Efficacy of EDS-FLU for Chronic Rhinosinusitis: Two Randomized Controlled Trials (ReOpen1 and ReOpen2).

BACKGROUND: Chronic rhinosinusitis (CRS) is a prevalent inflammatory disease. No medications are Food and Drug Administration-approved for the most common form, CRS without nasal polyps (also called "chronic sinusitis"). Novel biomechanics of the exhalation delivery system deliver fluticasone (EDS-FLU; XHANCE) to sinonasal areas above the inferior turbinate, especially sinus drainage pathways not reached by standard-delivery nasal sprays. OBJECTIVE: Assess EDS-FLU efficacy for CRS (irrespective of nasal polyps). METHODS: Two randomized, EDS-placebo-controlled trials in adults with CRS irrespective of polyps (ReOpen1) or exclusively without polyps (ReOpen2) were conducted at 120 sites in 13 countries. Patients received EDS-FLU 1 or 2 sprays/nostril, or EDS-placebo, twice daily for 24 weeks. Coprimary measures were composite symptom score through week 4 and ethmoid/maxillary sinus percent opacification by computed tomography at week 24. RESULTS: ReOpen1 (N = 332) composite symptom score least-squares mean change for EDS-FLU 1 or 2 sprays/nostril versus EDS-placebo was -1.58 and -1.60 versus -0.62 (P < .001, P < .001); ReOpen2 (N = 223), -1.54 and -1.74 versus -0.81 (P = .011, P = .001). In ReOpen1, sinus opacification least-squares mean change for EDS-FLU 1 or 2 sprays/nostril versus EDS-placebo was -5.58 and -6.20 versus -1.60 (P = .045, P = .018), and in ReOpen2, -7.00 and -5.14 versus +1.19 (P < .001, P = .009). Acute disease exacerbations were reduced by 56% to 66% with EDS-FLU versus EDS-placebo (P = .001). There were significant, and similar magnitude, symptom reductions in patients using standard-delivery nasal steroid products just before entering the study (P < .001). Adverse events were similar to standard-delivery intranasal steroids. CONCLUSIONS: EDS-FLU is the first nonsurgical treatment demonstrated to reduce symptoms, intrasinus opacification, and exacerbations in replicate randomized clinical trials in CRS, regardless of polyp status.

Management of Aspirin-Exacerbated Respiratory Disease: What Does the Future Hold?

Aspirin-exacerbated respiratory disease (AERD) is a subtype of chronic rhinosinusitis with polyps (CRSwNP) and asthma with higher recurrence of nasal polyps after surgery and severe asthma. Patients with CRSwNP and asthma should be screened for AERD by detailed history of aspirin/nonsteroidal anti-inflammatory drug reactions and review of medications that may mask aspirin reaction or directly by aspirin challenge. Treatment of AERD may require more intensive therapy, including endoscopic sinus surgery, daily aspirin therapy, leukotriene modifiers, or biologics.

Residential Proximity to a Commercial Pesticide Application Site and Risk of Chronic Rhinosinusitis.

