Pharmacokinetics/pharmacodynamics of benralizumab in chronic rhinosinusitis with nasal polyps: Phase III, randomized, placebo-controlled OSTRO trial.

AIMS: Benralizumab, a humanized, afucosylated monoclonal antibody against the interleukin 5 receptor, α subunit, causes rapid depletion of eosinophils by antibody-dependent cellular cytotoxicity. We investigated the pharmacokinetic and pharmacodynamic effects of benralizumab in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) from the phase III OSTRO trial. METHODS: Patients received a placebo or 30 mg of benralizumab by subcutaneous injection every 8 weeks (first three doses every 4 weeks) to week 48; a subset of patients continued in an extended follow-up period to assess treatment durability to week 80. Serum benralizumab concentrations and blood eosinophil and basophil counts were assessed to week 80. Biomarker assessments were performed on nasal polyp tissue biopsies at week 56 and nasal lining fluid at weeks 24 and 56 to examine changes in immune cells and inflammatory mediators. RESULTS: Among 185 patients in this analysis, 93 received benralizumab. Serum benralizumab concentrations reached a steady state by week 24 (median concentration 385.52 ng mL-1); blood eosinophils were almost fully depleted and blood basophils were reduced between weeks 16 and 56. Nasal polyp tissue eosinophils decreased with benralizumab from 57.6 cells mm-2 at baseline to 0 cells mm-2 at week 56 (P < .001 vs placebo), and tissue mast cells were numerically reduced. In nasal lining fluid, eosinophil-derived neurotoxin was significantly reduced at weeks 24 and 56 (P < .001) and interleukin-17 at week 56 (P < .05) with benralizumab. CONCLUSION: Benralizumab treatment led to rapid, sustained, nearly complete depletion of eosinophils from blood and nasal polyp tissue in patients with CRSwNP.

EUFOREA/EPOS2020 statement on the clinical considerations for chronic rhinosinusitis with nasal polyps care.

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.

Impact of Dupilumab on Sinonasal Symptoms and Outcomes in Severe Chronic Rhinosinusitis With Nasal Polyps.

OBJECTIVES: To assess the severity of the top 5 22-item Sino-Nasal Outcome Test (SNOT-22) items ranked most important by patients with chronic rhinosinusitis with nasal polyps (CRSwNP), the effect of dupilumab on these items, and their association with objective disease measures. STUDY DESIGN: Post hoc analysis of the SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) clinical trials. SETTING: Multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies. METHODS: Patients ranked the SNOT-22 items most affecting their health at baseline. Item symptom severity (0-5 scale) was assessed at baseline, Week 24 (W24), and Week 52 (W52). Changes in nasal polyps score (NPS) and Lund-Mackay (LMK) scores were assessed in patients with/without SNOT-22 items improvements of at least 1 severity group point at W24 and W52. RESULTS: The SNOT-22 items ranked most important at baseline were "decreased sense of smell/taste" (87% of patients), followed by "nasal blockage" (82%), "postnasal discharge" (40%), "thick nasal discharge" (37%), and "wake up at night" (26%); 82%, 61%, 32%, 40%, and 26% of patients reported severe symptoms (score 4 or 5) for these items, respectively. Dupilumab improved score severity for all top 5 items versus placebo at W24 and W52. Improvements in NPS and LMK scores were numerically greater in patients with improvements in the SNOT-22 top 5 items. CONCLUSION: Loss of smell/taste was ranked as the most important symptom by patients with CRSwNP. Dupilumab reduced the severity of the top 5 most important SNOT-22 items versus placebo, in parallel with improvements in objective disease measures. CLINICAL TRIAL REGISTRATION: SINUS-24 and SINUS-52 clinical trials were registered with ClinicalTrials.gov, identifiers NCT02912468 and NCT02898454, respectively.

DGAKI and PEI in dialogue 2023: Diagnostics and allergen immunotherapy.

A roundtable discussion on February 10, 2023 between the German Society for Allergology and Clinical Immunology (DGAKI) and the Paul-Ehrlich-Institut (PEI) aimed to discuss in detail current aspects of allergen immunotherapy (AIT), its regulatory framework under the transitional provision of the Therapy Allergen Ordinance (TAO), and the consequences for the planned guideline work of the DGAKI, regulatory challenges in the approval of AIT products for children and adolescents as well as allergy diagnostics. The content and discussion points of this dialogue are summarized and are set in context with the current literature.

Current situation of allergological health care at German hospitals.

