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Background: Current treatment paradigms recommend surgical intervention when conventional medical management proves ineffective in resolving chronic rhinosinusitis with nasal polyposis., Objectives: To assess and compare the efficacy of dupilumab and functional endoscopic sinus surgery (FESS) for the treatment of chronic rhinosinusitis with nasal polyp (CRSwNP) over time., Methods: Studies comparing CRSwNP patients who received dupilumab with those who underwent FESS were included. Outcome measures included the nasal congestion score (NCS), Sino-nasal Outcome Test-22 (SNOT-22), University of Pennsylvania Smell Identification Test-40 (UPSIT-40), and nasal polyp score (NPS). The risk of bias was evaluated using the Newcastle-Ottawa Scale., Results: A total of 4 studies with 724 participants were included. The dupilumab group had a superior NCS, but an inferior NPS, compared to the FESS group during the follow-up period. The SNOT-22 score of the dupilumab group was inferior to that of the FESS group until 6 months posttreatment, but the scores were similar at around 1 year. A similar trend was observed for the UPSIT-40 score, but the score of the dupilumab group was higher at around 1 year., Conclusion: Functional endoscopic sinus surgery was more effective than dupilumab for several months after treatment. However, at 1 year after treatment, the effects of the 2 treatments became similar, with greater olfactory improvement seen in the dupilumab group., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To evaluate the clinical efficacy of topical nasal Pomegranate Fruit Extract (PFE) for Chronic Rhinitis (CR), Chronic Rhinosinusitis with Nasal Polyposis (CRSwNP), and Chronic Rhinosinusitis without Nasal Polyposis (CRSsNP). Methods: Prospective, double-blinded, randomized study including 111 consecutive patients, between April 2012 and January 2017, afflicted by CRSwNP, CRSsNP, and CR. Patients from each group were randomly assigned to either PFE treatment or placebo twice daily for 30 days. Therapeutic efficacy was assessed by Ear Nose and Throat, blood and tomographic examinations, and the SNOT-20 questionnaire. Results: CR patients treated with PFE suffered significantly less from thick nasal discharge, difficulty falling asleep, reduced productivity, reduced concentration, and sadness ( P = .004, P = .02, P = .03, P = .007 and P = .02, respectively). Conclusions: Topical nasal PFE was found to have some benefits for CR patients, however, not for CRS with or without Nasal Polyposis., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Eosinophilic chronic rhinosinusitis (eCRS) is a type 2 inflammatory disease that frequently recurs after surgery. In recent years, dupilumab has been available for the treatment of refractory chronic rhinosinusitis since 2020 in Japan. Although there are some reports of its usefulness, there are not enough reports of its clinical efficacy for longer than 1 year, especially for olfactory recovery., Methods: Twenty patients with eCRS who had recurrence after surgery and had been receiving dupilumab were enrolled retrospectively. The nasal polyp score (NPS), computed tomography (CT) score, T&T olfactometer, and olfactory cleft opacification on CT were evaluated at baseline, at an average of 5.1 months later (short term), and at an average of 18.3 months later (long term)., Results: At the short-term evaluation, there were significant improvements in the NPS and CT scores ( P  < .001, P  = .008, respectively). The CT score was further improved at the long-term evaluation compared to the short-term evaluation ( P  = .018) and baseline ( P  = .008). T&T detection/recognition thresholds and olfactory cleft opacification showed significant improvements only at the long-term evaluation compared to baseline ( P  = .002, P  = .006, and, P  = .006, respectively)., Conclusion: The NPS remained improved, and the CT score showed further improvement with long-term treatment, whereas olfactory function and olfactory cleft opacification showed significant improvement only after long-term treatment. There was a dissociation between the time to improve in the NPS and CT scores and the time to improve in olfactory function and olfactory cleft opacification. Based on these results, dupilumab should be administered for longer than 1 year, especially for olfactory function., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: TN reports lecture fees and research grants, and TK and SH report lecture fees from Sanofi.

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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is subdivided into type 1 and type 2 inflammatory responses according to the mucosal inflammatory patterns. Crocin can reduce the level of T-helper type 2 cell (Th2) cytokines, such as interleukin-4 (IL-4), and inhibit the nuclear factor kappa-B (NF-κB) signaling pathway., Objective: This study aimed to investigate the role of group 2 innate lymphoid cells (ILC2s) in type 2 inflammation in eosinophilic nasal polyps and the inhibitory effect of crocin on this inflammation., Methods: Immunohistochemistry and immunofluorescence were used to detect the expression of transcription factors and the infiltration of ILC2s in tissues. An ILC2 stimulation model in vitro was constructed based on IL-33 stimulation and treated with crocin. The explant models were constructed and treated with crocin to detect the expression of type 2 inflammation-related factors., Results: Significantly more GATA-binding protein-3 (GATA3)-positive cells and chemoattractant receptor-homologous molecule expressed on T-helper type 2 cell (CRTH2)-positive cells, but fewer T-box expressed in T cell (T-bet)-positive cells, were found in eosinophilic nasal polyps (NPwEos). The expression levels of GATA3 and CRTH2 were significantly higher in NPwEos. Recombinant IL-33 stimulation increased the expression of GATA3, CRTH2, and type 2 cytokines (IL-4, IL-5, and IL-13) in ILC2s. In an IL-33-stimulated in vitro ILC2 culture model, crocin inhibited the type 2 inflammatory response, especially at lower concentrations (10 µM). The explant organoids of NPwEos were constructed in vitro , and Staphylococcus aureus enterotoxin B (SEB) was used to construct the type 2 inflammation model. Crocin at 10 µM concentration inhibited type 2 inflammation induced by SEB-stimulated explants., Conclusion: Crocin inhibited type 2 inflammation induced by ILC2 activation at low concentrations via inhibiting the activation of NF-κB., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex disorder and effective treatment remains a major challenge. Some antibiotics with anti-inflammatory properties are reported to have potential to be used as an adjunct therapy in the management of chronic airway inflammation., Objective: The aim of this study was to evaluate the efficacy of doxycycline in CRSwNP., Methods: In this randomized, double-blind, placebo-control study, we assessed the efficacy of doxycycline in patients with moderate to severe CRSwNP. A total of 100 patients were randomly assigned to receive either doxycycline (200 mg on the first day followed by 100 mg daily) or placebo for 6 weeks. All patients received baseline therapy with fluticasone, montelukast, and nasal irrigation during the study. The primary outcome was quality of life based on the sino-nasal outcome test (SNOT-22) questionnaire. We measured peak nasal inspiratory flow (PNIF) and severity of symptoms by visual analogue scale (VAS). Baseline blood eosinophil count, serum IgE level, eosinophil in nasal secretions, and Lund-Mackay score based on low dose paranasal CT scan were also recorded., Results: Treatment with doxycycline significantly improved SNOT-22 ( P  = .037) and sense of smell ( P  = .048). The baseline SNOT-22 score had no effect on outcomes. The effect of doxycycline on quality of life in patients with or without nasal eosinophilia was not significantly different. Change in SNOT-22 score was also not correlated with serum IgE ( P  = .220, r  = -0.186) and the eosinophil count ( P  = .190, r  = -0.198)., Conclusion: Doxycycline improves the quality of life in patients with CRSwNP. It also has temporarily beneficial effects in improving the sense of smell. The levels of eosinophil in the blood and nasal secretions do not affect the response to treatment. Hence, doxycycline can be used in both eosinophilic and non-eosinophilic nasal polyps.This study was registered at Iranian Registry of Clinical Trials. https://www.irct.ir/ IRCTID: IRCT20210403050817N1.

Background: Allergic fungal rhinosinusitis (AFRS) is an endotype of chronic rhinosinusitis (CRS) with nasal polyps characterized by eosinophilic mucin laden with fungal hyphae entrapped in expanded sinus cavities with an exaggerated hypersensitivity to fungal elements. The last decade has elucidated fungi-driven inflammatory pathways contributing to the pathophysiology of chronic inflammatory respiratory diseases. In addition, novel therapeutic biologic options have become available for CRS over the last several years., Objective: To review the current literature examining AFRS, focusing on recent developments in our understanding of its pathophysiology and implications for treatment options., Methods: Review article., Results: Fungi-driven respiratory inflammation has been linked to fungal proteinases and toxin activity. In addition, AFRS patients demonstrate a local sinonasal immunodeficiency in antimicrobial peptides and hence limited antifungal activity, along with an exaggerated type 2 inflammatory response, highlighting a possible imbalanced type 1, type 2, and type 3 profile. The elucidation of these dysregulated molecular pathways has highlighted novel potential therapeutic targets. As such, the clinical management of AFRS, which once included surgery and extended courses of oral corticosteroids, is transitioning away from long courses of oral corticosteroids to incorporate novel delivery mechanisms of topical therapeutic targets and biologics for recalcitrant disease., Conclusion: AFRS is an endotype of CRS with nasal polyps (CRSwNP) for which the molecular pathways leading to its inflammatory dysfunction are beginning to be illuminated. In addition to affecting treatment options, these understandings may shape necessary changes to diagnostic criteria and the extrapolated effects of environmental changes on AFRS. More critically, a better appreciation of fungi-driven inflammatory pathways may have implications for the understanding of broader CRS inflammation.

