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Respiratory allergy often begins in childhood and most commonly manifests as allergic rhinitis (upper airways) and/or asthma (lower airways). Children with upper respiratory allergy often suffer from coexisting asthma, and other comorbidities ranging from gastrointestinal disorders to emotional/mental health disorders. Consequently, the disease burden is considerable and profoundly impacts a child's daily life. Early identification and appropriate management are important to reduce disease burden, lower the risk of disease progression and additional comorbidities, and protect the child's future well-being. A window of opportunity for halting disease progression may open in the early stages of allergic disease and underlines the importance of early diagnosis and treatment of children at risk. This review offers advice on identifying children with a high disease burden who would benefit from early intervention. Allergen immunotherapy (AIT) modifies the cause of respiratory allergy and prevents disease progression. In clinical practice, AIT could be considered as an early treatment for eligible children, to achieve long-term symptom control and disease modification., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. EH has received grants from the German Ministry of Education and Research (BMBF), Network University Medicine (NUM), Ministry of Health and Social Affairs of Nordrhein-Westfalen (MAGS), and Federal Joint Committee (G-BA), and has received fees for lectures and consulting activities from Abbvie, Aimmune, ALK-Abelló, Allergopharma, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, DBV, GSK, LETI Pharma, Novartis, Nutricia, nutrimmun, Sanofi, and Stallergenes. EH is the Vice President of the German Allergy Society (DGAKI) and the President of the German Asthma Net (GAN e.V.). PC has received fees for consulting activities from ALK-Abelló, Thermo Fisher Scientific, Orion Pharma, and GSK. GR has received fees for lectures and consulting activities from ALK-Abelló, research support from AstraZeneca, and has been supported by Allergen Therapeutics. CV has received grants from the German Research Foundation (DFG), and has received fees for lectures and consulting activities from Abbvie, Aimmune, ALK-Abelló, Allergopharma, AstraZeneca, Allergy Therapeutics, Bencard Allergie, Boehringer Ingelheim, DBV, LETI Pharma, Novartis, Orion Pharma, Sanofi Aventis, and Stallergenes. EC-J is a member of the ALK-Abelló Paediatric Advisory Board and has received fees for lectures and consulting activities from ALK-Abelló, Stallergenes-Greer, GSK, Thermofisher Scientific, and Allergopharma. JJ is a member of the ALK-Abelló Paediatric Advisory Board and has received fees for lectures and consulting activities from ALK-Abelló, Stallergenes-Greer, GSK, Novartis, AstraZeneca, and Zambon. MJ has received consultancy/speaker honoraria from ALK-Abelló, Berlin-Chemie, Stallergenes-Greer, GSK, and Viatris, and is a member of Advisory Boards for ALK-Abelló, Stallergenes-Greer, and Viatris., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

After ingestion rubber gloves harden and can produce dangerous complications. Therefore the choice of treatment is of utmost importance. Aside from a surgical approach, endoscopy should also be considered as a treatment option on a case-to-case basis or if not applicable as a useful diagnostic tool., Competing Interests: The authors declare that they have no competing interests., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Aim: To provide paediatricians with a summary of efficacy and safety of SQ sublingual immunotherapy (SLIT) tablets from phase three, randomised, double-blind, placebo-controlled trials in children and adolescents with allergic rhinitis or rhinoconjunctivitis, with and without asthma., Methods: PubMed searches were conducted and unpublished data were included if necessary., Results: Of the 93 publications, 12 were identified reporting 10 trials. One trial was excluded as paediatric-specific efficacy data were unavailable. The nine eligible trials evaluated grass, house dust mite, ragweed and tree SLIT tablets. Consistent reductions in allergic rhinitis or rhinoconjunctivitis symptoms and medication use were observed with SQ SLIT tablets versus placebo. In a five-year trial, sustained reduction of allergic rhinoconjunctivitis symptoms, asthma symptoms and medication use were observed with SQ grass SLIT tablet versus placebo. The number-needed-to-treat to prevent asthma symptoms and medication use in one additional child during follow-up was lowest in younger children. SQ SLIT tablets were generally well tolerated across trials., Conclusion: Evidence supports use of SQ SLIT tablets in children and adolescents with allergic rhinitis or rhinoconjunctivitis, with and without asthma. Long-term data demonstrate disease-modifying effects of SQ grass SLIT tablet and suggest the clinical relevance of initiating allergy immunotherapy earlier in the disease course., (© 2024 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: Allergic rhinitis (AR) and allergic asthma (AA) are chronic respiratory diseases that represent a global health problem. One aim of this study was to analyze the Health-related Quality of Life (HRQoL) of the patients in order to identify statistically significant influencing factors that determine HRQoL. Another aim was to assess and analyze data on cost-of-illness from a statutory health insurance perspective., Methods:  The EQ-5D-5L was used to evaluate the patients' HRQoL. To identify the factors influencing the HRQoL, a multinomial logistic regression analysis was conducted using groups based on the EQ-5D-5L index value as dependent variable. Routine data were analyzed to determine total healthcare costs., Results:  The average EQ-5D-5L index was 0.85 (SD 0.20). A high age, the amount of disease costs, low internal health-related control beliefs and high ozone exposure in the residential area were found to be statistically significant influencing factors for a low HRQoL, whereas low age, male sex and a good possibility to avoid the allergens were found to be statistically significant factors influencing a high HRQoL. On average, the study participants incurred annual costs of €3072 (SD: 3485), of which €699 (SD: 743) could be assigned to allergic respiratory diseases., Conclusions:  Overall, the patients in the VerSITA study showed a high level of HRQoL. The identified influencing factors can be used as starting points for improving the HRQoL of patients with allergic respiratory diseases. From the perspective of a statutory health insurance, per person expenditures for allergic respiratory diseases are rather low., (© 2023. The Author(s).)

