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Alphaherpesviruses, including herpes simplex virus type 1 (HSV-1), pseudorabies virus (PRV), and bovine herpesvirus type 1 (BoHV-1), are significant pathogens affecting humans and animals. These viruses penetrate the upper respiratory tract mucosa, yet the mechanisms facilitating this invasion are not fully understood. This study investigates the role of the gE/gI glycoprotein complex and proteases in mucosal invasion by these viruses. Using species-specific respiratory mucosal explants, we observed that the removal of extracellular calcium disrupts epithelial junction integrity, enhancing viral infection across all viruses and suggesting a common mechanism of targeting a basolaterally located receptor. PRV exhibited significantly faster replication and deeper invasion compared to HSV-1 and BoHV-1. The gE glycoprotein was consistently polarized at the basement membrane across all viruses, indicating a critical role in the process of viral entry and subsequent spread through the epithelium. In this context, "infection" refers to the virus's attachment to its cell-surface receptor, entry into the cell, and completion of the viral life cycle, culminating in the production of progeny virions. Notably, in gE/gI null mutants of PRV and HSV-1, while the infection was not abortive and the viral life cycle was completed, the infection was delayed, and the invasion into the deeper layers of the epithelium and underlying mucosa was significantly reduced. In BoHV-1 mutants, this effect was even more pronounced, with infection restricted to the apical cells, failing to progress to the basal cells. In addition, PRV and HSV-1 invasion involved serine protease activity, unlike BoHV-1, which correlates with its slower invasion pace. Notably, the protease facilitating PRV invasion was identified as a urokinase plasminogen activator (uPA), while the specific protease for HSV-1 remains unidentified. These findings highlight the critical roles of the gE/gI complex and proteases in alphaherpesvirus pathogenesis, offering potential targets for therapeutic intervention., Importance: Herpes simplex virus type 1 (HSV-1) infections are a worldwide issue. More than three billion people are infected with HSV-1 globally. Although most infections with HSV-1 occur subclinically, severe symptoms and complications are numerous and can be life-threatening. Complications include encephalitis and blindness. Recently, HSV-1 infections have been associated with the development of Alzheimer's Disease. To date, no effective vaccines against HSV-1 are on the market. Pseudorabies virus (PRV) and bovine herpesvirus type 1 (BoHV-1) are two alphaherpesviruses of major veterinary importance. Although efforts have been made to eradicate these viruses from livestock animals, clinical problems still occur, resulting in great economic losses for farmers. It is evident that new insights into the pathogenesis of alphaherpesviruses are needed, to develop effective treatments and novel preventive therapies., Competing Interests: G.A.S. is a co-founder of Thyreos, Inc., which is producing recombinant herpesvirus vaccines, and serves on the scientific advisory board of EG427. G.A.S. has stock ownership in both entities.

Context: Recent insights into type 2 inflammation have led to the development of monoclonal antibody therapies for severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). Despite add-on therapy with a monoclonal antibody, some individuals remain uncontrolled in terms of upper and/or lower airway symptoms, prompting an exploration of the efficacy of combining biological therapies and their impact on inflammatory pathways., Objectives: In this article, we present a distinctive case of a patient with CRSwNP, severe eosinophilic asthma, and uncontrolled upper airway symptoms, who experienced substantial clinical and local inflammatory improvements through dual monoclonal antibody therapy., Methods: We provide a detailed case description and analysis of the patient's nasal tissue and secretions to gain insights into the local nasal inflammation under this unique therapeutic approach., Results: The addition of an anti-IL-4Rα antibody led to an improvement in upper airway symptoms and a reduction in both eosinophilic and neutrophilic inflammation, despite prior anti-IL-5 therapy. These effects were consistently observed in both polyp tissue and nasal secretions., Conclusion: Our patient, with CRSwNP, severe eosinophilic asthma, and uncontrolled upper airway symptoms, experienced substantial improvement with dual monoclonal antibody therapy, without major complications or side effects., Competing Interests: GB has received fees for advisory boards and/or speaker fees from Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Sanofi, and Teva Pharmaceuticals. BNL received research support from GSK and Sanofi. PG has served as an advisor or speaker and received grant/research support from ALK, GSK, Lilly, Novartis, Regeneron, Roche, Sanofi, and Stallergenes-Greer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Blauwblomme, Gevaert, Van Nevel, Riemann, Vandewalle, Holtappels, De Ruyck, Derycke, Eeckels, Vanhee, Lambrecht, Brusselle and Van Zele.)

Purpose: Intestinal-type adenocarcinoma (ITAC) is a rare sinonasal malignancy. Curative treatment requires multidisciplinary approach, with surgical options consist of the endonasal endoscopic approach (EEA) and external surgery (EXTS). Here, we provide the post-operative and survival results from a single-center long-term follow-up., Methods: We report long-term follow-up of 92 ITAC cases treated between 1998 and 2018, treated with EEA (n = 40) or EXTS (n = 52). Survival estimates, post-operative complications and duration of hospitalization were compared between surgical modalities., Results: Baseline characteristics were similar. A higher number of T4b tumors (16%), and subsequently more tumoral invasion (39%), was present in patients undergoing EXTS compared to EEA (3% and 18%, respectively). No difference in Barnes histology subtypes was noticed. Patients undergoing EEA had a shorter post-operative hospitalization stay versus EXTS (4 versus 7 days). Use of EEA was associated to improved disease-specific survival (DSS; 11.4 versus 4.4 years; HR EEA  = 0.53), especially for patients with T3-4a tumors (11.4 versus 3.0 years; HR EEA  = 0.41). Patients with T3-4 stage, tumoral invasion, positive surgical margins, mucinous or mixed histology, and prolonged post-operative hospital stay showed poor local relapse-free, disease-free, overall, and DSS., Conclusions: Long-term follow-up in locally advanced ITAC demonstrates that resection by EEA is correlated with improved DSS compared to EXTS, especially for T3-4 tumors. No significant differences between both treatment modalities was observed regarding per- and post-operative complications, although hospitalization in patients undergoing EEA was shorter than for patients treated with EXTS. These results confirm that EEA should remain the preferred surgical procedure in operable cases of sinonasal ITAC., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Following the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) treatment algorithm for chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), patients suffering from severe uncontrolled CRSwNP are recommended to receive oral corticosteroids, (revision) sinus surgery, systemic biologicals and/or aspirin treatment after desensitization (ATAD). Given the major differences in indications, outcomes, practical considerations, risks and costs of these key pillars of treatment, there is a growing need to define criteria for each treatment option and list the clinically relevant and major considerations for them. This EUFOREA document therefore provides an expert panel overview of the expected outcomes, specific considerations and (contra)indications of the five major treatment arms of severe uncontrolled CRSwNP: oral corticosteroids, primary and revision sinus surgery, biological treatment and ATAD. This overview of treatment considerations is needed to allow physicians and patients to consider the different options in the context of providing optimal and personalized care for severe uncontrolled CRSwNP. In conclusion, the five major treatment options for severe uncontrolled CRSwNP have intrinsic advantages, specific indications and considerations that are of importance to the patient, the physician and the society. This EUFOREA statement supports the unmet need to define criteria for the indication of every treatment pillar of CRSwNP., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Objectives: The immunocompromised status in transplant recipients promotes the development and exacerbation of rhinosinusitis. However, there are no formal guidelines on pretransplant sinonasal evaluations. Here, we aimed to identify the prevalence and mortality rates of rhinosinusitis in the transplant population and to provide an evidence-based pretransplant screening protocol., Materials and Methods: For our meta-analysis and systematic review of available literature, we performed an online search on PubMed, Scopus, and Google Scholar. We included 27 articles for review, which included 22 articles for meta-analysis. We assessed the risk of bias on outcome by using the GRADE system. Primary outcome measures were pretransplant prevalence of rhinosinusitis and overall mortality rates., Results: The prevalence of pretransplant rhinosinusitis in hematopoietic stem cell transplant recipients (22.2%) was significantly higher than the prevalence in solid-organ transplant recipients (3.9%) (relative risk 4.9; 95% CI, 4.2-5.6; P < .01). We found no significant difference in overall mortality between transplant recipients with or without rhinosinusitis. However, hematopoietic stem cell transplant recipients with pretransplant rhinosinusitis showed significantly higher risk of overall mortality (relative risk 2.8; 95% CI, 2.1-3.9; P < .05) compared with solid-organ transplant recipients., Conclusions: Our research assessed the need for a clinical pretransplant sinonasal assessment in all transplant recipients and advised for routine paranasal sinus computed tomography before hematopoietic stem cell transplant, due to the higher prevalence of rhinosinusitis and risk of mortality in this group. We also presented a proposed screening protocol on pretransplant sinonasal evaluation.