Importance: Environmental and occupational toxicants have been shown to be associated with an increased prevalence of chronic rhinosinusitis (CRS). However, few to no studies have evaluated patients for CRS using objective testing and workup protocols that fulfill guidelines for CRS diagnostic criteria. Furthermore, no study, to our knowledge, has investigated the risks of CRS in the context of residential exposure through proximity to a commercial pesticide application site. Objectives: To evaluate associations of residential proximity to a commercial pesticide application site and the prevalence of CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSwoNP). Design, Setting, and Participants: This was a retrospective cohort study of patients who presented to a tertiary care institution for rhinology evaluation between March 1, 2018, and December 31, 2022. Main Outcomes and Measures: The outcome variable was the clinical diagnosis of CRS (CRSwNP, CRSwoNP, or non-CRS control). Patients' residential addresses were utilized to determine pesticide exposure status based on a validated computational geographic information algorithm based on data from the California Pesticide Use Report System. The dichotomous independent variable of exposure status (exposed or non-exposed) was determined by assessing reports of any pesticide applications within 2000 m of each participant's residence in 2017. Multivariable logistic regressions assessing CRS status and CRS subtypes were conducted with pesticide exposure as the primary covariate of interest. The primary study outcome and measurements as well as study hypothesis were all formulated before data collection. Results: Among a total of 310 patients (90 CRSwNP, 90 CRSwoNP, and 130 control), the mean (SD) age was 50 (17) years; 164 (53%) were female. Race and ethnicity information was not considered. Controlling for patient demographic information, smoking history, county of residence, and medical comorbidities, pesticide exposure was associated with an approximately 2.5-fold increase in odds of CRS (adjusted odds ratio, 2.41; 95% CI, 1.49-3.90). Pesticide exposure was associated with similar risks for CRSwNP (adjusted relative risk ratio [aRRR], 2.34; 95% CI, 1.31-4.18) and CRSwoNP (aRRR, 2.42; 95% CI, 1.37-4.30). Conclusions and Relevance: The findings of this retrospective cohort study and analysis revealed that residential exposure to commercial pesticide application within a 2000-m buffer was independently associated with an approximately 2.5-fold increase in odds of being diagnosed with CRS. If validated by additional research, this association would have substantial implications for public health.

Systemic administration of budesonide in pegylated liposomes for improved efficacy in chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is a chronic inflammatory condition affecting the nasal and paranasal sinuses of approximately 11.5% of the United States adult population. Oral corticosteroids are effective in controlling sinonasal inflammation in CRS, but the associated adverse effects limit their clinical use. Topical budesonide has demonstrated clinical efficacy in patients with CRS. Herein, we investigated the systemic delivery of liposomes tethered with poly(ethylene glycol) (PEG) and loaded with budesonide in a murine model of CRS. PEGylated liposomes encapsulated with budesonide phosphate (L-BudP) were administered via tail vein injection, and the feasibility of L-BudP to reduce sinonasal inflammation was compared to that of free budesonide phosphate (F-BudP) and topical budesonide phosphate (T-BudP) treatment over a 14-day study period. Compared to a single injection of F-BudP and repeat T-BudP administration, a single injection of L-BudP demonstrated increased and prolonged efficacy, resulting in the significant improvement of sinonasal tissue histopathological scores (p < 0.05) with decreased immune cell infiltration (p < 0.05). Toxicities associated with L-BudP and T-BudP treatment, assessed via body and organ weight, as well as peripheral blood liver enzyme and differential white blood cell analyses, were transient and comparable. These data suggest that systemic liposomal budesonide treatment results in improved efficacy over topical treatment.

The role of intranasal corticosteroids in chronic rhinosinusitis with nasal polyposis treated with dupilumab.

PURPOSE: Dupilumab represents an innovative and effective therapy for refractory/recurrent severe chronic rhinosinusitis with nasal polyps (CRSwNP). Intranasal corticosteroids should be used during treatment with biological agents. However, adherence to nasal therapy may not be complete. The aim of this study was to evaluate the role of intranasal corticosteroids in patients with CRSwNP who underwent treatment with dupilumab. MATERIALS AND METHODS: Fifty-two patients treated with dupilumab for CRSwNP were enrolled. Clinical parameters (age, sex, comorbidities, blood eosinophils, Nasal Polyp Score - NPS, Visual Analogue Scale - VAS - for smell loss, Asthma Control Test - ACT), quality of life (Sino Nasal Outcome Test 22 - SNOT-22 questionnaire), nasal cytology, and adherence to regular administration of intranasal corticosteroids were recorded before treatment (T0), and after 3 (T1), 6 (T2), and 12 months (T3). RESULTS: NPS, VAS for smell, ACT and SNOT-22 total score and subscores improved during treatment (p < 0.05). Blood eosinophils reached a peak at T1-T2 and then decreased toward baseline at T3. Adherence to regular treatment with intranasal steroids was 61.5 %. No statistically significant differences in all the clinical outcomes were observed between patients who regularly used intranasal steroids and other subjects (p > 0.05). Nasal cytology showed a decrease of eosinophils and an increase of neutrophils during treatment. CONCLUSIONS: Dupilumab is still effective in patients who are using topical nasal steroids with variable adherence (real world settings).

