of disease across Europe is scarce. In addition, there is limited RWE that enables comparison of the effectiveness of marketed therapies including topical or systemic corticosteroids, sinus surgery, or biologics. OBJECTIVE: To establish an international CHRonic rhINOSinusitis Outcome Registry (CHRINOSOR) based on real-world data collection enabled by mobile health technology. METHODOLOGY: A digital platform, Galenus Health, supporting patients and physicians in the management of chronic respiratory diseases, is used to collect data on patient profile, disease history, patient outcomes, and a set of relevant clinical outcomes. Adult patients with a diagnosis of CRS are eligible for inclusion. RESULTS: A collaborative scientific network of 17 university ear-nose-throat (ENT) clinics from 10 European countries has been established with the aim to collect real-world data in a longitudinal and standardized manner. The Galenus Health digital platform is currently being implemented in these ENT clinics taking into account legal, privacy, and data security aspects. Up to 300 patients have already been included. CONCLUSIONS: CHRINOSOR is a collaborative effort that aims at improving our understanding of CRS, its comorbidities, and the effectiveness of its treatments. Ultimately, these insights will guide us as scientific community to develop future care pathways informed by RWE.

Reboot surgery for chronic rhinosinusitis with nasal polyposis: recurrence and smell kinetics.

OBJECTIVE: To evaluate the time for recovery of the sense of smell in patients with CRSwNP who underwent Reboot surgery compared to patients undergoing ESS in a long-term follow-up study. METHODS: Data were collected retrospectively from 168 patients with severe uncontrolled CRSwNP, who underwent revision surgery, either as Extended Endoscopic Sinus Surgery (Reboot, 140 patients) or as regular Endoscopic Sinus Surgery (ESS, 28 patients) between January 1, 2014, and December 31, 2015, aiming to compare the outcome of surgeries after 2 years of follow-up. Sense of smell was scored as judged by the patient using scores 0 to 3 reflecting a percentage estimate of remaining smell. RESULTS: Smell improved similarly in the Reboot and ESS groups over the first 9 months, which was maintained over 24 months in the Reboot, but not the ESS group (p = 0.007 after 18 months, p = 0.001 after 24 months). Furthermore, polyp recurrence rates were significantly lower in the Reboot group. CONCLUSION: Reboot surgery significantly improved olfactory function and significantly reduced nasal polyp recurrence rates over 2 years post-operatively. Therefore, Reboot should be considered for patients with uncontrolled severe CRSwNP, specifically when ESS failed, to offer long-term smell and a polyp-free status. LEVEL OF EVIDENCE: 3b.

The roles of eosinophils and interleukin-5 in the pathophysiology of chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is generally associated with eosinophilic tissue infiltration linked to type 2 inflammation and characterized by elevated levels of interleukin (IL)-5 and other type 2 inflammatory mediators. Although distinct and overlapping contributions of eosinophils and IL-5 to CRSwNP pathology are still being explored, they are both known to play an important role in NP inflammation. Eosinophils secrete numerous type 2 inflammatory mediators including granule proteins, enzymes, cytokines, chemokines, growth factors, lipids, and oxidative products. IL-5 is critical for the differentiation, migration, activation, and survival of eosinophils but is also implicated in the biological functions of mast cells, basophils, innate lymphoid cells, B cells, and epithelial cells. Results from clinical trials of therapeutics that target type 2 inflammatory mediators (including but not limited to anti-IL-5, anti-immunoglobulin-E, and anti-IL-4/13) may provide further evidence of how eosinophils and IL-5 contribute to CRSwNP. Finally, the association between eosinophilia/elevated IL-5 and greater rates of NP recurrence after endoscopic sinus surgery (ESS) suggests that these mediators may have utility as biomarkers of NP recurrence in diagnosing and assessing the severity of CRSwNP. This review provides an overview of eosinophil and IL-5 biology and explores the literature regarding the role of these mediators in CRSwNP pathogenesis and NP recurrence following ESS. Based on current published evidence, we suggest that although eosinophils play a key role in CRSwNP pathophysiology, IL-5, a cytokine that activates these cells, also represents a pertinent and effective treatment target in patients with CRSwNP.

Phase 3b randomized controlled trial of fevipiprant in patients with nasal polyposis with asthma (THUNDER).

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with asthma, particularly of late onset. Current treatment options for CRSwNP have limitations, and there is an unmet need for other safe and effective therapies. OBJECTIVE: The aim of the THUNDER study was to determine the efficacy and safety of the prostaglandin D2 receptor 2 (DP2) antagonist fevipiprant in patients with CRSwNP and concomitant asthma, measured by improvement in nasal polyp score (primary end point), nasal congestion score, Sinonasal Outcome Test 22 score, and University of Pennsylvania Smell Identification Test score. METHODS: THUNDER was a phase 3b, randomized, multicenter, double-blind, placebo-controlled, parallel-group, 16-week study of fevipiprant 150 mg or 450 mg once daily versus placebo. All patients received intranasal mometasone furoate 200 µg daily. RESULTS: Ninety-eight patients were randomly assigned to fevipiprant 150 mg (n = 32), fevipiprant 450 mg (n = 34), or placebo (n = 32). Mean (SE) change from baseline in nasal polyp score at week 16 was 0.20 (0.224) for fevipiprant 150 mg, -0.10 (0.216) for fevipiprant 450 mg, and 0.14 (0.233) for placebo. Mean treatment difference was 0.05 (95% confidence interval, -0.59, 0.70; adjusted P = .979) for fevipiprant 150 mg versus placebo and -0.25 (95% confidence interval, -0.88, 0.39; adjusted P = .656) for fevipiprant 450 mg versus placebo. There was no meaningful difference in the secondary end points for fevipiprant versus placebo. CONCLUSIONS: THUNDER provided no evidence of a role for fevipiprant in the treatment of patients with CRSwNP and asthma; future studies may establish a role for other DP2 antagonists, specifically in patients with aspirin-exacerbated respiratory disease.