Background: The expression of MZB1 genes is significantly elevated in patients who have chronic rhinosinusitis with nasal polyp (CRSwNP) disease compared with healthy controls., Objective: To characterize MZB1-positive B cells in CRSwNP and to estimate the contribution of distinct subsets of B cells to the local overproduction of immunoglobulins., Methods: Single-cell RNA-sequencing with Cellular Indexing of Transcriptomes and Epitopes by Sequencing technology, Switching Mechanism At the 5' end of RNA Template sequencing, flow cytometry, immunohistochemistry and immunofluorescence staining, Western blot, QuantiGene Plex assay, B-cell ImmunoSpot assay, Luminex assay, and enzyme-linked immunosorbent assay were performed., Results: Significantly higher mRNA expression of MZB1 and HSP90B1 was found in type 2 CRSwNP compared with controls. In CRSwNP, MZB1 expression correlated with the local production of IgE. MZB1 could be colocalized with plasma and mature B cells, especially marginal zone (MZ) B cells. Single-cell transcriptome and epitope studies revealed prominent populations of B cells in type 2 CRSwNP with unexpectedly high MZB1 gene expression. The MZ B-cell population was significantly increased in CRSwNP compared with healthy controls in both peripheral blood mononuclear cells and nasal tissue single-cell suspensions. When those single cells were cultured overnight, the MZ B-cell numbers were positively correlated with local IgE production but negatively correlated with local IgM production. In vitro, MZB1 stimulation up-regulated the mRNA expression of IgE., Conclusion: MZB1 was primarily expressed by plasma and mature B cells in nasal mucosa. MZB1 expression level was increased in CRSwNP compared with controls. MZB1 contributed to the local IgE production in type 2 CRSwNP., Competing Interests: Disclosures Dr Bachert is an advisory board member and speaker for Novartis, GlaxoSmithKline, AstraZeneca, Sanofi, ALK-Abelló, and Mylan. The other authors have no conflicts of interest to report., (Copyright © 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represent a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology-based topics spanning the field., Methods: In accordance with prior International Consensus Statement on Allergy and Rhinology documents, ICSNT assigned each topic as an Evidence-Based Review with Recommendations, Evidence-Based Review, and Literature Review based on the level of evidence. An international group of multidisciplinary author teams were assembled for the topic reviews using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses format, and completed sections underwent a thorough and iterative consensus-building process. The final document underwent rigorous synthesis and review prior to publication., Results: The ICSNT document consists of four major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology-based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention., Conclusion: As an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses., (© 2023 The Authors. International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with elevated levels of type 2 inflammatory cytokines and raised immunoglobulin concentrations in nasal polyp tissue. By using single-cell RNA sequencing, transcriptomics, surface proteomics, and T cell and B cell receptor sequencing, we found the predominant cell types in nasal polyps were shifted from epithelial and mesenchymal cells to inflammatory cells compared to nasal mucosa from healthy controls. Broad expansions of CD4 T effector memory cells, CD4 tissue-resident memory T cells, CD8 T effector memory cells and all subtypes of B cells in nasal polyp tissues. The T and B cell receptor repertoires were skewed in NP. This study highlights the deviated immune response and remodeling mechanisms that contribute to the pathogenesis of uncontrolled severe CRSwNP. CLINICAL IMPLICATIONS: We identified differences in the cellular compositions, transcriptomes, proteomes, and deviations in the immune profiles of T cell and B cell receptors as well as alterations in the intercellular communications in uncontrolled severe CRSwNP patients versus healthy controls, which might help to define potential therapeutic targets in the future., Competing Interests: Declaration of Competing Interest Claus Bachert: Advisory Board member and speaker for Novartis, GSK, Astra-Zeneca, Sanofi, ALK, and Mylan. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To report biomarkers present in the olfactory mucosa in chronic rhinosinusitis with nasal polyps (CRSwNP) in comparison with nasal polyps and to nasal mucosal tissues from control patients. To evaluate the kinetics of smell over 6 months in patients who underwent Reboot surgery., Methods: Cohort study from May 2021 to May 2022. We collected samples of olfactory mucosa and nasal polyps from 16 CRSwNP patients and inferior turbinate samples from 20 control subjects. The study was not randomized for surgical and/or medical treatment. Samples were analyzed by Luminex and Unicap 100 to measure biomarkers of inflammation (IL1-β, IL4, IL5, IL6, IL17, CCL3, CCL4, G-CSF, SE-IgE, total IgE and ECP). 12 of the CRSwNP patients underwent Extended Sniffin'tests at timepoints 1-4 days pre-surgery, and 1, 3 and 6 months after Reboot surgery., Results: Type-2 markers were significantly elevated in OM and polyp tissue in CRSwNP (n = 16) vs. controls (n = 20), P < 0.05. TDI scores improved already 1 month (P < 0.05) after surgery and remained stable for 6 months. Type-2 inflammation in nasal polyps was associated with decreased sense of smell and taste before surgery, but improved after surgery (P = 0.048). Type-3 inflammation was present in the olfactory mucosa and was associated with a better sense of smell before surgery, but a smaller improvement of smell afterward., Conclusions: Type-2 inflammation is present in the olfactory mucosa in CRSwNP patients and is associated with smell loss. Reboot surgery, aiming to completely remove inflamed sinus mucosa, significantly improves the smell in this group of patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Nasal endoscopy is not only used for the diagnosis of chronic rhinosinusitis with nasal polyps (CRSwNP), but also for monitoring the response to therapy playing an important role in both daily practice and research. In contrast to patient-reported outcomes, endoscopic nasal polyp scoring by independent blinded readers is an objective measurement, not influenced by the placebo effect. It is safer and cheaper compared with computed tomography imaging and therefore, better suited for regular assessments of the extent of the disease. Since the early 90s, a variety of endoscopic staging methods have been proposed and used in clinical research, making it hard to compare results from different studies. This paper resulted from a task force with experts in the field of CRSwNP, originated by the Ear, Nose and Throat section of the European Academy of Allergy and Clinical Immunology and aims to provide a unified endoscopic NP scoring system that can serve as a reference standard for researchers, but also as a useful tool for practitioners involved in the management of CRSwNP., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Chronic rhinosinusitis (CRS) is known to affect around 5 % of the total population, with major impact on the quality of life of those severely affected (1). Despite a substantial burden on individuals, society and health economies, CRS often remains underdiagnosed, under-estimated and under-treated (2). International guidelines like the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) (3) and the International Consensus statement on Allergy and Rhinology: Rhinosinusitis 2021 (ICAR) (4) offer physicians insight into the recommended treatment options for CRS, with an overview of effective strategies and guidance of diagnosis and care throughout the disease journey of CRS.