Ipratropium Bromide Nasal Spray in Non-Allergic Rhinitis: A Systematic Review and Meta-Analysis.

OBJECTIVE: This study aims to compare the effectiveness of intranasal ipratropium bromide (INIB) to a placebo in reducing nasal symptoms, particularly rhinorrhea, and enhancing quality of life in non-allergic rhinitis (NAR) patients. STUDY DESIGN: Systematic review and meta-analysis. METHODS: A comprehensive review of the literature was conducted on Medline, Embase, and Cochrane libraries. Randomized controlled trials (RCTs) and non-randomized comparative parallel group trials comparing IB nasal spray to placebo were included. RESULTS: Five RCTs assessed a total of 472 participants with a diagnosis of NAR. IB nasal spray 0.03% were used across all studies. IB has a better impact on decreasing rhinorrhea than the placebo, with a standardized mean difference (SMD) of 0.93 (95% CI 0.06-1.8). The mean change in rhinorrhea severity was 85% (95% CI 77-92%) and I^2 26% (p = 0.24). IB outperformed the placebo in terms of shortening the symptom's duration/day, as shown by an SMD of 0.35 (95% CI 0.15-0.55). The difference between treatments was noticeable within the first week and remained consistent throughout the treatment. Patients who were administered IB experienced a substantially greater improvement in physical and mental outcomes. Nasal adverse events with IB were generally intermittent and brief. CONCLUSION: Compared with a placebo, IB nasal spray is both safe and effective in treating the rhinorrhea associated with NAR. IB significantly reduces the severity and duration of rhinorrhea. The treatment was determined to be beneficial by both patients and physicians and resulted in a better quality of life. LEVEL OF EVIDENCE: 1 Laryngoscope, 133:3247-3255, 2023.

Quality of life after radio frequency ablation turbinate reduction (RFATR) among patients with rhinitis medicamentosa & withdrawal from decongestant topical spray abuse.

OBJECTIVE: Radiofrequency ablation (RFA) reliefs nasal obstruction and improves quality of life (QoL) in patients suffering from inferior turbinate hypertrophy (ITH). A substantial benefit was noted among patients suffering from Rhinitis Medicamentosa (RM), enabling ending decongestant spray abuse. Our aim was to establish the benefit from RFA with respect to QoL in patients suffering from ITH, due to the presence of RM. STUDY DESIGN: Prospective cohort study. METHODS: Prospective Cohort study, including patients suffering from ITH undergoing RFA between 9.2017 and 9.2019 in Tel Aviv Medical Center. The cohort was divided to RM and non-RM (including allergic, non-allergic) patients. The differences between the groups were compared before and after RFA, and included patients' complaints, clinical findings and QoL questionnaires (SNOT-22 & NOSE). In the RM group, the ability to wean from decongestants was also described. RESULTS: Our data demonstrated subjective QoL improvement following RFA (88.9 %, N = 90). All RM patients withdrawaled from nasal decongestant spray. NOSE questionnaire demonstrated a significant improvement in QoL after RFA in the RM group (PV = 0.025). SNOT-22 did not demonstrate significant difference in QoL between RM and the reference group (PV = 0.1). Rates of MCID>8.3 were high, without significant difference between the groups (PV = 0.2). CONCLUSION: RFA demonstrated effectiveness in achieving of withdrawal from decongestant spray in RM patients and may be a possible definitive treatment option for this group. The nasal obstruction component in SNOT-22 questionnaire & NOSE questionnaire showed improved QoL in comparison to controls. High QoL after RFA was established in our entire cohort.

Aspirin-Exacerbated Respiratory Disease and the Unified Airway: A Contemporary Review.

