Validation and shortcomings of the most common mouse model of chronic rhinosinusitis with nasal polyps

BACKGROUND: Chronic rhinosinusitis (CRS) is a highly prevalent airway disease worldwide. Whereas eosinophilic CRS with nasal polyps (eCRSwNP) represents its most severe phenotype, pathogenic mechanisms remain poorly understood despite a wide spectrum of in vitro and in vivo experimental models. A mouse model of experimental ovalbumin (OVA)-induced airway allergy with coadministration of Staphylococcus aureus enterotoxin B (SEB) has been widely used to study eosinophilic eCRSwNP. This study revisits the features of this model and its suitability for studying eCRS. METHODOLOGY: We implemented the most used eCRSwNP mouse model based on OVA+SEB intranasal challenges. Readouts including inflammatory features by (immuno)histology of the sinonasal epithelium (NP formation, eosinophils, epithelial and basement membrane thickness, fibrosis, goblet cells, Charcot-Leyden crystals (CLC)-like, tight junctions) and IgE production by enzyme-linked immunosorbent assay (ELISA), were compared to features of the corresponding human disease. RESULTS: The OVA+SEB model induced eosinophilic inflammation of upper and lower airways, with epithelial and basement membrane thickening, goblet cell hyperplasia and subepithelial fibrosis in the sinuses, along increased IgE production. Except local IgE in nasal lavage (NL), which was only increased in OVA+SEB group, all other features did not differ between OVA and OVA+SEB groups. Macro- or microscopic NP were not detected. CONCLUSIONS: With the notable exception of local IgE production, the addition of SEB did not induce additional inflammatory or structural change in the sinuses from mice exposed to and challenged with OVA. This model might represent a model for severe upper airway allergy rather than a specific model of human eCRSwNP.

EPOS2020/EUFOREA expert opinion on defining disease states and therapeutic goals in CRSwNP.

Severe chronic rhinosinusitis with nasal polyps (CRSwNP), a form of diffuse bilateral (usually type 2) CRS, is a debilitating disease with a significant impact on quality of life (QoL). With novel knowledge and treatment options becoming available, there is a growing need to update or revise key definitions to enable communication across different specialties dealing with CRS, and to agree on novel goals of care in CRSwNP. The European Forum for Research and Education in Allergy and Airway diseases (EUFOREA) and EPOS expert members discussed how to measure treatment responses and set new treatment goals for CRSwNP. In this paper a consensus on a list of definitions related to CRSwNP is provided: control, remission, cure, recurrence/exacerbation, treatable traits, remodeling, progression, and disease modification. By providing these definitions, the involved experts hope to improve communication between all stakeholders involved in CRSwNP treatment for use in routine care, basic and clinical research and international guidelines aimed to harmonize and optimize standard of care of patients with CRSwNP in the future.

Occupational exposure influences control of disease in patients with chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is a frequent condition that is treated by endoscopic sinus surgery (ESS) when medical treatment fails. Irritating or sensitizing airborne agents can contribute to uncontrolled CRS. A prior study showed a linear correlation between occupational exposure and the number of ESS. METHODS: In this cross-sectional study we tested the hypothesis that occupational exposure is a risk for undergoing ESS. We sent questionnaires enquiring occupational exposure in patients with CRS with nasal polyps (CRSwNP) or CRS without nasal polyps (CRSsNP). An expert assessed blindly the reported work exposures to inhaled agents. The relationship between occupational exposure on undergoing ESS was analysed. RESULTS: Among all patients who underwent ESS (n=343), 30% reported a relevant occupational exposure, which is significantly higher than the 4.8% found among CRS patients that underwent no prior sinus surgery (n=21). Besides occupational exposure, self-reported doctor-diagnosed asthma were independent variables contributing to the chance of undergoing ESS. CONCLUSION: In our study we confirm occupational exposure as a risk factor for uncontrolled CRS, if defined by undergoing ESS. In CRS patients with uncontrolled symptoms, despite maximal conservative therapy, the clinician should explore the possible contribution of occupational exposure.

