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.

Eosinophilic esophagitis as a side-effect of allergen immunotherapy: protocol for a systematic review and meta-analysis.

Summary: Background. Sensitization to food and airborne allergens is common in the majority of patients with eosinophilic esophagitis (EoE). Although there is not a direct cause-effect relationship of IgE-mediated allergy with the pathogenesis of EoE, there is a growing evidence that oral desensitization to food and sublingual immunotherapy (SLIT) may induce the development of EoE as an adverse effect. As part of the 'EoE and Allergen Immunotherapy (AIT)' Task Force funded by the European Academy of Allergy and Clinical Immunology (EAACI), a systematic approach will be followed to review the evidence from the published scientific literature on the development of EoE in children and adults under any type of AIT. Methods. This systematic review will be carried out following the PRISMA statement guidelines. Studies will be assessed for inclusion in the review according to the Population-Interventions-Comparators-Outcomes (PICO) criteria. Results. Expected outcomes will provide evidence on the AIT-EoE development connection. Conclusions. The findings from this review will be used as a reference to provide useful guidelines for physicians treating patients with EoE and/or are practicing AIT.

Adherence to inhaled corticosteroids and long-acting ß2-agonists in asthma: A MASK-air study.

INTRODUCTION: Adherence to controller medication is a major problem in asthma management, being difficult to assess and tackle. mHealth apps can be used to assess adherence. We aimed to assess the adherence to inhaled corticosteroids+long-acting ß2-agonists (ICS+LABA) in users of the MASK-air® app, comparing the adherence to ICS+formoterol (ICS+F) with that to ICS+other LABA. MATERIALS AND METHODS: We analysed complete weeks of MASK-air® data (2015-2022; 27 countries) from patients with self-reported asthma and ICS+LABA use. We compared patients reporting ICS+F versus ICS+other LABA on adherence levels, symptoms and symptom-medication scores. We built regression models to assess whether adherence to ICS+LABA was associated with asthma control or short-acting beta-agonist (SABA) use. Sensitivity analyses were performed considering the weeks with no more than one missing day. RESULTS: In 2598 ICS+LABA users, 621 (23.9%) reported 4824 complete weeks and 866 (33.3%) reported weeks with at most one missing day. Higher adherence (use of medication ≥80% of weekly days) was observed for ICS+other LABA (75.1%) when compared to ICS+F (59.3%), despite both groups displaying similar asthma control and work productivity. The ICS+other LABA group was associated with more days of SABA use than the ICS+F group (median=71.4% versus 57.1% days). Each additional weekly day of ICS+F use was associated with a 4.1% less risk in weekly SABA use (95%CI=-6.5;-1.6%;p=0.001). For ICS+other LABA, the percentage was 8.2 (95%CI=-11.6;-5.0%;p<0.001). CONCLUSIONS: In asthma patients adherent to the MASK-air app, adherence to ICS+LABA was high. ICS+F users reported lower adherence but also a lower SABA use and a similar level of control.

Empfehlungen zur Überprüfung der Wirksamkeit und Verlaufsdokumentation von Mepolizumab bei chronischer Rhinosinusitis mit Nasenpolypen (CRSwNP) im deutschen Gesundheitssystem ­ Empfehlungen des Ärzteverbandes Deutscher Allergologen (AeDA) und der AGs Klinische Immunologie, Allergologie und Umweltmedizin und Rhinologie und Rhinochirurgie der Deutschen Gesellschaft für HNO-Heilkunde, Kopf- und Halschirurgie (DGHNOKHC).

