Nasal Brushing Molecular Endotyping Distinguishes CRSwNP Patients with Better Response to Dupilumab.

BACKGROUND: There is evidence of pathophysiologic diversity in chronic rhinosinusitis with nasal polyps (CRSwNP), but data characterizing the molecular endotypes of CRSwNP and their association with treatment is lacking. OBJECTIVES: To identify gene signatures associated with CRSwNP endotypes, clinical features, and dupilumab treatment response. METHODS: Nasal brushing samples were collected from 89 patients randomized to dupilumab 300 mg every 2 weeks or placebo in the SINUS-52 trial (NCT02898454). Microarrays were used to identify transcriptional clusters and assess the relationship between gene expression and baseline clinical features and clinical response to dupilumab. Endotype signatures were determined using differential expression analysis. RESULTS: Two distinct transcriptional clusters (C1 and C2) were identified, both with elevated type 2 biomarkers. At baseline, C2 patients had higher mean Nasal Polyp Score and higher type 2 biomarker levels than C1 patients. At Week 24, significant improvements in clinical outcomes (dupilumab vs placebo) were observed in both clusters, although the magnitude of improvements was significantly greater in C2 than C1, and more C2 patients demonstrated clinically meaningful responses. Gene sets enrichment analyses supported the existence of two molecular endotypes: C2 was enriched in genes associated with type 2 inflammation (including periostin, cadherin-26, and type 2 cysteine protease inhibitors), while C1 was enriched in genes associated with T cell activation and interleukin-12 production. CONCLUSION: Two distinct gene signatures associated with CRSwNP clinical features were identified; the endotype signatures were associated with clinical outcome measures and magnitude of dupilumab response.

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.

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.

Cost-effectiveness analysis of biologics for the treatment of chronic rhinosinusitis with nasal polyps in Canada.

BACKGROUND: Dupilumab, omalizumab, and mepolizumab are the three biologics currently approved for use in CRSwNP in Canada. Despite evidence of efficacy, their cost-effectiveness, which is a key factor influencing prescribing patterns, has not yet been compared to each other. METHODS: A cost-effectiveness model using quality-adjusted life years (QALYs) was constructed using a Decision Tree Markov analysis. A third-party healthcare payer perspective and a 10-year time horizon was used. A willingness-to-pay (WTP) threshold of 50,000 Canadian dollars (CAD) per QALY was used to determine cost-effectiveness. Dupilumab, omalizumab, and mepolizumab were each compared to each other. RESULTS: Omalizumab was the most cost-effective biologic using current estimates of cost and efficacy in CRSwNP. Using omalizumab as a baseline, dupilumab had an ICER of $235,305/QALY. Mepolizumab was dominated by omalizumab and dupilumab at the current drug prices and estimates of efficacy. Sensitivity analyses determined that when increasing the WTP threshold to $150,000/QALY, dupilumab became cost-effective compared to omalizumab in 22.5% of simulation scenarios. Additionally, altering dosing frequency had a significant effect on cost-effectiveness. CONCLUSION: When comparing the relative cost-effectiveness of biologics in recalcitrant CRSwNP, omalizumab currently appears to be the most cost-effective option. Future reductions in drug prices, adjustments to currently approved dosing regimens, better patient selection, and improvements in sinus surgery outcomes will challenge the current cost-effectiveness models and necessitate reassessment as treatments for CRSwNP continue to evolve.

Utilization of Transcriptomic Profiling to Identify Molecular Markers Predicting Successful Recovery Following Endoscopic Sinus Surgery for Chronic Rhinosinusitis.