Background: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is an inflammatory disease with a treatment goal of controlling symptoms and limiting disease burden. While endoscopic sinus surgery is effective for removing polyps and aerating sinuses, proper medical management remains necessary for reducing inflammation and limiting polyp recurrence., Objective: This article aims to summarize the literature regarding medical treatment of chronic rhinosinusitis with nasal polyposis, with a specific focus on developments in the past 5 years., Methodology: We conducted a literature review using PubMed to identify studies assessing medical treatment strategies for patients with CRSwNP. Articles focusing on chronic rhinosinusitis without nasal polyposis were excluded unless specifically stated. Surgical treatment and biologic therapies for CRSwNP will be covered in subsequent chapters and are therefore not included., Results: Intranasal saline irrigations and topical steroids are mainstays of CRSwNP treatment in the pre-surgical, post-surgical, and maintenance phases of the disease. Alternative steroid delivery methods and adjunctive treatments with antibiotics, anti-leukotrienes, and other topical therapies have been investigated and may benefit certain patient populations, but convincing evidence does not exist to warrant addition of these treatments to the standard of care for CRSwNP., Conclusions: Topical steroid therapy is clearly effective for CRSwNP, and recent studies demonstrate the safety and efficacy of high-dose nasal steroid rinses. Alternate delivery methods for local steroids may be useful for patients who are not responding to or who are noncompliant with conventional intranasal corticosteroid sprays and rinses. Future studies are needed to clarify if oral or topical antibiotics, oral anti-leukotrienes, or other novel therapies are significantly effective in decreasing symptoms and improving the quality of life in patients with CRSwNP.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) has been traditionally managed with a combination of topical and systemic medical therapy as well as endoscopic sinus surgery. The emergence of biologic therapies that target specific aspects of the inflammatory cascade has ushered in a potentially new paradigm in the management options available for CRSwNP., Purpose: To summarize the current literature and recommendations supporting the use of available biologic therapies for CRSwNP and to develop an algorithm to aid clinical decision-making regarding treatment selection., Methods: A review of available literature and studies that demonstrated the clinical efficacy of biologic agents for the treatment of CRSwNP informing current CRSwNP consensus algorithms., Results: Current biologic medications target immunoglobulin E, interleukins, or interleukin receptors implicated in the Th2 inflammatory cascade. Institution of biologic therapy is now an option for patients who have disease refractory to topical medical therapy and endoscopic sinus surgery, those who cannot tolerate surgery, or patients with other comorbid Th2 diseases. Response to treatment should be monitored at 4-6 months and 1 year after initiating therapy. Across multiple indirect comparisons, dupilumab appears to have the largest therapeutic benefit across multiple subjective and objective outcomes. The choice of therapeutic agent also depends on drug availability, patient tolerance, presence of comorbid illnesses, and cost., Conclusions: Biologics are emerging as an important option in the management of patients with CRSwNP. While more data is required to fully inform indications, treatment selection, and health economics related to their use, biologics may offer robust symptom relief to patients who have failed other interventions.

Background: Conventional treatment for eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) is usually limited; consequently, relapses occur frequently, accurate local drug delivery is currently a research area of major interest., Methods: Based on postoperative nasal sinus computed tomography (CT) images, the 3D printing technique was used to design and fabricate a precise track-guided sinus drug delivery device. The control group was treated with glucocorticoids by nasal spray for 1 year according to the conventional method, while the experimental group received topical nasal glucocorticoids using the 3D-printed track-guided precise sinus drug delivery device for 1 year. Scores on the Sino-Nasal Outcome Test (SNOT-22) scale and the Lund-Kennedy nasal endoscopic scale during reexamination at 1 month, 3 months, 6 months, and 1 year after the operation were used as the basis for evaluation., Results: The follow-up duration was 12 months or more following endoscopic sinus surgery (ESS) with neosinus cavity formation. The two groups showed significant differences in SNOT-22 scores and nasal polyp Lund-Kennedy subscores at 3 months, 6 months, and 1 year (p < 0.001) and no differences in plasma cortisol at 6 months and 1 year (p > 0.05)., Conclusion: Local drug administration using our 3D-printed precise sinus drug delivery device is superior to conventional nasal cavity administration in controlling eCRS recurrence.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma are chronic type 2 inflammatory diseases that are frequently associated with each other. Dupilumab inhibits the dual signaling pathways of interleukin (IL)-4 and IL-13, which are key and central drivers of type 2 inflammation in CRSwNP. Omalizumab blocks the action of immunoglobulin E. Head-to-head studies are required to investigate the comparative efficacy and safety of these interventions. EVEREST (EValuating trEatment RESponses of dupilumab vs omalizumab in Type 2 patients) trial is designed to evaluate whether the efficacy of dupilumab is superior to omalizumab in treating patients with CRSwNP and comorbid asthma (ClinicalTrials.gov Identifiers: NCT04998604)., Objective: Here, we describe the EVEREST study design to compare the efficacy and safety of dupilumab compared to omalizumab over 24 weeks of treatment in patients with severe CRSwNP and comorbid asthma., Methods: EVEREST is a global, phase 4 multicenter, randomized (1:1), double-blind, active-controlled trial. Approximately 422 adult patients with severe CRSwNP, symptoms of nasal congestion and loss of smell, and coexisting asthma will be recruited across 15 countries. The primary objective is to assess the efficacy of dupilumab compared to omalizumab in reducing the nasal polyp size and improving the sense of smell. The key secondary objectives are to evaluate the comparative efficacy in improving CRSwNP symptoms (eg, nasal congestion) and lung function. The safety will be evaluated in terms of treatment-emergent adverse events (AEs), serious AEs, and AEs of special interest., Conclusions: EVEREST is the first head-to-head trial assessing the comparative efficacy and safety of 2 biologics in patients with severe CRSwNP and comorbid asthma. The study will provide evidence to help optimize treatment plans for patients that suffer from severe CRSwNP and comorbid asthma.

Background: Nasal sprays with corticosteroids deliver medication to the restricted areas including anterior and inferior parts of the nasal cavity. The fluticasone exhalation delivery system (EDS-FLU) has recently been proved to improve care by increasing superior/posterior intranasal corticosteroid deposition., Objective: This study aims to evaluate the efficacy of EDS-FLU in patients with chronic rhinosinusitis with nasal polyps (CRSwNP)., Methodology: A systematic literature review using Pubmed, Embase, Cochrane Library, and Web of Science was conducted to identify studies assessing the effect of EDS-FLU on outcomes in patients with CRSwNP., Results: Of the initial 108 abstracts reviewed, 4 full-text articles were included. The 22-item sinonasal outcome test scores were significantly decreased in patients with CRSwNP after receiving EDS-FLU twice a day (93, 186, or 372 μg) for 16 weeks when compared with exhalation delivery system (EDS)-placebo (all P  < .001). Patients with CRSwNP reported significant improvement of smell after receiving twice daily EDS-FLU twice a day (93, or 372 μg) for 4 weeks when compared with EDS-placebo (all P  < .05). The proportions of patients achieving ≥1-point improvement in total polyp grade were significantly higher in EDS-FLU group and dose dependent, with the highest rates in the 372 μg group. The proportions of patients achieving polyp elimination were significantly higher in EDS-FLU group with the highest rates in the 372 μg group., Conclusion: This is the first systematic review of the clinical outcomes in patients with CRSwNP treated with EDS-FLU. EDS-FLU produced significant improvements regarding the quality of life, smell, and endoscopic assessment of polyp grade.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease with variable underlying pathophysiologies. Numerous patient factors have been linked to differences in disease severity, control, and response to treatment, including asthma status, aspirin sensitivity, previous sinonasal surgery, and blood eosinophil levels., Objective: The present study examines the efficacy of the anti-immunoglobulin E therapy, omalizumab, versus placebo in patients with CRSwNP from the replicate POLYP 1 (NCT03280550) and POLYP 2 (NCT03280537) trials, grouped by inherent patient characteristics to determine the response to therapy., Methods: Patients in prespecified subgroups from POLYP 1 and POLYP 2 (studies pooled for analysis) were examined. Subgroups included blood eosinophil count at baseline (>300 or ≤300 cells/μL), previous sinonasal surgery (yes or no), asthma status (yes or no), and aspirin sensitivity status (yes or no). Subgroups were examined for subgroup-specific adjusted mean difference (95% confidence interval [CI]) (omalizumab-placebo) in change from baseline at week 24 in Nasal Congestion Score (NCS), Nasal Polyp Score (NPS), Sino-Nasal Outcome Test-22 (SNOT-22), Total Nasal Symptom Score (TNSS), and University of Pennsylvania Smell Identification Test (UPSIT)., Results: Adjusted mean difference (95% CI) (omalizumab-placebo) in NCS, NPS, SNOT-22, TNSS, and UPSIT change from baseline at week 24 consistently favored omalizumab treatment over placebo in patients with blood eosinophil count >300 and ≤300 cells/μL, with or without previous sinonasal surgery, asthma, and aspirin sensitivity., Conclusion: Together, these data suggest broad efficacy of omalizumab across clinical and patient-reported outcomes in patients with CRSwNP, independent of the underlying patient factors examined, including those with high eosinophil levels and those who have undergone previous surgery, which are associated with high recurrence., Clinical Trial Registration: ClinicalTrials.gov identifiers: POLYP 1: ClinicalTrials.gov identifier NCT03280550 (https://clinicaltrials.gov/ct2/show/NCT03280550); POLYP 2: ClinicalTrials.gov identifier NCT03280537 (https://clinicaltrials.gov/ct2/show/NCT03280537).