EPOS 4 Patients.

EPOS2020 is the 4th and most recent version of the European Position Paper on Rhinosinusitis and Nasal Polyps which was first published in 2005. It aims to provide the most up to date scientifically robust information on the topic published in the literature which has been critically analysed by an international group of clinicians drawn from all disciplines dealing with these problems together with patients. The guidelines offer evidence-based recommendations and care pathways for acute and chronic rhinosinusitis in both adults and children. Management of these diseases from the patients' perspective is an important part of EPOS2020. Not only is this included in the main document but, for the first time, we have produced a separate supplement dedicated to and in collaboration with patients, EPOS4Patients, which aims to provide information in an accessible format, to answer frequently asked questions about these diseases and their treatment options as well as including useful patient resources and websites. It has never been more important for patients to be actively involved in their care. Being well informed helps you to make the best decisions together with your doctor.

Personal protection and delivery of rhinologic and endoscopic skull base procedures during the COVID-19 outbreak.

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.

Development of a new psychophysical method to assess intranasal trigeminal chemosensory function.

BACKGROUND: The aim of this study was to develop a new psychophysical test to assess intranasal trigeminal chemosensory function. METHODOLOGY: The test is similar to the Sniffin’ Sticks test, but using pens impregnated with substances preferentially activating trigeminal afferents. Our test comprises detection threshold, discrimination, identification and lateralization tasks. In a first study, we evaluated healthy controls. In a second study, we evaluated the potential usefulness of this test in patients with rhinological conditions. RESULTS: Study 1: 86 controls were included. Threshold, identification and lateralization performance decreased with age. Test-retest reliability was similar to that of olfactory tests. Study 2: results of the controls group were compared to those of 59 patients (14 allergic rhinitis, 11 chronic rhinosinusitis with nasal polyps (CRSwNP), 9 without nasal polyps (CRSsNP), and 25 with an olfactory disorder (OD)). Controls had 1) lower detection thresholds compared to CRSwNP, CRSsNP and OD, 2) better discrimination and identification scores compared to OD, and 3) better lateralization scores compared to CRSwNP and CRSsNP. CONCLUSIONS: Our test allows to identify age-related changes in trigeminal chemosensory function. Trigeminal function seems to be differently affected in different pathologies. Further studies are necessary to validate our results and evaluate the impact of olfactory co-activation on the observed results.

The Global Allergy and Asthma European Network (GALEN rhinosinusitis cohort: a large European cross-sectional study of chronic rhinosinusitis patients with and without nasal polyps.

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.

The GALEN rhinosinusitis cohort: chronic rhinosinusitis with nasal polyps affects health-related quality of life.

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.

EAACI Position paper on the standardization of nasal allergen challenges.

Nasal allergen challenge (NAC) is an important tool to diagnose allergic rhinitis. In daily clinical routine, experimentally, or when measuring therapeutic success clinically, nasal allergen challenge is fundamental. It is further one of the key diagnostic tools when initiating specific allergen immunotherapy. So far, national recommendations offered guidance on its execution; however, international divergence left many questions unanswered. These differences in the literature caused EAACI to initiate a task force to answer unmet needs and find a consensus in executing nasal allergen challenge. On the basis of a systematic review containing nasal allergen challenges of the past years, task force members reviewed evidence, discussed open issues, and studied variations of several subjective and objective assessment parameters to propose a standardized way of a nasal allergen challenge procedure in clinical practice. Besides an update on indications, contraindications, and preparations for the test procedure, main recommendations are a bilaterally challenge with standardized allergens, with a spray device offering 0.1 mL per nostril. A systematic catalogue for positivity criteria is given for the variety of established subjective and objective assessment methods as well as a schedule for the challenge procedure. The task force recommends a unified protocol for NAC for daily clinical practice, aiming at eliminating the previous difficulty of comparing NAC results due to unmet needs.

Nasal symptoms, epithelial injury and neurogenic inflammation in elite swimmers.