OBJECTIVES: Successful recovery from chronic rhinosinusitis (CRS) following endoscopic sinus surgery (ESS) can be characterized by minimal presence of symptoms and absence of disease on endoscopy. However, molecular markers of surgical success remain to be characterized. These could allow for better tailoring of perioperative therapy. This study aims to identify novel molecular markers associated with surgery responsive patient. STUDY DESIGN: Prospective cohort study. SETTING: Single academic hospital center. METHOD: One hundred eighteen consecutive patients with CRS at high risk of recurrence after surgery were followed prospectively following ESS in an academic medical center. Symptomatic and endoscopic outcomes were assessed at 4 months, with success rigorously defined subjectively as minimal or no symptoms (no symptom greater than 1 on an ordinal scale of 0-3) and objectively by the absence of nasal polyposis on sinus cavity endoscopy and Lund-Kennedy endoscopic edema score no greater than 1. Samples were obtained at the time of surgery and at 4-month postoperatively. Changes associated with surgery were determined by gene expression profiling using Affymetrix's Clariom S Human HT arrays. RESULTS: Successful ESS was characterized by a mild upregulation in Type 1 inflammation, upregulation of cell cycle progression, and epithelial barrier and proliferation-associated genes and pathways. ESS failure was associated to very high levels of Type 1 inflammation along with downregulation of epithelial barrier function and regeneration genes and pathways. CONCLUSION: Successful recovery from ESS involves restoration of epithelial function and regulated activation of Type 1 inflammation. Excessively elevated Type 1 inflammation is associated with epithelial barrier dysfunction.

The Effect of Corticosteroids on Sinus Microbiota in Chronic Rhinosinusitis Patients with Nasal Polyposis.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a multifactorial disease with no known single cause, but it is thought that bacteria play a role in the disease process. OBJECTIVE: This pilot study aims to assess the longitudinal effect of corticosteroid therapy on sinus microbiota in chronic rhinosinusitis patients with nasal polyposis (CRSwNP). METHODS: A longitudinal prospective case-control study was done on patients with CRSwNP and healthy controls. Patients with CRSwNP were randomly allocated to a corticosteroids and antibiotics treatment group (CRSwNP-SA) or a corticosteroid-only treatment group (CRSwNP-S). Data were collected at three-time points (before treatment, 1, and 3 months after treatment). Specimens were cultured and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry (MS) was used as a bacterial detection method. RESULTS: Data from 29 patients with CRSwNP (16 CRSwNP-SA and 13 CRSwNP-S) was compared to 15 healthy subjects. Patients reported significant symptom improvement initially (1 month), but not in the long-term (3 months). This result was found in both treatment groups, whether or not antibiotics were used. After 3 months from treatment, the prevalence of Corynebacterium genera tended to increase in the CRSwNP-SA, while Staphylococcus and Gram-negative genera (Pseudomonas) tended to increase in the CRSwNP-S. Smoking, aspirin sensitivity, and previous endoscopic sinus surgery were found to be co-factors significantly associated with the response to systemic corticosteroid therapy. CONCLUSION: In this pilot study, both treatment options were effective to improve symptoms in the short-term but not in the long-term, and were not linked to any clear sinus microbiota response. As a result, this study supports the avoidance of systemic antibiotics without evidence of active infection.

Remission: does it already exist in chronic rhinosinusitis with nasal polyposis?