Objective: To analyze the effect of benralizumab in severe eosinophilic asthma (SA) and chronic rhinosinusitis with polyps (CRSwP)., Methods: Retrospective review of patients with both SA and CRSwP that were treated with benralizumab. Asthma controlled test (ACT), pulmonary function metrics (FEV1), Meltzer endoscopic polyp scores, SNOT-22 scores, were collected before and after at least 4 months of benralizumab therapy., Results: 23 patients were included. The mean age at the time of enrollment into benralizumab therapy was 50.47 ± 17.3 years and majority (65.2%, n = 15) were males.Pulmonary Effects: In comparison to baseline ACT, scores at four months showed significant improvement (p = 0.03). In those with pre and post spirometry measurements, mean FEV1 showed significant increase following benralizumab therapy (p = 0.04) with a mean increase of 547 mL ± 597 mL following therapy.Sinonasal Effects: 78.5% of subjects on benralizumab had a significant improvement in sinonasal symptoms (p = 0.009) based on their SNOT-22 scores. Additionally, there was an improvement in endoscopic polyp scores, although not statistically significant, following benralizumab therapy (p = 0.2) with 54.5% patients showing improvement., Conclusion: Usage of benralizumab in patients with SA and CRSwNP can lead to significantly improved asthma control, lung function, and sinonasal quality of life. Additionally, in this patient population, there was a subset of patients that showed a significant reduction in polyp burden.

Background: Aspirin-exacerbated respiratory disease (AERD) is characterized by eosinophilic rhinosinusitis, nasal polyposis, aspirin sensitivity, and asthma. Aims/Objectives: This study aims to identify a mechanism to target for the future treatment of AERD via the elucidation of the effect of systemic steroids on the expression of hematopoietic prostaglandin D 2 synthase (HPGDS) and chemotaxic prostaglandin D 2 (DP2) receptor relative to eosinophil activation in the nasal polyps of patients with AERD., Materials and Methods: Among 37 patients undergoing endoscopic sinus surgery, 28 received systemic steroids preoperatively. Nasal polyps were harvested from all 37 patients. After routine processing of paraffin sections, immunohistochemistry was performed using specific antibodies for HPGDS, eosinophil peroxidase (EPX), and DP2., Results: Expression of HPGDS, DP2, and EPX by eosinophils was higher and more frequent in patients with non-preoperative steroid therapy. Likewise, HPGDS and DP2 were highly expressed in activated eosinophils in the nasal polyps, but not in normal eosinophils., Conclusion and Significance: This study provides clear evidence that systemic steroid therapy inhibits eosinophil activation and decreases HPGDS and DP2 expression in patients with AERD, indicating a reduction in prostaglandin D 2 production and hence control hyperplasia of nasal polyps.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a clinical entity with specific features that impacts significantly on patient quality of life (QoL). CRSwNP is often associated with asthma and is difficult to control and manage despite pharmacological and/or surgical treatment. Omalizumab, a monoclonal anti-IgE antibody, has emerged as a putative therapeutic option., Objective: To evaluate the effects of omalizumab on nasal polyp (NP) size and QoL assessed by Sino-Nasal Outcome Test-22 (SNOT-22) in patients with recalcitrant CRSwNP and mild asthma., Methods: A multicenter retrospective analysis of patient data from the Community of Valencia (Spain) was performed. Adult patients with recalcitrant CRSwNP and comorbid mild asthma receiving compassionate use of omalizumab were included. NP size measured by total nasal endoscopic polyp score (TPS) and QoL evaluated through the SNOT-22 questionnaire were assessed at baseline and monthly over 12 months. An ordinal regression model was built to analyze the results., Results: A total of 23 CRSwNP patients with a mean age (± SD) of 54.78 ± 9.46 years were included. Nineteen suffered from aspirin-exacerbated respiratory disease (AERD). In all patients, a significant and sustained reduction in TPS was observed over time, accompanied by improvements in QoL reflected in lower SNOT-22 scores. In the ordinal regression model, time but not total IgE, age or tissue eosinophilia impacted on NP size and SNOT-22 outcomes. Additionally, improvements in QoL were not explained by reductions in the size of polyps., Conclusion: Omalizumab was effective for the treatment of patients with recalcitrant CRSwNP and mild asthma, even when AERD was present, by reducing NP size and improving QoL; treatment time was a key factor. SNOT-22 improvements were not explained by decreases in TPS, indicating that omalizumab may be effective in all patients, regardless of polyp size.

Background: Aspirin-exacerbated respiratory disease (AERD) affects 7% of asthmatics. Usual therapies are inadequate for asthma and/or nasal polyposis, leading to decreased quality of life., Objective: Our objective was to evaluate the efficacy of dupilumab in AERD patients with uncontrolled, chronic rhinosinusitis with nasal polyposis (CRSwNP)., Methods: Patients 18 years and older with a physician diagnosis of AERD and sino-nasal outcome test 22 (SNOT 22) score ≥19 despite standard medical therapy were eligible for the study. Patients received one month of placebo dosing, followed by 6 months of dupilumab. Patients were blinded to the order of therapy. Wilcoxon-paired rank sum test was used to compare study outcomes at baseline and the completion of the study., Results: Ten patients completed the study. The median baseline SNOT 22 score improved from 46 [IQR: 34 to 64.8] to 9.5 [IQR: 2.5 to 19] after 6 months of therapy (p = 0.0050). The median baseline Lund MacKay score improved from 21.5 [IQR: 17 to 23.3] to 4 [IQR: 1.2 to 6] after 6 months of therapy (p = 0.0050). There was also improvement in the following secondary outcomes: asthma control test (ACT), mini asthma quality of life questionnaire (AQLQ), and University of Pennsylvania Smell Identification test (UPSIT). Exhaled nitric oxide (FeNO), total serum IgE, 24-hour urinary leukotriene E 4 , and serum thymus and activation regulated cytokine (TARC) also decreased. There were no significant study-related adverse events., Conclusion: Dupilumab was highly effective as add-on therapy for CRSwNP in AERD, improving patient-reported outcomes, sinus opacification, and markers of T2 inflammation.

Background: in the era of new biological agents it is important to identify patients who may benefit from conventional therapies such as endoscopic sinus surgery (ESS) plus long-term local corticosteroids from those with patterns of inflammation that are more difficult to control post-operatively and who may benefit from other therapies., Objective: determine if preoperative assessment of type and grade of inflammation and clinical factors can predict disease control with ESS plus long-term local corticosteroids in chronic rhinosinusitis with nasal polyps (CRSwNP)., Methods: Eighty patients treated with ESS plus mometasone-furoate 200 μg BID for CRSwNP and followed for at least 1 year were enrolled (November 2017-December 2018) in this prospective observational study. Type and grade of inflammation were evaluated preoperatively by nasal cytology. Based on cellular pattern, patients were grouped as neutrophilic (n = 20), eosinophilic (n = 38), or mixed eosinophil-neutrophilic (n = 22). SNOT-22 and Lund-Kennedy Endoscopic Score were evaluated at baseline and at 3, 6, 9, and 12 months after surgery and used to define disease control., Results: The cumulative probability of remaining free of significant modification of endoscopic score (Lund-Kennedy Endoscopic Score >2) at 3, 6, 9, and 12 months was 0.84, 0.76, 0.71, and 0.68, respectively. At 12-month postoperative evaluation good disease control was observed in 54 of 80 patients (67.5%). Compared to those with good post-operative disease control, those with poor control had a significantly higher pre-operative mean count of eosinophils and neutrophils (p < 0.05). The preoperative inflammatory pattern was associated with relative risk of poor control: neutrophilia (RR: 3.10; CI:1.24-7.71), eosinophilia (RR:8.42; CI:2.72-15.12), and mixed eosinophilic and neutrophilic (RR:25.11; CI:19.41-30.01). We also confirmed that asthma, allergy, blood eosinophilia, and ASA triad could predict poor control., Conclusions: The type and load of inflammation evaluated preoperatively and selected clinical factors can predict poor control of CRSwNP treated with ESS and local corticosteroids.