BACKGROUND: Allergic medical care in Germany is organized on an interdisciplinary basis. An overview of the current care situation is necessary to manage and improve interdisciplinary cooperation. METHODS: Between January and February 2022, questionnaires were sent online and by mail to chief physicians of inpatient clinical departments to which most allergological diseases are assigned (dermatology, otorhinolaryngology [ENT], pulmonology, pediatrics, environmental/occupational medicine, gastroenterology; n = 899). RESULTS: The response rate was 52.1%. Allergology departments of dermatology, ENT and pulmonology were predominantly located in metropolitan areas (> 100,000 inhabitants), whereas responses of pediatric departments were mostly from smaller towns. 76.8% of the respondents reported existing interdisciplinary treatment plans with other specialties. Pediatric and pulmonology clinics stated disproportionately few interdisciplinary treatment concepts with dermatology and ENT clinics, especially in smaller cities with < 100,000 inhabitants. Diagnosis and therapy of allergic rhinitis were performed in particular by the departments of ENT, asthma mainly by the pulmonology departments. Care of other allergological diseases was most frequently reported by chief physicians of dermatology and pediatrics. CONCLUSIONS: In metropolitan areas, participating departments provide allergology care in a cooperative manner. A large spectrum of care is covered in cooperation with dermatological clinics. In more rural areas, cooperation is rarer; here, mainly pediatric departments provide allergological care, which may explain the more limited range of services compared to metropolitan areas.

Dupilumab efficacy in patients with chronic rhinosinusitis with nasal polyps with and without allergic rhinitis.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease, which often coexists with allergic rhinitis (AR). Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation. Objective: This post hoc analysis investigated the efficacy and safety of dupilumab in patients with severe CRSwNP with or without coexisting AR in the pooled phase III SINUS-24/SINUS-52 studies. Methods: Patients randomized to subcutaneous dupilumab 300 mg (n = 438) or placebo (n = 286) every 2 weeks for 24 (SINUS-24) or 52 weeks (SINUS-52) were analyzed. Pooled data from the first 24 weeks of treatment are presented. Changes from baseline in disease outcome measures and biomarker levels were analyzed by the patient-reported history of AR status. Results: Overall, 338 of 724 patients (46.7%) had AR. Baseline characteristics were generally similar between patients with and those without AR. Dupilumab significantly improved objective and patient-reported measures of CRSwNP, including loss of smell, and reduced systemic and nasal biomarker levels versus placebo at week 24, with no significant treatment difference between patients with and those without AR. Use of systemic corticosteroids and/or sinonasal surgery during treatment was significantly reduced with dupilumab versus placebo, irrespective of AR status (p ≤ 0.0029). The safety profile of dupilumab was similar in patients with and in patients without AR. Conclusion: Dupilumab demonstrated significant improvements in both clinical end points and symptom scores versus placebo in patients with severe CRSwNP, irrespective of comorbid AR status, a common subgroup of patients often associated with poorer CRSwNP outcomes. Clinical trials NCT02912468 (SINUS-24) and NCT02898454 (SINUS-52), www.clinicaltrials.gov.

Health-Related Quality of Life Impairment Among Patients with Severe Chronic Rhinosinusitis with Nasal Polyps in the SINUS-24 Trial.

Purpose: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease with a high symptom burden. Data are lacking on the comparative health status of patients with CRSwNP. This analysis compared baseline physical and mental health-related quality of life (HRQoL) and overall health status of patients with severe CRSwNP enrolled in a Phase 3 clinical trial with general population norms and with other chronic diseases. Methods: In this post hoc cross-sectional analysis of baseline data from the SINUS-24 study (NCT02912468), HRQoL was measured using the 36-item Short Form (SF-36) questionnaire and general health status was measured using the EuroQol-5 Dimension visual analog scale (EQ-VAS). Analyses included the intention-to-treat (ITT) population and subgroups defined by prior sinonasal surgery, systemic corticosteroid use, and coexisting asthma or non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). Scores were compared with published values for population norms (50 for SF-36 physical component summary (PCS) and mental component summary (MCS), 70.4-83.3 for EQ-VAS) and for rheumatoid arthritis, type 2 diabetes, and asthma. Results: In the ITT population (n=276), mean SF-36 physical component summary (PCS), SF-36 mental component summary (MCS), and EQ-VAS scores were below general population norms (46.4, 48.6, and 66.0, respectively). Mean SF-36 PCS and EQ-VAS scores were below population norms across all subgroups; mean SF-36 MCS scores were below the population norm in all subgroups except no prior surgery. SF-36 PCS and MCS scores from SINUS-24 were generally similar to other chronic diseases, except SF-36 PCS which was lower in rheumatoid arthritis. EQ-VAS scores in SINUS-24 were lower than in other chronic diseases. HRQoL scores weakly correlated with objective measures of disease severity. Conclusion: In patients with severe CRSwNP, including those with coexisting asthma/NSAID-ERD, HRQoL was worse than population norms and as burdensome as diseases such as type 2 diabetes, asthma, and rheumatoid arthritis.