BACKGROUND: Remission, defined as absence of symptoms and objective markers of disease, is emerging as the penultimate goal in the management of several chronic diseases. The concept of remission, well-established in Rheumatology as well as Gastroenterology, is currently emerging in Respiratory Medicine for asthma. It is interesting to consider whether the disease remission concept might successfully be applied to Otolaryngology-Head and Neck Surgery in the management of chronic rhinosinusitis with nasal polyposis (CRSwNP). OBJECTIVE: The purpose of this letter is to explore the evidence supporting the concept of remission under continued medical therapy in chronic rhinosinusitis with nasal polyposis. METHODS: The authors reviewed the literature and summarized studies in chronic rhinosinusitis with nasal polyposis evaluating for evidence of clinical, biochemical, and endoscopic remission. RESULTS: Findings of the studies revealed that endoscopic sinus surgery with continued medical therapy achieved remission in approximately 50% of all patients. CRSwNP patients after primary endoscopic sinus surgery were able to achieve remission in 72% of instances, however this drops to 42% for patients having revision sinus surgery. For CRSwNP patients with co-morbidities such as asthma and aspirin exacerbated respiratory disease, remission rate drops to 23% and 23.5%, respectively compared to non-asthmatic CRSwNP patients who present a remission rate under continued medical therapy of 60%. CONCLUSION: Remission of symptoms and evidence of disease under medical therapy is indeed a concept achievable in patients with CRSwNP, as demonstrated by studies in the literature. Various co-morbidities, notably asthma, apparently influence rate of remission. Better defining this outcome through consensus-based definitions will allow for the development of strategies in CRSwNP care that can help affected patients attain complete relief from clinical, biochemical, and endoscopic markers of CRS with judicious use of medication and surgery. Future efforts will attempt to improve on these outcomes by achieving symptomatic and endoscopic control of disease following cessation of therapy, potentially paving the way towards clinical remission or a 'cure' in CRS.

Azithromycin Mechanisms of Action in CRS Include Epithelial Barrier Restoration and Type 1 Inflammation Reduction.

OBJECTIVE: Previous in vitro transcriptomic profiling suggests azithromycin exerts its effects in patients with chronic rhinosinusitis (CRS) via modulation of type 1 inflammation and restoration of epithelial barrier function. We wished to verify these postulated effects using in vitro models of epithelial repair and in vivo transcriptional profiling. STUDY DESIGN: Functional effects of azithromycin in CRS were verified using in vitro models of wounding. The mechanism of the effect of azithromycin was assessed in vivo using transcriptomic profiling. SETTING: Academic medical center. METHODS: Effects of azithromycin on the speed of epithelial repair were verified in a wounding model using primary nasal epithelial cells (pNEC) from CRS patients. Nasal brushings collected pre-and posttreatment during a placebo-controlled trial of azithromycin for CRS patients unresponsive to surgery underwent transcriptomic profiling to identify implicated pathways. RESULTS: Administration of azithromycin improved the wound healing rates in CRS pNECs and prevented the negative effect of Staphylococcus aureus on epithelial repair. In vivo, response to azithromycin was associated with downregulation in pathways of type 1 inflammation, and upregulation of pathways implicated in the restoration of the cell cycle. CONCLUSION: Restoration of healthy epithelial function may represent a major mode of action of azithromycin in CRS. In vitro models show enhanced epithelial repair, while in vivo transcriptomics shows downregulation of pathways type 1 inflammation accompanied by upregulation of DNA repair and cell-cycle pathways. The maximal effect in patients with high levels of type 1-enhanced inflammation suggests that azithromycin may represent a novel therapeutic option for surgery-unresponsive CRS patients.

Canadian multidisciplinary expert consensus on the use of biologics in upper airways: a Delphi study.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) often coexists with lower airway disease. With the overlap between upper and lower airway disease, optimal management of the upper airways is undertaken in conjunction with that of the lower airways. Biologic therapy with targeted activity within the Type 2 inflammatory pathway can improve the clinical signs and symptoms of both upper and lower airway diseases. Knowledge gaps nevertheless exist in how best to approach patient care as a whole. There have been sixteen randomized, double-blind, placebo-controlled trails performed for CRSwNP targeted components of the Type 2 inflammatory pathway, notably interleukin (IL)-4, IL-5 and IL-13, IL- 5R, IL-33, and immunoglobulin (Ig)E. This white paper considers the perspectives of experts in various disciplines such as rhinology, allergy, and respirology across Canada, all of whom have unique and valuable insights to contribute on how to best approach patients with upper airway disease from a multidisciplinary perspective. METHODS: A Delphi Method process was utilized involving three rounds of questionnaires in which the first two were completed individually online and the third was discussed on a virtual platform with all the panelists. A national multidisciplinary expert panel of 34 certified specialists was created, composed of 16 rhinologists, 7 allergists, and 11 respirologists who evaluated the 20 original statements on a scale of 1-9 and provided comments. All ratings were quantitively reviewed by mean, median, mode, range, standard deviation and inter-rater reliability. Consensus was defined by relative interrater reliability measures-kappa coefficient ([Formula: see text]) value > 0.61. RESULTS: After three rounds, a total of 22 statements achieved consensus. This white paper only contains the final agreed upon statements and clear rationale and support for the statements regarding the use of biologics in patients with upper airway disease. CONCLUSION: This white paper provides guidance to Canadian physicians on the use of biologic therapy for the management of upper airway disease from a multidisciplinary perspective, but the medical and surgical regimen should ultimately be individualized to the patient. As more biologics become available and additional trials are published we will provide updated versions of this white paper every few years.