Background: Severe eosinophilic asthma is frequently associated to chronic rhinosinusitis and nasal polyposis (CRSwNP) that contribute to poor asthma control. Mepolizumab is an anti-IL-5 monoclonal antibody, approved for the treatment of severe eosinophilic asthma. A limited number of studies have assessed the efficacy of mepolizumab on CRSwNP in severe asthmatics. We aim to evaluate the efficacy of mepolizumab on sino-nasal symptoms, polyp growth and asthma control in severe eosinophilic asthma patients with CRSwNP in real life., Methods: In this study 44 severe eosinophilic asthma patients with CRSwNP were treated with mepolizumab (100 mg q4w) for 1 year. The following outcomes were assessed before (T0), after 6 (T6) and 12 months (T12) of treatment: sino/nasal outcome test (SNOT-22), Total Endoscopic Nasal Polyp Score (TENPS), %FEV1 (FEV1/FEV1 predicted) and Asthma control test (ACT). Blood eosinophil count, exhaled nitric oxide (FENO) and prednisone intake were measured. In a subgroup of patients, nasal cytology was performed before (T0), after 6 (T6) and after 12 months (T12) of treatment with mepolizumab., Results: We reported a significant reduction of SNOT-22 [from 51.5 ± 21.2 at baseline (T0) to 31.70 ± 17.36 at T6 and 29.7 ± 21.5 at T12 (T0-T12 p  < 0.001)] and a decrease of TENPS (from 2.88 ± 3.07 to 1.70 ± 2.37 and 1.77 ± 2.56 at T0, T6 and T12, respectively, T0-T12 p  = 0.99). A significant improvement of %FEV 1 , ACT and a decrease in blood eosinophils and mean prednisone intake were also reported. No statistically significant decreasing trend was measured for FENO. Nasal cytology findings suggest a significant reduction of eosinophil percentage following mepolizumab treatment (from 16.8 ± 7.2% to 3.6 ± 6.2% and 0.8 ± 2.4% at T0, T6 and T12 respectively, T0 to T12: p  < 0.001)., Conclusions: Mepolizumab improves sino-nasal and asthma symptoms and reduces polyp growth in patients with severe eosinophilic asthma and concomitant CRSwNP in real life. The reviews of this paper are available via the supplemental material section.

Background: Chronic rhinosinusitis (CRS) is a common chronic condition classically divided into two phenotypes according to the presence or absence of nasal polyps. The effects of both medical and surgical treatment are often temporary, encouraging research into new treatment options., Methods: We performed a systematic review related to dosages, effects, side effects, and safety of intrapolyp steroid injection in patients with nasal polyps. We identified five studies with a total of 386 patients and 2490 intrapolyp steroid injections., Results: Treatment with intrapolyp steroid injection leads to a decrease in the Total Nasal Polyps Score (TNPS), Total Nasal Symptom Score (TNSS), and Lund-Mackay Score. The dosage regimens vary from 10 to 40 mg triamcinolone acetonide. Only two cases of temporary visual complications were reported., Conclusion: This review found that intrapolyp steroid injection may be an effective and safe treatment for patients with nasal polyps. However, there exist no large, randomized, clinical trials. We found no association between dose and effect, or dose and the risk of visual complications.

The aim of this study was to assess whether the chronic preoperative administration of intranasal corticosteroids (INCs) in chronic rhinosinusitis with/without nasal polyposis (CRSwNP/CRSsNP, respectively) could significantly influence bleeding during functional endoscopic sinus surgery (FESS). We prospectively enrolled 109 patients (56 CRSwNP and 53 CRSsNP) candidate for FESS who underwent clinical evaluation and anamnestic data collection. They were allocated to 2 groups depending on whether or not they were chronic INC users, as declared at their first medical evaluation: chronic "INC users" represented the treated group, while "INC nonusers" formed the control group. Lund-Mackay and American Society of Anesthesiology (ASA) scores, blood loss expressed both in milliliters and using the Boezaart scale, operation time in minutes, pre- and postoperative 22-item Sino Nasal Outcome Scores (SNOT-22) were collected. Each sample underwent histopathological evaluation. The results showed that anamnestic information, Lund-Mackay, and SNOT-22 scores were similar between the 2 groups ( P > .05). The average blood loss expressed in milliliters and operative time were slightly, but not significantly, higher in the INC user group, while the Boezaart scores proved significantly higher in the INC users ( P = .038). No differences emerged between CRSwNP and CRSsNP within each group in terms of bleeding. The pathologist described common features in the majority (78%) of INC group samples: ectatic venules embedded in a fibrous stroma and hypertrophy of the arterial muscular layer. In our experience, despite the presence of NP, chronic preoperative administration of INCs was associated with increased intraoperative bleeding according the Boezaart scale although objective recordings of blood loss were not statistically different between the INC users and nonusers.

Introduction: Nonsteroidal anti-inflammatory drugs (NSAID)-exacerbated respiratory disease (NERD) is defined by intolerance to cyclooxygenase 1 inhibitors, chronic rhinosinusitis with recurrent nasal polyps, and/or intrinsic bronchial asthma. Long-term administration of acetylsalicylic acid (ASA) after desensitization has been used to mitigate these sequelae, but the optimal dose and balancing symptom relief and side effects remain unsettled., Methods: Retrospective data analysis of 85 patients with NERD receiving maintenance therapy of 300 mg ASA was followed by questionnaires (our own, not validated and the Sino-Nasal Outcome Test-20). We received responses from 55 patients and examined 30 of them clinically., Results: Patients with no ASA-associated side effects were 56.4% (56 of 85 patients) of the cohort. In this study, 60% (33 of 55 patients) continued prophylaxis of 300 mg ASA daily for an average of 34.7 months. Elective surgery was the most frequent cause of discontinuation of ASA (21.8%; 12 of 55 patients). Rhinomanometry values were significantly improved with ASA ( P  < .05; Wilcoxon), but there was no significant reduction in nasal polyposis or improvement in olfaction at the time of follow-up examination., Conclusions: Minor clinical improvements were identified. Side effects were well tolerated by most patients, and no serious sequelae occurred. The indications for long-term ASA therapy in NERD patients remain unsettled.

The aim of this study has been to evaluate the efficacy of the IL-5 receptor blocker benralizumab on chronic rhinosinusitis with nasal polyposis (CRSwNP), associated with severe eosinophilic allergic asthma. Ten patients with severe eosinophilic allergic asthma and CRSwNP were enrolled. Sino-nasal outcome test (SNOT-22), numerical rating scale (NRS), endoscopic nasal polyp score, Lund Mackey CT (computed tomography) score, and blood eosinophil count were measured at baseline and after 24 weeks of treatment with benralizumab. All the above clinical, endoscopic, imaging, and hematological parameters significantly improved after 24 weeks of treatment with benralizumab. In particular, SNOT-22 decreased from 61.10 ± 17.20 to 26.30 ± 19.74 ( P < 0.001), NRS decreased from 7.20 ± 1.55 to 3.40 ± 2.22 ( P < 0.001), the endoscopic polyp nasal score decreased from 4.20 ± 1.32 to 2.50 ± 1.78 ( P < 0.001), the Lund-Mackay CT score decreased from 16.60 ± 5.50 to 6.90 ± 5.99 ( P < 0.001), and blood eosinophil count decreased from 807.3 ± 271.1 cells/μL to 0 cells/μL ( P < 0.0001). These results strongly suggest that benralizumab exerted a very effective therapeutic action on CRSwNP associated with severe asthma, thus improving nasal symptoms and decreasing polyp size.