Limited Reimbursement and Underuse of Digital Healthcare Concepts Are Major Barriers to Clinical Allergological Care in Germany.

INTRODUCTION: Allergic diseases represent a broad spectrum of high-prevalence, chronic conditions that remain underdiagnosed and undertreated. The aims of this interdisciplinary, questionnaire-based, non-interventional study were to identify and analyze potential barriers to clinical allergological care in Germany. METHODS: All hospitals listed in the German hospital register involved in the treatment of allergological patients (n = 899) were invited to participate. The study yielded a response rate of 52.1% (n = 468). RESULTS: Overall, 88.5% of clinics agreed that allergological care in Germany needs improvement, especially in terms of reimbursement for diagnostics and therapy. More than 80% of participating clinics reported that the decreased availability of test substances and the time-intensity of allergological testing represent relevant barriers. For dermatology and pulmonology, the former is the strongest barrier, while for pediatric and ENT clinics, time-intensity is regarded as the strongest barrier. The availability of good therapy and appropriate guidelines present no barriers to allergological care. Regarding the use of digital healthcare concepts, a very large majority of clinics (n = 352; 91.4%) do not offer video consultations or the use of health applications in patient care. CONCLUSION: In conclusion, we have identified several structural barriers to allergological care in Germany. Reimbursement and the use of digital healthcare concepts in German clinics providing allergological care need improvement. Based on the results of this study, there is an urgent need for researchers and policymakers to further investigate and support allergology departments in their clinical work and in their implementation of digital healthcare concepts.

Dupilumab provides early and durable improvement of symptoms in patients with chronic rhinosinusitis with nasal polyps.

Objectives: To evaluate within-patient symptom improvement in the dupilumab SINUS-24/-52 studies in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) (NCT02912468/NCT02898454). Methods: Patients received dupilumab 300 mg or placebo every 2 weeks for 24 (SINUS-24) or 52 weeks (SINUS-52) on background intranasal corticosteroids. Patients daily reported symptoms of nasal congestion (NC), loss of smell (LoS) and rhinorrhoea on a scale of 0-3 (0 - no symptoms, 1 - mild, 2 - moderate, 3 - severe symptoms). The proportions of patients with moderate-to-severe symptoms (score ≥ 2) at baseline who improved to no-to-mild symptoms (score ≤ 1) were determined at Weeks 2, 24 (pooled studies) and 52 (SINUS-52). Subgroups with prior sinonasal surgery and coexisting asthma were analysed. Results: At baseline in the pooled intention-to-treat population (n = 724), the proportions of patients with scores ≥ 2 for NC, LoS and rhinorrhoea were 87, 94 and 64%, respectively. Significantly, more patients achieved scores ≤ 1 (no/mild symptoms) with dupilumab vs placebo for each symptom at each time point {Week 2 NC 12% vs 2% [odds ratio 8.9 (95% CI 3.0-26.3)], LoS 5% vs 1% [4.6 (1.3-16.8)], rhinorrhoea 9% vs 2% [4.8 (1.5-15.4)], all P < 0.05; Week 24 NC 54% vs 14% [8.7 (5.6-13.5)], LoS 43% vs 6% [14.4 (7.9-26.0)], rhinorrhoea 53% vs 16% [6.6 (4.1-10.9)], all P < 0.0001}. Results were similar in subgroups with prior surgery and coexisting asthma. Conclusion: Significantly, more patients achieved improvement from moderate-to-severe symptoms to no-to-mild symptoms with dupilumab than placebo, regardless of prior surgery or coexisting asthma. Improvement was observed as early as Week 2 and continued through to Week 52.

Nasal allergen challenge (NAC): Practical aspects and applications from an EU/US perspective-a Work Group Report of the AAAAI Rhinitis, Rhinosinusitis and Ocular Allergy Committee.