Response to intranasal Lactococcus lactis W136 probiotic supplementation in refractory CRS is associated with modulation of non-type 2 inflammation and epithelial regeneration.

Justification: We have previously documented that in individuals with chronic rhinosinusitis (CRS) refractory to surgery, intranasal application of live Lactococcus lactis W136, a probiotic bacterium, improves sinus-specific symptoms, SNOT-22, and mucosal aspect on endoscopy, accompanied by a reduction in sinus pathogens and an increase in protective bacteria. The present work explores the molecular mechanisms underpinning these observations using transcriptomics of the sinus mucosa. Method: Epithelial brushings collected prospectively as a sub-study of the L. lactis W136 clinical trial were used to probe epithelial responses to microbiome supplementation using a hypothesis-free bioinformatic analysis of gene expression analysis. Samples from twenty-four patients with CRS refractory to medical and surgical management were prospectively collected during a clinical trial assessing the effect of 14 days of BID nasal irrigation with 1.2 billion CFU of live L. lactis W136 probiotic bacteria (CRSwNP = 17, CRSsNP = 7). Endoscopically guided sinus brushings were collected as part of the initial study, with brushings performed immediately before and after treatment. Following RNA extraction, samples were assessed using the Illumina HumanHT-12 V4 BeadChip. Differential gene expression was calculated, and pathway enrichment analysis was performed to identify potentially implicated processes. Results: Differentially identified transcripts and pathways were assessed for the overall population and the clinical phenotypes of CRSwNP and CRSsNP. Patterns of response to treatment were similar across all groups, implicating pathways for the regulation of immunity and epithelial cell regulation. These resemble the patterns of improvement observed following successful treatment with endoscopic sinus surgery or azithromycin. Conclusion: Gene expression profiling following the application of live bacteria to the diseased sinus epithelium highlights the implication of multiple components of the inflammation-microbiome-epithelial barrier axis implicated in CRS. These effects appear to involve both epithelial restoration and modulation of innate and adaptive immunity, supporting the potential interest of targeting the sinus epithelium and the microbiome as potential CRS therapies.

Dupilumab Demonstrates Rapid Onset of Response Across Three Type 2 Inflammatory Diseases.

BACKGROUND: Type 2 inflammatory diseases often coexist in patients. Dupilumab targets type 2 inflammation and has demonstrated treatment benefits in patients with atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP) with an acceptable safety profile. OBJECTIVE: This post hoc analysis across five phase 3 studies in patients with moderate to severe AD or asthma, or severe CRSwNP, evaluated time of onset and duration of the treatment response. METHODS: Patients received subcutaneous dupilumab 200/300 mg or placebo. Assessments included the Eczema Area and Severity Index, Peak Pruritus Numerical Rating Scale, and Dermatology Life Quality Index in AD; pre-bronchodilator FEV1, daily morning peak expiratory flow, and symptom scores in asthma; and University of Pennsylvania Smell Identification Test, daily nasal congestion, and loss of smell scores in CRSwNP. RESULTS: At week 2 after the initiation of dupilumab versus placebo, 67.8% versus 36.5% of AD patients achieved a clinically meaningful benefit (Eczema Area and Severity Index: 50% or greater improvement; Peak Pruritus Numerical Rating Scale: 3 point or greater improvement; or Dermatology Life Quality Index: 4 point or greater improvement) (P < .001). Moreover, 61.6% versus 39.9% of asthma patients achieved improvements in pre-bronchodilator FEV1 of 100 mL or greater and 48.8% versus 26.3% achieved 200 mL or greater improvement (both P < .001); 33.2% versus 5.6% of CRSwNP patients regained a sense of smell (P < .001). Treatment effects further improved or were sustained to the end of treatment. CONCLUSIONS: Clinically meaningful responses were achieved rapidly after the first dupilumab dose in AD, asthma, or CRSwNP and were sustained throughout treatment (see Video in this article's Online Repository at www.jaci-inpractice.org).