Background: Real-world evidence (RWE) is a valuable instrument to better understand the patient journey and effectiveness of therapies. RWE on the prevalence of uncontrolled chronic rhinosinusitis (CRS) and CRS natural course of disease across Europe is scarce. In addition, there is limited RWE that enables comparison of the effectiveness of marketed therapies including topical or systemic corticosteroids, sinus surgery, or biologics., Objective: To establish an international CHRonic rhINOSinusitis Outcome Registry (CHRINOSOR) based on real-world data collection enabled by mobile health technology., Methodology: A digital platform, Galenus Health, supporting patients and physicians in the management of chronic respiratory diseases, is used to collect data on patient profile, disease history, patient outcomes, and a set of relevant clinical outcomes. Adult patients with a diagnosis of CRS are eligible for inclusion., Results: A collaborative scientific network of 17 university ear-nose-throat (ENT) clinics from 10 European countries has been established with the aim to collect real-world data in a longitudinal and standardized manner. The Galenus Health digital platform is currently being implemented in these ENT clinics taking into account legal, privacy, and data security aspects. Up to 300 patients have already been included., Conclusions: CHRINOSOR is a collaborative effort that aims at improving our understanding of CRS, its comorbidities, and the effectiveness of its treatments. Ultimately, these insights will guide us as scientific community to develop future care pathways informed by RWE., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the time for recovery of the sense of smell in patients with CRSwNP who underwent Reboot surgery compared to patients undergoing ESS in a long-term follow-up study., Methods: Data were collected retrospectively from 168 patients with severe uncontrolled CRSwNP, who underwent revision surgery, either as Extended Endoscopic Sinus Surgery (Reboot, 140 patients) or as regular Endoscopic Sinus Surgery (ESS, 28 patients) between January 1, 2014, and December 31, 2015, aiming to compare the outcome of surgeries after 2 years of follow-up. Sense of smell was scored as judged by the patient using scores 0 to 3 reflecting a percentage estimate of remaining smell., Results: Smell improved similarly in the Reboot and ESS groups over the first 9 months, which was maintained over 24 months in the Reboot, but not the ESS group (p = 0.007 after 18 months, p = 0.001 after 24 months). Furthermore, polyp recurrence rates were significantly lower in the Reboot group., Conclusion: Reboot surgery significantly improved olfactory function and significantly reduced nasal polyp recurrence rates over 2 years post-operatively. Therefore, Reboot should be considered for patients with uncontrolled severe CRSwNP, specifically when ESS failed, to offer long-term smell and a polyp-free status., Level of Evidence: 3b., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The association between spontaneous cerebrospinal fluid (CSF) leak/rhinorrhea and idiopathic intracranial hypertension (IIH) has been increasingly recognized over the last years. However, considerable variability of opinion regarding the assessment, investigations, and management of patients with spontaneous CSF rhinorrhea remains., Methods: A consensus group was formed from experts from Europe, Asia, Australia, South and North America. Following literature review and open discussions with members of the panel, a set of 61 statements was produced. A modified Delphi method was used to refine expert opinion with 3 rounds of questionnaires and a consensus group meeting in Santo-Rhino meeting in September 2019., Results: Fifty statements (82% of total) on spontaneous CSF leak and IIH reached consensus. In 38 of 50 statements, the median response was 7 (strongly agree) and in the 12 remaining statements the median response was 6 (agree). Eleven statements were excluded because they did not reach consensus and one new statement was added during SantoRhino meeting. The final statements refer to patient history and clinical examination ("History taking should include presence of headache, tinnitus and visual defects"), investigations (role of Thin Slice Computed Tomography and CISS/FLAIR sequences in Magnetic Resonance Imaging), principles of management (watchful waiting or measures to reduce ICP are supplementary but cannot subsitute surgical closure), surgical technique, intraoperative, early postoperative and long term management., Conclusion: We present fifty consensus statements on the diagnosis, investigation, and management of spontaneous CSF rhinorrhea based on the currently available evidence and expert opinion. Although by no means comprehensive and final, we believe they can contribute to the standardization of clinical practice. Early diagnosis, prompt surgical closure of the defect, assesment for and treatment of potentially co-existing idiopathic intracranial hypertension in a comprehensive multidisciplinary approach are essential in order to successfully manage spontaneous CSF rhinorrhea, reduce associated morbidity and prevent recurrence., (© 2020 ARS-AAOA, LLC.)

Introduction and Importance: Bilateral congenital dacryocystocoele with intranasal extension is very rare and may lead to mild to severe respiratory distress, depending on the degree of obstruction, in an otherwise healthy newborn. If severe, an urgent surgical intervention may be life saving. Our aim is to alert paediatric surgeons to this rare condition. Early detection and early treatment with a minimally invasive surgical procedure may be life saving and prevent severe sequelae due to respiratory distress., Case Presentation: We present a healthy newborn girl who was admitted to neonatal intensive care with progressive respiratory distress. After a full work-up, she was diagnosed with bilateral dacryocystocoele with intranasal extension and complete obstruction of the anterior nasal cavity. Emergency bilateral endoscopic marsupialization of the cysts with probing of the nasolacrimal duct was performed. The girl recovered without sequelae., Clinical Discussion: In congenital dacryocystocoele, coexistent obstruction of the valve of Rosenmüller and the valve of Hasner is observed. Subsequent intranasal protrusion with obstruction of the inferior nasal cavity may occur. The incidence is unknown, but if bilateral, it is very rare. In most cases, a dacryocystocoele is uncomplicated and may be treated conservatively. However, if intranasal protrusion occurs, and especially if the involvement is bilateral, it is a surgical emergency., Conclusion: Early diagnosis with subsequent minimally invasive surgical treatment of bilateral congenital dacryocystocoele with intranasal protrusion may prevent serious complications due to respiratory distress., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Chronic rhinosinusitis (CRS) is a chronic inflammatory disease associated with a substantial personal and socioeconomic burden. Monitoring of patient-reported outcomes by mobile technology offers the possibility to better understand real-life burden of CRS., Methods: This study reports on the cross-sectional evaluation of data of 626 users of mySinusitisCoach (mSC), a mobile application for CRS patients. Patient characteristics of mSC users were analysed as well as the level of disease control based on VAS global rhinosinusitis symptom score and adapted EPOS criteria., Results: The mSC cohort represents a heterogeneous group of CRS patients with a diverse pattern of major symptoms. Approximately half of patients reported nasal polyps. 47.3% of all CRS patients were uncontrolled based on evaluation of VAS global rhinosinusitis symptom score compared to 40.9% based on adapted EPOS criteria. The impact of CRS on sleep quality and daily life activities was significantly higher in uncontrolled versus well-controlled patients. Half of patients had a history of FESS (functional endoscopic sinus surgery) and reported lower symptom severity compared to patients without a history of FESS, except for patients with a history of more than 3 procedures. Patients with a history of FESS reported higher VAS levels for impaired smell., Conclusion: Real-life data confirm the high disease burden in uncontrolled CRS patients, clearly impacting quality of life. Sinus surgery improves patient-reported outcomes, but not in patients with a history of more than 3 procedures. Mobile technology opens a new era of real-life monitoring, supporting the evolution of care towards precision medicine., (© 2020 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

On March 11th 2020, the World Health Organization (WHO) declared COVID-19 pandemic, with subsequent profound impact on the entire health care system. During the COVID-19 outbreak, activities in the rhinology outpatient clinic and operation rooms are limited to emergency care only. Health care practitioners are faced with the need to perform rhinological and skull base emergency procedures in patients with a positive or unknown COVID-19 status. This article aims to provide recommendations and relevant information for rhinologists, based on the limited amount of (anecdotal) data, to guarantee high-quality patient care and adequate levels of infection prevention in the rhinology clinic.

Because of the inflammatory mechanisms of most chronic upper airway diseases such as rhinitis and chronic rhinosinusitis, systemic steroids have been used for their treatment for decades. However, it has been very well documented that-potentially severe-side-effects can occur with the accumulation of systemic steroid courses over the years. A consensus document summarizing the benefits of systemic steroids for each upper airway disease type, as well as highlighting the potential harms of this treatment is currently lacking. Therefore, a panel of international experts in the field of Rhinology reviewed the available literature with the aim of providing recommendations for the use of systemic steroids in treating upper airway disease., Competing Interests: Competing interestsGS: Honoraria for articles, speaker and advisory boards: ALK, Astra Zeneca, Brittania Pharmaceuticals, Capnia, Church & Dwight, Circassia, Groupo Uriach, GSK, Meda/Mylan, Merck, MSD, Ono Pharmaceuticals, Oxford Therapeutics, Sanofi-Aventis, UCB. Travel funding: ALK, Bayer, GSK, Meda. Chair of BSACI Rhinitis guidelines, EAACI Ethics Committee, Rhinology & Laryngology Research Fund. Chair of Data Monitoring Board for Acarizax paediatric AR trial. CH: Reimbursed for Advisory Board work for sanofi, Smith and Nephew and speakers bureau for Medtronic. CB: Advisory board of Sanofi, GSK, Novartis, Astra-Zeneca, Mylan and reimbursed for presentations and travel. TVZ: Consultant for Medtronic and 3NT. STS: has acted as paid consultant for ERT and Roche Products. All these are outside the submitted work. All other authors declare that they have no competing interests., (© The Author(s) 2020.)