Nasal allergen challenge (NAC) is applied in a variety of settings (research centers, specialty clinics, and hospitals) as a useful diagnostic and research tool. NAC is indicated for diagnosis of seasonal and perennial allergic rhinitis, local allergic rhinitis, and occupational rhinitis; to design the composition of allergen immunotherapy in patients who are polysensitized; and to investigate the physio-pathological mechanisms of nasal diseases. NAC is currently a safe and reproducible technique, although it is time- and resource-consuming. NAC can be performed by a variety of methods, but the lack of a uniform technique for performing and recording the outcomes represents a challenge for those considering NAC as a clinical tool in the office. The availability of standardized allergens for NAC is also different in each country. The objective of this workgroup report is to review the current information about NAC, focusing on the practical aspects and application for diagnosis of difficult rhinitis phenotypes (eg, local allergic rhinitis, occupational rhinitis), taking into account the particular context of practice in the United States and the European Union.

European Academy of Allergy and Clinical Immunology position paper on endoscopic scoring of nasal polyposis.

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.

Lack of Harmonized Adherence Criteria in Allergen Immunotherapy Prevents Comparison of Dosing and Application Strategies: A Scoping Review.

Allergen immunotherapy (AIT) involves the application of increasing doses of allergen extract (as oral, sublingual, or subcutaneous immunotherapy) until immunologic tolerance is reached. Successful AIT relies on the consistent administration of allergen extract; therefore, adherence to these treatments is vital for compelling long-term results. Our review discusses the current terminology from adherence research in general, summarizes 25 current studies on adherence research in AIT in a scoping literature review, and delineates recommendations for tools and parameters for adherence research, aiming to improve outcomes in AIT. Almost every adherence study in AIT published to date used different tools, parameters, and data sources for measuring adherence and persistence rates. Unfortunately, an easily accessible, objective parameter or biomarker for monitoring treatment adherence and success has not yet been established for AIT. This situation calls for the development of an international core outcomes set for AIT that defines what is exactly meant by AIT adherence and how AIT adherence should be consistently measured. Therefore, we exemplarily present results and conclusions from adherence research in chronic diseases other than allergology. We aim to facilitate the development of advanced methods, considering the challenging disease specificities of these parameters in a routine care setting of AIT.

Chronic Rhinosinusitis Outcome Registry (CHRINOSOR): Establishment of an International Outcome Registry Driven by mHealth Technology.

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.

Guideline on allergen immunotherapy in IgE-mediated allergic diseases: S2K Guideline of the German Society of Allergology and Clinical Immunology (DGAKI), Society of Pediatric Allergology and Environmental Medicine (GPA), Medical Association of German Allergologists (AeDA), Austrian Society of Allergology and Immunology (ÖGAI), Swiss Society for Allergology and Immunology (SSAI), German Dermatological Society (DDG), German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (DGHNO-KHC), German Society of Pediatrics and Adolescent Medicine (DGKJ), Society of Pediatric Pulmonology (GPP), German Respiratory Society (DGP), German Professional Association of Otolaryngologists (BVHNO), German Association of Paediatric and Adolescent Care Specialists (BVKJ), Federal Association of Pneumologists, Sleep and Respiratory Physicians (BdP), Professional Association of German Dermatologists (BVDD).

Not available.

Evaluating enrollment and outcome criteria in trials of biologics for chronic rhinosinusitis with nasal polyps.

OBJECTIVE: Treatment for chronic rhinosinusitis with nasal polyps (CRSwNP) generally involves intranasal corticosteroids (INCS) and saline irrigation, followed by short courses of systemic corticosteroids (SCS) or surgery with postoperative medical therapy for patients who do not respond to INCS. However, both SCS use and surgery are associated with a range of adverse effects or complications, have a high recurrence rate, and are unsuitable for some patients. Biologics targeting the underlying pathophysiology are promising treatment alternatives for these patients. Dupilumab, omalizumab, and mepolizumab are approved for use in patients with severe, uncontrolled CRSwNP. However, the lack of a consistent definition of severe CRSwNP makes the decision to initiate biologic treatment particularly complex. Furthermore, the position of each biologic in the overall management of CRSwNP remains to be clarified. DATA SOURCES: Publications reporting results of phase III trials of dupilumab, omalizumab, mepolizumab, and benralizumab in the treatment of CRSwNP. STUDY SELECTIONS: Randomized, controlled phase III trials of biologics approved for CRSwNP. RESULTS: These trials all used different enrollment criteria. We discuss the complexities of assessing CRSwNP disease severity and highlight how these impact comparisons of the populations and outcomes of the phase III biologic trials. CONCLUSION: To position biologic agents appropriately within the existing CRSwNP treatment paradigm, future trials will need to include comparable patient populations and standardized outcome measures. Such trials will help to ensure that biologic treatment is targeted appropriately to support optimal clinical outcomes.