Olfactory Outcomes With Dupilumab in Chronic Rhinosinusitis With Nasal Polyps.

BACKGROUND: Loss of smell (LoS) is one of the most troublesome and difficult-to-treat symptoms of severe chronic rhinosinusitis with nasal polyps (CRSwNP). OBJECTIVE: To assess the impact of dupilumab on sense of smell in severe CRSwNP. METHODS: In the randomized SINUS-24 and SINUS-52 studies, adults with severe CRSwNP received dupilumab 300 mg subcutaneously or matching placebo every 2 weeks for 24 or 52 weeks, respectively. Smell was assessed using daily patient-reported LoS score (0-3) and University of Pennsylvania Smell Identification Test (UPSIT; 0-40). Data from the 2 studies were pooled through week 24. Relationships between patient phenotypes and smell outcomes were also assessed. RESULTS: We randomized 724 patients (286 placebo, 438 dupilumab); mean CRSwNP duration was 11 years; 63% had prior sinonasal surgery. Mean baseline LoS was 2.74. Dupilumab produced rapid improvement in LoS, evident by day 3, which improved progressively throughout the study periods (least squares mean difference vs placebo -0.07 [95% CI -0.12 to -0.02]; nominal P < .05 at day 3, and -1.04 [-1.17 to -0.91]; P < .0001 at week 24). Dupilumab improved mean UPSIT by 10.54 (least squares mean difference vs placebo 10.57 [9.40-11.74]; P < .0001) at week 24 from baseline (score 13.90). Improvements were unaffected by CRSwNP duration, prior sinonasal surgery, or comorbid asthma and/or nonsteroidal anti-inflammatory drug-exacerbated respiratory disease. Baseline olfaction scores correlated with all measured local and systemic type 2 inflammatory markers except serum total immunoglobulin E. CONCLUSIONS: Dupilumab produced rapid and sustained improvement in sense of smell, alleviating a cardinal symptom of severe CRSwNP.

Efficacy and safety of benralizumab in chronic rhinosinusitis with nasal polyps: A randomized, placebo-controlled trial.

BACKGROUND: Eosinophilic inflammation has been implicated in the pathogenesis, severity, and treatment responsiveness of chronic rhinosinusitis with nasal polyps (CRSwNP). OBJECTIVE: We sought to assess the efficacy and safety of benralizumab-mediated eosinophil depletion for treating CRSwNP. METHODS: The phase 3 OSTRO study enrolled patients with severe CRSwNP who were symptomatic despite treatment with intranasal corticosteroids and who had a history of systemic corticosteroid (SCS) use and/or surgery for nasal polyps (NP). Patients were randomized 1:1 to treatment with benralizumab 30 mg or placebo every 4 weeks for the first 3 doses and every 8 weeks thereafter. Coprimary end points were change from baseline to week 40 in NP score (NPS) and patient-reported mean nasal blockage score reported once every 2 weeks. RESULTS: The study population comprised 413 randomized patients (207 in the benralizumab group and 206 in the placebo group). Benralizumab significantly improved NPS and nasal blockage score compared to placebo at week 40 (P ≤ .005). Improvements in Sinonasal Outcome Test 22 score at week 40, time to first NP surgery and/or SCS use for NP, and time to first NP surgery were not statistically significant between treatment groups. Nominal significance was obtained for improvement in difficulty in sense of smell score at week 40 (P = .003). Subgroup analyses suggested influences of comorbid asthma, number of NP surgeries, sex, body mass index, and baseline blood eosinophil count on treatment effects. Benralizumab was safe and well tolerated. CONCLUSION: Benralizumab, when added to standard-of-care therapy, reduced NPS, decreased nasal blockage, and reduced difficulty with sense of smell compared to placebo in patients with CRSwNP. TRIAL REGISTRATION: ClinicalTrials.gov NCT03401229.

