European Position Paper on Rhinosinusitis and Nasal Polyps 2020.

The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.

EPOS2020: development strategy and goals for the latest European Position Paper on Rhinosinusitis.

BACKGROUND: The European Position Papers on Rhinosinusitis from 2005, 2007 and 2012 have had a measurable impact on the way this common condition with high impact on quality of life is managed around the world. EPOS2020 will be the latest iteration of the guideline, addressing new stakeholders and target users, presenting a summary of the latest literature and evolving treatment modalities, and formulating clear recommendations based on all available evidence. METHODOLOGY: Based on the AGREE II framework, this article demonstrates how the EPOS2020 steering group will address six key areas to ensure consistency in quality and presentation of information in the latest rhinosinusitis clinical practice guideline: scope and purpose; stakeholder involvement; rigour of development; clarity of presentation; recommendations and applicability; editorial independence. RESULTS: By analysing the guidance from AGREE II, we formulated a detailed development strategy for EPOS2020. We identify new stakeholders and target users and ratify the importance of patient involvement in the latest EPOS guideline. New and expanded areas of research to be addressed are highlighted. We confirm our intention to use mixed methodologies, combining evidence-based medicine with real life studies; when no evidence can be found, use Delphi rounds to achieve clear, inclusive recommendations. We also introduce new concepts for dissemination of the guideline, using Internet and social media to improve accessibility. CONCLUSION: This article is an introduction to the EPOS2020 project, and presents the key goals, core stakeholders, planned methodology and dissemination strategies for the latest version of this influential guideline.

Evolution of the IgE and IgG repertoire to a comprehensive array of allergen molecules in the first decade of life.

BACKGROUND: In early childhood, the allergen-specific IgG repertoire is mainly directed to animal and vegetable food molecules and infrequently to airborne molecules. It is unknown whether this early pattern is maintained throughout childhood. OBJECTIVE: To investigate the evolution of IgG and IgE responses to a broad panel of allergenic molecules from birth to age 10 years. METHODS: We examined the sera collected between birth and age 10 years from participants in the German Multicentre Allergy Study, a birth cohort born in 1990. The IgE (cutoff ≥0.30 ISU) and IgG (cutoff ≥0.10 ISU) responses to 35 genuine allergenic molecules were measured with a multiplex microarray approach (ImmunoCAP ISAC™). RESULTS: IgE responses were mostly directed against a restricted group of airborne molecules, with a sequence and prevalence hierarchy (Phl p 1> Bet v 1> Fel d 1> Phl p 5> Der p 2> Der p 1) largely maintained over time. Conversely, the IgG repertoire was much broader, starting with animal foodborne, then spreading to vegetable foodborne and finally to airborne molecules. A strong and persistent IgG response to a given airborne molecule almost invariably preceded or accompanied an IgE response to that molecule. CONCLUSIONS: The evolution of IgG and IgE responses throughout childhood differs widely at population level. IgG responses are mostly directed to animal food allergens, while IgE responses are dominated by airborne allergens. However, a strong IgG response almost invariably precedes or accompanies the appearance of IgE to the same molecule in specifically sensitized subjects.

Diagnostic relevance of IgE sensitization profiles to eight recombinant Phleum pratense molecules.

BACKGROUND: Grass pollen-related seasonal allergic rhinoconjunctivitis (SARg) is clinically heterogeneous in severity, comorbidities, and response to treatment. The component-resolved diagnostics disclosed also a high heterogeneity at molecular level. Our study aimed at analyzing the characteristics of the IgE sensitization to Phleum pratense molecules and investigating the diagnostic relevance of such molecules in childhood. METHODS: We examined 1120 children (age 4-18 years) with SARg. Standardized questionnaires on atopy were acquired through informatics platform (AllergyCARD™). Skin prick tests were performed with pollen extracts. Serum IgE to airborne allergens and eight P. pratense molecules (rPhl p 1, rPhl p 2, rPhl p 4, rPhl p 5b, rPhl p 6, rPhl p 7, rPhl p 11, rPhl p 12) were tested by ImmunoCAP FEIA. RESULTS: The analysis of IgE responses against eight P. pratense molecules showed 87 profiles. According to the number of molecules recognized by IgE, the more complex profiles were characterized by higher serum total IgE, higher grass-specific serum IgE, and higher number and degree of sensitization to pollens. The most frequent IgE sensitization profile was the monomolecular Phl p 1. Sensitization to Phl p 7 was a reliable biomarker of asthma, whereas Phl p 12 of oral allergy syndrome. Sensitization to Phl p 7 was associated with a higher severity of SARg, and complex profiles were associated with longer disease duration. CONCLUSIONS: In a large pediatric population, the complexity of IgE sensitization profiles against P. pratense molecules is related to high atopic features although useless for predicting the clinical severity. The detection of serum IgE to Phl p 1, Phl p 7, and Phl p 12 can be used as clinical biomarkers of SARg and comorbidities. Further studies in different areas are required to test the impact of different IgE molecular profiles on AIT response.