Allergen immunotherapy during the COVID-19 pandemic-A survey of the German Society for Allergy and Clinical Immunology.

BACKGROUND: When the coronavirus pandemic 2019 (COVID-19) emerged, concerns were also raised regarding the safety of allergen immunotherapy (AIT). The German Society for Allergology and Clinical Immunology (DGAKI) conducted a survey to collect real-world data on the daily routine of administering subcutaneous AIT (SCIT) and sublingual AIT (SLIT) during the COVID-19 pandemic. METHODS: A web-based retrospective survey using the online platform survio with 26 standardized questions was used to survey physicians treating allergic patients during the pandemic. RESULTS: Three hundred and forty-five physicians who regularly offer and perform AIT in German-speaking countries responded to the questions. 70.4% of the respondents stated that they regularly initiated and dosed up SCIT for inhalant allergies (41.4% venom-SCIT, 73.6% SLIT), and 85.2% of the respondents stated that they continued SCIT for inhalant allergies during the maintenance phase in a regular way (59.1% venom-SCIT, 90.4% SLIT) in healthy patients without current symptoms indicating an infection with COVID-19. With regard to tolerability, there was no evidence for increased occurrence of adverse events in patients without current symptoms of COVID-19 infection during the pandemic. CONCLUSIONS: This retrospective study demonstrated adherence to national and international position papers of AIT during the COVID-19 pandemic in German-speaking countries. Besides, the survey has confirmed a good tolerability of AIT for both SCIT and SLIT.

S3 guideline Allergy Prevention.

BACKGROUND: The persistently high prevalence of allergic diseases in Western industrial nations and the limited possibilities of causal therapy make evidence-based recommendations for primary prevention necessary. METHODS: The recommendations of the S3 guideline Allergy Prevention, published in its last version in 2014, were revised and consulted on the basis of a current systematic literature search. The evidence search was conducted for the period 06/2013 - 11/2020 in the electronic databases Cochrane and MEDLINE, as well as in the reference lists of current reviews and through references from experts. The literature found was screened in two filtering processes, first by title and abstract, and the remaining papers were screened in the full text for relevance. The studies included after this were sorted by level of evidence, and the study quality was indicated in terms of potential bias (low/high). The revised recommendations were formally agreed and consented upon with the participation of representatives of the relevant professional societies and (self-help) organizations (nominal group process). Of 5,681 hits, 286 studies were included and assessed. RESULTS: Recommendations on maternal nutrition during pregnancy and breastfeeding as well as on infant nutrition in the first months of life again play an important role in the updated guideline: Many of the previous recommendations were confirmed by the current data. It was specified that breastfeeding should be exclusive for the first 4 - 6 months after birth, if possible, and that breastfeeding should continue with the introduction of complementary foods. A new recommendation is that supplementary feeding of cow's milk-based formula should be avoided in the first days of life if the mother wishes to breastfeed. Furthermore, it was determined that the evidence for a clear recommendation for hydrolyzed infant formula in non-breastfed infants at risk is currently no longer sufficient. It is therefore currently recommended to check whether an infant formula with proven efficacy in allergy prevention studies is available until the introduction of complementary feeding. Finally, based on the EAACI guideline, recommendations were made for the prevention of chicken egg allergy by introducing and regularly giving thoroughly heated (e.g., baked or hard-boiled) but not "raw" chicken egg (also no scrambled egg) with the complementary food. The recommendation to introduce peanut in complementary feeding was formulated cautiously for the German-speaking countries: In families who usually consume peanut, the regular administration of peanut-containing foods in age-appropriate form (e.g., peanut butter) with the complementary diet can be considered for the primary prevention of peanut allergy in infants with atopic dermatitis (AD). Before introduction, a clinically relevant peanut allergy must be ruled out, especially in infants with moderate to severe AD. There is still insufficient evidence for an allergy-preventive efficacy of prebiotics or probiotics, vitamin D, or other vitamins in the form of supplements so that recommendations against their supplementation were adopted for the first time in the current guideline. Biodiversity plays an important role in the development of immunological tolerance to environmental and food allergens: there is clear evidence that growing up on a farm is associated with a lower risk of developing asthma and allergic diseases. This is associated with early non-specific immune stimulation due to, among other things, the greater microbial biodiversity of house dust in this habitat. This aspect is also reflected in the recommendations on animal husbandry, on which a differentiated statement was made: In families without a recognizable increased allergy risk, pet keeping with cats or dogs should not generally be restricted. Families with an increased allergy risk or with children with already existing AD should not acquire a new cat - in contrast, however, dog ownership should not be discouraged. Interventions to reduce exposure to dust mite allergens in the home, such as the use of mite allergen-proof mattress covers ("encasings"), should be restricted to patients with already proven specific sensitization against house dust mite allergen. Children born by caesarean section have a slightly increased risk of asthma - this should be taken into account when advising on mode of delivery outside of emergency situations. Recent work also supports the recommendations on air pollutants: Active and passive exposure to tobacco smoke increase the risk of allergies, especially asthma, and should therefore be avoided. Exposure to nitrogen oxides, ozone, and small particles (PM 2.5) is associated with an increased risk, especially for asthma. Therefore, exposure to emissions of nitrogen oxides, ozone, and small particles (PM 2.5) should be kept low. The authors of this guideline are unanimously in favor of enacting appropriate regulations to minimize these air pollutants. There is no evidence that vaccinations increase the risk of allergies, but conversely there is evidence that vaccinations can reduce the risk of allergies. All children, including children at risk, should be vaccinated according to the current recommendations of the national public health institutes, also for reasons of allergy prevention. CONCLUSION: The consensus of recommendations in this guideline is based on an extensive evidence base. The update of the guideline enables evidence-based and up-to-date recommendations for the prevention of allergic diseases including asthma and atopic dermatitis.