The Effect of Radiation and Chemoradiation Therapy on the Head and Neck Mucosal Microbiome: A Review.

Radiation (RT) and chemoradiation therapy (CRT) play an essential role in head and neck cancer treatment. However, both cause numerous side effects in the oral cavity, paranasal sinuses, and pharynx, having deleterious consequences on patients' quality of life. Concomitant with significant advances in radiation oncology, much attention has turned to understanding the role of the microbiome in the pathogenesis of treatment-induced tissue toxicity, to ultimately explore microbiome manipulation as a therapeutic intervention. This review sought to discuss current publications investigating the impact of RT and CRT-induced changes on the head and neck microbiome, using culture-independent molecular methods, and propose opportunities for future directions. Based on 13 studies derived from a MEDLINE, EMBASE, and Web of Science search on November 7, 2021, use of molecular methods has uncovered various phyla and genera in the head and neck microbiome, particularly the oral microbiome, not previously known using culture-based methods. However, limited research has investigated the impact of RT/CRT on subsites other than the oral cavity and none of the studies aimed to examine the relationship between the head and neck microbiome and treatment effectiveness. Findings from this review provide helpful insights on our current understanding of treatment-induced oral mucositis, dental plaque, and caries formation and highlight the need for future research to examine the effect of RT/CRT on the sinonasal and oropharyngeal microbiome. In addition, future research should use larger cohorts, examine the impact of the microbiome on treatment response, and study the effect of manipulating the microbiome to overcome therapy resistance.

Patient perspectives on endoscopic sinus surgery for chronic rhinosinusitis.

BACKGROUND: Through shared decision-making, physicians and patients can elect endoscopic sinus surgery (ESS) when maximal medical therapy fails in patients with chronic rhinosinusitis (CRS). In this study, we aim to explore the most important themes with regards to patients' perspectives on ESS. Our objective was to define the patient experience and ensure that we have congruent physician and patient goals for obtaining success. METHODS: Semi-structured face-to-face interviews were conducted with 22 patients at a tertiary-care institution in Montreal. Three themes were established a priori: living with CRS, objectives and expectations and criteria for success. This thematic approach allowed the identification, analysis and reporting of patterns found across the data set. A phenomenological methodological orientation was used. Interviews were audio-recorded and transcribed verbatim for continuous analysis. These were coded by hand by a single coder who read the transcripts multiple times and relistened to the recordings. RESULTS: Exploration of themes on patients' perspectives on ESS for CRS yielded multiple anecdotal findings, and some recurring patterns. There is a tendency for patients to focus on one principal symptom that drives their decrease in QoL. Headaches and nasal congestion seemed to impact patients' QoL the most amongst rhinologic symptoms. Hyposmia was rarely spontaneously by patients but was often a significant source of distress when prompted during interviews. Objectives and expectations seemed to be inversely proportional to number of previous surgeries and severity of symptoms preoperatively. There was a clear association between preoperative expectations and postoperative satisfaction. There was no clear pattern in the improvement magnitude or time improved postoperatively for patients to consider the surgery a success. CONCLUSIONS: Patients' level of satisfaction postoperatively and with their care in general is multifactorial. We believe the topic of goals and expectations regarding ESS should be discussed preoperatively for every patient with CRS. This includes patients with seemingly minor disease and patients naive to surgery, as can sometimes have exceedingly high expectations. Preoperative counselling must also include an assessment of what symptom is the most cumbersome to that particular patient, as patients tend to focus a lot on one or two symptoms. Postoperatively, we encourage clinicians to be attentive to the change in each patient's principal complaints within the context of a personalized approach and to refer back to patients' preoperative goals in their assessment of operative success.