Endotypes of pollen-food syndrome in children with seasonal allergic rhinoconjunctivitis: a molecular classification.

BACKGROUND: Pollen-food syndrome (PFS) is heterogeneous with regard to triggers, severity, natural history, comorbidities, and response to treatment. Our study aimed to classify different endotypes of PFS based on IgE sensitization to panallergens. METHODS: We examined 1271 Italian children (age 4-18 years) with seasonal allergic rhinoconjunctivitis (SAR). Foods triggering PFS were acquired by questionnaire. Skin prick tests were performed with commercial pollen extracts. IgE to panallergens Phl p 12 (profilin), Bet v 1 (PR-10), and Pru p 3 (nsLTP) were tested by ImmunoCAP FEIA. An unsupervised hierarchical agglomerative clustering method was applied within PFS population. RESULTS: PFS was observed in 300/1271 children (24%). Cluster analysis identified five PFS endotypes linked to panallergen IgE sensitization: (i) cosensitization to ≥2 panallergens ('multi-panallergen PFS'); (ii-iv) sensitization to either profilin, or nsLTP, or PR-10 ('mono-panallergen PFS'); (v) no sensitization to panallergens ('no-panallergen PFS'). These endotypes showed peculiar characteristics: (i) 'multi-panallergen PFS': severe disease with frequent allergic comorbidities and multiple offending foods; (ii) 'profilin PFS': oral allergy syndrome (OAS) triggered by Cucurbitaceae; (iii) 'LTP PFS': living in Southern Italy, OAS triggered by hazelnut and peanut; (iv) 'PR-10 PFS': OAS triggered by Rosaceae; and (v) 'no-panallergen PFS': mild disease and OAS triggered by kiwifruit. CONCLUSIONS: In a Mediterranean country characterized by multiple pollen exposures, PFS is a complex and frequent complication of childhood SAR, with five distinct endotypes marked by peculiar profiles of IgE sensitization to panallergens. Prospective studies in cohorts of patients with PFS are now required to test whether this novel classification may be useful for diagnostic and therapeutic purposes in the clinical practice.

EAACI Molecular Allergology User's Guide.

The availability of allergen molecules ('components') from several protein families has advanced our understanding of immunoglobulin E (IgE)-mediated responses and enabled 'component-resolved diagnosis' (CRD). The European Academy of Allergy and Clinical Immunology (EAACI) Molecular Allergology User's Guide (MAUG) provides comprehensive information on important allergens and describes the diagnostic options using CRD. Part A of the EAACI MAUG introduces allergen molecules, families, composition of extracts, databases, and diagnostic IgE, skin, and basophil tests. Singleplex and multiplex IgE assays with components improve both sensitivity for low-abundance allergens and analytical specificity; IgE to individual allergens can yield information on clinical risks and distinguish cross-reactivity from true primary sensitization. Part B discusses the clinical and molecular aspects of IgE-mediated allergies to foods (including nuts, seeds, legumes, fruits, vegetables, cereal grains, milk, egg, meat, fish, and shellfish), inhalants (pollen, mold spores, mites, and animal dander), and Hymenoptera venom. Diagnostic algorithms and short case histories provide useful information for the clinical workup of allergic individuals targeted for CRD. Part C covers protein families containing ubiquitous, highly cross-reactive panallergens from plant (lipid transfer proteins, polcalcins, PR-10, profilins) and animal sources (lipocalins, parvalbumins, serum albumins, tropomyosins) and explains their diagnostic and clinical utility. Part D lists 100 important allergen molecules. In conclusion, IgE-mediated reactions and allergic diseases, including allergic rhinoconjunctivitis, asthma, food reactions, and insect sting reactions, are discussed from a novel molecular perspective. The EAACI MAUG documents the rapid progression of molecular allergology from basic research to its integration into clinical practice, a quantum leap in the management of allergic patients.

Diagnostic test allergens used for in vivo diagnosis of allergic diseases are at risk: a European Perspective.