Background: Chronic rhinosinusitis is a common, high-morbidity chronic inflammatory disease, and patients often experience suboptimal outcomes with current medical treatment. The exhalation delivery system with fluticasone (EDS-FLU) may improve care by increasing superior/posterior intranasal corticosteroid deposition., Objective: To evaluate the efficacy and safety of EDS-FLU versus EDS-placebo in patients with nasal polyps (NP). Coprimary end points were change in nasal congestion and polyp grade. Key secondary end points were Sino-Nasal Outcome Test-22 (SNOT-22) and Medical Outcomes Study Sleep Scale-Revised (MOS Sleep-R). Other prespecified end points included all 4 cardinal symptoms of NP, 36-Item Short Form Health Survey (SF-36), Patient Global Impression of Change (PGIC), Rhinosinusitis Disability Index (RSDI), and key indicators for surgical intervention., Design: Randomized, double-blind, EDS-placebo-controlled, multicenter study., Methods: Three hundred twenty-three subjects with NP and moderate-severe congestion/obstruction, most with history of corticosteroid use (94.4%) and/or prior surgery (60.4%), were randomized to EDS-FLU 93 µg, 186 µg, or 372 µg or EDS-placebo twice daily (BID) for 24 weeks (16 double-blind + 8 single-arm extension with EDS-FLU 372 µg BID)., Results: All EDS-FLU doses produced significant improvement in both coprimary end points ( P < .05) and in SNOT-22 total score ( P ≤ .005). EDS-FLU significantly improved all 4 cardinal symptoms of NP ( P < .05), including congestion/obstruction, facial pain/pressure, rhinorrhea/post-nasal drip, and hyposmia/anosmia. Approximately 80% of subjects reported improvement with EDS-FLU, with 65% reporting "much" or "very much" improvement by week 16. Adverse events were generally local in nature and similar to other intranasal steroids studied for similar durations in similar populations, with the most common being epistaxis., Conclusions: In patients with chronic rhinosinusitis with NP (CRSwNP) who were symptomatic despite high rates of prior intranasal steroid use and/or surgery, EDS-FLU produced statistically significant and clinically meaningful improvements compared to EDS-placebo in multiple subjective and objective outcomes (symptoms, SNOT-22, RSDI, SF-36, PGIC, and NP grade), including all 4 cardinal symptoms of CRSwNP.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly prevalent disease of the nasal cavity and paranasal sinus, but its exact etiology is still unclear and remains a difficult-to-treat condition., Hypothesis: Endoscopic sinus surgery (ESS) is an effective treatment for medically recalcitrant CRSwNP. There are independent variables that can predict surgical outcomes in patients with CRSwNP., Objectives: To evaluate ESS efficacy in CRSwNP treatment and to establish prognostic factors for disease recurrence., Methods: Eighty-five patients with CRSwNP submitted to ESS, and a minimum follow-up of 9 months was selected. Patient demographics, occupational organic exposure (e.g., cotton, fuel gas, wood dust) and inorganic dust exposure (e.g., bleach, metals, cement), comorbidities, previous nasal surgeries, pre- and postoperative symptoms, ear, nose and throat examination findings, computed tomography results, and medical and surgical treatment information were collected from medical records. Statistical analysis was performed., Results: All rhinologic symptoms improved after surgery, in a statistically significant way, with the best recovery rate for nasal obstruction and the worst for hyposmia. The major and minor complications rates were 1.2 and 15.3%, respectively. Disease recurrence occurred in 31% of the patient, but only 7% required surgical reintervention. Multivariate logistic regression analysis identified occupational dust exposure (p = 0.001) and non-immunoglobulin E (IgE) mediated asthma (p = 0.012) as independent predictive variables in CRSwNP recurrence, unlike the other tested variables: age, sex, IgE-mediated asthma, allergic rhinitis, smoking habits, nasal polyps endoscopic grade, Lund-Mackay score, and postoperative topical corticoid use. The adjusted logistic model presented a good discriminatory capacity with a receiver operating characteristic area under the curve of 0.82 (95% confidence interval, 0.73-0.91; p < 0.001)., Conclusion: ESS proved to be an effective treatment in CRSwNP but with a considerable rate of recurrence. These results indicated an important correlation of occupational dust exposure and non-IgE-mediated asthma with disease recurrence.

Purpose: Rapamycin has antiproliferative and antifibrogenic effects in vitro and in vivo. The purpose of this study was to evaluate the effects of rapamycin on transforming growth factor (TGF) beta 1 induced myofibroblast differentiation (alpha smooth-muscle actin [SMA]), extracellular matrix production, and collagen contraction in nasal polyp-derived fibroblasts (NPDF). The underlying molecular mechanisms of rapamycin were also determined in NPDFs., Methods: NPDFs were grown in culture and transformed into myofibroblasts by using TGF beta 1 (5 ng/mL). For cytotoxicity evaluation, a 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide assay was used. Expression levels of alpha SMA, phosphorylated phosphatidylinositol 3-kinase (PI3K), and phosphorylated mammalian target of rapamycin (mTOR) were determined by using Western blot, reverse transcription-polymerase chain reaction, and immunofluorescence staining. The total amount of collagen was analyzed by using the Sircol collagen assay, and contractile activity was measured with a collagen gel contraction assay. Silencing mTOR with mTOR-specific small interference RNA was determined by using reverse transcription-polymerase chain reaction., Results: Whereas rapamycin (range, 0-400 nM) had no significant cytotoxic effects on TGF beta 1 induced NPDFs, it significantly reduced the expression levels of alpha-SMA in TGF beta 1 induced NPDFs in a dose-dependent manner. TGF beta 1 induced collagen production and collagen contraction were significantly inhibited by rapamycin treatment. Rapamycin also attenuated the TGF beta 1 induced activation of PI3K and mTOR, and its inhibitory effects were similar to those of mTOR silencing and a specific PI3K inhibitor., Conclusions: Rapamycin inhibited TGF beta 1 induced myofibroblast differentiation, extracellular matrix production, and collagen contraction through the PI3K/mTOR signal pathways in NPDFs.

Purpose: It is well known that doxycycline has antibacterial and anti-inflammatory effects. In this study, we aimed to investigate the effects of doxycycline on the transforming growth factor (TGF) beta 1-induced matrix metalloproteinase (MMP) 2 expression, migration, and collagen contraction, and to determine its molecular mechanism on nasal polyp-derived fibroblasts (NPDF)., Methods: NPDFs were isolated from the nasal polyps of six patients. Doxycycline was used to pretreat TGF-beta-1-induced NPDFs and ex vivo organ cultures of nasal polyps. Cytotoxicity was evaluated by using a 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide assay. Smad2/3 is one of the major transcription factors of TGF-beta signaling. The expression levels of MMP2 and Smad2/3 were measured by using Western blotting, reverse transcription-polymerase chain reaction, and immunofluorescence staining. The enzymic activity of MMP2 was analyzed by using gelatin zymography. Fibroblast migration was evaluated by using transwell migration assays. Contractile activity was measured by a collagen gel contraction assay., Results: The expression level of MMP2 in nasal polyp tissues increased in comparison with inferior turbinate tissues. TGF-beta-1-induced NPDFs were not affected by doxycycline (0-40 μg/mL). The expression levels of MMP2 and activation of Smad2/3 in TGF-beta-1-induced NPDFs and in organ cultures of nasal polyps were significantly downregulated with doxycycline pretreatment. Doxycycline also reduced TGF-beta-1-induced fibroblast migration and collagen contraction in NPDFs., Conclusion: Doxycycline inhibited TGF-beta-1-induced MMP2 expression, migration, and collagen contraction via the Smad2/3 signal pathways in NPDFs.

Background: Available medical treatments for chronic rhinosinusitis (CRS) with nasal polyposis (CRSwNP) comprise systemic and topical therapies. Although topical corticosteroids are effective in the treatment of CRS, they are not completely devoid of adverse effects. Thus, care has to be taken when long-term treatments are prescribed. There is recent evidence that sodium hyaluronate (SH), the major component of many extracellular matrices, promotes tissue healing, including activation and moderation of the inflammatory responses, cell proliferation, migration, and angiogenesis., Objective: The aim of the study was to evaluate clinical outcomes and quality of life in two groups of patients with CRSwNP treated with topical corticosteroids alone or in combination with 9 mg of high-molecular-weight SH., Methods: The impact of treatments was determined by using nasal endoscopy and validated quality of life questionnaires (Short Form-36, 22-item Sino-Nasal Outcome Test, visual analog scale [VAS]). Eighty subjects who had CRS with grade IV nasal polyposis: 40 diagnosed with allergic rhinitis (AR) and 40 with non-allergic-eosinophilic rhinitis (NARES) based on skin-prick test and nasal cytology results, were divided in two groups. Group I comprised 40 subjects (20 AR and 20 NARES), who received mometasone furoate plus SH; group II comprised 40 subjects (20 AR and 20 NARES), who received mometasone furoate plus saline solution alone. All the patients were followed up for 3 months., Results: At baseline, no statistically significant differences were observed between the groups and the VAS score showed a moderate-to-severe degree of disease. After treatments, Lund and Kennedy, Short Form-36, 22-item Sino-Nasal Outcome Test, and VAS scores were statistically significant in both groups but slightly in favor of the group I and in the subjects with allergic CRSwNP., Conclusion: Analysis of our data indicated that an SH supplement to standard corticosteroid seems to play an important role in improving the severity of symptoms, the endoscopic appearance, and discomfort associated with CRSwNP. This effect seems to be strongest in patients with allergic CRSwNP.

Background: Although nasal steroids are the mainstay treatments in nasal polyposis, up to one-half of patients do not respond and need surgical treatment. This study aimed to evaluate whether oxymetazoline administration produces any additive effect on nasal steroid therapy and whether rebound congestion develops after oxymetazoline treatment., Methods: Sixty-eight patients with nasal polyposis were randomly assigned in a 1:1 ratio to receive either oxymetazoline plus mometasone furoate nasal spray (MFNS) or placebo plus MFNS, 2 sprays per nostril twice daily, with an interval of 5 minutes between each medication for 4 weeks. All the patients were then treated with MFNS, 2 sprays per nostril twice daily for 2 weeks. The nasal symptoms score, peak inspiratory flow index, nasal mucociliary clearance time (NMCCT), and total nasal polyps score were used to evaluate treatment outcomes. An intention-to-treat analysis was performed, and a worst case sensitivity analysis was applied to missing cases., Results: Thirty-four patients were allocated to the oxymetazoline-MFNS group, and 34 to the placebo-MFNS group. One patient in each group was lost to last-visit follow-up. At 4 weeks after beginning treatment, the oxymetazoline-MFNS group showed significantly greater improvement in blocked nose, hyposmia, peak flow, NMCCT, and total nasal polyps score than the placebo-MFNS group. During the nasal steroid phase, both groups showed continuing improvement in all outcome variables. However, the oxymetazoline-MFNS group still showed significantly greater improvement in blocked nose, hyposmia, NMCCT, and total nasal polyps score, but not peak flow, than the placebo-MFNS group at the end of the study., Conclusion: The use of nasal steroids with oxymetazoline was more effective over 6 weeks than nasal steroids alone in improving blocked nose, hyposmia, nasal mucociliary clearance, and polyp size in treatment of nasal polyposis. There was no evidence of rebound congestion after 4 weeks of oxymetazoline treatment.