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the mucous membranes of the nose and sinuses. Eosinophilic inflammation is described as a common endotype. The anti-IL5 antibody mepolizumab was approved in November 2021 as an add-on therapy to intranasal glucocorticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps when systemic glucocorticosteroids or surgery do not provide adequate disease control. While national and international recommendations exist for the use of mepolizumab in CRSwNP, it has not yet been adequately specified how this therapy is to be monitored, what follow-up documentation is necessary, and when it should be terminated if necessary. METHODS: A literature search was performed to analyze previous data on the treatment of CRSwNP with mepolizumab and to determine the available evidence by searching Medline, Pubmed, the national and international trial and guideline registries and the Cochrane Library. Human studies published in the period up to and including 10/2022 were considered. RESULTS: Based on the international literature and previous experience by an expert panel, recommendations for follow-up, adherence to therapy intervals and possible therapy breaks, as well as termination of therapy when using mepolizumab for the indication CRSwNP in the German health care system are given on the basis of a documentation sheet. CONCLUSIONS: Understanding the immunological basis of CRSwNP opens up new non-surgical therapeutic approaches with biologics for patients with severe, uncontrolled courses. Here, we provide recommendations for follow-up, adherence to therapy intervals, possible therapy pauses, or discontinuation of therapy when mepolizumab is used as add-on therapy with intranasal glucocorticosteroids to treat adult patients with severe CRSwNP that cannot be adequately controlled with systemic glucocorticosteroids and/or surgical intervention.

Empfehlungen zur Überprüfung der Wirksamkeit und Verlaufsdokumentation von Dupilumab bei chronischer Rhinosinusitis mit Nasenpolypen (CRSwNP) im deutschen Gesundheitssystem.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the nasal and paranasal mucosa. A Type-2 inflammation is described as the most common endotype. Since October 2019 the anti-IL-4/-IL-13 antibody dupilumab has been approved in Germany as an add-on therapy to intranasal corticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps, when systemic corticosteroids alone or surgery do not provide adequate disease control. While recommendations for the use of dupilumab in CRSwNP exist at both national and international levels, until now it has not been adequately established, how therapy should be monitored and when it should be discontinued in the German Health Care System. METHODS: A literature search was performed analyzing previous data on the treatment of CRSwNP with dupilumab and to determine the available evidence by searching Medline, Pubmed, the national and international trial and guideline registries and the Cochrane Library. Human studies published in the period up to 05/2022 were included. RESULTS: Based on international literature and previous experience, recommendations are given by an expert panel for follow-up and possible therapy breaks, therapy intervals or termination of therapy when using dupilumab for the indication CRSwNP in the German health care system based on a documentation form. CONCLUSIONS: Understanding the immunological basis of CRSwNP opens new non-surgical therapy approaches with biologics for patients with severe courses. The authors give recommendations for follow-up, possible therapy breaks, therapy intervals and a termination for dupilumab treatment as add-on therapy with intranasal corticosteroids for the treatment of adult patients with severe CRSwNP that cannot be adequately controlled with systemic corticosteroids and/or surgical intervention.

[Guideline for the Diagnosis and Treatment of Asthma - Addendum 2020 - Guideline of the German Respiratory Society and the German Atemwegsliga in Cooperation with the Paediatric Respiratory Society and the Austrian Society of Pneumology]. / S2k-Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma ­ Addendum 2020.

The present addendum of the guideline for the diagnosis and treatment of asthma (2017) complements new insights into the diagnosis and management of asthma as well as for the newly approved drugs for the treatment of asthma. Current, evidence-based recommendations on diagnostic and therapeutic approaches are presented for children and adolescents as well as for adults with asthma.

Treatment of allergic rhinitis during and outside the pollen season using mobile technology. A MASK study.