Background: Numerous children present with early wheeze symptoms, yet solely a subgroup develops childhood asthma. Early identification of children at risk is key for clinical monitoring, timely patient-tailored treatment, and preventing chronic, severe sequelae. For early prediction of childhood asthma, we aimed to define an integrated risk score combining established risk factors with genome-wide molecular markers at birth, complemented by subsequent clinical symptoms/diagnoses (wheezing, atopic dermatitis, food allergy)., Methods: Three longitudinal birth cohorts (PAULINA/PAULCHEN, n = 190 + 93 = 283, PASTURE, n = 1133) were used to predict childhood asthma (age 5-11) including epidemiological characteristics and molecular markers: genotype, DNA methylation and mRNA expression (RNASeq/NanoString). Apparent (ap) and optimism-corrected (oc) performance (AUC/R2) was assessed leveraging evidence from independent studies (Naïve-Bayes approach) combined with high-dimensional logistic regression models (LASSO)., Results: Asthma prediction with epidemiological characteristics at birth (maternal asthma, sex, farm environment) yielded an ocAUC = 0.65. Inclusion of molecular markers as predictors resulted in an improvement in apparent prediction performance, however, for optimism-corrected performance only a moderate increase was observed (upto ocAUC = 0.68). The greatest discriminate power was reached by adding the first symptoms/diagnosis (up to ocAUC = 0.76; increase of 0.08, p = .002). Longitudinal analysis of selected mRNA expression in PASTURE (cord blood, 1, 4.5, 6 years) showed that expression at age six had the strongest association with asthma and correlation of genes getting larger over time (r = .59, p < .001, 4.5-6 years)., Conclusion: Applying epidemiological predictors alone showed moderate predictive abilities. Molecular markers from birth modestly improved prediction. Allergic symptoms/diagnoses enhanced the power of prediction, which is important for clinical practice and for the design of future studies with molecular markers., (© 2024 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

After the GINA update in 2019, the proportion of SMART therapy increased with evidence for better disease control in SMART patients compared to SABA alone https://bit.ly/3SSPX1C., Competing Interests: Conflict of interest: C.A. Hinze has nothing to disclose. Conflict of interest: R. Ehmann has nothing to disclose. Conflict of interest: M. Jandl has nothing to disclose. Conflict of interest: K. Milger reports fees for lectures or consultation from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis and Sanofi, all outside the submitted work. Conflict of interest: O. Schmidt reports fees for lectures or consultations from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis and Sanofi, all outside the submitted work. Conflict of interest: C. Schulz reports fees for lectures or consultations from AstraZeneca, Novartis and Sanofi, all outside the submitted work. Conflict of interest: D. Skowasch reports fees for lectures or consultation from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Janssen, MSD and Sanofi, all outside the submitted work. Conflict of interest: T. Welte and/or his institution received grants advisory/lecture/clinical trial fees and non-financial support from BMBF (German Ministry of Research and Education), AstraZeneca, GSK, Sanofi Aventis and Biotest, outside the submitted work. Conflict of interest: R. Buhl reports grants to Mainz University from Boehringer Ingelheim, GSK, Novartis, and Roche, as well as personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GSK, Novartis, Roche, Sanofi and Teva, all outside the submitted work. Conflict of interest: E. Hamelmann is funded by the BMBF (CHAMP, project number 01GL1742D) for characterisation of children and adolescents with severe asthma; he reports personal fees from ALK, Boehringer Ingelheim, GSK, Leti Pharma, Novartis, Nutricia, Sanofi and Stallergenes, all outside the submitted work. Conflict of interest: M. Idzko has received fees for lectures and/or advisory board meetings from Alk Pharma, AstraZeneca, Berlin-Chemie, Chiesi, CSL-Behring, Jansen & Jansen, Menarini, Novartis, Roche, Sanofi Aventis and Teva, all outside the submitted work. Conflict of interest: C. Taube has nothing to disclose. Conflict of interest: S. Korn has received fees for lectures and/or advisory board meetings from AstraZeneca, Chiesi, GSK, Novartis, Roche, Sanofi Aventis and Teva, all outside the submitted work. Conflict of interest: H. Suhling reports fees for lectures or consultation from AstraZeneca, GSK, Novartis and Sanofi, all outside the submitted work., (Copyright ©The authors 2024.)

Background: Button battery (BB) ingestions (BBI) are increasingly prevalent in children and constitute a significant, potentially life-threatening health hazard, and thus a pediatric emergency. Ingested BBs are usually charged and can cause severe symptom within 2 h. Discharged BBs ingestion is very rare and protracted symptom trajectories complicate diagnosis. Timely imaging is all the more important. Discharged BBs pose specific hazards, such as impaction, and necessitate additional interventions., Case Presentation: We present the case of a previously healthy 19-month-old girl who was admitted to our pediatric university clinic in Germany for assessment of a three-month history of intermittent, mainly inspiratory stridor, snoring and feeding problems (swallowing, crying at the sight of food). The child's physical examination and vital signs were normal. Common infectious causes, such as bronchitis, were ruled out by normal lab results including normal infection parameters, negative serology for common respiratory viruses, and normal blood gas analysis, the absence of fever or pathological auscultation findings. The patient's history contained no evidence of an ingestion or aspiration event, no other red flags (e.g., traveling, contact to TBC). Considering this and with bronchoscopy being the gold standard for foreign body (FB) detection, an x-ray was initially deferred. A diagnostic bronchoscopy, performed to check for airway pathologies, revealed normal mucosal and anatomic findings, but a non-pulsatile bulge in the trachea. Subsequent esophagoscopy showed an undefined FB, lodged in the upper third of the otherwise intact esophagus. The FB was identified as a BB by a chest X-ray. Retrieval of the battery proved extremely difficult due to its wedged position and prolonged ingestion and required a two-stage procedure with consultation of Ear Nose Throat colleagues. Recurring stenosis and regurgitation required one-time esophageal bougienage during follow-up examinations. Since then, the child has been asymptomatic in the biannual endoscopic controls and is thriving satisfactorily., Conclusion: This case describes the rare and unusual case of a long-term ingested, discharged BB. It underscores the need for heightened vigilance among healthcare providers regarding the potential hazards posed by discharged BBIs in otherwise healthy children with newly, unexplained stridor and feeding problems. This case emphasizes the critical role of early diagnostic imaging and interdisciplinary interventions in ensuring timely management and preventing long-term complications associated even to discharged BBs., (© 2024. The Author(s).)