Background: Given the differences in pathophysiology between allergic fungal rhinosinusitis (AFRS) and other chronic rhinosinusitis (CRS) subgroups, it remains unclear about whether these patients respond differently to a combination of surgical and medical treatments., Objective: To evaluate differences in quality-of-life (QoL) outcomes for a cohort of patients who underwent endoscopic sinus surgery (ESS) for CRS., Methods: This retrospective review included patients with CRS who underwent ESS between 2010 and 2013. QoL was measured by using the 22-item Sino-Nasal Outcome Test (SNOT-22). Variables collected included baseline demographics, SNOT-22 scores before ESS and at 1, 3, 6, 9, and 12 months after ESS. Groups tested were CRS with nasal polyposis, CRS without nasal polyposis (CRSsNP), and patients with AFRS. A linear mixed- effects regression model was used to calculate the adjusted mean QoL differences., Results: Among the 250 patients included, 61.6% had CRS with nasal polyposis (n = 154), 28.8% had CRSsNP (n = 72), and 9.6% had AFRS (n = 24). Significant differences were seen in SNOT-22 scores between pre- and postoperative visits and between the etiologic subgroups (p < 0.001). Multivariate analysis revealed significantly greater improvement in QoL for patients with AFRS in comparison with those with CRSsNP at the 9-month follow-up (change in SNOT-22 score, 22.6 [95% confidence interval, 1.2-44.1]; p < 0.0) and the 12-month follow-up (change in SNOT-22 score, 20.2 [95% confidence interval, 0.5-39.9]; p < 0.04)., Conclusions: Patients with AFRS experienced a more-prolonged QoL benefit from surgical and targeted medical intervention compared with those with CRSsNP, which may reflect the severity of inflammation that they presented with compared with other CRS subtypes.

Background: The decision to resect the middle turbinate (MT) during functional endoscopic sinus surgery is controversial. Although there have been a variety of studies that examined the functional outcome related to this maneuver, very few studies evaluated the potential for complications, in particular, epistaxis., Objective: We sought to determine if resection of the MT during functional endoscopic sinus surgery leads to an increased risk for postoperative bleeding., Methods: Patients who underwent functional endoscopic sinus surgery for chronic sinusitis or nasal polyposis between 2004 and 2014 at a single institution were analyzed for bleeding and other complications after resection of the MT., Results: Between 2004 and 2014, 1185 sinus surgeries were performed by 18 surgeons. A propensity matched set of 228 patients who underwent turbinate resection, and 228 controls were selected based on predicted probabilities from a logistic regression that predicted turbinate resection and that was adjusted for age, sex, and procedure. There were 89 patients with bilateral turbinates removed and 139 with unilateral turbinates removed. There was no significant difference in major bleeding or other complication rates between the two groups. Patients who underwent resection of at least one MT were 3.95 times more likely to have minor bleeding compared with those who did not; this risk increased with the number of turbinates resected (trend p = 0.008). Patients on anticoagulation medications were at a significant risk of bleeding if their MT was removed (p = 0.007), whereas patients on aspirin or antiplatelet therapy were not at a significant risk., Conclusion: There was no increased risk of major bleeding or other complication associated with resection of the MT. However, there was a significantly increased minor bleeding rate associated with MT resection, particularly if the patient was on anticoagulants.

Purpose: Pirfenidone has been shown to have antifibrotic and anti-inflammatory effects in the lungs. The purpose of this study was to evaluate the inhibitory effects of pirfenidone on transforming growth factor (TGF)-β1-induced myofibroblast differentiation and extracellular matrix accumulation. We also determined the molecular mechanisms of pirfenidone in nasal polyp-derived fibroblasts (NPDF)., Methods: NPDFs were isolated from nasal polyps from eight patients who had chronic rhinosinusitis with nasal polyp. Pirfenidone was used to treat TGF-β1-induced NPDFs. Cytotoxicity was evaluated by using a 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide assay. Fibroblast migration was evaluated with scratch assays. Expression levels of α-smooth muscle actin (SMA), fibronectin, and phosphorylated Smad2/3 were determined by Western blot and/or reverse transcription-polymerase chain reaction and immunofluorescent staining. Total collagen production was analyzed with the Sircol collagen assay and contractile activity was measured by a collagen gel contraction assay., Results: Pirfenidone (0-2 mg/mL) has no significant cytotoxic effects in TGF-β1-induced NPDFs. Migration of NPDFs was significantly inhibited by pirfenidone treatment. The expression levels of α-SMA and fibronectin were significantly reduced in pirfenidone-treated NPDFs. Collagen contraction and production were also significantly decreased by pirfenidone treatment. Finally, pirfenidone significantly inhibited phosphorylation of the Smad2/3 pathway in TGF-β1-induced NPDFs., Conclusions: Pirfenidone has an inhibitory effect on TGF-β1-induced migration, myofibroblast differentiation (α-SMA), extracellular matrix accumulation, and collagen contraction by blocking the phosphorylation of Smad2/3 pathways in NPDFs. Thus, pirfenidone may inhibit TGF-β1-induced extracellular matrix by regulating Smad2/3.

Background: Oral steroids are synthetic mimics of adrenal cortex hormones and are considered a staple in the management of chronic rhinosinusitis due to their anti-inflammatory effects. Despite their common use, many providers are not familiar with the potential risks of the drugs., Methods: Literature review., Results: An overview of the existing data on the risks of oral steroids is presented as well as a review of the malpractice lawsuits with regard to oral steroid use and a discussion of the data that support the use of oral steroids in patients with chronic rhinosinusitis with and those without nasal polyps., Conclusion: It is essential for providers to be aware of the potential complications of a medication, the medical jurisprudence of the drugs, and the data that support their use.

Background: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is a principally type 2 T helper cell (Th2)-mediated inflammatory disease. Systemic corticosteroids currently represent the most effective treatment for CRSwNP, but their long-term use is constrained due to their detrimental side effects. Long-term use of topical steroids is safe, but their efficacy is often limited. Topical cyclosporine has proven to be safe and effective for Th2-mediated diseases such as allergic conjunctivitis., Objective: It was hypothesized that topical cyclosporine would be an effective novel drug for the treatment of CRSwNP; its therapeutic efficacy was assessed using a previously established mouse model., Methods: After induction of eosinophilic CRSwNP in four-week-old BALB/c mice according to previous protocols, the therapeutic effects of intranasal cyclosporine were evaluated and compared with those of triamcinolone acetonide (TAC). Histopathologic changes were evaluated using hematoxylin and eosin for polyp formation and Sirius red staining for eosinophilic infiltration. The production of cytokines in sinonasal tissues, including tumor necrosis factor (TNF), interleukin (IL)-2, interferon (IFN)-γ, IL-4, IL-5, IL-13, and IL-17A, was measured using a cytometric bead array., Results: The number of polyp-like lesions was reduced significantly only by systemic TAC, but the degree of eosinophilic infiltration was decreased significantly by topical cyclosporine, the potency of which was similar to that of topical or systemic TAC. Except for IFN-γ, the majority of measured cytokines were reduced significantly by topical cyclosporine, although their effects on IL-2 and IL-13 were less potent than those of systemic TAC., Conclusion: Topical cyclosporine might be an effective drug for the management of CRSwNP.

Background: Chronic rhinosinusitis with nasal polyposis (CRS/NP) is a medical disease that is managed more effectively after endoscopic sinus surgery (ESS). Despite topical treatment with intranasal steroids, acute inflammatory exacerbations (AEs) are common and are typically treated with oral prednisone, which has significant and well-documented side effects. The objective of the current study was to critically evaluate the topical application of triamcinolone acetonide (80) in carboxymethylcellulose (TA/CMC) foam for AEs in CRS/NP patients after ESS., Methods: CRS/NP patients managed with ESS by a single rhinologist over a 5-year period were included in the study. Data were reviewed regarding demographics, number of AEs, revision surgery, 22-item Sino-Nasal Outcomes Test (SNOT-22) scores, frequency of oral prednisone and/or TA/CMC, and notable side effects., Results: A total of 371 CRS/NP patients were treated with ESS over a 5-year period. Mean follow-up was 49.3 weeks (range, 2-249 weeks). During this time period, 130 patients (46 years; range, 28-48 years) developed a cumulative 267 AEs. Before initiating use of TA/CMC in 2010, 66 AEs were treated with prednisone. Subsequently, 116 of 201 AEs were managed with TA/CMC with a sequential decrease in prednisone use over the last 3 years (77, 39, and 32%). SNOT-22 scores (n = 33) decreased significantly after TA/CMC instillation (preinstillation, 1.69 ± 0.86, versus postinstillation, 1.23 ± 0.8; p < 0.01)., Conclusion: Management of AEs with TA/CMC decreased overall prednisone use in a large population of CRS/NP patients in this retrospective evaluation. TA/CMC appears well tolerated and is a useful treatment option for AEs in postoperative CRS/NP patients.