In the European Union (EU), allergens used for diagnostic tests (TAs) are defined as medicinal products and have to be registered by national authorities. The current situation is not homogeneous. Existing authorizations need to be kept in the market in some EU states, while others need complete new authorizations requiring clinical trials, quality assurance methods, stability studies, and periodic safety update reports. Allergen manufacturers argue that offering a comprehensive panel of TAs may be economically disastrous. Expenses for initiation and maintenance of TA authorizations far exceed their related revenues and manufacturers may be forced to significantly limit their allergen portfolios. The availability of a wide range of high-quality TAs is very important for in vivo diagnoses of IgE-mediated allergies. Increased regulatory demands induce costs that need to be covered by public health organizations or reimbursed by health insurance companies.

The impact of telemonitoring on adherence to nasal corticosteroid treatment in children with seasonal allergic rhinoconjunctivitis.

BACKGROUND: Adherence to controller therapy in allergic diseases is low. Telemonitoring has been proposed to improve adherence to treatment in chronic diseases. However, this strategy has never been tested in allergic rhinoconjunctivitis. OBJECTIVE: To test whether Internet-based telemonitoring during the grass-pollen season of children with allergic rhinoconjunctivitis may enhance adherence to treatment. METHODS: Children and adolescents, 5-18 years old, with moderate-to-severe seasonal allergic rhinoconjunctivitis to grass pollen requiring daily administration of nasal corticosteroid (NCS) (mometasone) were recruited (April 2013) in a paediatric allergy practice. Participants were randomized to Internet-based monitoring (AllergyMonitor(™) , AM) or to usual care (no diary at all, controls) and followed from 13 May (T0) to 15 June 2013 (T2). An intermediate visit (T1) was performed between 31 May and 2 June. Optimal adherence to therapy was expressed as the use of at least 0.190 g/day of mometasone, corresponding to 1 puff/nostril/day, and it was measured by canister weights during (T1) and at the end (T2) of the study period. Main secondary outcomes included the reported disease severity (validated self-questionnaire) and quality of life (AdoIRQLQ questionnaire), disease knowledge (multiple-choice questionnaire), nasal flow and resistance at baseline and at T2. RESULTS: The use of mometasone, expressed as both optimal adherence rate (48.4% vs. 12.5%; P = 0.002) and average daily use (0.20 ± 0.12 g/day vs. 0.15 ± 0.07 g/day; P = 0.037), was higher in the AM group (n = 31) than among controls (n = 32). Disease knowledge improved among the patients using AM (83.3% vs. 68.3%; P < 0.001) but not among controls (68.2% vs. 67.7% right answers; P > 0.05). No differences were observed in the reported severity of disease, nasal flow and resistance and quality of life both at baseline and at follow-up visits. CONCLUSIONS: Internet-based telemonitoring improves adherence to NCS treatment and disease knowledge among children and adolescents with seasonal allergic rhinoconjunctivitis.

The relation of airway obstruction to asthma, chronic rhinosinusitis and age: results from a population survey of adults.

RATIONALE: There is conflicting evidence on whether patients with asthma experience an accelerated decline in lung function with age. We examined the association between postbronchodilator lung function, asthma, chronic rhinosinusitis (CRS), and atopy with age using a large European sample. METHODS: In 17 centers in 11 European countries, case-control studies were nested within representative cross-sectional surveys of adults aged less than 75 years. Representative samples of participants with asthma, CRS or both and controls were assessed for postbronchodilator ventilatory function, smoking history, atopy, and treatment. Multiple regression was used to assess the interactive effects of age and diagnostic group on decline in postbronchodilator ventilatory function. RESULTS: A total of 3337 participants provided adequate data (778 with asthma, 399 with CRS, 244 with both asthma and CRS and 1916 controls who had neither asthma nor CRS). Participants with asthma had lower FEV1 /FVC (-4.09% (95% CI: -5.02, -3.15, P < 0.001) and a steeper slope of FEV1 /FVC against age (-0.14%/annum [95%CI: -0.19, -0.08]) equivalent to smoking 1-2 packs of cigarettes per day. Those with atopy had a slope equivalent to controls. CONCLUSIONS: People with asthma have a steeper decline in postbronchodilator lung function with age, but neither CRS nor atopy alone were associated with such decline.

Immunoglobulin G in IgE-mediated allergy and allergen-specific immunotherapy.