What is the optimal outcome after endoscopic sinus surgery in the treatment of chronic rhinosinusitis? A consultation of Canadian experts.

OBJECTIVES: Many experts feel that in the absence of well-defined goals for success, they have an easier time identifying failure. As success ought to not be defined only by absence of failure, we aimed to define optimal outcomes for endoscopic sinus surgery (ESS) in chronic rhinosinusitis (CRS) by obtaining expert surgeon perspectives. METHODS: A total of 12 surgeons participated in this targeted consultation. Face to face semi-structured interviews were performed with expert surgeons in the field of CRS and ESS. General impressions and personal definitions of acceptable operative success and optimal operative outcomes were compiled and summarized. RESULTS: According to an expert survey, patients' main objectives are an improvement in their chief complain, a general improvement in quality of life (QoL), and a better overall symptomatic control. The most important aspects of endoscopy for defining a successful intervention were an adequate mucus circulation, a healthy mucosa, minimal edema, and patency of all explored cavities or ostia. In the assessment of surgical outcomes, it was determined that both objective and patient reported data must be carefully examined, with more attention given to subjective outcomes. CONCLUSIONS: According to data gathered from a Canadian expert consultation, a definition of success must be based on both subjective data and nasal endoscopy. We propose to define an acceptable outcome as either a subjective improvement of at least the minimal clinically improvement difference of a validated patient reported outcome questionnaire, along with a satisfactory endoscopic result (1) or a complete subjective resolution with a sub-optimal endoscopy (2).

Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Chronic rhinosinusitis with nasal polyps affects approximately 2-4% of the general population, and long-term use of systemic corticosteroids is associated with adverse effects. The aim of this study was to assess the efficacy and safety of mepolizumab in adults with recurrent, refractory severe bilateral chronic rhinosinusitis with nasal polyps. METHODS: SYNAPSE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done at 93 centres, mainly hospitals, in 11 countries. Eligible patients were aged 18 years or older with recurrent, refractory, severe, bilateral nasal polyp symptoms (nasal obstruction symptom visual analogue scale [VAS] score of >5), were eligible for repeat nasal surgery (overall symptoms VAS score >7 and endoscopic nasal polyps score of ≥5, with a minimum score of 2 in each nasal cavity) despite standard of care treatment, and had to have at least one nasal surgery in the past 10 years. Patients were randomly assigned (1:1), using permuted block design, to receive either 100 mg mepolizumab subcutaneously or placebo once every 4 weeks, in addition to standard of care (mometasone furoate intranasal spray for at least 8 weeks before screening and during the study, saline nasal irrigations, systemic corticosteroids or antibiotics, or both), as required, for 52 weeks. Site staff, the central study team, and patients were masked to study treatment and absolute blood eosinophil counts. The coprimary endpoints were change from baseline in total endoscopic nasal polyp score at week 52 and in mean nasal obstruction VAS score during weeks 49-52, assessed in the intention-to-treat population (ITT). This study is registered with ClinicalTrials.gov, NCT03085797. FINDINGS: From May 25, 2017, to Dec 12, 2018, 854 patients were screened for eligibility. 414 patients were randomly assigned with 407 included in the ITT population; 206 received mepolizumab and 201 received placebo. Total endoscopic nasal polyp score significantly improved at week 52 from baseline with mepolizumab versus placebo (adjusted difference in medians -0·73, 95% CI -1·11 to -0·34; p<0·0001) and nasal obstruction VAS score during weeks 49-52 also significantly improved (-3·14, -4·09 to -2·18; p<0·0001). Adverse events considered related to study treatment were reported in 30 (15%) of 206 patients receiving mepolizumab and 19 (9%) of 201 receiving placebo. On-treatment serious adverse events occurred in 12 (6%) patients receiving mepolizumab and 13 (6%) receiving placebo; none were considered related to treatment in those receiving mepolizumab. One death was reported in the placebo group (myocardial infarction; death occurred 99 days after the last dose) and was considered unrelated to the treatment. INTERPRETATION: Mepolizumab treatment improved nasal polyp size and nasal obstruction compared with placebo, with no new safety indications, in patients with recurrent, refractory severe chronic rhinosinusitis with nasal polyps. These findings suggest that mepolizumab provides an effective add-on treatment option to standard of care in this population. FUNDING: GlaxoSmithKline.