In this study, we review our current knowledge of the autoimmune etiopathogenesis of chronic rhinosinusitis with nasal polyps including bacterial infections, viral infections and immunomediated mechanisms and to discuss pathogenesis with relevance for pharmacotherapy. Relevant publications on the etiopathogenesis and treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) from 1977 to 2013 were analyzed. The characteristic signs and symptoms include appearance of relapsing nasal polyps, with typical symptoms such as nasal obstruction, nasal discharge and, usually, loss of the sense of smell. The etiology and pathogenesis remain unknown. Proposed theories of causation include bacterial or viral infections and immunomediated mechanisms. The autoimmune aetiology of unknown origin or failure to respond to classic pharmacological treatments with nasal and oral steroids is now suspected. At present, the nature of the antigen trigger, the exact role played by B/T cells and anti-dsDNA autoantibodies in the pathogenesis of nasal polyposis remains unclear. Corticosteroids and surgery are the first line of treatment in CRSwNP. In the case of corticosteroid treatment failure, other drugs can be used such as rituximab, belimumab or omalizumab which have demonstrated clinical efficacy in the treatment of nasal polyposis with comorbid asthma. Immunosuppressive drugs such as methotrexate, and cyclophosphamide have also been used with varying degrees of success.

Background: Nasal polyps occur in a significant fraction of patients with chronic rhinosinusitis. However, patterns of medical management in nasal polyp cases are unknown. We sought to determine actual national estimates and contemporary prescribing patterns for ambulatory care visits with a diagnosis of nasal polyposis (NP)., Methods: The National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey 2004-2010 were accessed, extracting all adult office visits with a diagnosis of NP. Demographic, provider type, and medication classes prescribed were determined. National estimates for the number of ambulatory medical care visits along with medications prescribed by provider type (otolaryngologist versus nonotolaryngologist) were determined., Results: There were an estimated 442,024 ± 49,609 adult office visits annually with an NP diagnosis (54.8% men; mean age, 52.3 years); 64.6% of these visits were with otolaryngologists. Medication prescribing rates with a diagnosis of NP were nasal steroids (43.7%), oral steroids (26.9%), antibiotics (26.0%), and oral antihistamines (18.5%). Medication use rates for nasal steroids, oral steroids, oral antihistamines, and antibiotics were 36.3, 25.9, 15.3, and 22.2% for otolaryngology visits, respectively. Analogous medication use rates were 57.1, 28.8, 24.2, and 32.9% of nonotolaryngology visits, respectively. These differences by provider were not statistically significant (all, p ≥ 0.113)., Conclusion: Although nasal steroids are efficacious in NP, they are likely underprescribed. Oral steroids are also commonly prescribed for NP and should be considered a standard option in the treatment of NP.

Background: Leukotriene antagonists (LTAs) provide a potential strategy for the management of chronic rhinosinusitis with nasal polyposis (CRSwNP), which is often refractory to medical and surgical treatment. The purpose of this study is to determine the impact of LTA treatment alone and in conjunction with intranasal corticosteroids (INCSs) on nasal symptoms, objective clinical outcomes, and immune parameters in CRSwNP., Methods: A systematic review was performed including studies that assessed the effectiveness of LTAs on clinical outcome measures of CRSwNP. Exclusion criteria were trials assessing LTAs in CRS without nasal polyps or asthma symptoms only. Quantitative analysis was performed using a random effects model., Results: Twelve studies fulfilled eligibility: five randomized control trials and seven case series. LTAs showed significant improvements in CRSwNP symptoms over placebo; however, these randomized trials were unable to be combined via meta-analysis. The two studies used in meta-analysis showed a standardized mean difference of pooled overall symptom scores of 0.02 (95% confidence interval, -0.39-0.44) between LTA and INCS study arms, indicating no difference between the treatment modalities. Improvement was described by all studies in symptoms, clinical outcomes, and/or immune parameters after LTA treatment, with greater improvements in a subset of symptoms beyond that observed with INCSs. Concomitant asthma, aspirin-exacerbated respiratory disease, and atopy did not significantly or consistently affect these results., Conclusion: LTAs are an effective tool for treating CRSwNP, with limited benefit as an adjunctive therapy. Additional study is required to determine the most beneficial strategy and patient population for their use.

Background: Topical intranasal corticosteroids (INCSs) are used to control disease symptoms in patients with chronic rhinosinusitis with nasal polyposis (CRSwNP). The evidence to recommend INCSs as part of the postoperative care is limited. This study was designed to assess the efficacy of INCSs in the postoperative care of patients undergoing functional endoscopic sinus surgery (FESS) during the 1st year postoperatively., Methods: We searched the Cochrane Central Register of Controlled Trials (1995 to May 2012), MEDLINE (January 1948 to May 2012), EMBASE (January 1980 to May 2012), and the reference lists of articles. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Randomized controlled trials (RCT) and cohort studies comparing INCSs with placebo or comparing different types of INCSs were included., Results: Eleven studies (n = 945 patients) were RCTs and one prospective cohort study (n = 32 patients). As measured by the standardized mean difference (SMD) INCSs had a beneficial effect on symptom scores (SMD, -1.35; 95% CI, -2.05 to -0.64; p = 0.0002; 3 trials; 137 patients) and polyp score (SMD, 0.53; 95% CI, -0.91 to -0.14; p = 0.007; 5 trials; 223 patients). Compared with placebo, the use of INCSs decreased the odds of polyp recurrence (odds ratio, 0.17; 95% CI, 0.06-0.51; p = 0.002; 2 trials; 74 patients). Two RCTs (n = 105) and one cohort study (n = 32) reported normal adrenocorticotropic hormone levels postintervention., Conclusion: INCS use is a safe therapy in postoperative management of CRSwNP patients. INCS showed significant improvement in polyp score, patients' symptoms and significant decrease in polyp recurrence in the first year postoperatively.

Background: Published randomized controlled trials (RCTs) on the efficacy of intranasal corticosteroid (INCS) in chronic rhinosinusitis (CRS) use either nasal delivery (nasal drop or nasal spray) or sinus delivery (sinus catheter or sinus irrigation) in patients with or without sinus surgery. This influences topical drug delivery and distribution. The effect of these factors on the published results of RCTs is assessed. This systematic review explores the strength of evidence supporting the influence of sinus surgery and delivery methods on the effectiveness of topical steroids in studies for CRS with meta-analyses., Methods: A systematic review was conducted of RCTs comparing INCS with either placebo or no intervention for treating CRS. Data were extracted for meta-analysis and subgroup analyses by sinus surgery status and topical delivery methods., Results: Forty-eight studies (3961 patients) met the inclusion criteria. INCS improved overall symptoms (standardized mean difference [SMD], -0.49; p < 0.00001) and the proportion of responders (risk ratio [RR], 0.59; p < 0.00001) compared with placebo. It decreased nasal polyp size with a greater proportion of responders (RR, 0.48; p < 0.00001) and prevented polyp recurrence (RR, 0.59; p = 0.0004) compared with placebo. Reduction of polyp size was greater in patients with sinus surgery (RR, 0.31; 95% confidence interval [CI], 0.20, 0.48) than those without (RR, 0.61; 95% CI, 0.46, 0.81; p = 0.009). Greater symptom improvement occurred when sinus delivery methods (SMD, -1.32; 95% CI, -2.26, -0.38) were compared with nasal delivery methods (SMD, -0.38; 95% CI, -0.55, -0.22; p < 0.00001)., Conclusion: INCS is effective for CRS. Prior sinus surgery and direct sinus delivery enhance the effectiveness of INCS in CRS.