Monitoring is a major component of asthma management in children. Regular monitoring allows for diagnosis confirmation, treatment optimization, and natural history review. Numerous factors that may affect disease activity and patient well-being need to be monitored: response and adherence to treatment, disease control, disease progression, comorbidities, quality of life, medication side-effects, allergen and irritant exposures, diet and more. However, the prioritization of such factors and the selection of relevant assessment tools is an unmet need. Furthermore, rapidly developing technologies promise new opportunities for closer, or even "real-time," monitoring between visits. Following an approach that included needs assessment, evidence appraisal, and Delphi consensus, the PeARL Think Tank, in collaboration with major international professional and patient organizations, has developed a set of 24 recommendations on pediatric asthma monitoring, to support healthcare professionals in decision-making and care pathway design., (© 2024 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Allergic rhinitis (AR) is a chronic inflammatory disease of the upper airway, which progresses into allergic asthma (AA) in up to 45% of children. This analysis aimed to investigate clinical and economic benefits of sublingual allergen immunotherapy (SLIT tablets) initiated early in childhood for the treatment of AR by quantifying the long-term reduction in new cases of AA., Methods: A Markov model was developed to estimate the long-term effects of SLIT tablets on the risk of developing asthma. Key parameters were primarily based on data from the GRAZAX® Asthma Prevention trial and included the age- and treatment-dependent risk of developing AA as well as annual probabilities of progression/remission in AR severity. Healthcare costs were estimated using data from the REACT study., Results: In a modelled cohort of children with moderate-to-severe seasonal AR initiated on SLIT tablets at ages 7 and 12, 24% and 29%, respectively, develop AA during a 20-year period. In comparison, when initiated at age 5, 19% develop AA. Additionally, initiation of SLIT tablets at age 5 is associated with a total healthcare cost of EUR 20,429 per patient, whereas initiation at ages 7 and 12 is associated with, respectively, EUR 21,050 and EUR 22,379 per patient 20 years after AR diagnosis., Conclusion: Initiation of SLIT tablets in early childhood is associated with a clinically meaningful and permanent reduction in new cases of AA and lower healthcare costs among children with AR. This finding supports the clinical relevance of initiating SLIT tablets early for children with AR to obtain long-term clinical benefits., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Severe, uncontrolled asthma and asthma exacerbations in children are associated with abnormal lung function and airway development, and increased risk of chronic obstructive lung disease in adulthood. The rationale for this post hoc analysis was to explore the relationship between changes in asthma exacerbation rates and lung function in children treated with dupilumab., Methods: This post hoc analysis included children aged 6 to 11 years with uncontrolled, moderate-to-severe type 2 asthma (blood eosinophils ≥150 cells/μL or fractional exhaled nitric oxide ≥20 ppb) who received dupilumab or placebo in the phase 3 LIBERTY ASTHMA VOYAGE study (NCT02948959). Endpoints were the proportion of patients achieving clinically meaningful improvements (≥5% or ≥10%) in pre-bronchodilator percent-predicted forced expiratory volume in 1 second (ppFEV 1 ) by Week 12, annualized severe asthma exacerbation rates from Week 12-52, and mean change from baseline in ppFEV 1 to Week 12., Results: At Week 12 of VOYAGE, 141/236 (60%) of children treated with dupilumab and 57/114 (50%) of children receiving placebo showed improvements of ≥5% in ppFEV 1 ; 106/236 (45%) children receiving dupilumab and 36/114 (32%) receiving placebo achieved improvements in ppFEV 1 ≥10%. During the Week 12-52 treatment period, dupilumab vs placebo significantly reduced severe exacerbation rates in all subgroups by 52-60% (all P <0.05). Dupilumab treatment resulted in rapid and sustained improvements in ppFEV 1 (Week 12 least squares mean difference [95% CI] vs placebo: 3.54 [0.30, 6.78] percentage points; P =0.03) in children who achieved improvements of ≥5%., Conclusion: Dupilumab vs placebo significantly improved pre-bronchodilator ppFEV 1 , with a higher proportion of patients achieving a clinically meaningful response at Week 12. Dupilumab also significantly reduced severe exacerbation rates, independent of pre-bronchodilator ppFEV 1 response at Week 12., Trial Registration: NCT02948959., Competing Interests: Theresa W Guilbert has received personal fees from AiCME, Amgen, AstraZeneca, Best Pharmaceuticals for Children Act (BPCA), Genentech, Novartis, OM Pharma, Polarean, Regeneron Pharmaceuticals Inc., and Sanofi, research grants from Amgen, AstraZeneca, GSK, NIH, Regeneron Pharmaceuticals Inc., and Sanofi, and royalties from UpToDate. Kevin R Murphy has acted as a speaker and/or advisory board member for AstraZeneca, GSK, Novartis, Genentech, Sanofi, and Regeneron Pharmaceuticals Inc. Eckard Hamelmann has acted as a speaker and/or advisory board member for Aimmune Therapeutics, ALK, AstraZeneca, Boehringer Ingelheim, GSK, HAL Allergy, Novartis, Nutricia, Sanofi, and Stallergenes Greer. Kristie Ross has received research grants from AstraZeneca, Boehringer Ingelheim, and GSK, and has acted as a consultant for AstraZeneca, Boehringer Ingelheim, and Sanofi. Atul Gupta has received grants/research support from Airosnett, Boehringer Ingelheim, GSK, and Novartis and has acted as an advisory board member and received panel fees from AstraZeneca, Boehringer Ingelheim, GSK, and Novartis. Alessandro Fiocchi has acted as advisory board member for Abbott, Danone, DBV Technologies, HiPP Organic, Novartis, and Stallergenes Greer, and has received research grants from Danone, Ferrero, HiPP Organic, and Sanofi. Juby A Jacob-Nara, Olivier Ledanois, and Paul J Rowe are Sanofi employees, and may hold stock and/or stock options in the company. Amr Radwan, Changming Xia, Rebecca Gall, and Yamo Deniz are Regeneron Pharmaceuticals Inc. employees and shareholders., (© 2024 Guilbert et al.)