BACKGROUND: A high burden of lower airway symptoms is found in elite swimmers. To what extent elite swimmers suffer from upper airway symptoms and how these associate with nasal inflammation is less clear. We here aimed to evaluate upper airway symptoms and nasal inflammation in elite athletes. METHODOLOGY: Elite swimmers, indoor athletes and age-matched controls were recruited. Upper airway symptoms were assessed by sino-nasal outcome test (SNOT)-22 questionnaire. Visual Analogue score (VAS) for nasal symptoms as well as neurogenic and inflammatory mediators in nasal fluid were assessed at baseline, immediately and 24-hours after sport-specific training. The effect of hypochlorite on nasal epithelial cells was evaluated in vitro. RESULTS: Baseline SNOT-22 and VAS for nasal itch and impaired smell were significantly higher in swimmers compared to controls. Nasal substance P and uric acid levels were increased in elite swimmers 24-hours after swimming compared to baseline. In elite swimmers, uric acid levels 24-hours post-exercise correlated with baseline SNOT-22. As increased symptoms and inflammation were found in swimmers but not in indoor athletes, we hypothesized that hypochlorite exposure might be the underlying mechanism. In vitro, the highest dose of hypochlorite decreased nasal epithelial cell integrity and induced release of uric acid. CONCLUSION: Upper airway symptoms are frequently reported in elite swimmers. Intensive swimming resulted in a delayed increase of epithelial injury and neurogenic inflammation.

mySinusitisCoach: patient empowerment in chronic rhinosinusitis using mobile technology.

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.

Non-allergic rhinitis: Position paper of the European Academy of Allergy and Clinical Immunology.

This EAACI position paper aims at providing a state-of-the-art overview on nonallergic rhinitis (NAR). A significant number of patients suffering from persistent rhinitis are defined as nonallergic noninfectious rhinitis (NANIR) patients, often denominated in short as having NAR. NAR is defined as a symptomatic inflammation of the nasal mucosa with the presence of a minimum of two nasal symptoms such as nasal obstruction, rhinorrhea, sneezing, and/or itchy nose, without clinical evidence of endonasal infection and without systemic signs of sensitization to inhalant allergens. Symptoms of NAR may have a wide range of severity and be either continuously present and/or induced by exposure to unspecific triggers, also called nasal hyperresponsiveness (NHR). NHR represents a clinical feature of both AR and NAR patients. NAR involves different subgroups: drug-induced rhinitis, (nonallergic) occupational rhinitis, hormonal rhinitis (including pregnancy rhinitis), gustatory rhinitis, senile rhinitis, and idiopathic rhinitis (IR). NAR should be distinguished from those rhinitis patients with an allergic reaction confined to the nasal mucosa, also called "entopy" or local allergic rhinitis (LAR). We here provide an overview of the current consensus on phenotypes of NAR, recommendations for diagnosis, a treatment algorithm, and defining the unmet needs in this neglected area of research.

EUFOREA Rhinology Research Forum 2016: report of the brainstorming sessions on needs and priorities in rhinitis and rhinosinusitis.

The first European Rhinology Research Forum organized by the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) was held in the Royal Academy of Medicine in Brussels on 17th and 18th November 2016, in collaboration with the European Rhinologic Society (ERS) and the Global Allergy and Asthma European Network (GA2LEN). One hundred and thirty participants (medical doctors from different specialties, researchers, as well as patients and industry representatives) from 27 countries took part in the multiple perspective discussions including brainstorming sessions on care pathways and research needs in rhinitis and rhinosinusitis. The debates started with an overview of the current state of the art, including weaknesses and strengths of the current practices, followed by the identification of essential research needs, thoroughly integrated in the context of Precision Medicine (PM), with personalized care, prediction of success of treatment, participation of the patient and prevention of disease as key principles for improving current clinical practices. This report provides a concise summary of the outcomes of the brainstorming sessions of the European Rhinology Research Forum 2016.

A chest physician's guide to mechanisms of sinonasal disease.