A novel CD34-derived hinge for rapid and efficient detection and enrichment of CAR T cells.

Immunotherapy including chimeric antigen receptor (CAR) T cell therapy has revolutionized modern cancer therapy and has achieved remarkable remission and survival rates for several malignancies with historically dismal outcomes. The hinge of the CAR connects the antigen binding to the transmembrane domain and can be exploited to confer features to CAR T cells including additional stimulation, targeted elimination or detection and enrichment of the genetically modified cells. For establishing a novel hinge derived from human CD34, we systematically tested CD34 fragments of different lengths, all containing the binding site of the QBend-10 monoclonal antibody, in a FMC63-based CD19 CAR lentiviral construct. A final construct of 99 amino acids called C6 proved to be the best candidate for flow cytometry-based detection of CAR T cells and >95% enrichment of genetically modified T cells on MACS columns. The C6 hinge was functionally indistinguishable from the commonly used CD8α hinge in vitro as well as in in vivo experiments in NSG mice. We also showed that the C6 hinge can be used for a variety of different CARs and mediates high killing efficacy without unspecific activation by target antigen-negative cells, thus making C6 ideally suited as a universal hinge for CARs for clinical applications.

COVID-19 vaccination and allergen immunotherapy (AIT) - A position paper of the German Society for Applied Allergology (AeDA) and the German Society for Allergology and Clinical Immunology (DGAKI).

BACKGROUND: Vaccinations against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are intended to induce an immune response to protect against infection/disease. Allergen immunotherapy (AIT) is thought to induce a (different) immune response, e.g., to induce tolerance to allergens. In this position paper we clarify how to use AIT in temporal relation to COVID-19 vaccination. Four SARS-CoV-2 vaccines are currently approved in the EU, and their possible immunological interactions with AIT are described together with practical recommendations for use. MATERIALS AND METHODS: Based on the internationally published literature, this position paper provides specific recommendations for the use of AIT in temporal relation to a SARS-CoV-2 vaccination. RESULTS: AIT is used in 1) allergic rhinitis, 2) allergic bronchial asthma, 3) insect venom allergy, 4) food allergy (peanut). CONCLUSION: For the continuation of an ongoing AIT, we recommend an interval of 1 week before and after vaccination for subcutaneous immunotherapy (SCIT). For sublingual immunotherapy (SLIT) and oral immunotherapy (OIT), we recommend taking them up to the day before vaccination and a break of 2 - 7 days after vaccination. Initiation of a new SCIT, SLIT, or OIT should be delayed until 1 week after the day of the second vaccination. For SCIT, we generally recommend an interval of ~ 1 week to COVID-19 vaccination.