Background and Objective: Positive bronchodilator reversibility (BDR) is a diagnostic criterion for asthma. However, patients with asthma may exhibit a negative BDR response. Aim: To describe the frequency of positive and Negative BDR response in patients with severe asthma and study associations with phenotypic characteristics., Methods: A positive BDR response was defined as an increase in FEV1 >200 mL and >12% upon testing with a short-acting ß-agonist., Results: BDR data were available for 793 of the 2013 patients included in the German Asthma Net (GAN) severe asthma registry. Of these, 250 (31.5%) had a positive BDR response and 543 (68.5%) a egative BDR response. Comorbidities significantly associated with a negative response were gastroesophageal reflux disease (GERD) (28.0% vs 40.0%, P<.01) and eosinophilic granulomatosis with polyangiitis (0.4% vs 3.0%; P<.05), while smoking history (active: 2.8% vs 2.2%; ex: 40.0% vs 41.7%) and comorbid chronic obstructive pulmonary disease (COPD) (5.2% vs 7.2%) were similar in both groups. Patients with a positive BDR response had worse asthma control (median Asthma Control Questionnaire 5 score, 3.4 vs 3.0, P<.05), more frequently reported dyspnea at rest (26.8% vs 16.4%, P<.001) and chest tightness (36.4% vs 26.2%, P<.001), and had more severe airway obstruction at baseline (FEV1% predicted, 56 vs 64, P<.001) and higher fractional exhaled nitric oxide (FeNO) levels (41 vs 33 ppb, P<0.05). There were no differences in diffusion capacity of the lung for carbon monoxide, single breath (% pred, 70% vs 71%). Multivariate linear regression analysis identified an association between positive BDR response and lower baseline FEV1% (P<.001) and chest tightness (P<.05) and a negative association between BDR and GERD (P<.05)., Conclusion: In this real-life setting, most patients with severe asthma had a negative BDR response. Interestingly, this was not associated with smoking history or COPD, but with lower FeNO and presence of GERD.

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., Competing Interests: O. Pfaar declares: Grants and/or personal fees and/or travel-support from ALK-Abelló, Allergopharma, Stallergenes Greer, HAL Allergy Holding B.V./HAL Allergie GmbH, Bencard Allergie GmbH/Allergy Therapeutics, Lofarma, ASIT Biotech Tools S.A., Laboratorios LETI/LETI Pharma, GlaxoSmithKline, ROXALL Medizin, Novartis, Sanofi-Aventis und Sanofi-Genzyme, Med Update Europe GmbH, streamedup! GmbH, Pohl-Boskamp, Inmunotek S.L., John Wiley and Sons, AS, Paul-Martini-Stiftung (PMS), Regeneron Pharmaceuticals Inc., RG Aerztefortbildung, Institut für Disease Management, Springer GmbH, AstraZeneca, IQVIA Commercial, Ingress Health, Wort&Bild Verlag, Verlag ME, Procter&Gamble, ALTAMIRA, Meinhardt Congress GmbH, Deutsche Forschungsgemeinschaft, Thieme, Deutsche AllergieLiga e.V., AeDA, Alfried-Krupp Krankenhaus, Red Maple Trials Inc., Königlich Dänisches Generalkonsulat, Medizinische Hochschule Hannover, ECM Expro&Conference Management, Technische Universität Dresden, Lilly, Paul Ehrlich Institut (PEI), FoMF GmBH, all outside the submitted work and within the last 36 months; and he is member of EAACI Excom, member of ext. board of directors DGAKI; coordinator, main- or co-author of different position papers and guidelines in rhinology, allergology and allergen-immunotherapy. E. Hamelmann declares: Research funding from the Bundesministeriums für Bildung und Forschung (BMBF) and the Landesministerien für Gesundheit (LMG) and for Forschung (LMF) of Nordrhein-Westfalen. He received honorarium for counseling from AImmune, ALK, Astra, GSK und SANOFI. C. Taube declares: No conflict of interest. M. Wagenmann declares: Lectures and adboards: ALK-Abelló, AstraZeneca, CSL Behring, Genzyme, GSK, HAL Allergie, Infectopharm, LETI Pharma, Novartis, Regeneron, Sanofi, Stallergenes; Research funding: ALK-Abelló, AstraZeneca, EU, GlaxoSmithKline, Novartis, Regeneron, Sanofi-Aventis, Takeda. B. Wedi declares: Honoraria for presentations, half-day advisory boards or travel/congress support from ALK-Abéllo, Bencard, Biocryst, CSL-Behring, HAL-Allergy, Novartis, Sanofi-Aventis, Takeda, ThermoFisherScientific. T. Werfel declares: grants from AbbVie, Beiersdorf, LEO, Novartis, Vortragstätigkeit: AbbVie, Allmiral, Galderma, Janssen, LEO, Lilly, Mylan/Viatris, Novartis, Pfizer, Sanofi/Regeneron; honorarium from Abbvie, Allmiral, LEO, Lilly, Mylan/Viatris, Novartis, Pfizer, Regeneron/Sanofi. D. Bartel declares: No conflict of interest.* A.Bonertz declares: No conflict of interest*. D. Hartenstein declares: No conflict of interest*. S. Kaul declares: No conflict of interest*. V. Mahler declares: No conflict of interest*. M. Worm declares: Receipt of honoraria or consultation fees by the following companies: Novartis Pharma GmbH, Sanofi-Aventis Deutschland GmbH, DBV Technologies S.A, Aimmune Therapeutics UK Limited, Regeneron Pharmaceuticals, Inc, Leo Pharma GmbH, AstraZenceca GmbH, ALK-Abelló Arzneimittel GmbH, Lilly Deutschland GmbH, Kymab Limited, Amgen GmbH, Abbvie eutschland GmbH & Co. KG, Pfizer Pharma GmbH, Mylan Germany GmbH (A Viatris Company), AstraZeneca GmbH, Lilly Deutschland GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, GlaxoSmithKline GmbH & Co. KG and FomF GmbH. *The views expressed in this paper are the personal views of the author as an expert in the field of allergology and may not be understood or quoted as being made on behalf of or reflecting the position of the respective national competent authority, the European Medicines Agency, or one of its committees or working parties. Table 1.DGAKI-PEI dialogue: Allergen immunotherapy (AIT) 2023 – key messages and next steps. TopicsKey messageNecessary further stepsS2k AIT guideline 2022The current literature contains an increasing number of methodologically high-quality studies on AIT. The growing evidence for the efficacy and safety of AIT will enable the current AIT guidelines to be updated to S3 level in the medium and long term.The increasing number of study results makes it possible to re-evaluate the AIT evidence through systematic meta-analyses to further develop the AIT guideline to S3 level. This will be an important step towards a “National Allergy Action Plan”.TAO – current status of the MA processThe TAO, which came into force in 2008, aims to transfer AIT products