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.

Staphylococcus aureus impairs sinonasal epithelial repair: Effects in patients with chronic rhinosinusitis with nasal polyps and control subjects.

BACKGROUND: The effect of Staphylococcus aureus on nasal epithelial repair has never been assessed in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). OBJECTIVE: This study aimed to determine whether (1) nasal epithelial cell cultures from patients with CRSwNP and control subjects repair differently; (2) S aureus exoproducts compromise nasal epithelial repair; (3) S aureus alters lamellipodial dynamics; and (4) deleterious effects could be counteracted by the Rho-associated coiled-coil kinase inhibitor Y-27632. METHODS: Primary nasal epithelial cells (pNECs) collected during surgeries were cultured and injured under 3 conditions: (1) basal conditions, (2) exposed to S aureus exoproducts, and (3) exposed to S aureus exoproducts and Y-27632. Epithelial repair, lamellipodial dynamics, and cytoskeletal organization were assessed. RESULTS: Under basal conditions, pNEC cultures from patients with CRSwNP presented significantly lower repair rates and reduced lamellipodial protrusion length and velocity than those from control subjects. S aureus exoproducts significantly decreased repair rates and protrusion dynamics in both control subjects and patients with CRSwNP; however, the effect of S aureus on cell protrusions was more sustained over time in patients with CRSwNP. Under basal conditions, immunofluorescence assays showed significantly reduced percentages of cells with lamellipodia at the wound edge in patients with CRSwNP compared with control subjects. S aureus altered cell polarity and decreased the percentage of cells with lamellipodia in both groups. Finally, Y-27632 prevented the deleterious effects of S aureus exoproducts on CRSwNP repair rates, as well as on lamellipodial dynamics and formation. CONCLUSIONS: S aureus exoproducts significantly alter epithelial repair and lamellipodial dynamics on pNECs, and this impairment was more pronounced in patients with CRSwNP. Importantly, Y-27632 restored epithelial repair and lamellipodial dynamics in the presence of S aureus exoproducts.

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

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

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

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

Genetics of rhinosinusitis.

Suggestion for a potential genetic basis to chronic rhinosinusitis (CRS) is afforded by degree of inheritability suggested from family and twin studies, existence of CRS in simple mendelian diseases, and development of sinusitis as part of the phenotype of certain gene "knockout" murine models. Genetic association studies are expected to identify novel genes associated with CRS and suggest novel mechanisms implicated in disease development. Although these studies are subject to methodologic difficulties, associations of CRS and polymorphisms in more than 30 genes have been published, with single nucleotide polymorphisms in 3 (IL1A, TNFA, AOAH) replicated. While the individual risk conferred by these single nucleotide polymorphisms remains modest, taken as a group, they suggest an important implication of pathways of innate immune recognition and in regulation of downstream signaling in the development of CRS. In a demonstration of these techniques' potential to identify new targets for research, the authors present a functional investigation of LAMB1, the top-rated gene from a pooling-based genome-wide association study of CRS. Upregulation of gene expression in LAMB1 and associated laminin genes in primary epithelial cells from CRS patients implicates the extracellular matrix in development of CRS and offers a new avenue for further study.

The Role of Biologics in Chronic Rhinosinusitis with Nasal Polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common and heterogeneous inflammatory disease of the upper respiratory tract. This article provides expert opinion and points of view from both allergists and rhinologists who specialize in CRSwNP. Despite the potential value of biomarker-based endotyping to provide guidance regarding optimal care and treatment choices for patients with CRSwNP, current practice is largely not biomarker-based. In general, there is agreement that for patients with symptomatic CRSwNP who have failed a trial of a course of at least 3 months of intranasal steroids and a short course of oral corticosteroids, a surgical intervention will often be the next treatment of choice. Biologics may be considered before an initial surgery in patients with comorbid severe asthma and in those for whom surgery is less available, refused by the patient, or likely to be associated with a higher-than-average complication rate. Biologic use immediately following surgery may be considered in patients who have a history of nasal polyp recurrence within 12 months of a prior surgery. For many patients with recalcitrant disease, a combination of sinus surgery and use of a biologic that is targeted to their precise endotype may be the optimal treatment strategy, though which surgical approach and which biologics are best for each patient are debates that remain ongoing.

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

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

Treatment alternatives for chronic rhinosinusitis persisting after ESS: what to do when antibiotics, steroids and surgery fail.