Aspirin-exacerbated respiratory disease (AERD) is characterized by abnormal arachidonic acid metabolism leading to chronic rhinosinusitis with nasal polyposis (CRSwNP), asthma, and upper and/or lower respiratory symptoms after ingestion of cyclooxygenase-1 inhibiting nonsteroidal antiinflammatory drugs. Diagnosis is clinical and may involve an aspirin challenge. Inflammatory biomarkers may be useful for diagnosis and treatment monitoring. Conventional medical management for asthma and CRSwNP is often inadequate. Endoscopic sinus surgery followed by continued medical management with or without aspirin desensitization frequently improves symptoms and objective disease measures. Biological agents targeting eosinophilic inflammation are promising alternatives to conventional management.

Subendotyping of Dermatophagoides pteronyssinus-Induced Rhinitis and Its Impact on Respiratory Comorbidities.

BACKGROUND: The impact of delayed hypersensitivity to Dermatophagoides pteronyssinus (DP) on comorbidities of allergic rhinitis (AR) is unknown. OBJECTIVE: The primary end point was to test the hypothesis that DP-induced AR could be divided into 2 subendotypes on the basis of presence or absence of a delayed-type mite sensitization detected by the positive result of atopy patch test for DP (DP-APT). The second end point was to evaluate differences in the long-term risk of respiratory comorbidities and nasal airway response to mite exposure. METHODS: In a prospective observational study, we included 472 patients with DP-induced AR. A total of 343 patients had positive results of skin prick test/serum specific IgE and DP-APT and were assigned to a subendotype with both IgE- and T-cell-mediated mite sensitization (BMSS). The remaining 129 patients without delayed-type mite sensitization were included in the subendotype with only IgE-mediated mite sensitization. Nasal allergen provocation test with active anterior rhinomanometry, paranasal sinuses computed tomography scan, nasal endoscopy, and spirometry were performed. RESULTS: At baseline, BMSS showed a larger increase in nasal airway resistance, total nasal score, and visual analogue scale score to mite exposure. During a 15-year follow-up, 56 patients developed chronic rhinosinusitis with nasal polyps, with higher incidence in BMSS than in the subendotype with only IgE-mediated mite sensitization (50 patients, 14.6% vs 6 patients, 12.4%; P < .001). BMSS also showed a higher incidence of conjunctivitis (25.7% vs 12.4%; P < .01). The rate of adult-onset asthma did not differ between groups, but patients with BMSS showed a more frequent link to chronic rhinosinusitis with nasal polyps (6 of 29 patients, 20.7% vs 0 of 10 patients, 0%). DP-APT independently predicted chronic rhinosinusitis with nasal polyps and conjunctivitis. CONCLUSIONS: Two subendotypes with significantly different clinical outcome can be identified among patients with DP-induced AR according to the presence of delayed-type mite sensitization detected by positive DP-APT result.

A new classification option for NSAID hypersensitivity: Kalyoncu classification

Background The European Network for Drug Allergy (ENDA) proposed a consensus document for hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) in 2011. A subgroup of patients with NSAIDs-exacerbated respiratory disease (NERD) develop urticaria/angioedema type reactions in response to NSAIDs. The Kalyoncu classification might be a novel option to classify patients with NSAID hypersensitivity (NH). In this study, we compare the ENDA and the Kalyoncu classifications. Methods This study enrolled a total of 196 patients. NH reaction types were categorized as asthma, rhinitis, urticaria/angioedema and anaphylaxis. Based on the reaction history and oral provocation test findings, patients were grouped according to ENDA and Kalyoncu classifications. Results The mean age of the 196 patients was 40.32±13.28 years, and 130 (66.3%) of them were female. Under the ENDA and Kalyoncu classifications, the most common NH subgroups were NERD (32%), and isolated NH (34.2%), the least prevalent NH subgroups were single NSAID-induced delayed reactions (SNIDR) (1.5%), and pseudo Samter’s syndrome (11.7%). Conclusions Our research revealed that the Kalyoncu classification is more descriptive of patients with NERD exhibiting urticaria/angioedema-type reactions. It also provides future risk assessment for development of NERD. For controversial cases, the Kalyoncu classification can be utilized as a new complimentary option alone or in conjunction with ENDA classification (AU)

Does early life exposure to exogenous sources of reactive oxygen species (ROS) increase the risk of respiratory and allergic diseases in children? A longitudinal cohort study.