Efficacy of dupilumab in patients with a history of prior sinus surgery for chronic rhinosinusitis with nasal polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2 inflammatory disease treated with sinus surgery when refractory to medical intervention. However, recurrence postsurgery is common. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor for interleukin 4 (IL-4) and IL-13, key and central drivers of type 2 inflammation. We report the efficacy of dupilumab in patients with CRSwNP from the SINUS-24/SINUS-52 trials (NCT02912468/NCT02898454), by number of prior surgeries and time since last surgery. METHODS: Patients were randomized to placebo or dupilumab 300 mg every 2 weeks. Post hoc subgroup analyses were performed for patients with 0, ≥1, 1/2, or ≥3 prior surgeries, and for patients who had surgery within <3, 3 to <5, 5 to <10, or ≥10 years. Efficacy outcomes at 24 weeks included co-primary endpoints nasal polyp score (NPS) and nasal congestion (NC), and Lund-Mackay (LMK), 22-item Sino-Nasal Outcome Test (SNOT-22), and smell scores. RESULTS: Of 724 patients randomized, 459 (63.4%) had ≥1 prior surgery. Baseline sinus disease (NPS, NC, LMK) and olfactory dysfunction (University of Pennsylvania Smell Identification Test [UPSIT] and loss of smell) scores were worse for patients with ≥3 prior surgeries vs no surgery. Baseline NPS and LMK were worse in patients with <3 years since last surgery than in patients with ≥5 years since last surgery. Dupilumab significantly improved all outcome measures vs placebo in all subgroups by number of surgeries and by time since last surgery. Improvements in NPS and LMK were greater in patients with <3 years since last surgery than patients with ≥5 years. Safety results were consistent with the known dupilumab safety profile. CONCLUSION: Dupilumab improved CRSwNP outcomes irrespective of surgery history, with greater improvements in endoscopic outcomes in patients with shorter duration since last surgery.

Burden of Disease in Chronic Rhinosinusitis with Nasal Polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammation-mediated disease of the nasal mucosa and paranasal sinuses with an under-recognized clinical, humanistic, and economic burden. Patients with CRSwNP experience a high symptom burden, including nasal congestion, loss of smell, and rhinorrhea, which has a negative impact on physical and mental health-related quality of life, including sleep quality. Existing medical and surgical interventions, including local and systemic corticosteroids and endoscopic sinus surgery, may be associated with recurrence of nasal polyps and associated symptoms and with an increased risk of short- and long-term adverse effects, especially with repeated or long-term use. Because type 2 inflammation is implicated in the pathogenesis of several coexisting diseases, patients with CRSwNP often have comorbid asthma and/or nonsteroidal anti-inflammatory drug-exacerbated respiratory disease. These patients, as well as those with high corticosteroid use and/or sinonasal surgical history, have more severe disease and associated symptom burden and represent a difficult-to-treat population under the existing management paradigm. This article reviews the clinical, humanistic, and economic burden of CRSwNP; it highlights the unmet need for effective and safe CRSwNP therapies that effectively control symptoms and minimize recurrence by targeting the underlying type 2 inflammatory disease pathophysiology.