Allergen-specific IgG antibodies play a significant role in allergen-specific tolerance, either naturally induced or generated by specific immunotherapy. Nevertheless, the underlying mechanisms are still debated, and allergen-specific IgG determinations are not recommended as a diagnostic tool in IgE-mediated allergy. This review summarizes the latest findings on the immunological and diagnostic role of IgG antibodies in respiratory and food allergies, and during allergen-specific immunotherapy.

Pilot study on the short-term prediction of symptoms in children with hay fever monitored with e-Health technology.

Forecasting symptoms of pollen-related allergic rhinoconjunctivitis at the level of individual patients would be useful to improve disease control and plan pharmacological intervention. Information Technology nowadays facilitates a more efficient and easier monitoring of patients with chronic diseases. We aimed this study at testing the efficiency of a model to short-term forecast symptoms of pollen-AR at the "individual" patient level. We analysed the data prospectively acquired from a group of 21 Italian children affected by pollen-related allergic rhinoconjunctivitis and recorded their symptoms and medication "Average Combined Score" (ACS) on a daily basis during April-June 2010-2011 through an informatics platform (Allergymonitor™). The dataset used for prediction included 15 variables in four categories: (A) date, (B) meteo-climatic, (C) atmospheric concentration of 5 pollen taxa, and (D) intensity of the patient's IgE sensitization. A Partial Least Squares Discriminant Analysis approach was used in order to predict ACS values above a fixed threshold value (0.5). The best performing predicting model correctly classified 77.8% ± 10.3% and 75.5% ± 13.2% of the recorded days in the model and test years, respectively. In this model, 9/21 patients showed ≥ 80% correct classification of the recorded days in both years. A better performance was associated with a higher degree of patient's atopic sensitization and a time lag > 1. Symptom forecasts of seasonal allergic rhinitis are possible in highly polysensitised patients in areas with complex pollen exposure. However, only predictive models tailored to the individual patient's allergic susceptibility are accurate enough. Multicenter studies in large population samples adopting the same acquisition data system on smart phones are now needed to confirm this encouraging outcome.

Staphylococcus aureus enterotoxin-specific IgE is associated with asthma in the general population: a GA(2)LEN study.

BACKGROUND: Specific IgE to Staphylococcus aureus enterotoxins (SE-IgE) has been associated with asthma. In the general population, we aimed to determine the prevalence of and risk factors for serum SE-IgE and to examine the association with asthma. METHODS: A postal questionnaire was sent to a random sample of adults in 19 centers across Europe. A random sample of respondents was invited for clinical examination upon which they answered a questionnaire, underwent skin prick tests (SPTs) for common aeroallergens, and provided blood for measurement of total IgE and SE-IgE. Risks were analyzed within centers using weighted logistic regression, and overall estimates calculated using fixed-effects meta-analysis. RESULTS: 2908 subjects were included in this analysis. Prevalence of positive SE-IgE was 29.3%; no significant geographic variation was observed. In contrast to positive skin prick tests, SE-IgE was more common in smokers (<15 pack-year: OR 1.11, P = 0.079, ≥15 pack-year: OR 1.70, P < 0.001), and prevalence did not decrease in older age-groups or in those with many siblings. Total IgE concentrations were higher in those with positive SE-IgE than in those with positive SPT. SE-IgE was associated with asthma (OR 2.10, 95% confidence interval [1.60-2.76], P = 0.001) in a concentration-dependent manner. This effect was independent of SPT result and homogeneous across all centers. CONCLUSIONS: We report for the first time that SE-IgE is common in the general population throughout Europe and that its risk factors differ from those of IgE against aeroallergens. This is the first study to show that SE-IgE is significantly and independently associated with asthma in the general population.

Testing children for allergies: why, how, who and when: an updated statement of the European Academy of Allergy and Clinical Immunology (EAACI) Section on Pediatrics and the EAACI-Clemens von Pirquet Foundation.

Allergic diseases are common in childhood and can cause a significant morbidity and impaired quality-of-life of the children and their families. Adequate allergy testing is the prerequisite for optimal care, including allergen avoidance, pharmacotherapy and immunotherapy. Children with persisting or recurrent or severe symptoms suggestive for allergy should undergo an appropriate diagnostic work-up, irrespective of their age. Adequate allergy testing may also allow defining allergic trigger in common symptoms. We provide here evidence-based guidance on when and how to test for allergy in children based on common presenting symptoms suggestive of allergic diseases.

Factors predicting the outcome of allergen-specific nasal provocation test in children with grass pollen allergic rhinitis.