BACKGROUND: Excess reactive oxygen species (ROS) can cause oxidative stress damaging cells and tissues, leading to adverse health effects in the respiratory tract. Yet, few human epidemiological studies have quantified the adverse effect of early life exposure to ROS on child health. Thus, this study aimed to examine the association of levels of ROS exposure at birth and the subsequent risk of developing common respiratory and allergic diseases in children. METHODS: 1,284 Toronto Child Health Evaluation Questionnaire (T-CHEQ) participants were followed from birth (born between 1996 and 2000) until outcome, March 31, 2016 or loss-to-follow-up. Using ROS data from air monitoring campaigns and land use data in Toronto, ROS concentrations generated in the human respiratory tract in response to inhaled pollutants were estimated using a kinetic multi-layer model. These ROS values were assigned to participants' postal codes at birth. Cox proportional hazards regression models, adjusted for confounders, were then used to estimate hazard ratios (HR) with 95% confidence intervals (CI) per unit increase in interquartile range (IQR). RESULTS: After adjusting for confounders, iron (Fe) and copper (Cu) were not significantly associated with the risk of asthma, allergic rhinitis, nor eczema. However, ROS, a measure of the combined impacts of Fe and Cu in PM2.5, was associated with an increased risk of asthma (HR = 1.11, 95% CI: 1.02-1.21, p < 0.02) per IQR. There were no statistically significant associations of ROS with allergic rhinitis (HR = 0.96, 95% CI: 0.88-1.04, p = 0.35) and eczema (HR = 1.03, 95% CI: 0.98-1.09, p = 0.24). CONCLUSION: These findings showed that ROS exposure in early life significantly increased the childhood risk of asthma, but not allergic rhinitis and eczema.

Real-world-effectiveness of biological treatment for severe chronic rhinosinusitis with nasal polyps.

BACKGROUND: During the last two years, three different monoclonal antibodies have been approved in many countries for the treatment of patients suffering from severe chronic rhinosinusitis with nasal polyps (CRSwNP). Their efficacy has been demonstrated through large double-blind placebo-controlled clinical studies. Until now, only very limited reports on real-world data regarding this therapy have been published. METHODS: This per protocol analysis included patients with an indication for biological treatment because of uncontrolled CRSwNP, despite long-term nasal steroid treatment, systemic steroid use and/ or endonasal sinus surgery. Baseline data on demographics, medical history and comorbidities, polyp score, quality of life and sense of smell (using Sniffin' Sticks) were assessed and a treatment with either dupilumab or omalizumab was started. The patients were followed up after three and six months. The changes in polyp score, quality-of-life measures and olfaction were noted. RESULTS: 70 consecutive patients were evaluated during the study. Of the patients, 49 were treated with dupilumab and 21 with omalizumab. The polyp score decreased significantly after three and six months, and the quality-of-life parameters and olfaction increased. More than 90% of patients showed a moderate to excellent response to the therapy and there was no difference in the overall response between the two treatments. Olfaction improved in two thirds of the patients, but one third was still anosmic after six months treatment. CONCLUSIONS: This real-world study shows the effectiveness of the monoclonal antibodies dupilumab and omalizumab in the treatment of severe CRSwNP. Nasal polyp scores and quality-of-life parameters as well as measured olfactory function were improved after just three months. The response after guideline-based criteria was insufficient only in 5 patients of this cohort.

Rapid and sustained effect of dupilumab on clinical and mechanistic outcomes in aspirin-exacerbated respiratory disease.