BACKGROUND: It is estimated that over 500,000 individuals in the United States currently suffer from chronic rhinosinusitis (CRS), which has persisted or recurred despite maximal medical therapy and endoscopic sinus surgery (ESS). Management of these individuals remains uncertain, as recent published guidelines on CRS do not extend to this population. OBJECTIVE: Our objective is to provide a framework for the management of patients who fail standard therapy for CRS while providing recommendations based on the strength of the evidence for alternative medical therapies that can be used for the treatment of recurrent CRS. This guideline targets ENT physicians and allergists managing this increasingly frequent clinical situation and attempts to assist them in selecting from the increasing array of potential therapies available. To this end, factors contributing to the pathophysiology of post-ESS CRS are reviewed to identify method of action of existing and potential therapies and recommendations are made for their use. RESULTS: Given the accessibility of the sinus cavities after ESS, topical therapies are privileged. Saline spray or irrigation is recommended for all patients. Corticosteroids in oral or topical forms are recommended for controlling the inflammatory component, while the use of a short term course of oral or topical antibiotics are recommended mainly for the treatment of exacerbations. Long-term therapy with oral macrolides is also recommended as an alternative therapy. Desensitization with acetylsalicylic acid (ASA) for individuals with documented ASA sensitivity is recommended where available, while revision surgery, anti-leukotriene agents and intravenous immunoglobulins are options in management in selected patients. Antifungal therapy is not recommended. No recommendations for potentially experimental strategies are made in the absence of published experience and safety data in human subjects.

Staphylococcus aureus on Sinus Culture Is Associated With Recurrence of Chronic Rhinosinusitis After Endoscopic Sinus Surgery.

Objectives: Identify whether identification of S. aureus on conventional culture is a predictor of success or failure after ESS followed by budesonide nasal irrigations (BUD) in chronic rhinosinusitis (CRS) patients at high risk of recurrence. Methodology: Prospective clinical trial including 116 patients from a tertiary care center at high-risk of disease recurrence following ESS+BUD. Blood samples, microbial swabs, and SNSS/SNOT-22 were taken on the day of surgery (Visit-1) and 4 months postoperatively (Visit-2). Outcomes were evaluated using symptoms and mucosal status as assessed by the Lund-Kennedy endoscopic score. Results: Seventy-five patients (69.4%) attained SNOT-22 MCID or higher. (Mean = 33.4, range 9-75). Objective documentation of recurrence of disease, as defined by combined endoscopic/symptomatic criteria, was noted in 58/116 patients (50%). Revision surgery was associated with a significantly higher rate of disease recurrence (60.0 vs. 28.0%; p < 0.001). Culture for Staphylococcus aureus was associated with disease recurrence, preoperatively and at 4 months post-surgery (p = 0.020; p < 0.001). This was restricted to post-operative cultures in the revision group (10.0 vs. 48.8%; p < 0.001). Other factors associated with poor outcome included intolerance to non-steroidal anti-inflammatory drugs (NSAID) (p = 0.036). Significantly higher Lund-Kennedy scores in the recurrence groups despite similar symptom intensity, emphasizing the importance of considering objective outcome in addition to patient-reported ones. Conclusion: Patients undergoing revision ESS are at high risk of disease recurrence, even when budesonide irrigations are used post operatively. Presence of S. aureus on culture pre-operatively or at 4 months post-ESS is associated with a negative outcome. This suggests that S. aureus negatively influences outcome, possibly via a number of mechanisms, including interactions with the (i) immune system, (ii) regeneration and repair of the sinus epithelium, or (iii) via interference with the sinus microbiome. This suggests that S. aureus may be a simple and inexpensive biomarker for disease severity and indicates a clear need to better appreciate S. aureus on how it contributes mechanistically to disease development and persistence in order to develop targeted therapeutic strategies.

Algorithms for management of chronic rhinosinusitis.

Chronic rhinosinusitis poses numerous challenges for the practitioner. This article presents strategies for making the diagnosis and managing chronic rhinosinusitis with and without nasal polyposis, and for assessing and managing disease persisting or recur-ring after endoscopic sinus surgery.

Polymorphisms in the SERPINA1 (Alpha-1-Antitrypsin) gene are associated with severe chronic rhinosinusitis unresponsive to medical therapy.