The upper and lower airways are closely linked from an anatomical, histological and immunological point of view, with inflammation in one part of the airways influencing the other part. Despite the concept of global airway disease, the upper airways tend to be overlooked by respiratory physicians. We provide a clinical overview of the most important and recent insights in rhinitis and rhinosinusitis in relation to lower airway disease. We focus on the various exogenous and endogenous factors that play a role in the development and aggravation of chronic upper airway inflammation. In addition to the classical inhaled allergens or microorganisms with well-defined pathophysiological mechanisms in upper airway disease, environmental substances such as cigarette smoke, diesel exhaust particles and occupational agents affecting lower airway homeostasis have recently gained attention in upper airway research. We are only at the beginning of understanding the complex interplay between exogenous and endogenous factors like genetic, immunological and hormonal influences on chronic upper airway inflammation. From a clinical perspective, the involvement of upper and lower airway disease in one patient can only be fully appreciated by doctors capable of understanding the interplay between upper and lower airway inflammation.

Damage-associated molecular pattern and innate cytokine release in the airways of competitive swimmers.

BACKGROUND: Daily intensive exercise by elite athletes can result in exercise-induced asthma especially in elite swimmers and this may be linked to epithelial damage. OBJECTIVE: To study airway epithelial damage and release of damage-associated molecular patterns (DAMPs) after intensive exercise in elite athletes and controls. METHODS: We recruited competitive swimmers (n = 26), competitive indoor athletes (n = 13) and controls (n = 15) without any history of asthma. Lung function was measured before, immediately after and 24 h after a 90-min intensive exercise protocol. Sputum induction was performed at baseline and 24 h after exercise. Exercise-induced bronchoconstriction (EIB) was assessed by the eucapnic voluntary hyperventilation test. RESULTS: Baseline sputum uric acid, high mobility group box-1, CXCL8 mRNA, sputum neutrophils and serum Clara cell protein-16 (CC-16) were significantly higher in competitive swimmers compared with controls. Intensive swimming for 90 min resulted in an increase of sputum IL-1ß, IL-6 and TNF mRNA in competitive swimmers, and of sputum IL-6 mRNA and sputum neutrophils in controls. Although all participants were asymptomatic, seven competitive swimmers, one indoor athlete and one control met the criteria for EIB. CONCLUSION: Our findings show that the intensive training combined with exposure to by-products of chlorination induces airway epithelial damage in competitive swimmers. This is associated with increased damage-associated molecular patterns, innate cytokine release and neutrophilic airway inflammation.

Occupational upper airway disease: how work affects the nose.

Chronic inflammation of the upper airways is common and can arbitrarily be divided into rhinitis and rhinosinusitis. Infection and allergy represent two well-characterized and most frequently diagnosed etiologies of upper airway inflammation. Persistent upper airway inflammation caused by agents inhaled in the work environment represents a diagnostic challenge in clinical practice, and its pathophysiology has been little studied. Occupational rhinitis is a recognized medical condition with diagnostic and therapeutic guidelines. In contrast, only limited evidence is available about the relationship between work exposures and rhinosinusitis. This review aims at providing a comprehensive overview of the available literature on occupational upper airway disease with a focus on pathophysiological mechanisms and with an emphasis on the current unmet needs in work-related upper airway disease.

Vascular endothelial growth factor receptor 1 expression in nasal polyp tissue.