Background: Chronic rhinosinusitis (CRS) significantly affects health-related quality of life (HRQoL). Few multinational observational studies have evaluated the impact of CRS with nasal polyps (CRSwNP) on patients’ HRQoL. This study aimed to assess HRQoL outcomes (including analyses by disease severity and impact of comorbidities and refractory disease) in CRSwNP patients from a large European database., Methodology: Data were analysed from the Global Allergy and Asthma European Network (GALEN) Rhinosinusitis Cohort, including sociodemographic data, patient-reported disease severity (visual analogue scale), and scores on the 36-Item ShortForm Health Survey (SF-36) questionnaire. Differences in mean SF-36 scores were evaluated between patients with CRSwNP and population norms and between subgroups of interest (disease severity, comorbidity, and refractory disease, defined by a history of sinonasal surgery)., Results: Patients with CRSwNP (N = 445) had significantly lower mean SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores vs population norms, demonstrating that CRSwNP negatively affects HRQoL. The presence of comorbidities affected HRQoL, as shown by significant differences in PCS scores in patients with asthma or non-steroidal antiinflammatory drug-exacerbated respiratory disease, compared with patients without asthma. Patients with moderate-to-severe disease had significantly lower PCS scores than patients with mild disease. Severe disease had a significant impact on MCS score. History of surgery had a clinically meaningful negative effect on HRQoL compared with no history of surgery., Conclusions: CRSwNP patients have significantly lower HRQoL compared with population norms. The impact is greater in patients with greater disease severity, comorbidities, or refractory disease.

Purpose: To carry out a pilot study to evaluate the efficacy of a novel, drivable endoscope (the Peregrine™ Drivable ENT Scope), compared to standard rigid endoscopes in the access, visualization, and irrigation of the paranasal sinus anatomy., Methods: A prospective, multi-center, feasibility study was conducted on seventeen subjects who underwent primary functional endoscopic sinus surgery and were evaluated with the drivable endoscope and standard, rigid endoscopes (0°, 30° and 70°, as applicable). A CT scan was available for image guidance, as needed. The primary efficacy endpoint was the ability to access and visualize sinonasal anatomic landmarks. Secondary endpoints included device usability, as measured by a usability questionnaire given to surgeons postoperatively; the device's ability to irrigate the sinuses and patient reports of tolerability and pain during postoperative procedures., Results: The drivable endoscope success rate in visualizing all paranasal sinus anatomic landmarks was 55.6% better than the standard rigid endoscopes: 98.3% (178/181) versus 42.7% (76/178); p < 0.001. Surgeons rated scores of over 4 (on a 1-5 scale) for the usability of the drivable endoscope to enter the maxillary, frontal and sphenoid sinuses. The ability to irrigate the sinuses using the drivable endoscope was given a mean score of 4.3, and image quality was given a mean score of 3.4. The three patients evaluated postoperatively reported low pain and high tolerability scores with the drivable endoscope., Conclusions: These preliminary results indicate that the drivable endoscope is effective, easy to use and highly tolerable in sinonasal endoscopy.

Objective . The introduction of advanced endoscopic systems, such as the Storz Image1S and the Olympus Endoeye, heralds a new era of 3-dimensional (3D) visualization. The aim of this report is to provide a comprehensive overview of the neurophysiology of 3D view, its relevance in videoscopy, and to quantify the benefit of the new 3D technologies for both rigid and articulated instruments. Method . Sixteen medical students without any laparoscopic experience were trained each for a total of 27 hours. Proficiency scores were determined for rigid and articulated instruments under 2D and 3D visualization conditions. Results . A reduction in execution time of 14%, 28%, and 36% was seen for the rigid instruments, the da Vinci, and Steerable instruments, respectively. A reduction in errors of 84%, 92%, and 87% was seen for the rigid instruments, the da Vinci, and Steerable instruments, respectively. Conclusion . 3D visualization greatly augments endoscopic procedures. The advanced endoscopic systems employed in the recent study caused no visual fatigue or discomfort. The benefit of 3D was most distinct with articulated instruments.

Background: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a therapeutic challenge because of the high recurrence rate. Surgical intervention should be considered in patients who fail to improve after medical treatment. We monitored recurrence and revision surgery over 12 years after endoscopic sinus surgery in CRSwNP patients., Methods: In this prospective cohort study, 47 patients with CRSwNP, who underwent primary or revision extended endoscopic sinus surgery, were followed. Clinical symptoms and total nasal endoscopic polyp score were evaluated before, 6 years and 12 years after surgery., Results: Twelve years after surgery, 38 out of 47 patients (80.9%) were available for examination. There still was a significantly better symptom score and total nasal endoscopic polyp score compared to before surgery (P < 0.001). Within the 12-year follow-up period, 30 out of 38 patients developed recurrent nasal polyps, of which 14 patients underwent additional revision surgery. Comorbid allergic sensitization and tissue IL-5 levels were found to be significant predictors for the need of revision surgery., Conclusions: This long-term cohort study, investigating the outcome after surgery in CRSwNP, showed that, despite the low number of patients, 78.9% of patients with CRSwNP were subject to recurrence of the disease and 36.8% to revision surgery over a 12-year period., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Purpose: To investigate the clinical profile and outcomes of different treatment strategies in patients hospitalized for spontaneous severe epistaxis., Methods: This is a retrospective descriptive study of a case series of patients hospitalized for epistaxis in the University Hospital of Ghent between 2005 and 2012., Results: 124 patients with, respectively, 132 episodes were included. 64% were male. The mean age was 65 years. 73% had comorbidities of which arterial hypertension was the most common. 61% were taking one or more antithrombotics and in 25.7% a recent change in the medication schedule took place. 47% of the episodes necessitated a vascular intervention. The most performed surgery was endoscopic sphenopalatine artery ligation. The 1-year success rate of conservative treatment was 47% and of vascular intervention 81%. No significant difference between the recurrence rates and need for vascular intervention of the different comorbidities and medications was detected using Pearson chi-squared and Fisher's exact testing. The overall 5-year survival rate was 83.6%., Conclusions: The typical pattern of a patient presenting with severe epistaxis was a patient in the sixth decade, male, suffering from comorbidities and taking one or more antithrombotic agents. Based on the above-mentioned success rates of the different treatment options, we think all centres treating epistaxis should apply a well-defined protocol to guide the decision when to proceed with surgery. Furthermore, prospective research needs to precisely investigate the role played by comorbidities and their treatment in the occurrence of epistaxis and to test the effectiveness of proposed algorithms.