containing active ingredients from sweet grasses (excluding maize), birch, alder, hazel, house dust mites, bee venom, and/or wasp venom from existing named patient products into products with MA of proven quality, efficacy, and safety. For this purpose, clinical development programs with studies of appropriate methodological quality are carried out under the transitional provision of the TAO, the results of which must be available by 2026 at the latest in order to be included in the assessment by the higher federal authority (PEI).The data required for the approval of AIT products according to the modern methodological criteria of the TAO must be available by the end of the product-specific deadlines under the TAO at the latest; incomplete MA dossiers will result in the decline of a MA and loss of marketability in Germany. If there is no proof of clinical efficacy or if there are safety concerns, market access is stopped already during the ongoing TAO process before the maximum extension is granted or by refusing further batch releases.Challenges of pivotal studies in children and adolescentsThe PDCO of the EMA has provided a standard PIP after consultation with the manufacturers. According to this standard PIP, manufacturers are obliged to plan a long-term study in children for each product and to carry out a long-term study in adults and children for at least one product in their portfolio in order to create a data basis for the long-term efficacy of the AIT and to be able to extrapolate data from adults to children in the future if necessary. However, only a few clinical trials are currently being conducted in children and adolescents. The feasibility of long-term placebo-controlled studies in children has been the subject of controversial debate for years.An important goal for the use of AIT in children and adolescents is to have authorized products for which the indication of treatment in children is confirmed by the results of clinical trials in children and adolescents. To this end, alternative, feasible, and realistic study designs must be developed for this age group.MA of allergy diagnosticsThe portfolio of test allergens offered for allergy diagnostics is continuously decreasing. The reason given by the manufacturers is an imbalance between the costs of producing test allergens from rare allergen sources and the potential revenue from them.The manufacturing companies, authorities, allergology associations, doctors, and political decision-makers are called upon to develop a joint concept to prevent a possible undersupply of allergy diagnostics.AIT = allergen immunotherapy; DGAKI = German Society for Allergology and Clinical Immunology; EMA = European Medicines Agency; MA = marketing authorization; PDCO = Pediatric Committee; PEI = Paul-Ehrlich-Institut; PIP = pediatric investigation plan; TAO = Therapy Allergen Ordinance., (© Dustri-Verlag Dr. K. Feistle.)

Background: For therapy of severe asthma 5 monoclonal antibodies have been available in Germany up to November 2022, but no clear rules exist on choice of initial therapy, assessment of response, and switch., Objective: To assess current practice on all aspects of biologic therapy by specialists in Germany., Methods: A questionnaire was created by specialists for severe asthma, which was tested and modified by further experts. We invited 119 pulmonologists of the German Asthma Net (GAN) to complete the survey and used SoSci Survey and SPSS for data collection and analysis., Results: Forty-seven pulmonologists took part in the survey with a median annual number of patients treated with biologics of 35, 55% worked in an outpatient practice, and 40% in a hospital. Exacerbations and oral steroid use were the most important factors for the decision to start a biologic therapy. Accordingly, these parameters were also the most relevant for assessment of response. Most participants considered type-2 inflammation biomarkers and comorbidities (foremost CRSwNP and AD) for choosing initial biologic. Asthma Control Test (ACT) was the most common instrument for assessing status of disease control. There was no consensus on thresholds for response of pulmonary function tests including FEV1, FVC, and RV. Eighty-five percent of participants distinguished between "responders", "partial responders" and "non-responders". Comorbidities played an important role for the decision to switch to another biologic, eg, when initial therapy had insufficient effectiveness on CRSwNP., Conclusion: This study provides a detailed insight into current opinions and practice of biologic use in severe asthma in Germany., Competing Interests: HS reports fees for lectures or consultations from Astrazeneca, GSK, Novartis, Sanofi all outside the submitted work. DS reports fees for lectures or consultations from AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, GSK, Janssen, MSD, Sanofi, all outside the submitted work. KCB reports speaker fees from AstraZeneca, GSK, Novartis, Sanofi all outside the submitted work. CM no conflicts of interest. RB reports consulting fees or honoraria for lectures from ALK, AstraZeneca, Berlin-Chemie, Boehringer-Ingelheim, Chiesi, Cipla, GSK, Novartis, Roche, Sanofi, and TEVA, and grants to Mainz University Hospital for research or clinical trials, or both from Boehringer Ingelheim, GSK, Novartis, and Roche. RE no conflicts of interest. EH is funded by the German Ministry of Education and Research (BMBF) (CHAMP, Project Number: 01GL1742D) for characterisation of children and adolescents with severe asthma. He reports personal fees from ALK, Boehringer Ingelheim, GSK, Leti Pharma, Novartis, Nutricia, Sanofi, and Stallergenes all outside the submitted work. MI reports personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, CSL-Behring, Menarini, MSD, Novartis, Roche, Sanofi, all outside the submitted work. MJ no conflicts of interest. CS received personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Sanofi, all outside the submitted work. OS reports speaker fees from AstraZeneca, Novartis, Sanofi and Boehringer Ingelheim, all outside the submitted work. CT no conflicts of interest. KM reports speaker fees from AstraZeneca, GSK, Novartis, Sanofi, all outside the submitted work. SK reports speaker fees from AstraZeneca, GSK, Novartis, Sanofi, all outside the submitted work., (© 2023 The Authors.)