BACKGROUND: Edema represents a key feature of nasal polyp (NP) disease. Members of the vascular endothelial growth factor (VEGF) family may be involved, but the precise role of VEGF-A, VEGF-B, placental growth factor (PlGF), and their receptors VEGFR1 and VEGFR2 in NP edema formation remains elusive. OBJECTIVE: Exploring the expression of VEGF family members and their receptors and their correlation with clinical, radiological, and edema markers in NP. METHODS: The expression of VEGF-A, VEGF-B, PlGF, VEGFR1, and VEGFR2 was measured in NP (n = 23) and control tissue (n = 22) at mRNA and protein level. Edema was evaluated by measuring albumin levels and wet/dry ratios. Computed tomography (CT) scans were scored using the Lund-Mackay scoring system. IL-5 mRNA expression was determined by real-time RT-PCR. Cell suspensions from NP (n = 10) and control tissue (n = 12) were stimulated in vitro with IL-1ß or TNFα. RESULTS: mRNA expression of VEGFR1 and VEGF-B was significantly higher in NP compared with control tissue. Expression levels of VEGF-B and VEGFR1 significantly correlated with NP albumin content (VEGF-B: P = 0.0208; VEGFR1: P = 0.0293), CT scan scores (VEGF-B: P = 0.0075; VEGFR1: P = 0.0068), and IL-5 mRNA (VEGF-B: P = 0.0027; VEGFR1: P = 0.0001). In vitro stimulation of control and NP tissue cell suspensions with IL-1ß or TNFα significantly reduced the expression of VEGFR2 in control tissue, without altering VEGFR1 and VEGF-B expression. hVEGF-B induced nitric oxide production in NP macrophages (P < 0.05). CONCLUSION: Expression levels of VEGFR1 and VEGF-B correlate with edema and clinical markers of NP disease and therefore represent potential therapeutic targets.

Uncontrolled allergic rhinitis and chronic rhinosinusitis: where do we stand today?

State-of-the-art documents like ARIA and EPOS provide clinicians with evidence-based treatment algorithms for allergic rhinitis (AR) and chronic rhinosinusitis (CRS), respectively. The currently available medications can alleviate symptoms associated with AR and RS. In real life, a significant percentage of patients with AR and CRS continue to experience bothersome symptoms despite adequate treatment. This group with so-called severe chronic upper airway disease (SCUAD) represents a therapeutic challenge. The concept of control of disease has only recently been introduced in the field of AR and CRS. In case of poor control of symptoms despite guideline-directed pharmacotherapy, one needs to consider the presence of SCUAD but also treatment-related, diagnosis-related and/or patient-related factors. Treatment-related issues of uncontrolled upper airway disease are linked with the correct choice of treatment and route of administration, symptom-oriented treatment and the evaluation of the need for immunotherapy in allergic patients. The diagnosis of AR and CRS should be reconsidered in case of uncontrolled disease, excluding concomitant anatomic nasal deformities, global airway dysfunction and systemic diseases. Patient-related issues responsible for the lack of control in chronic upper airway inflammation are often but not always linked with adherence to the prescribed medication and education. This review is an initiative taken by the ENT section of the EAACI in conjunction with ARIA and EPOS experts who felt the need to provide a comprehensive overview of the current state of the art of control in upper airway inflammation and stressing the unmet needs in this domain.

Negative impact of occupational exposure on surgical outcome in patients with rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is a frequent condition that is treated by functional endoscopic sinus surgery (FESS) when medical treatment fails. Endogenous as well as exogenous factors may be responsible for persisting symptoms after FESS. The role of occupational exposures on success of FESS has never been investigated. METHODS: In this case-control study, we tested the hypothesis that the outcome of FESS procedures is related to exposures at work. Questionnaires were sent to 890 patients who had undergone one or more FESS procedures and to 182 controls. Three independent experts assessed blindly the reported work exposures to inhaled agents. The relationship between exposure and the number of FESS procedures was analyzed. RESULTS: Relevant occupational exposure was reported by 25% of all responding patients undergoing FESS (n = 467) and 12% of controls (n = 69). The prevalence of occupational exposures increased linearly with the number of FESS procedures from 21% in those who had one FESS to 44% in those who had four or more FESS (χ(2)  = 12.74, P < 0.001). Logistic regression analysis with adjustments for potential confounders, including smoking, atopy, and asthma, confirmed that the odds ratio (OR) for reporting occupational exposures was significantly higher in those needing more than one FESS (OR = 1.64) or more than two FESS (OR = 1.97). These results were mainly driven by exposure to low molecular weight agents. CONCLUSION: Exposure at work appears to be a risk factor for the occurrence of CRS and for its recurrence or persistence, as evidenced by the need for revision surgery.