BACKGROUND: The analysis of mobile health (mHealth) data has generated innovative insights into improving allergic rhinitis control, but additive information is needed. A cross-sectional real-world observational study was undertaken in 17 European countries during and outside the estimated pollen season. The aim was to collect novel information including the phenotypic characteristics of the users. METHODS: The Allergy Diary-MASK-air-mobile phone app, freely available via Google Play and App, was used to collect the data of daily visual analogue scales (VASs) for overall allergic symptoms and medication use. Fluticasone Furoate (FF), Mometasone Furoate (MF), Azelastine Fluticasone Proprionate combination (MPAzeFlu) and eight oral H1-antihistamines were studied. Phenotypic characteristics were recorded at entry. The ARIA severity score was derived from entry data. This was an a priori planned analysis. RESULTS: 9037 users filled in 70,286 days of VAS in 2016, 2017 and 2018. The ARIA severity score was lower outside than during the pollen season. Severity was similar for all treatment groups during the pollen season, and lower in the MPAzeFlu group outside the pollen season. Days with MPAzeFlu had lower VAS levels and a higher frequency of monotherapy than the other treatments during the season. Outside the season, days with MPAzeFlu also had a higher frequency of monotherapy. The number of reported days was significantly higher with MPAzeFlu during and outside the season than with MF, FF or oral H1-antihistamines. CONCLUSIONS: This study shows that the overall efficacy of treatments is similar during and outside the pollen season and indicates that medications are similarly effective during the year.

Allergen exposure chambers: implementation in clinical trials in allergen immunotherapy.

Allergen exposure chambers (AECs) have been developed for controlled allergen challenges of allergic patients mimicking natural exposure. As such, these facilities have been utilized e.g., for proof of concept, dose finding or the demonstration of onset of action and treatment effect sizes of antiallergic medication. Moreover, clinical effects of and immunological mechanisms in allergen immunotherapy (AIT) have been investigated in AECs. In Europe AIT products have to fulfill regulatory requirements for obtaining market authorization through Phase I to III clinical trials. Multiple Phase II (dose-range-finding or proof-of-concept) trials on AIT products have been performed in AECs. However, they are not accepted by regulatory bodies for pivotal (Phase III) trials and a more thorough technical and clinical validation is requested. Recently, a Position Paper of the European Academy of Allergy and Clinical Immunology (EAACI) has outlined unmet needs in further development of AECs. The following review aims to address some of these needs on the basis of recently published data in the first part, whereas the second part overviews published examples of most relevant Phase II trials in AIT performed in AEC facilities.

Allergen Immunotherapy (AIT) in children: a vulnerable population with its own rights and legislation - summary of EMA-initiated multi-stakeholder meeting on Allergen Immunotherapy (AIT) for children, held at Paul-Ehrlich-Institut, Langen, Germany, 16.1.2019.

Concerning development of medicinal products, children belong to a so-called "special population" for which additional legislation applies: Regulation (EC) No 1901/2006 on medicinal products for paediatric use sets up a system of requirements, rewards and incentives to ensure that medicinal products are researched, developed and authorized to meet the therapeutic needs of children. Allergen Immunotherapy (AIT) is believed to contain a strong potential for immunomodulatory effects inducing sustained clinical efficacy after cessation of treatment (disease modifying effect) and thereby may prevent the progression of the atopic march towards asthma manifestation. However, to this day only few data on long-term effects in general exist and even fewer in children. These are predominantly data from open studies, which are strongly influenced in their validity by the known placebo effect of AIT. Furthermore, there are no studies allowing for the conclusion that efficacy in adults are mirrored by a similar efficacy in children and thus, up to now, it is not possible to extrapolate data from adults to children. The Paediatric Committee (PDCO)-European Medicines Agency's (EMA) scientific committee responsible for activities on medicines for children-initiated a Multi-Stakeholder Meeting on AIT for Children held at the Paul-Ehrlich-Institut in Langen, Germany, to provide a platform for discussion and exchange of thoughts to this topic between allergy experts from academia, regulators and AIT-manufacturers. The consented meeting minutes, conclusions and participants are presented.

Clinical trials in allergen immunotherapy in the age group of children and adolescents: current concepts and future needs.