Introduction: The Severe Asthma Registry, founded by German Asthma Net (GAN) in 2011, is a prospective registry recording clinical parameters from participating centers in Germany, Austria and Switzerland. This article presents the baseline characteristics of severe asthma patients from Austrian centers., Methods: We analyzed the baseline visit data of all patients recruited to the GAN Severe Asthma Registry from participating Austrian centers., Results: Baseline visit data were available for 214 Austrian severe asthma patients from 6 Austrian centers from 2013 to 2022. Mean age was 53.7 years. Mean BMI was 26.4 kg/m2. More than a third (37.4%) of all patients had daily daytime asthma symptoms at baseline and had to use their reliever medication at least once per day. Forty-one percent of patients were classified as uncontrolled according to GINA and 24.8% as partially controlled at baseline visit. The median annual exacerbation frequency was 3 in the previous 12 months. At the time of baseline visit, 23.4% of all patients had regular treatment with oral corticosteroids. Furthermore, 23.9% had received any severe asthma monoclonal antibody prior to the baseline visit. There were no notable differences in baseline characteristics between patients categorized by smoking history or measurable type 2 inflammation., Conclusions: This study provides the first multi-center characterization of Austrian severe asthma patients. Patients in this cohort had better asthma control and less frequent exacerbations compared to most international registries., Competing Interests: Declaration of competing interest Andreas Renner: None. Slagjana Stoshikj: Speaker fees from AstraZeneca, all outside the submitted work. Wolfgang Pohl: Speaker fees from AstraZeneca, Chiesi, GSK, Novartis, and Sanofi, all outside the submitted work. Christina Bal: speaker fees from AstraZeneca and IVEPA, all outside the submitted work. Matthias Reisinger: None. Judith Löffler-Ragg: None. Angela Zacharasiewicz: None. Roland Buhl: Grants to Mainz University and personal fees from Boehringer Ingelheim, GSK, Novartis, and Roche, as well as personal fees from AstraZeneca, Chiesi, Cipla, Sanofi, and Teva, all outside the submitted work. Eckard Hamelmann: funded by the German Ministry of Education and Reserch (BMBF) as consortional partner in CHAMP (01GL1742D) for research in severe asthma in children. Christian Taube: None. Stephanie Korn: speaker fees from AstraZenca, GSK, Novartis, and Sanofi, all outside the submitted work. Marco Idzko: lecture fees from AstraZeneca, Bayer, Berlin-Chemie, Boehringer Ingelheim, Chiesi, CSL-Behring, GSK, Menarini, MSD, Novartis, Roche, Sanofi, and Thermofischer; and advisory board fees from Alk-Pharma, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, CSL-Behring, GSK, Novartis, and Sanofi, all outside the submitted work., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Asthma is increasingly recognized as heterogeneous, characterized by different endotypes, with obesity not only a distinct phenotype but a risk factor for severe asthma., Objective: We sought to understand the associations of obesity with relevant parameters of severe asthma, including asthma control, disease burden, and lung function., Methods: The German Asthma Net registry is a multicenter international real-life registry capturing long-term follow-up data. This analysis included 2213 patients (52 ± 16 years, 58% female, 29% with obesity [body mass index ≥30 kg/m 2 ], 4.2 ± 4.3 exacerbations/year). The primary analysis assessed relationships between BMI and variables through univariate tests, followed by a multiple regression model. Secondary outcomes regarded clinically relevant variables in relation to weight groups., Results: Patients with obesity were more frequently female, more likely to have depression and gastroesophageal reflux, and suffered from worse asthma control, lower quality of life, reduced static lung volumes, more pronounced hypoxemia, and higher blood neutrophil counts, all statistically significant. Blood eosinophils, exhaled nitric oxide, and total IgE were independent of obesity. In the multiple regression analysis, obesity was significantly associated with more frequent reflux and depression, reduced static lung function values, older age, poor asthma control, and long-acting muscarinic antagonist therapy, and inversely associated with bronchiectasis and nonsmoking status., Conclusion: In this large, well-characterized cohort, we identified the association of obesity with a significantly higher disease burden and a similar portfolio of inflammation type 2 markers in patients with and without obesity; therefore, patients with obesity seem similarly eligible for the treatment with biologics targeting these disease endotypes., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: In allergic asthma patients, one of the more common phenotypes might benefit from allergen immunotherapy (AIT) as add-on intervention to pharmacological treatment. AIT is a treatment with disease-modifying modalities, the evidence for efficacy is based on controlled clinical trials following standardized endpoint measures. However, so far there is a lack of a consensus for asthma endpoints in AIT trials. The aim of a task force (TF) of the European Academy of Allergy and Clinical Immunology (EAACI) is evaluating several outcome measures for AIT in allergic asthma., Methods: The following domains of outcome measures in asthmatic patients have been evaluated for this position paper (PP): (i) exacerbation rate, (ii) lung function, (iii) ICS withdrawal, (iv) symptoms and rescue medication use, (v) questionnaires (PROMS), (vi) bronchial/nasal provocation, (vii) allergen exposure chambers (AEC) and (viii) biomarkers., Results: Exacerbation rate can be used as a reliable objective primary outcome; however, there is limited evidence due to different definitions of exacerbation. The time after ICS withdrawal to first exacerbation is considered a primary outcome measure. Besides, the advantages and disadvantages and clinical implications of further domains of asthma endpoints in AIT trials are elaborated in this PP., Conclusion: This EAACI-PP aims to highlight important aspects of current asthma measures by critically evaluating their applicability for controlled trials of AIT., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Hymenoptera venom (HV) is injected into the skin during a sting by Hymenoptera such as bees or wasps. Some components of HV are potential allergens and can cause large local and/or systemic allergic reactions (SAR) in sensitized individuals. During their lifetime, ~ 3% of the general population will develop SAR following a Hymenoptera sting. This guideline presents the diagnostic and therapeutic approach to SAR following Hymenoptera stings. Symptomatic therapy is usually required after a severe local reaction, but specific diagnosis or allergen immunotherapy (AIT) with HV (VIT) is not necessary. When taking a patient's medical history after SAR, clinicians should discuss possible risk factors for more frequent stings and more severe anaphylactic reactions. The most important risk factors for more severe SAR are mast cell disease and, especially in children, uncontrolled asthma. Therefore, if the SAR extends beyond the skin (according to the Ring and Messmer classification: grade > I), the baseline serum tryptase concentration shall be measured and the skin shall be examined for possible mastocytosis. The medical history should also include questions specific to asthma symptoms. To demonstrate sensitization to HV, allergists shall determine concentrations of specific IgE antibodies (sIgE) to bee and/or vespid venoms, their constituents and other venoms as appropriate. If the results are negative less than 2 weeks after the sting, the tests shall be repeated (at least 4 - 6 weeks after the sting). If only sIgE to the total venom extracts have been determined, if there is double sensitization, or if the results are implausible, allergists shall determine sIgE to the different venom components. Skin testing may be omitted if in-vitro methods have provided a definitive diagnosis. If neither laboratory diagnosis nor skin testing has led to conclusive results, additional cellular testing can be performed. Therapy for HV allergy includes prophylaxis of reexposure, patient self treatment measures (including use of rescue medication) in the event of re-stings, and VIT. Following a grade I SAR and in the absence of other risk factors for repeated sting exposure or more severe anaphylaxis, it is not necessary to prescribe an adrenaline auto-injector (AAI) or to administer VIT. Under certain conditions, VIT can be administered even in the presence of previous grade I anaphylaxis, e.g., if there are additional risk factors or if quality of life would be reduced without VIT. Physicians should be aware of the contraindications to VIT, although they can be overridden in justified individual cases after weighing benefits and risks. The use of β-blockers and ACE inhibitors is not a contraindication to VIT. Patients should be informed about possible interactions. For VIT, the venom extract shall be used that, according to the patient's history and the results of the allergy diagnostics, was the trigger of the disease. If, in the case of double sensitization and an unclear history regarding the trigger, it is not possible to determine the culprit venom even with additional diagnostic procedures, VIT shall be performed with both venom extracts. The standard maintenance dose of VIT is 100 µg HV. In adult patients with bee venom allergy and an increased risk of sting exposure or particularly severe anaphylaxis, a maintenance dose of 200 µg can be considered from the start of VIT. Administration of a non-sedating H1-blocking antihistamine can be considered to reduce side effects. The maintenance dose should be given at 4-weekly intervals during the first year and, following the manufacturer's instructions, every 5 - 6 weeks from the second year, depending on the preparation used; if a depot preparation is used, the interval can be extended to 8 weeks from the third year onwards. If significant recurrent systemic reactions occur during VIT, clinicians shall identify and as possible eliminate co-factors that promote these reactions. If this is not possible or if there are no such co-factors, if prophylactic administration of an H1-blocking antihistamine is not effective, and if a higher dose of VIT has not led to tolerability of VIT, physicians should should consider additional treatment with an anti IgE antibody such as omalizumab as off lable use. For practical reasons, only a small number of patients are able to undergo sting challenge tests to check the success of the therapy, which requires in-hospital monitoring and emergency standby. To perform such a provocation test, patients must have tolerated VIT at the planned maintenance dose. In the event of treatment failure while on treatment with an ACE inhibitor, physicians should consider discontinuing the ACE inhibitor. In the absence of tolerance induction, physicians shall increase the maintenance dose (200 µg to a maximum of 400 µg in adults, maximum of 200 µg HV in children). If increasing the maintenance dose does not provide adequate protection and there are risk factors for a severe anaphylactic reaction, physicians should consider a co-medication based on an anti-IgE antibody (omalizumab; off-label use) during the insect flight season. In patients without specific risk factors, VIT can be discontinued after 3 - 5 years if maintenance therapy has been tolerated without recurrent anaphylactic events. Prolonged or permanent VIT can be considered in patients with mastocytosis, a history of cardiovascular or respiratory arrest due to Hymenoptera sting (severity grade IV), or other specific constellations associated with an increased individual risk of recurrent and/or severe SAR (e.g., hereditary α-tryptasemia). In cases of strongly increased, unavoidable insect exposure, adults may receive VIT until the end of intense contact. The prescription of an AAI can be omitted in patients with a history of SAR grade I and II when the maintenance dose of VIT has been reached and tolerated, provided that there are no additional risk factors. The same holds true once the VIT has been terminated after the regular treatment period. Patients with a history of SAR grade ≥ III reaction, or grade II reaction combined with additional factors that increase the risk of non response or repeated severe sting reactions, should carry an emergency kit, including an AAI, during VIT and after regular termination of the VIT., Competing Interests: The conflicts of interest were recorded using the AWMF portal interessenerklaerungonline.de, evaluated by the conflict of interest officer of the DGAKI (for details see the guideline report) and tabulated in accordance with the AWMF. The guideline report and conflict of interest table are available at www.awmf.org/leitlinien/. AbbreviationsAbbreviations.AAIAdrenaline auto-injectorABDWorking Group for Occupational and Environmental Dermatology e.V.AeDAMedical Association of German AllergologistsAITAllergen immunotherapyAWMFAssociation of the Scientific Medical SocietiesbSTBaseline serum tryptase concentrationCCDCross-reactive carbohydrate determinantsDDGGerman Society of DermatologyDELBIGerman Guideline Assessment ToolDGAKIGerman Society for Allergology and Clinical ImmunologyDGHNO-KHCGerman Society of Oto-Rhino-Laryngology, Head and Neck SurgeryDGKJGerman Society of Pediatrics and Adolescent MedicineDGPGerman Respiratory SocietyEAACIEuropean Academy of Allergology and Clinical ImmunologyGPASociety for Pediatric Allergy and Environmental MedicineH1Histamine 1HBHoney beeHIVHuman immunodeficiency virusHVHymenoptera venomHVAHymenoptera venom allergyHVSHymenoptera venom sensitizationHV-sIgEHymenoptera venom-specific IgE antibodiesILInterleukinÖGAIAustrian Society for Allergy and ImmunologySARSystemic allergic reactionssIgESpecific IgE antibodiesVITVenom immunotherapyVVVespid venom Table 1.Participating organizations and delegated representatives. German Respiratory Society (DGP)Dr. Wolfgang Sieber Norbert K. MülleneisenGerman Society for Allergology and Clinical Immunology (DGAKI)Prof. Dr. Margitta Worm Prof. Dr. Knut Brockow Univ.