Objectives: Nasal polyps are often characterized by type 2 inflammation and disease recurrence. We developed a new surgical technique, referred to as reboot approach, which aims to maximally remove all sinus mucosa and allow healthy re-epithelialization from the preserved nasal mucosa. We here review type 2 endotype chronic rhinosinusitis with nasal polyps (CRSwNP) patients who underwent classical mucosa-sparing endoscopic sinus surgery (ESS) or the reboot approach., Methods: Retrospective case-control study of 50 consecutive CRSwNP patients who underwent endoscopic sinus surgery between 2015 and 2017, either as a classical non-reboot ESS (n = 20); a partial reboot approach removing the mucosa of the ethmoidal, sphenoidal, and maxillary sinuses (n = 18); or a complete reboot approach including Draf III and removal of all frontal sinus mucosa (n = 12). Polyp recurrence over the follow-up period of 2 years served as the primary outcome., Results: All patients demonstrated a type 2 inflammation of the mucosal tissue harvested during surgery. In the classical approach group (n = 20), nine patients relapsed within 2 years (45%); in the partial reboot group, three out of 18 patients (17%) relapsed; and in the full reboot group one out of 12 patients (8%) relapsed. The relapse rates were significantly different between the non-reboot and the reboot groups (P = 0.02) but also between all treatment groups (P = 0.038)., Conclusion: Complete removal of diseased mucosa from the paranasal sinuses (reboot approach) significantly reduces the recurrence of nasal polyps for 30 months postoperatively compared to the current mucosa-sparing approach in type 2 inflammatory CRSwNP., Level of Evidence: 3b Laryngoscope, 129:1286-1292, 2019., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Introduction  The importance of our study lies in the fact that we have demonstrated the occurrence of mechanical dysfunction within polypoid tissues, which promotes the development of polyps in the nasal cavity. Objective  To change the paradigm of nasal polyposis (NP). In this new conception, the chronic nasal inflammatory process that occurs in response to allergies, to pollution, to changes in the epithelial barrier, or to other factors is merely the trigger of the development of the disease in individuals with a genetic predisposition to an abnormal tissue remodeling process, which leads to a derangement of the mechanical properties of the nasal mucosa and, consequently, allows it to grow unchecked. Data Synthesis  We propose a fundamentally new approach to intervening in the pathological process of NP, addressing biomechanical properties, fluid dynamics, and the concept of surface tension. Conclusion  The incorporation of biomechanical knowledge into our understanding of NP provides a new perspective to help elucidate the physiology and the pathology of nasal polyps, and new avenues for the treatment and cure of NP.

Background: Chronic rhinosinusitis (CRS) is a common yet under-recognised chronic inflammatory disease of the nose and paranasal sinuses that is classified according to the presence (CRSwNP) or absence (CRSsNP) of nasal polyps., Methods: This paper reports the methodology and descriptive results of the Global Allergy and Asthma European Network (GALEN) rhinosinusitis cohort. We established a large CRS cohort within the GALEN consortium (European FP6 research initiative) to identify inflammatory endotypes, the natural disease course, and its impact on health-related quality of life (HRQoL). Detailed information on the impact of CRS on HRQoL, comorbidity incidence, objective disease measures, and medical and surgical treatments were collected., Results: This multicentre cross-sectional case-control study recruited 935 adults (869 eligible for analysis: 237 CRSsNP; 445 CRSwNP; 187 controls [reference group]). Comorbidities such as asthma, allergy, eczema, food allergy, urticaria, and chronic obstructive pulmonary disease were significantly more frequent in CRS patients. Nasal corticosteroids, antibiotics, and oral corticosteroids were the most common treatments. Significantly more CRSwNP patients reported previous sinonasal surgery., Conclusions: This study provides detailed information that facilitates studying CRS and its main phenotypes. However, patient distribution of this study does not necessarily reflect disease distribution in the general population.

Mobile health technology is emerging to take a prominent position in the management of chronic diseases. These technologies aim at enhancing patient empowerment via education and self-management. To date, of all the different apps available for patients with sinus disease, none were developed by medical experts dealing with chronic rhinosinusitis (CRS). The European Forum for Research and Education in Allergy and Airway diseases (EUFOREA) has undertaken a multi-stakeholder approach for designing, developing and implementing a tool to support CRS patients in monitoring their symptoms and to provide patients with a digital support platform containing reliable medical information about their disease and treatment options. mySinusitisCoach has been developed by medical experts dealing with CRS in close collaboration with patients, primary care physicians and community pharmacists, meeting the needs of both patients and health care providers. From a research perspective, the generation of real life data will help to validate clinical studies, patient stratification and improve understanding of the socio-economic impact of CRS, thereby paving the way for better treatment strategies.

Background: Chronic sphenoid sinusitis refractory to both medical therapy and sphenoidotomy requires a more extended intervention based on the principles of salvage surgery. Our aim is to describe the sphenoid drill out technique as a sphenoid salvage intervention and to outline its implications on clinical outcome and quality of life., Methodology: 12 patients with chronic sphenoiditis undergoing a sphenoid drill out procedure were examined by nasal endoscopy preoperatively and postoperatively for one year. Preoperative and postoperative quality of life questionnaires (RSOM-31 and SF-36) were obtained., Results: All but one patient had a completely patent neostium without scar formation. No major complications occurred after this procedure. All patients reported at least an improvement of their symptoms, 50% of patients were even symptom free at one year after surgery. The median postoperative RSOM-31 score was significantly lower than the preoperative score. Both the physical component summary (PCS) and the mental component summary (MCS) of the SF-36 score improved significantly. None of the patients needed a revision procedure., Conclusion: Sphenoid drill out is a safe and effective technique with a high success rate. In patients with chronic sphenoid sinusitis refractory to medical therapy and surgery it could be a valid alternative to revision sphenoidotomy.

Chronic rhinosinusitis with nasal polyp (CRSwNP) patients are often characterized by asthma comorbidity and a type-2 inflammation of the sinonasal mucosa. The mucosal microbiota has been suggested to be implicated in the persistence of inflammation, but associations have not been well defined. To compare the bacterial communities of healthy subjects with CRSwNP patients, we collected nasal swabs from 17 healthy subjects, 21 CRSwNP patients without asthma (CRSwNP-A), and 20 CRSwNP patients with co-morbid asthma (CRSwNP+A). We analysed the microbiota using high-throughput sequencing of the bacterial 16S rRNA. Bacterial communities were different between the three groups. Haemophilus influenzae was significantly enriched in CRSwNP patients, Propionibacterium acnes in the healthy group; Staphylococcus aureus was abundant in the CRSwNP-A group, even though present in 57% of patients. Escherichia coli was found in high amounts in CRSwNP+A patients. Nasal tissues of CRSwNP+A patients expressed significantly higher concentrations of IgE, SE-IgE, and IL-5 compared to those of CRSwNP-A patients. Co-cultivation demonstrated that P. acnes growth was inhibited by H. influenzae, E. coli and S. aureus. The nasal microbiota of healthy subjects are different from those of CRSwNP-A and CRSwNP+A patients. However, the most abundant species in healthy status could not inhibit those in CRSwNP disease.

Background: Flavonoids exert anti-inflammatory properties and modulate oxidative stress in vitro, suggesting a protective effect on lung function, but epidemiological studies examining this association are scarce., Methods: A stratified random sample was drawn from the GA²LEN screening survey, in which 55,000 adults aged 15 to 75 answered a questionnaire on respiratory symptoms. Post-bronchodilator spirometry was obtained from 2850 subjects. Forced vital capacity (FVC), the ratio between the forced exhaled volume in 1 second (FEV₁) and FVC (FEV₁/FVC), FVC below lower limit of normal (FVC < LLN), and FEV₁/FVC < LLN were calculated. Intake of the six main subclasses of flavonoids was estimated using the GA²LEN Food Frequency Questionnaire. Adjusted associations between outcomes and each subclass of flavonoids were examined with multivariate regressions. Simes' procedure was used to test for multiple comparisons., Results: A total of 2599 subjects had valid lung function and dietary data. A lower prevalence of FVC < LLN (airway restriction) was observed in those with higher total flavonoid (adjusted odds ratio (aOR), higher vs. lowest quintile intake 0.58; 95% Confidence Interval (CI) 0.36, 0.94), and pro-anthocyanidin intakes (aOR 0.47; 95% CI 0.27, 0.81). A higher FEV₁/FVC was associated with higher intakes of total flavonoids and pro-anthocyanidins (adjusted correlation coefficient (a β-coeff 0.33; 0.10, 0.57 and a β-coeff 0.44; 95% CI 0.19, 0.69, respectively). After Simes' procedure, the statistical significance of each of these associations was attenuated but remained below 0.05, with the exception of total flavonoids and airway restriction., Conclusions: This population-based study in European adults provides cross-sectional evidence of a positive association of total flavonoid intake and pro-anthocyanidins and ventilatory function, and a negative association with spirometric restriction in European adults., Competing Interests: The authors declare no conflict of interest.