Allergen immunotherapy (AIT) is the only treatment option available for allergic patients with disease-modifying intention. Both efficacy and safety has been demonstrated for multiple trials in children, adolescents and adults. Though regulatory requirements for marketing authorization have been clearly outlined and an increasing number of high quality trials has been initiated, multiple concepts and details in study design may be further elaborated, harmonized and improved. An international group of experts in the field of AIT has thoroughly reviewed and discussed current concepts and provided an outlook on further improvement especially in the age group of children and adolescents. Emphasis of the group's discussion as a basis for this article was put on (i) the regulatory background of marketing authorization of AIT products including the 'Pediatric Investigational Plan', (ii) patient reported outcomes and endpoints in AIT trials, (iii) considerations regarding the 'minimal clinically important difference', (iv) the role of placebo effects in AIT clinical trials and clinical routine and (v) the potential of mobile Health for future development of AIT. Current concepts in AIT have been optimized throughout the recent decades, but there remains room for improvement e.g., in the topics outlined in this article.

Strong dose response after immunotherapy with PQ grass using conjunctival provocation testing.

BACKGROUND: Pollinex Quattro Grass (PQ Grass) is an effective, well-tolerated, short pre-seasonal subcutaneous immunotherapy to treat seasonal allergic rhinoconjunctivitis (SAR) due to grass pollen. In this Phase II study, 4 cumulative doses of PQ Grass and placebo were evaluated to determine its optimal cumulative dose. METHODS: Patients with grass pollen-induced SAR were randomised to either a cumulative dose of PQ Grass (5100, 14400, 27600 and 35600 SU) or placebo, administered as 6 weekly subcutaneous injections over 31-41 days (EudraCT number 2017-000333-31). Standardized conjunctival provocation tests (CPT) using grass pollen allergen extract were performed at screening, baseline and post-treatment to determine the total symptom score (TSS) assessed approximately 4 weeks after dosing. Three models were pre-defined (Emax, logistic, and linear in log-dose model) to evaluate a dose response relationship. RESULTS: In total, 95.5% of the 447 randomized patients received all 6 injections. A highly statistically significant (p < 0.0001), monotonic dose response was observed for all three pre-specified models. All treatment groups showed a statistically significant decrease from baseline in TSS compared to placebo, with the largest decrease observed after 27600 SU (p < 0.0001). The full course of 6 injections was completed by 95.5% of patients. Treatment-emergent adverse events were similar across PQ Grass groups, and mostly mild and transient in nature. CONCLUSIONS: PQ Grass demonstrated a strong curvilinear dose response in TSS following CPT without compromising its safety profile.

Contraindications to immunotherapy: a global approach.

BACKGROUND: Recommendations on contraindications to allergen immunotherapy (AIT) have been independently developed by National and International Societies/Academies. AIT contraindications are mainly based on case reports, case-series, or experts' opinion, while evidence-based information is limited. The aim of the present review was to describe existing guidelines on contraindications to AIT and to highlight differences between them. MAIN BODY: An extended review of the literature regarding contraindications to AIT for respiratory allergy and venom hypersensitivity was performed. Furthermore, Societies and Academies registered in the World Allergy Organization and EAACI databases, were asked for additional information. Only AIT guidelines published under official auspicies were included. A large heterogeneity among the various recommendations on contraindications was registered. Common contraindications to most of the guidelines were: lack of adherence, pregnancy before the start of AIT, the use of beta-blockers, certain age groups, uncontrolled asthma, autoimmune diseases and malignancies. CONCLUSION: As new data arise, revisions might soon be needed allowing AIT in the cases of patients treated with ACE inhibitors and beta-blockers, in elderly patients and in patients with concomitant autoimmune diseases and neoplasias in remission. The decision to prescribe AIT is always tailor-made, balancing risk vs benefit. Creating globally accepted guidelines would help Allergologists in their decision making.

ARIA masterclass 2018: From guidelines to real-life implementation.