BACKGROUND: Dupilumab, a mAb targeting IL-4Rα, improves upper and lower airway symptoms in patients with aspirin-exacerbated respiratory disease (AERD), but the mechanisms leading to clinical improvement are not fully elucidated. OBJECTIVE: Our aim was to identify the mechanistic basis of clinical improvement in patients with AERD treated with dupilumab. METHODS: A total of 22 patients with AERD were treated with dupilumab for 3 months for severe asthma and/or chronic rhinosinusitis with nasal polyps. Clinical outcomes were assessed at baseline and at 1 and 3 months after initiation of dupilumab. Nasal fluid, urine, blood, and inferior turbinate scrapings were collected at the 3 time points for determination of mediator levels, cellular assays, and RNA sequencing. RESULTS: Participants had rapid improvement in clinical measures, including sense of smell, sinonasal symptoms, and lung function after 1 month of treatment with dupilumab; the improvements were sustained after 3 months of dupilumab. Baseline severity of smell loss was correlated with lower nasal prostaglandin E2 levels. Dupilumab increased nasal prostaglandin E2 level and decreased levels of nasal albumin, nasal and urinary leukotriene E4, and serum and nasal IgE. Transcripts related to epithelial dysfunction and leukocyte activation and migration were downregulated in inferior turbinate tissue after treatment with dupilumab. There were no dupilumab-induced changes in nasal eosinophilia. CONCLUSION: Inhibition of IL-4Rα in AERD led to rapid improvement in respiratory symptoms and smell, with a concomitant improvement in epithelial barrier function, a decrease in inflammatory eicosanoid levels, and an increase in the anti-inflammatory eicosanoid prostaglandin E2 level. The therapeutic effects of dupilumab are likely due to decreased IL-4Rα signaling on respiratory tissue granulocytes, epithelial cells, and B cells.

Therapeutic applications of capsaicin in humans to target conditions of the respiratory system: A scoping review.

BACKGROUND: Various studies have explored potential therapeutic applications of capsaicin in human medicine, for example in pain, obesity, cancer, cardiovascular and respiratory disease. The aim of this scoping review was to identify and chart available evidence on therapeutic applications of capsaicin in humans using any mode of capsaicin delivery to treat conditions of the respiratory system. METHODS: Electronic bibliographic databases (Web of Science, PubMed, Medline, ScienceDirect, Embase, Scopus) were searched from inception to 2021 to identify experimental studies reporting clinical outcomes of therapeutic applications of capsaicin. Studies with or without control group published in peer-reviewed journals were included. Animal studies, studies of human cell lines, and physiological proof of concept studies were excluded. Reviewer pairs independently double-screened 2799 search results for inclusion. RESULTS: Twenty-three original studies were included. Capsaicin has been investigated for the treatment of non-allergic rhinitis (n = 15), nasal polyposis (n = 3), allergic rhinitis (n = 2), unexplained chronic cough (n = 2), and prevention of aspiration pneumonia (n = 1). Modes of delivery included intranasal application (nasal spray, soaked pads, solution), inhalation, ingestion, and aural ointment. Seventeen studies reported positive effects of capsaicin on clinical outcomes for rhinitis, nasal polyposis, chronic cough, and pneumonia. Sixteen studies reported on the safety of capsaicin, with no reports of significant adverse events and overall fair to good patient acceptability. CONCLUSION: While the evidence identified in this review has limited implications for clinical practice, studies support the general safety of capsaicin as administered in these studies and highlight emerging strands of research and clinical hypotheses which warrant further examination.

Air Pollution Exposure Affects Severity and Cellular Endotype of Chronic Rhinosinusitis With Nasal Polyps.