Background: Nasal provocation testing (NPT) is a reference methodology to identify the culprit allergen in patients with allergic rhinitis. Selecting the right allergen for NPT is particularly difficult in poly-sensitized patients with seasonal allergic rhinitis (SAR). Predictors of NPT outcomes may facilitate the proper use of this test or even substitute it. Objective: To identify predictors of grass pollen NPT outcome from an array of clinical data, e-diary outcomes, and allergy test results in poly-sensitized pediatric patients with SAR. Methods: Poly-sensitized, SAR patients with grass pollen allergy, participating in the @IT.2020 pilot project in Rome and Pordenone (Italy), participated in a baseline (T0) visit with questionnaires, skin prick testing (SPT), and blood sampling to measure total (ImmunoCAP, TFS, Sweden) and specific IgE antibodies to grass pollen extracts and their major allergenic molecules (ESEP, Euroimmun Labordiagnostika, Germany). During the pollen season, patients filled the AllergyMonitor® e-diary app measuring their symptoms, medication intake, and allergy-related well-being via the Visual Analogue Scale (VAS). After the pollen season (T1), patients answered clinical questionnaires and underwent a nasal provocation test (NPT) with grass pollen extract. Results: We recruited 72 patients (age 14.3 ± 2.8 years, 46 males) sensitized to grass and/or other pollens, including olive (63; 87.5%) and pellitory (49; 68.1%). Patients positive to grass pollen NPT (61; 84.7%), compared to the negative ones, had worse VAS values in the e-diary, larger SPT wheal reactions, and higher IgE levels, as well as specific activity to timothy and Bermuda grass extracts, rPhl p 5 and nCyn d 1. A positive NPT to grass pollen was predicted by an index combining the specific activity of IgE towards Phl p 5 and Cyn d 1 (AUC: 0.82; p < 0.01; best cut-off ≥7.25%, sensitivity 70.5%, specificity: 90.9%). VAS results also predicted NPT positivity, although with less precision (AUC: 0.77, p < 0.01; best cut-off ≥7, sensitivity: 60.7%, specificity: 81.8%). Conclusions: An index combining the specific activity of IgE to rPhl p 5 and nCyn d 1 predicted with moderate sensitivity and high specificity the outcome of a grass pollen NPT in complex, poly-sensitized pediatric patients with seasonal allergic rhinitis. Further studies are needed to improve the index sensitivity and to assess its usefulness for NPT allergen selection or as an alternative to this demanding test procedure.

Hyaluronan-estradiol nanogels as potential drug carriers to target ER+ breast cancer cell line.

An innovative hyaluronan-based nano-delivery system is proposed for the active targeting towards ER+ breast cancer. Hyaluronic acid (HA), an endogenous and bioactive anionic polysaccharide, is functionalized with estradiol (ES), a sexual hormone involved in the development of some hormone-dependent tumors, to give an amphiphilic derivative (HA-ES) able to spontaneously self-assemble in water to form soft nanoparticles or nanogels (NHs). The synthetic strategy used to obtain the polymer derivatives and the physico-chemical properties of the obtained nanogels (ES-NHs) are reported. ES-NHs ability to entrap hydrophobic molecules has also been investigated, by loading curcumin (CUR) and docetaxel (DTX), both able to inhibit the growth of ER+ breast cancer. The formulations are studied for their capability to inhibit the growth of the MCF-7 cell line, thus evaluating their efficacy and potential as a selective drug delivery systems. Our results demonstrate that ES-NHs have not toxic effects on the cell line, and that both ES-NHs/CUR and ES-NHs/DTX treatments inhibit MCF-7 cell growth, with ES-NHs/DTX effect higher than that of free DTX. Our findings support the use of ES-NHs to deliver drugs to ER+ breast cancer cells, assuming a receptor-dependent targeting.

Perspectives on allergen-specific immunotherapy in childhood: an EAACI position statement.

This article is the result of consensus reached by a working group of clinical experts in paediatric allergology as well as representatives from an ethical committee and the European Medicine Agency (EMA). The manuscript covers clinical, scientific, regulatory and ethical perspectives on allergen-specific immunotherapy in childhood. Unmet needs are identified. To fill the gaps and to bridge the different points of view, recommendations are made to researchers, to scientific and patient organizations and to regulators and ethical committees. Working together for the benefit of the community is essential. The European Academy of Allergy and Clinical Immunology (EAACI) serves as the platform of such cooperation.