Background: The topical application of mitomycin C has been evaluated as a complementary therapy for eosinophilic nasal polyposis (ENP). However, the mechanism underlying the additional benefits of mitomycin C for the control of eosinophilic inflammation and prevention of posttherapeutic relapse remains to be elucidated. In this work, the aim was to characterize the gene expression profile by quantitative real-time polymerase chain reaction (qPCR) of proinflammatory and regulatory biomarkers that are typically associated with ENP and to assess the impact of the topical application of mitomycin C on the nasal mucosal tissue immunologic milieu after ENP surgery., Methods: We have selected 20 patients with ENP that were recommended to undergo surgical intervention. Normal mucosal tissue was obtained from healthy nasal mucosa from six patients with absence of eosinophilic infiltration. To test the effect of mitomycin C, one side of the maxillary sinus mucosa was selected for topical application of this drug and the other received no further treatment and acted as the control. The genes interleukin-4 (IL-4), IL-5, IL-10, IL-13, chemokine (C-C motif) ligand 5 (CCL5), CCL24, colony-stimulating factor 2 (CSF2), transforming growth factor beta 1 (TGFB1), tumor necrosis factor alpha (TNF-alpha), and beta actin (ACTB) were selected for gene expression analysis by qPCR., Results: The data showed higher expression of proinflammatory biomarkers and lower levels of regulatory TGFB1 transcripts in ENP mucosal tissue. Surgery with topical application of mitomycin C induced a prominent transcriptional down-regulation of the immunologic biomarkers, CCL24, TNF-alpha, CSF2, and IL-5, in ENP mucosal tissue. Additionally, this treatment restored the levels of chemokines and cytokines to those observed in the nasal mucosal tissue of control subjects, except for TGFB1, which remained below the reference pattern. Moreover, CSF2 was identified as a putative biomarker with significant predictive value for complementary prophylactic purposes after surgery in ENP patients., Conclusion: After the characterization of the expression signatures of immunologic biomarkers in ENP, we observed that the topical use of mitomycin C is important for the reestablishment of the immunologic microenvironment of a normal expression profile of biomarkers involved in ENP mucosal tissue.

Background: Methotrexate (MTX) is a very effective treatment for chronic inflammatory diseases that induces apoptosis in nasal polyps (NPs). However, the precise apoptotic pathway in NPs remains unclear. The aim of this study was to identify the apoptotic signaling pathways activated by MTX in NPs., Methods: NP tissues were organ cultured using an air-liquid interface method. Cultures were maintained in the presence or absence of MTX (10 or 100 μM) for 24 hours. To investigate apoptotic signaling in NPs, we performed reverse transcription-polymerase chain reaction and Western blotting., Results: MTX-treated NPs contained significantly increased amounts of the active forms of caspase 8, caspase 9, and caspase 3 and displayed increased cleavage of poly(ADP-ribose) polymerase. Expression of the proapoptotic molecules Bax and Bad at the mRNA and protein levels and of the activated molecules p-Bad and tBid was significantly higher in MTX-treated NPs than in nontreated NPs. In contrast, expression of the antiapoptotic molecule Bcl-2 at the mRNA and protein levels was significantly lower in MTX-treated NPs than in nontreated NPs. Expression of the phosphorylated forms of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) was significantly higher in MTX-treated NPs than in nontreated NPs. In contrast, expression of the phosphorylated form of Akt was significantly lower in MTX-treated NPs than in nontreated NPs., Conclusion: MTX induces apoptosis in NPs via caspase cascades and both mitochondria-mediated and p38 MAPK/JNK pathways. We suggest that MTX can be used to treat NPs.

Background: Although combined oral and nasal steroid therapy is widely used in nasal polyposis, a subset of patients show an unfavorable therapeutic outcome. This study aimed to evaluate whether oral prednisolone produces any additive effects on subsequent nasal steroid therapy and to evaluate if any clinical variables can predict therapeutic outcome., Methods: Using a 3:2 randomization ratio, 67 patients with nasal polyposis received 50 mg of prednisolone and 47 patients received placebo daily for 2 weeks, followed by mometasone furoate nasal spray (MFNS) at 200 micrograms twice daily for 10 weeks. Clinical response was evaluated by nasal symptom score (NSS), peak expiratory flow index (PEFI), and total nasal polyps score (TNPS). Potential predictor variables were assessed by clinical history, nasal endoscopy, allergy skin test, and sinus radiography., Results: At the end of the 2-week oral steroid phase, the prednisolone group showed significantly greater improvements in all nasal symptoms, nasal airflow, and polyp size than the placebo group. In the nasal steroid phase, while the MFNS maintained the outcome improvements in the prednisolone group, all outcome variables in the placebo group showed continuing improvements. At the end of the nasal steroid phase, there were no significant differences of most outcome improvements between the two groups, except in hyposmia, PEFI, and TNPS (p = 0.049, p = 0.029, and p = 0.005, respectively). In the prednisolone group, patients with polyps grade 3 and endoscopic signs of meatal discharge showed significantly less improvement in total NSS, PEFI, and TNPS than patients with grade 1-2 size and negative metal discharge., Conclusion: In the 12-week treatment evaluation of nasal polyposis, pretreatment with oral steroids had no significant advantage for most nasal symptoms other than earlier relief; however, combined oral and nasal steroid therapy more effectively improved hyposmia, polyps size, and nasal airflow. Polyps size grade 3 and/or endoscopic signs of meatal discharge predisposed to a poorer treatment outcome.

Background: This study was designed to examine the efficacy of Chinese herbal medicine (CHM) in the treatment of chronic rhinosinusitis (CRS) without nasal polyps., Methods: Patients with CRS without nasal polyps were enrolled in the study. Before treatment, they were evaluated by the Taiwanese version of the 20-item Sino-Nasal Outcome Test (TWSNOT-20), nasal endoscopy, saccharin test, and bacterial culture. Then, they were randomized to take CHM (Tsang-Erh-San extract granules and Houttuynia extract powder) or erythromycin for 8 weeks. After treatment, they were evaluated again by the TWSNOT-20, nasal endoscopy, saccharin test, and bacterial culture., Results: Fifty-three patients completed the study with 26 in the CHM group and 27 in the erythromycin group. In both the CHM and the erythromycin groups, TWSNOT-20 scores significantly decreased after treatment, but the decrease was not significantly different between the two groups. However, the saccharin transit times were shortened in more patients in the CHM group than in patients in the erythromycin group., Conclusion: Our results showed CHM had an efficacy similar to that of macrolides in the treatment of CRS without nasal polyps. However, a placebo effect remained possible in both treatment groups.

Background: Corticosteroids are a mainstay of treatment for chronic rhinosinusitis with nasal polyposis (CRSwNP). Data related to the effect of systemic methylprednisolone on surfactant protein (SP) expression in CRSwNP is limited. This study aimed to reveal the consequences of systemic methylprednisolone treatment on levels of SP-A and SP-D, which play a role in innate immunity, in patients with CRSwNP., Methods: Twenty-one patients with CRSwNP were included in the study, along with 15 control patients scheduled for dacryocystorhinostomy. A polypoid tissue biopsy was taken under local anesthesia, and 15 CRSwNP patients were scheduled for endoscopic sinus surgery after 3 weeks of oral methylprednisolone. Posttreatment biopsies were performed perioperatively. Pre- and posttreatment endoscopic polyp grades were determined, as were symptom scores regarding nasal obstruction, headache, and nasal discharge using a visual analog scale (VAS). SP-A and SP-D levels were measured using enzyme-linked immunosorbent assay and the results were compared., Results: All patients reported relief from clinical symptoms through VAS after methylprednisolone treatment. The posttreatment polyp grade was reduced (p < 0.0001). SP-A and SP-D levels did not yield a significant difference between CRSwNP patients and controls (p = 0.25 and p = 0.13, respectively). Statistically significant up-regulation was detected in SP-A and SP-D levels after oral methylprednisolone (p = 0.0002 and p = 0.0004, respectively)., Conclusion: In this study, significant up-regulation of SP-A and SP-D was revealed in patients with CRSwNP after systemic steroid treatment. The role of SP-A and SP-D up-regulation in CRSwNP pathogenesis and therapeutic outcomes of corticosteroids have potential importance for the introduction of new therapeutic modalities that are more effective and produce fewer adverse effects.

Background: [6]-Gingerol is one of the major pungent principles of ginger and has diverse effects, including anti-inflammatory, and antioxidative effects. Reactive oxygen species (ROS) are released during the phenotypic transformation of fibroblasts to myofibroblasts, a process that is involved in the growth of nasal polyps by inducing extracellular matrix (ECM) accumulation. The purpose of this study was to determine the effect of [6]-gingerol on myofibroblast differentiation and collagen production of nasal polyp-derived fibroblasts (NPDFs) and to determine if the effect of [6]-gingerol is linked to an antioxidant effect., Methods: NPDFs were incubated and treated with transforming growth factor (TGF) beta 1. The ROS generated by NPDFs were determined using 2″,7″-dichlorfluorescein-diacetate. The fluorescence was captured by a fluorescent microscope and measured using a fluorometer. The expression of alpha-smooth muscle actin (SMA) and collagen type IV mRNA was determined by a reverse transcription-polymerase chain reaction, and the expression of α-SMA protein and pSmad2/3 was determined by immunofluorescence microscopy and or Western blotting. The amount of total soluble collagen production was analyzed by the SirCol collagen dye-binding assay., Results: TGF-beta 1 stimulation increased ROS production by NPDFs. [6]-Gingerol decreased the production of ROS in TGF-beta 1-induced NPDFs. Myofibroblast differentiation, collagen production, and phosphorylation of Smad2/3 were prevented by [6]-gingerol and inhibition of ROS generation with antioxidant such as diphenyliodonium, N-acetylcysteine, and ebselen., Conclusion: These results suggest the possibility that [6]-gingerol may play an important role in inhibiting the production of the ECM in the development of nasal polyps through an antioxidant effect.