Over the past 20 years, ARIA (Allergic Rhinitis and its Impact on Asthma) has developed various guidelines for the treatment of allergic rhinitis (AR) and asthma multimorbidity. Over time, the ARIA initiative has evolved to ensure the highest level of bestpractices adoption in real life settings. It has evolved towards Integrated Care Pathways (ICPs) using mobile technology, and has now entered a new phase in which change management is key to provide an active and healthy life to all AR patients. With that in mind, the first ARIA masterclass was held on 12th September 2018 in Brussels, Belgium. The masterclass aimed at informing clinicians about the principles of change management, providing unbiased education on diagnosis and treatments, sharing the most recent research data on AR and multimorbidities, and creating a snowball effect to increase the adoption of best practices around the globe. This report provides an overview of the ARIA masterclass concept, summarizes the key lectures and discussions, and gives an outline of the future key development.

[Reasons for the development of allergies in children]. / Gründe für die Entstehung von Allergien bei Kindern.

Allergies are one of the most common chronic diseases in childhood, contributing to a tremendous medical and economical burden in health care systems of most industrialized countries. The development of allergies is dependent on a complex interaction of-among others-environmental factors, nutrition, genetic and epigenetic mechanisms as well as the microbiome. These diverse factors can influence early life immune regulation including innate and adaptive immune mechanisms in a complex fashion. In case of any Childhood allergies have increased significantly in past decades. In addition to environmental factors and nutrition, genetic and epigenetic mechanisms as well as the microbiome of children play an important role. Of relevance is the way in which these diverse factors influence early immune development of the innate and adaptive immune systems of children. Their complex regulation is decisive for whether or not a child develops an allergy that manifests in most cases as atopic dermatitis, bronchial asthma, or allergic rhino conjunctivitis, or whether a child develops an immune tolerance. These influences can begin prenatally, already setting the course for later immune system development and occurrence of disease.

Rhinology future trends: 2017 EUFOREA debate on allergic rhinitis.

The 2nd Rhinology Future Debate, organized by EUFOREA (European Forum for Research and Education in Allergy and Airways diseases) was held in Brussels in December 2017. One of these debates addressed the position of MP-AzeFlu in allergic rhinitis (AR) treatment. The current article summarizes this debate; reviewing recent data, and exploring how this has been interpreted by experts and incorporated into AR management guidelines and a clinical decision support system (CDSS). The Allergic Rhinitis & its Impact on Asthma (ARIA) guideline position MP-AzeFlu firstline for the treatment of AR, and in preference to intranasal corticosteroids (INSs) during the first 2 weeks of treatment. The AR CDSS recommends MP-AzeFlu as one of the firstline treatments for patients with a visual analogue scale (VAS) score lower than 5/10 cm, and in preference (along with INS) for those with a VAS score equal or higher than5/10 cm. Panellists agreed that AR management should be kept as simple as possible, with some preferring a one treatment fits all approach, while others preferred a step-up approach. The need to change the AR management mentality was acknowledged, accepting that most patients use their medication as needed and use multiple treatments; AR medications are needed which have a very fast onset of action and which target breakthrough symptoms. Panellists agreed that MP-AzeFlu has a role to play here, since it has a 5 minute onset-of-action, provides clinically-relevant symptom relief in 15 mins and AR control in less than 3 days, targets nasal hyper-reactivity (NHR) which likely contributes to uncontrolled AR and breakthrough symptoms, and provides more effective AR symptom relief than INS monotherapy or INS + oral antihistamine. Finally, experts considered it likely that MP-AzeFlu should have a greater impact on asthma control than INS in co-morbid patients, but clinical data is required to back up existing pharmacoeconomic evidence. The next Rhinology Future Debate will be in held in Brussels in Dec 2019.

2020 ARIA CARE PATHWAYS FOR ALLERGIC RHINITIS - GEORGIA.

Allergic rhinitis is the most common chronic disease worldwide. Treatment guidelines have improved the knowledge on rhinitis and have had a significant impact on AR management. In 20 years, ARIA has considerably evolved from the first multi-morbidity guideline in respiratory diseases to the digital transformation of health and care. Allergic rhinitis in Georgia, Next-generation ARIA-GRADE guidelines and ARIA, 2020 care pathways for Allergen Immunotherapy have been discussed in this review.