OBJECTIVES/HYPOTHESIS: Air pollution has emerged as an important environmental risk factor for chronic rhinosinusitis (CRS) progression. This study assessed exposure to five types of air pollution (PM2.5/10 , SO2 , NO2 , CO, O3 ) and explored their effects on CRS with nasal polyps (CRSwNP) severity and endotype. STUDY DESIGN: Retrospective cohort study. METHODS: Air pollution data from monitoring sites in Beijing were obtained to assess individual air pollution exposure. Outcomes of CRSwNP (n = 282) including Lund-Mackay (L-M) score, Lund-Kennedy (L-K) score, visual analogue scale (VAS) score and nasal patency/airflow resistance and so on were measured to analyze correlations with air pollution and compare groups with different exposure types. Multivariable-adjusted binary logistic regression was used to determine potential air pollution risk factors of the endotype of eosinophilic CRSwNP (ECRSwNP). RESULTS: Short-term exposures to PM2.5/10 , SO2 , CO, NO2 , and O3 were weak but significantly associated with increased L-M scores. Short-term exposures to PM10 , CO, and NO2 were correlated with increased VAS headache/facial pain scores. The L-M scores of the group of the highest PM2.5 (≥150 µg/m3 ) exposure were significantly higher than those of control group. For each increased unit of the average concentration of PM2.5 , there was a 1.047-fold (95% confidence interval, 1.005-1.091) increased risk of the endotype of ECRSwNP. CONCLUSIONS: Air pollution exposure exacerbated CRSwNP severity and PM2.5 could be a risk factor for endotype of ECRSwNP, suggesting the role of air pollution in CRSwNP pathogenesis. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:2103-2110, 2022.

Chronic Rhinosinusitis Outcomes of Patients With Aspirin-Exacerbated Respiratory Disease Treated With Budesonide Irrigations: A Case Series.

BACKGROUND: Pathophysiology-targeting treatments exist for aspirin-exacerbated respiratory disease (AERD) through aspirin desensitization and biologics, such as dupilumab. With increasing attention paid to these treatments, which may be associated with significant side effects and/or cost, there is little description of chronic rhinosinusitis with nasal polyps (CRSwNP) response to treatment with intranasal corticosteroids and saline irrigations in AERD. OBJECTIVE: To determine the effect of intranasal budesonide irrigations for the treatment of CRSwNP in AERD. METHODS: This is an observational study of 14 AERD patients presenting to a rhinology clinic for CRS who were treated with twice daily high volume, low pressure irrigations with 240 mL of saline to which a 0.5 mg/2 mL respule of budesonide was added. All participants completed a 22-item Sinonasal Outcome Test (SNOT-22) at enrollment and at follow up 1 to 6 months later. Polyp scores were also calculated at each time point. RESULTS: SNOT-22 scores ranged from 26 to 98 (median: 40.5) at enrollment and 3 to 85 (median: 38.5) at follow-up. Polyp scores ranged from 2 to 6 (median: 4) at enrollment at 0 to 6 (median: 2) at follow-up. Over the treatment period, change in SNOT-22 score ranged from -38 to 16 (median: -18) and change in polyp score ranged from -2 to 0 (median: -0.5). Approximately 57% of participants experienced at least 1 minimal clinically important difference in SNOT-22 score and 21% of participants had a SNOT-22 score <20 at follow-up. CONCLUSION: Medical management with intranasal corticosteroids and saline irrigations alone leads to significant improvement in sinonasal symptomatology in a subset of AERD.

The importance of vascular epithelial growth factor (VEGF) and inducible nitric oxide synthase (INOS) in rhinitis medicamentosa pathogenesis: An experimental rat model study.

OBJECTIVE: Our aim in this study is to reveal the expression of Vascular Endothelial Growth Factor (VEGF) and Inducible Nitric Oxide Synthase (iNOS) in the pathogenesis of rhinitis medicamentosa (RM), which occurs as a result of the overdose and long-term use of topical nasal decongestants. METHODS: In this study, 24 Wistar albino rats were divided into two groups as experimental and control groups. In the experimental group, 50 µl of 0.05% oxymetazoline (iliadin® merck) was applied intranasally to each nostril three times a day for 2 months with the help of a micropipette. 50 µl saline was applied to the control group. At the end of the second month, the rats were examined. RM was detected in the experimental group. Then the nasal tissues of the rats were removed and fixed with 10% phosphate buffered neutral formaldehyde (pH=7.4). Nasal tissues were decalcified in Morse's solution (10% sodium citrate and 22.5% formic acid). Histopathological evaluations of the preparations were stained using Masson Trichrome (TCM) and Hematoxylin Eosin (H&E) techniques and immunohistochemical examinations of the preparations were stained with VEGF and iNOS antibodies and photographed using the Leica DM6000B microscope and the Leica Application Suite Program. RESULTS: In the RM group, we found a significant increase in VEGF and iNOS expression in the nasal mucosa compared to the control group (p<0.001). We also observed the main histopathological changes in the nasal mucosa under a light microscope, including squamous metaplasia in the epithelium of the tunica mucosa, submucosal perivascular edema and degeneration of the submucosal glands. CONCLUSIONS: According to these results, increased expression levels of VEGF and iNOS play an important role in rebound swelling in RM pathogenesis.