BACKGROUND: Alpha-1-antitrypsin (AAT) is a serine protease inhibitor that blocks the protease, neutrophil elastase. Previous population studies have suggested that heterozygote status for the AAT gene (SERPINA1) is a risk factor for chronic rhinosinusitis with nasal polyposis (CRSwNP). This implies a potential genetic predisposition to CRS tied to AAT deficiency. The purpose of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in the SERPINA1 gene and CRS. METHODS: DNA extracted from a population of 206 patients diagnosed with CRSwNPs and 196 postal code-matched controls was used. A maximally informative set of tagging SNPs from SERPINA1 on chromosome 14q were selected from the HapMap data set (International HapMap Consortium, Nature 437:1299-1320, 2005) and genotyped on the Sequenom platform (Sequenom, San Diego, CA). RESULTS: Successful genotyping was performed for 32 of 33 SNPs. Two SNPs (rs1243168 and rs4900229) located upstream of the SERPINA1gene, were associated with CRS. Individuals homozygous (TT) for these SNPs had an increased probability of having CRS with an odds ratio of 5.95 and 1.49, respectively. Subgroup analysis according to severity of disease identified each SNP to be increasingly common in individuals as disease severity increased (p < 0.001). These individuals were also less likely to be responsive to medical therapy (p < 0.001). CONCLUSION: Polymorphisms of the SERPINA1 gene are associated with clinically severe CRS. These results, from a small subset of individuals with CRS, suggest that defects in AAT may be implicated in a subset of individuals unresponsive to conventional therapy and suggests that alternate therapies may be required for their management.

Are biofilms the answer in the pathophysiology and treatment of chronic rhinosinusitis?

Chronic rhinosinusitis is a complex heterogeneous disease. Infection in the form of biofilm may have an important, if not central, role in the maintenance of the recalcitrant inflammation for this increasingly common chronic disease. Therefore, the importance of understanding the interaction of biofilm disease with the respiratory mucosa is imperative. Novel, minimally invasive methods of testing for the presence of this form of disease will need to become clinically accessible in order for equally innovative therapies to be widely applicable.

The role of bacterial biofilms and the pathophysiology of chronic rhinosinusitis.

The earliest description of a bacterial biofilm is likely centuries old. However, only in the past few decades has a wealth of knowledge developed pertaining to this bacterial form of existence. Biofilms have been implicated mainly in chronic disease states, and the current available treatment modalities for infection have demonstrated limited efficacy against bacteria in this form. There is evidence associating bacterial biofilm formation in chronic infections of the upper airway, and therefore we examine the possible role of a bacterial biofilm in chronic rhinosinusitis while drawing parallels with recent data from other bodily regions. Lastly, directions for contemporary biofilm research are reviewed and highlighted in terms of their application to chronic rhinosinusitis.

Evaluating the reproducibility of sinus lavages with a saline solution administered directly in the maxillary sinus of patients after endoscopic sinus surgery.

INTRODUCTION: Chronic sinusitis is recognized as having a strong inflammatory component, and failures of endoscopic sinus surgery (ESS) are frequently attributed to persistent inflammation. A test that would allow rhinologists to evaluate the inflammatory state of a patient's sinuses would be helpful to evaluate cases refractory to therapy, determine appropriate medical therapy, and monitor the response to therapy. OBJECTIVES: The goal of this preliminary research is to assess the optimal method of collection and the reproducibility and specificity of sinus lavages. METHOD: Twelve patients who had undergone ESS were recruited. They were divided into two groups according to the persistence of their symptoms and the recurrence of acute sinusitis after ESS. The subjects were seen twice. Three successive lavages were collected from each maxillary sinus and were analyzed by cell count. RESULTS: Intrasession cell counts were most reproducible (Spearman rank correlation .7 for eosinophils and .6 for neutrophils) for the second lavage. Intersession cell counts were highly reproducible for eosinophils (r = .7) for the second lavage. The two-tailed t-test did not reveal any statistically significant differences between the good and the poor outcome groups. CONCLUSION: Assessment of eosinophil cell counts on sinus lavage is a feasible and reproducible method to evaluate the inflammatory state of a patient's sinuses in patients who have undergone ESS.

Use of hylan B gel as a wound dressing after endoscopic sinus surgery.

Although serious sequelae of endoscopic sinus surgery are infrequent, more commonplace surgical management often involves the control of mucosal bleeding. This study was conducted to assess the efficacy of an elastoviscous hylan gel as a postsurgical wound dressing for promotion of hemostasis. Twenty patients with a diagnosis of chronic sinusitis were evaluated. In randomized fashion, the gel dressing was placed into one operated cavity while the contralateral side served as the control. The results indicated that hylan gel was effective in stilling postsurgical bleeding, particularly in the fulminant polyposis cases who had a larger and more exposed cavity. These early results indicate a potential benefit of a gel dressing for hemostasis when used at the conclusion of the operative procedure. In addition, other parameters were evaluated in this study, including prevention of postoperative adhesions and the effect on mucosal healing. These parameters showed a positive result compared with the control group.