Background: Periostin is a recently discovered biomarker for eosinophilic inflammation. Chronic rhinosinusitis with nasal polyps is a T-helper 2-skewed chronic inflammatory airway disease. Medical treatments aim to relieve symptoms and maintain clinical control by interfering with the inflammatory cascade. The effect on nasal and serum periostin levels is however yet unknown. We aimed to evaluate the effect of omalizumab, mepolizumab, methylprednisolone and doxycycline on nasal and systemic periostin expression., Methods: This study is based on 3 previously published trials. Nasal and systemic periostin were assessed in CRSwNP patients, randomly assigned to receive doxycycline (n=14), methylprednisolone (n=14), mepolizumab (n=20) or omalizumab (n=15). There was a control group for each treatment scheme. Doxycycline (200 mg on the first day, followed by 100 mg once daily) and methylprednisolone (32-8 mg once daily) were administered during 20 days; mepolizumab was injected at baseline and at 4 weeks. Omalizumab was injected every 2 or 4 weeks, following the official drug leaflet., Results: Methylprednisolone and omalizumab significantly reduced serum periostin levels at 4 and 8 weeks, respectively, after the start of the treatment. The effect of methylprednisolone was transient. Nasal periostin levels decreased significantly after 8 weeks of treatment with mepolizumab. The periostin expression is in accordance with the previously reported effect on the eosinophilic inflammation and clinical outcome., Conclusion: All treatment options distinctly influence periostin expression, reflecting the interference with the local or systemic eosinophilic inflammatory cascade.

Background: This study aimed to assess clinical outcomes of long-term low-dose oral doxycycline therapy in difficult-to-treat chronic rhinosinusitis with polyps (CRSwNP)., Methods: This was a prospective, open-label study of 60 patients with difficult-to-treat CRSwNP who had undergone endoscopic sinus surgery. Patients were divided into two groups: 28 received nasal steroids, saline irrigation, and doxycycline (200 mg on the first day, followed by 100 mg once daily) for 12 weeks, while 30 received only nasal steroids and saline irrigation. The main outcome measure was an adequate effect size of doxycycline treatment on clinically meaningful significant improvement of SNOT-20. Other outcome measures were the SNOT-20, NOSE, and Lund-Kennedy scores. The following parameters were also analyzed: asthma, rhinitis, non-steroidal-exacerbated respiratory disease (NERD), and baseline serum IgG, IgA, IgE, IgM, ANCA, and eosinophil count., Results: There was an adequate effect size of doxycycline treatment on clinically meaningful significant improvement of SNOT-20. Patients who received doxycycline also had significantly better outcomes regarding SNOT-20, NOSE, and Lund-Kennedy scores. There was a negative association among a clinically significant improvement of SNOT-20 and presence of asthma, NERD, and elevated serum IgE levels before treatment., Conclusion: These findings suggest that doxycycline may have a beneficial role for CRSwNP patients, especially for patients without asthma, NERD or high levels of serum IgE before treatment.

Background: An important percentage of subjects diagnosed with chronic upper airway disease report alcohol-induced worsening of their symptoms. The prevalence and characteristics of respiratory reactions provoked by alcohol-containing drinks have not been fully investigated yet., Objective: The aim of this study was to estimate the prevalence and characteristics of alcohol hyper-responsiveness in patients with chronic airway disease and healthy controls. Furthermore, nasal inflammation was evaluated in nasal polyp patients with and without hyper-responsiveness., Methods: We evaluated the prevalence and characteristics of alcohol-induced respiratory complaints in 1281 subjects. Chronic rhinosinusitis with nasal polyps (CRSwNP) patients with and without NSAID exacerbated respiratory disease (NERD), chronic rhinosinusitis patients without nasal polyps (CRSsNP), allergic rhinitis (AR) patients and healthy controls were approached by means of a questionnaire. Inflammatory markers (eosinophilic cationic protein (ECP), IL-5, IgE, SAE-specific IgE, IL-17, TNFα and IFNγ) in tissue were then compared between alcohol hyper-responsive and non-hyper-responsive CRSwNP patients., Results: The highest prevalence of nasal and bronchial alcohol hyper-responsiveness was observed in patients with NERD, followed by CRSwNP, and less frequent in CRSsNP, AR and healthy controls. Alcohol hyper-responsiveness is significantly more prevalent in CRSwNP patients suffering from recurrent disease and in patients with severe symptomatology. In nasal tissue of the hyper-responsive CRSwNP group, we observed significantly higher nasal levels of the eosinophilic biomarker ECP., Conclusion and Clinical Relevance: Nasal hyper-responsiveness to alcohol is significantly more prevalent in severe eosinophilic upper airway disease., (© 2016 John Wiley & Sons Ltd.)

Background: Fruits and vegetables are rich in compounds with proposed antioxidant, anti-allergic and anti-inflammatory properties, which could contribute to reduce the prevalence of asthma and allergic diseases., Objective: We investigated the association between asthma, and chronic rhino-sinusitis (CRS) with intake of fruits and vegetables in European adults., Methods: A stratified random sample was drawn from the Global Allergy and Asthma Network of Excellence (GA 2 LEN) screening survey, in which 55,000 adults aged 15-75 answered a questionnaire on respiratory symptoms. Asthma score (derived from self-reported asthma symptoms) and CRS were the outcomes of interest. Dietary intake of 22 subgroups of fruits and vegetables was ascertained using the internationally validated GA 2 LEN Food Frequency Questionnaire. Adjusted associations were examined with negative binomial and multiple regressions. Simes procedure was used to control for multiple testing., Results: A total of 3206 individuals had valid data on asthma and dietary exposures of interest. 22.8% reported having at least 1 asthma symptom (asthma score ≥1), whilst 19.5% had CRS. After adjustment for potential confounders, asthma score was negatively associated with intake of dried fruits (β-coefficient -2.34; 95% confidence interval [CI] -4.09, -0.59), whilst CRS was statistically negatively associated with total intake of fruits (OR 0.73; 95% CI 0.55, 0.97). Conversely, a positive association was observed between asthma score and alliums vegetables (adjusted β-coefficient 0.23; 95% CI 0.06, 0.40). None of these associations remained statistically significant after controlling for multiple testing., Conclusion and Clinical Relevance: There was no consistent evidence for an association of asthma or CRS with fruit and vegetable intake in this representative sample of European adults.

Background: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is an inflammatory disease associated with lymphoid aggregates and local IgE production related to Staphylococcus aureus enterotoxins. T-follicular helper cells and their effector cytokine interleukin (IL)-21 play an important role in germinal center proliferation., Methods: IL-21 was determined on the mRNA level by qPCR in nasal tissue of 3 groups of patients: control (n = 17), chronic rhinosinusitis without nasal polyposis (CRSsNP; n = 23), and CRSwNP (n = 35). The expression of IL-21 by CD4+ T cells was analyzed in tissue at baseline and after 24-h stimulation of tissue fragments with S. aureus enterotoxin B (SEB) using flow cytometry. Finally, human nasal IL-21+CXCR5+CD4+ T cells were isolated and coincubated with human blood naive B cells to investigate their functionality., Results: IL-21 mRNA expression was increased in the CRSwNP group (p < 0.05) compared to the control group, and B-cell lymphoma-6 and B-lymphocyte-induced maturation protein-1 were upregulated in CRSwNP versus CRSsNP. Furthermore, SEB was able to increase IL-21 mRNA expression significantly (p < 0.01) in nasal polyps. Flow cytometry revealed that the source of IL-21 was predominantly CD4+ T cells and that IL-21+CD4+ T cells were significantly increased in polyp tissue and further increased after SEB stimulation. Finally, tissue CXCR5+CD4+ T cells derived from nasal polyp tissue were able to induce maturation of human naive B cells., Conclusions: IL-21- and IL-21-producing CD4+ T cells were increased in CRSwNP. In addition, SEB induced an increase in IL-21 and IL-21+CD4+ T cells, suggesting that S. aureus can modulate the function of Tfh cells in nasal polyps. We speculate that T-follicular helper cells and IL-21 are important in the pathophysiology of CRSwNP., (© 2017 S. Karger AG, Basel.)