MASK 2017: ARIA digitally-enabled, integrated, person-centred care for rhinitis and asthma multimorbidity using real-world-evidence.

mHealth, such as apps running on consumer smart devices is becoming increasingly popular and has the potential to profoundly affect healthcare and health outcomes. However, it may be disruptive and results achieved are not always reaching the goals. Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline using the best evidence-based approach to care pathways suited to real-life using mobile technology in allergic rhinitis (AR) and asthma multimorbidity. Patients largely use over-the-counter medications dispensed in pharmacies. Shared decision making centered around the patient and based on self-management should be the norm. Mobile Airways Sentinel networK (MASK), the Phase 3 ARIA initiative, is based on the freely available MASK app (the Allergy Diary, Android and iOS platforms). MASK is available in 16 languages and deployed in 23 countries. The present paper provides an overview of the methods used in MASK and the key results obtained to date. These include a novel phenotypic characterization of the patients, confirmation of the impact of allergic rhinitis on work productivity and treatment patterns in real life. Most patients appear to self-medicate, are often non-adherent and do not follow guidelines. Moreover, the Allergy Diary is able to distinguish between AR medications. The potential usefulness of MASK will be further explored by POLLAR (Impact of Air Pollution on Asthma and Rhinitis), a new Horizon 2020 project using the Allergy Diary.

Geolocation with respect to personal privacy for the Allergy Diary app - a MASK study.

BACKGROUND: Collecting data on the localization of users is a key issue for the MASK (Mobile Airways Sentinel networK: the Allergy Diary) App. Data anonymization is a method of sanitization for privacy. The European Commission's Article 29 Working Party stated that geolocation information is personal data.To assess geolocation using the MASK method and to compare two anonymization methods in the MASK database to find an optimal privacy method. METHODS: Geolocation was studied for all people who used the Allergy Diary App from December 2015 to November 2017 and who reported medical outcomes. Two different anonymization methods have been evaluated: Noise addition (randomization) and k-anonymity (generalization). RESULTS: Ninety-three thousand one hundred and sixteen days of VAS were collected from 8535 users and 54,500 (58.5%) were geolocalized, corresponding to 5428 users. Noise addition was found to be less accurate than k-anonymity using MASK data to protect the users' life privacy. DISCUSSION: k-anonymity is an acceptable method for the anonymization of MASK data and results can be used for other databases.

New European Academy of Allergy and Clinical Immunology definition on pollen season mirrors symptom load for grass and birch pollen-induced allergic rhinitis.

BACKGROUND: The use of allergen immunotherapy (AIT) for allergic rhinitis and its clinical efficacy in clinical trials depends on the effective determination of pollen allergen exposure time periods. We evaluate pollen data from Germany to examine the new definitions on pollen season and peak pollen period start and end as proposed by the European Academy of Allergy and Clinical Immunology (EAACI) in a recently published Position Paper. The aim was to demonstrate the ability of these definitions to mirror symptom loads for grass and birch pollen-induced allergic rhinitis based on real-life data. METHODS: Data coming from four pollen monitoring stations in the Berlin and Brandenburg area in Germany and for 3 years (2014-2016) were used to investigate the correlation of season definitions, birch and grass pollen counts and total nasal symptom and mediation scores as reported by patients in "Patients Hay fever Diaries" (PHDs). After the identification of pollen periods on the basis of the EACCI criteria, a statistical analysis was employed, followed by a detailed graphical investigation. RESULTS: The analysis revealed that the definitions of pollen season as well as peak pollen period start and end as proposed by the EAACI are correlated to symptom loads for grass and birch pollen-induced allergic rhinitis reported by patients in PHDs. CONCLUSION: Based on our analysis, the validity of the EAACI definitions on pollen season is confirmed. Their use is recommended in future clinical trials on AIT as well as in daily routine for optimal patient care.