Budesonide transnasal pulsating nebulization after surgery in chronic rhinosinusitis with nasal polyps.

Intranasal corticosteroid drugs are widely used in chronic rhinosinusitis with nasal polyps (CRSwNP). In contrast to classical delivery with nasal pump sprays, pulsating aerosols can deliver significant doses into superior and posterior sinonasal spaces. A case-control study was designed to assess the efficacy of corticosteroid transnasal nebulization on short-term mucosal recovery and quality of life (QoL) following endoscopic sinus surgery in CRSwNP. Thirty patients were prospectively enrolled to receive either 1-month budesonide nasal pump spray or 1-month budesonide 100-Hz acoustic pulsating nebulization at the first postoperative visit (day 8). Patients were evaluated with Lund-Kennedy endoscopic score at day 8 (D8) and 1 month later (M1). CRS-related QoL questionnaires (SNOT22 and RhinoQOL) were fulfilled at M1. The Lund-Kennedy endoscopic scores compared between D8 and M1 were suggestively improved in the group treated with budesonide nebulization (mean difference between groups, - 18.28 units; 95%CI, - 31.29 to - 5.28 units, p = 0.014). QoL measurements were comparable at M1 between the groups of patients. No unexpected adverse event was described with both budesonide delivery protocols. In the early postoperative period, patients with CRswNP may benefit from pulsating nebulization. Large studies should be conducted to confirm the results. Safety profile related to systemic steroid absorption and bioavailability in chronic respiratory diseases also need to be addressed for further use.

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.

Long-term role of zileuton in the treatment of chronic rhinosinusitis in aspirin exacerbated respiratory disease.

BACKGROUND: Chronic rhinosinusitis (CRS) in the setting of Aspirin Exacerbated Respiratory Disease (AERD) have high rate of treatment failure and disease recurrence. OBJECTIVE: Evaluate the long-term effect of zileuton on sinonasal outcomes in patients with AERD. METHODS: AERD patients were reviewed and divided into two cohorts, depending if they were treated with zileuton during their clinical course. Demographic data, 22-item sinonasal outcome test (SNOT-22), Lund-Kennedy (LK) endoscopy score, duration of treatment, and number of sinus surgeries performed were collected. RESULTS: 40 AERD patients were included, with follow-up duration up to 10 years (avg of 5.2 years). All patients were treated with topical saline and budesonide irrigations, intranasal steroid spray, and montelukast. 19 patients had uncontrolled sinus disease requiring multiple steroid tapers and were switched from montelukast to zileuton (cohort 1, 47.5%) at some point in their treatment. 21 patients (cohort 2, 52.5%) never needed zileuton. The average duration of treatment with zileuton was 6 years. Patients who required zileuton had a worse SNOT-22 (32.1 vs 19, p = 0.117), worse LK score (8.1 vs 7.5, p = 0.504), and higher average number of surgeries (1.9 vs 1.6, p = 0.343). The outcomes in the zileuton cohort trended toward improvement, however these did not reach statistical significance with an improved SNOT-22 from 32.1 to 27.4 (p = 0.617) and LK score from 7.9 to 6.2 (p = 0.092); The addition of zileuton significantly lowered the number of surgeries needed to an average of 0.5 (p < 0.0001). CONCLUSION: Zileuton may help decrease the number of sinus surgeries needed in AERD.