Background: Current phenotyping of chronic rhinosinusitis (CRS) into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP) might not adequately reflect the pathophysiologic diversity within patients with CRS., Objective: We sought to identify inflammatory endotypes of CRS. Therefore we aimed to cluster patients with CRS based solely on immune markers in a phenotype-free approach. Secondarily, we aimed to match clusters to phenotypes., Methods: In this multicenter case-control study patients with CRS and control subjects underwent surgery, and tissue was analyzed for IL-5, IFN-γ, IL-17A, TNF-α, IL-22, IL-1β, IL-6, IL-8, eosinophilic cationic protein, myeloperoxidase, TGF-β1, IgE, Staphylococcus aureus enterotoxin-specific IgE, and albumin. We used partition-based clustering., Results: Clustering of 173 cases resulted in 10 clusters, of which 4 clusters with low or undetectable IL-5, eosinophilic cationic protein, IgE, and albumin concentrations, and 6 clusters with high concentrations of those markers. The group of IL-5-negative clusters, 3 clusters clinically resembled a predominant chronic rhinosinusitis without nasal polyps (CRSsNP) phenotype without increased asthma prevalence, and 1 cluster had a TH17 profile and had mixed CRSsNP/CRSwNP. The IL-5-positive clusters were divided into a group with moderate IL-5 concentrations, a mixed CRSsNP/CRSwNP and increased asthma phenotype, and a group with high IL-5 levels, an almost exclusive nasal polyp phenotype with strongly increased asthma prevalence. In the latter group, 2 clusters demonstrated the highest concentrations of IgE and asthma prevalence, with all samples expressing Staphylococcus aureus enterotoxin-specific IgE., Conclusion: Distinct CRS clusters with diverse inflammatory mechanisms largely correlated with phenotypes and further differentiated them and provided a more accurate description of the inflammatory mechanisms involved than phenotype information only., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The majority of grass pollen-sensitized rhinitis patients develops allergic symptoms when exposed to the causal allergen and shows a positive nasal allergen provocation test (NAPT). Chronic rhinosinusitis with nasal polyposis (CRSwNP) patients, also characterized by eosinophilic inflammation and local IgE production, can suffer from comorbid inhalant allergy, but may show a different response to allergens., Objective: We aimed to explore the allergic response to grass pollen allergens by NAPT in grass pollen-sensitized CRSwNP patients., Methods: Twelve grass pollen-sensitized CRSwNP patients underwent NAPT with grass pollen and were compared with 12 grass pollen allergic rhinitis patients, 12 control patients and 12 CRSwNP patients without grass pollen sensitization. A positive NAPT was based on change in nasal airflow and symptoms. Further, VAS scores of different symptoms were noted before and after NAPT. Biomarkers such as total IgE, grass pollen-specific IgE and tryptase were measured in serum and nasal secretions., Results: NAPT was positive in 6 of 12 of the grass pollen-sensitized CRSwNP patients, and another four patients developed allergic symptoms not fulfilling the criteria of positivity. In contrast, all patients with allergic rhinitis developed a positive provocation test, whereas in the control group one of the patients and in the non-sensitized CRSwNP group two of the patients developed a positive provocation test., Conclusion and Clinical Relevance: These results show that allergen exposure induces an attenuated clinical response in patients with CRSwNP and sensitization to grass pollen as compared with grass pollen allergic rhinitis patients., (© 2015 John Wiley & Sons Ltd.)

Traumatic CSF leaks of the anterior skull base. Skull base fractures are a frequent complication of high-impact trauma; due to the inherent anatomic relationships of the skull base, they may be associated with significant intracranial complications, including CSF leakage, and their detection is therefore important. The ethmoid roof and the cribriform plate region are the sites most vulnerable to fractures and dural tears. Rhinorrhoea is a non-specific finding; the presence of CSF in a sample must be confirmed with beta 2 transferin or beta trace protein. Accurate identification of the leakage site is necessary for a successful surgical treatment. Various modalities are available for this purpose, such as CT scan and MRI. Persistent CSF rhinorrhoea necessitates surgical intervention, due to the risk of meningitis. Continued improvements in endoscopic reconstruction techniques have led to fewer open surgeries for repair. Smaller defects can be closed with fat gasket technique or free grafts, while larger defects necessitate a multilayer closure with local vascularized flaps. These techniques have shown consistently high success rates.

Immunoglobulin E (IgE) can be highly elevated in the airway mucosa independently of IgE serum levels and atopic status. Mostly, systemic markers are assessed to investigate inflammation in airway disease for research or clinical practice. A more accurate but more cumbersome approach to determine inflammation at the target organ would be to evaluate markers locally. We review evidence for local production of IgE in allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyps (CRSwNP). Diagnostic and therapeutic consequences in clinical practice are discussed. We describe that the airway mucosa has the intrinsic capability to produce IgE. Moreover, not only do IgE-positive B cells reside within the mucosa, but all tools are present locally for affinity maturation by somatic hypermutation (SHM), clonal expansion, and class switch recombination to IgE. Recognizing local IgE in the absence of systemic IgE has diagnostic and therapeutic consequences. Therefore, we emphasize the importance of local IgE in patients with a history of AR or CRSwNP.

Background: Surgery for chronic rhinosinusitis with nasal polyps (CRSwNPs) often fails because of recurrence of disease. So far, we do not know if specific cytokine profiles are linked to recurrence after functional endoscopic sinus surgery (FESS) or can predict recurrence. In this study we investigate the cytokine profile in CRSwNPs that underwent FESS for the first time and recurrent CRSwNPs., Methods: Tissue samples (n = 21) of CRSwNP patients with no recurrence after the first surgery were randomly selected out of 131 primary FESS surgeries and compared with tissue samples (n = 15) from patients who had a first and second surgery because of recurrence. Interleukin (IL)-1beta, IgE, specific IgE, IL-5, interferon (IFN) gamma, IL-6, IL-17, transforming growth factor (TGF) beta1, and myeloperoxidase were measured on tissue homogenates., Results: Levels of IgE, specific IgE to Staphylococcus aureus enterotoxin, eosinophilic cationic protein (ECP), and IL-5 were significantly increased in recurrent versus nonrecurrent CRSwNPs at the moment of the first surgery, whereas IL-17, IL-6, TGF-beta1,and IL-1beta did not show any significant difference. IFN-gamma protein levels were significantly higher in nonrecurrent CRSwNPs. The odds ratio for recurrence of CRSwNPs was reduced to 0.029, if IFN-gamma was present in tissue homogenates. Asthma and aspirin intolerance were significantly more frequent in the recurrent CRSwNPs compared with nonrecurrent CRSwNPs., Discussion: Nonrecurrent and recurrent CRSwNPs needing revision surgery have different types of inflammatory patterns. Nonrecurrent CRSwNPs exhibits a mixed pattern of T helper (Th) cytokines with significant higher levels of IFN-gamma and lower concentrations of IgE, ECP, and IL-5 as compared with recurrent CRSwNPs that had a predominant Th2 type of inflammation.

Background: Inflammatory patterns of nasal polyps (NPs) may vary. Changes over time have not been investigated so far. This study was designed to evaluate the inflammatory patterns of NPs in Thailand at two time points 12 years apart, explore differences in Staphylococcus aureus (SA) mucosal carriage rates over time, and the latter's relationship with the inflammatory patterns., Methods: Formalin-fixed nasal tissue was obtained from 89 (47 in 1999 and 42 in 2011) patients suffering from chronic rhinosinusitis with NPs (CRSwNPs). Tissues were evaluated for eosinophils, neutrophils, IgE(+) cells, IgE and macrophage mannose receptors, interleukin (IL)-5 and IL-17 cytokine profile, and the presence of SA, using automated immunohistochemistry and peptide nucleic acid-fluorescence in situ hybridization., Results: We found a significant increase in the absolute values of eosinophils and IgE(+) cells in the 2011 CRSwNP tissue series compared with 1999 and a significant but smaller increase in neutrophils. Semiquantitative evaluation revealed significantly higher mean values of positive cells for all studied inflammatory markers in the 2011 group of patients, except for the high-affinity IgE receptor. This "eosinophilic shift" of inflammation was accompanied by higher SA carriage, as well as higher frequencies of SA invasion (54.8% versus 10.6%; p < 0.001) in the 2011 compared with 1999 subjects. Patients with asthma were more likely to have higher SA carriage rates compared with nonasthmatic patients., Conclusion: There was a shift from predominantly neutrophilic to eosinophilic CRSwNPs in Thai patients within 12 years, with an increase in various inflammatory markers including IgE, which is associated with an increase in intramucosal presence of SA.

Transclival meningoceles and primary spontaneous cerebrospinal fluid (CSF) leaks at the clivus are extremely rare lesions and only few of them have been reported in the literature. We report here six cases of transclival primary spontaneous CSF leaks through the clivus. A retrospective case study was performed. We reviewed six cases involving sinonasal CSF leaks located at the clivus treated between 1997 and 2009. Presenting symptoms, duration of symptoms, defect size, site of defect, surgical approach and technique of defect closure, intraoperative complications, postoperative complications, and recurrences are discussed. All CSF leaks were located in the upper central part of the clivus. two of six patients showed signs of increased intracranial pressure (ICP) including arachnoid pits and/or empty sella. For three patients a purely transnasal approach was used with multilayer reconstruction using a nonvascularized graft, and three patients underwent a transnasal transseptal approach with a multilayer reconstruction, with nasoseptal flap. No recurrences of CSF leaks at clivus or other sites were observed to date with a mean follow-up of 10.3 years (range, 3-15 years). Spontaneous CSF rhinorrhea located at the clivus is an extremely rare condition. To date, only eight cases have been described. Here, we report the largest group of six consecutive cases. Irrespective of the used reconstruction technique in all cases a 100% closure rate was achieved. However, identification of increased ICP is an essential aspect and this condition should be treated either medically or surgically.

This review is addressed two pathophysiologic mechanisms implicated in the pathogenesis of nasal polyposis: the unique remodeling process found in nasal polyp tissue and the immune response of patients with nasal polyposis to Staphylococcus aureus. These two theories converge to the same direction in different aspects, including decreased extracellular matrix production, impaired T regulation and favoring of a Th2 immune response.In patients with nasal polyposis, an exaggerated immune response to Staphylococcus aureus may aggravate the airway remodeling process.

Background: Adult patients with nasal polyps often have comorbid asthma, adding to the serious effect on the quality of life of these patients. Nasal polyps and asthma might represent a therapeutic challenge; inflammation in both diseases shares many features, such as airway eosinophilia, local IgE formation, and a T(H)2 cytokine profile. Omalizumab is a human anti-IgE mAb with proved efficacy in patients with severe allergic asthma. Omalizumab could be a treatment option for patients with nasal polyps and asthma., Objective: The goal of this study was to investigate the clinical efficacy of omalizumab in patients with nasal polyps and comorbid asthma., Methods: A randomized, double-blind, placebo-controlled study of allergic and nonallergic patients with nasal polyps and comorbid asthma (n = 24) was conducted. Subjects received 4 to 8 (subcutaneous) doses of omalizumab (n = 16) or placebo (n = 8). The primary end point was reduction in total nasal endoscopic polyp scores after 16 weeks. Secondary end points included a change in sinus computed tomographic scans, nasal and asthma symptoms, results of validated questionnaires (Short-Form Health Questionnaire, 31-item Rhinosinusitis Outcome Measuring Instrument, and Asthma Quality of Life Questionnaire), and serum/nasal secretion biomarker levels., Results: There was a significant decrease in total nasal endoscopic polyp scores after 16 weeks in the omalizumab-treated group (-2.67, P = .001), which was confirmed by means of computed tomographic scanning (Lund-Mackay score). Omalizumab had a beneficial effect on airway symptoms (nasal congestion, anterior rhinorrhea, loss of sense of smell, wheezing, and dyspnea) and on quality-of-life scores, irrespective of the presence of allergy., Conclusion: Omalizumab demonstrated clinical efficacy in the treatment of nasal polyps with comorbid asthma, supporting the importance and functionality of local IgE formation in the airways., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Chronic rhinosinusitis (CRS) has now been discovered as a frequent disease affecting about 11% of the European population. In clinical terms, CRS may be differentiated in two phenotypes, CRS with and without nasal polyps. This differentiation is also confirmed by immunohistochemical studies on the remodeling pattern of those diseases, identifying TGF-ß as the key regulator. Further differentiation may be based on the inflammatory patterns, differentiating endotypes based on prominent T helper cell cytokines such as interleukin-5 and the presence of IgE antibodies against Staphylococcus aureus enterotoxins. The importance of those endotypes has been confirmed by innovative studies using humanized antibodies applied to nasal polyp disease, and by their predictive value for asthma comorbidity. Biomarkers may thus be needed to fully appreciate the CRS disease spectrum and its link to asthma., (© 2012 John Wiley & Sons A/S.)

Chronic Rhinosinusitis (CRS), a chronic upper airway inflammation, is an inflammation of the nose and the paranasal cavities and is highly prevalent. Chronic rhinosinusitis is currently classified as CRS with nasal polyps or CRS without nasal polyps. This review highlights the pathophysiological differences in CRS on remodeling and on T-cell patterns. Nasal polyps have a high co-morbidity with the lower airway inflammatory disease, asthma. Evidence is accumulating for the role of superantigens, Staphylococcus aureus enterotoxins, in CRS with nasal polyps and asthma, both T helper 2 -biased diseases. Until today there are no biomarkers involved in the diagnosis of CRS or the treatment follow-up. Further differentiation of the phenotype of the disease is needed, which will reflect in the development of new biomarkers and in new innovative treatment options. Defining and predicting response to therapy in individual CRS patients is a challenge for future research.

Background: Approximately 85% of nasal polyps (NPs) in white subjects are characterized by prominent eosinophilia. IL-5 is the key driver of eosinophilic differentiation and survival., Objective: We sought to investigate the therapeutic potential of inhibiting IL-5 with a humanized mAb as treatment for severe nasal polyposis., Methods: Thirty patients with severe nasal polyposis (grade 3 or 4 or recurrent after surgery) refractory to corticosteroid therapy were randomized in a double-blind fashion to receive either 2 single intravenous injections (28 days apart) of 750 mg of mepolizumab (n = 20) or placebo (n = 10). Change from baseline in NP score was assessed monthly until 1 month after the last dose (week 8). Computed tomographic scans were also performed at week 8., Results: Twelve of 20 patients receiving mepolizumab had a significantly improved NP score and computed tomographic scan score compared with 1 of 10 patients receiving placebo at week 8 versus baseline., Conclusion: Mepolizumab achieved a statistically significant reduction in NP size for at least 1 month after dosing in 12 of 20 patients. IL-5 inhibition is a potential novel therapeutic approach in patients with severe eosinophilic nasal polyposis., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Rhinosinusitis (RS) is a heterogeneous group of diseases. It is a significant and increasing health problem that affects about 15% of the population in Western countries. It has a substantial impact on patients' health-related quality of life and daily functioning and represents a huge financial burden to society and the health care system as a result of the direct and indirect costs. In addition, RS is not well-understood, and little is known about the etiology and pathophysiology. In the past decade, many papers have been published that have changed our understanding of RS. RS is commonly classified into acute and chronic RS based on symptom duration. In acute RS, an inflammatory reaction initiated by a viral infection characterizes most uncomplicated, mild to moderate cases. Therefore, the first line of treatment for these cases are intranasal steroids and not antibiotics. In severe and complicated cases, antibiotics combined with topical steroids remain the treatment of choice. On the other hand, chronic RS is actually subdivided into two distinct entities (chronic rhinosinusitis with and without polyps), as growing evidence indicates that these entities have specific inflammatory pathways and cytokine profiles. The authors review recent data regarding the clinical presentations, cytokine profiles, tissue remodeling, and modalities of treatment for each form of RS.