-Prof. Dr. Thilo Jakob Prof. Dr. Bettina Wedi Prof. Dr. Franziska RuëffGerman Society of Dermatology (DDG)Prof. Dr. Ulf Darsow Prof. Dr. Regina Treudler Prof. Dr. Wolfgang Pfützner Dr. Jörg FischerAustrian Society for Allergy and Immunology (ÖGAI)Prof. Dr. Wolfram Hötzenecker Priv.-Doz. Mag. Dr. Stefan WöhrlMedical Association of German Allergists (AeDA)Prof. Dr. Randolf Brehler Prof. Dr. Thomas Fuchs Univ.-Prof. Dr. Hans Merk Prof. Dr. Ludger KlimekGerman Society of Oto-Rhino-Laryngology, Head and Neck Surgery (DGHNO-KHC)Priv.-Doz. Dr. Adam Chaker Priv.-Doz. Dr. Sven BeckerSociety for Pediatric Allergy and Environmental Medicine (GPA)Dr. Sunhild Gernert Dr. Michael Gerstlauer Dr. Irena NeustädterArbeitsgemeinschaft für Berufs- und Umweltdermatologie e.V. (Association for Occupational and Environmental Dermatology, ABD)Prof. Dr. Andrea Bauer Prof. Dr. Christoph SkudlikGerman Society for Pediatrics and Adolescent Medicine (DGKJ)Dr. Lars Lange Prof. Dr. Eckhard Hamelmann Table 2.Recommendation strengths. StrengthSyntaxStrong recommendationShallWeak recommendationShouldOpen recommendationCan Table 3.Severity scale for the classification of anaphylactic reactions (according to Ring and Messmer) [7]*. GradeSkin#AbdomenRespiratory tractCardiovascular systemIItch Flush Urticaria Angioedema–––IIItch Flush Urticaria AngioedemaNausea CrampsRhinorrhea Hoarseness DyspneaTachycardia (increase of heart rate ≥ 20/minutes) Hypotension (decrease of systolic blood pressure ≥ 20 mmHg) ArrhythmiaIIIItch Flush Urticaria AngioedemaVomiting DefecationLaryngeal Edema Bronchospasm CyanosisShock Loss of consciousnessIVItch Flush Urticaria AngioedemaVomiting DefecationRespiratory arrestCardiac arrest #Generalized skin symptoms apart from the sting area; *Classification is based on the most severe symptoms encountered (none of the symptoms is obligatory). Box 1.Recommendations on the indication of allergological testing (skin test, IgE detection). Strength of consensus1. If there is a history of a general allergic reaction after a Hymenoptera sting, allergy testing shall be performed.Strong2. Without evidence of a general allergic reaction after Hymenoptera sting(s) („exclusion of insect venom allergy“), no diagnostic procedures should be undertaken.Majority3. If therapeutic consequences are unlikely because of only a mild systemic reaction limited to the skin, allergy testing should be avoided.Majority Table 4.Questionnaire for taking medical history in case of a systemic insect sting reaction. Insect venom allergy questionnaireDatePatient:       female □       male □Weight:       kgHeight:       cmSeverity of reaction1st sting2nd sting3rd stingSymptoms1st sting2nd sting3rd stingSting date (day/month/year)Itching all over the bodyInsectBeeHeat sensationVespulaRash all over the bodyOtherTingling in hands/feetCertainFace swellingUncertainRunny noseLocalization of the stingRedness of the eye conjunctivaInterval until symptom onset (min/h)Lump/tightness in the throatSite and circumstances of the eventCough irritationPhysical effort?Shortness of breathMental stress when reacting?NauseaDid the sting remain in the skin?VomitingOccupation?Urinary (stool) urgency/dischargeOutdoor activities?DizzinessLater tolerated stings?       Yes □       No □Feeling of weakness (circulatory disorder)Beekeeper?       Yes □       No □HeadacheIs there a beekeeper in the neighborhood?       Yes □       No □Unconsciousness (duration)OtherOtherHay fever □       Asthma □       Atopic eczema □Treatment: self/doctorComorbiditiesAdrenalineGlucocorticoidAntihistaminesIntravenous fluidsHospital admissionMedication at reaction (R) or currently (C)Intensive Care UnitRecovery after (hour(s)/day(s)/week(s))Information sheet handed out       Yes □       No □Emergency kit available       Yes □       No □Adrenaline auto-injector (trade name)Other medications: Table 5.Clues about the kind of insect causing the reaction [44]. BeeVespidRather “peaceful” (except at the hive)Rather “aggressive”, sting can also occur in “passing flight”.Main flying season spring to late summer(even on warm winter days!)Main flying season summer until late autumnAfter a sting, the stinger usually remains in the skinSting usually does not remain in the skin (exceptions are possible due to shearing, if the insect was trapped, for example)Occurrence mainly in the vicinity of bee hives, flowers, and cloverOccurrence mainly in the vicinity of food or garbage Table 6.Variables increasing exposure risk. (Hobby) beekeepers, family members and neighbors of beekeepersProfessions such as fruit or bakery seller, forestry worker, gardener, firefighter, farmer, roofer, construction workerIntensive practice of outdoor activities Box 2.Recommendations on the recording of risk factors. Strength of consensus4. Risk factors for an increased sting risk shall be obtained when taking the medical history.Strong5. The medical history shall capture possible risk factors for more severe anaphylaxis.Strong6. If a systemic allergic reaction has not only affected the skin, basic diagnosis for the detection of mastocytosis shall involve a skin inspection to detect mastocytosis of the skin and a determination of basal serum tryptase concentration.Consensus Box 3.Recommendations on the in-vitro diagnostics of sIgE against Hymenoptera venoms and their components. Strength of consensus7. A determination of specific IgE antibodies against bee and/or Vespula venom/components shall be performed; in case of a suspected sting reaction caused by other Hymenoptera, this determination shall be also directed against the corresponding other venom.Strong8. In the case of negative test results obtained shortly (less than 2 weeks) after the sting reaction, the tests shall be repeated (no sooner than 4 – 6 weeks after the sting reaction).Strong9. In case of double sensitization against whole bee and Vespula venom extract, or if an implausible result is suspected, testing of sIgE against recombinant components shall be performed.Strong Box 5.Recommendations on the determination of bST. Strength of consensus12. All patients with anaphylaxis (severity grade ≥ II) after a Hymenoptera sting shall have a determination of bST.Strong13. In case of elevated serum tryptase measured within 24 hours after the acute sting event, a control measurement shall be performed in the symptom-free interval.Strong14. If the bST concentration is permanently elevated (> 20 µg/L), further diagnostic measures shall be performed to clarify mastocytosis.Consensus Box 6.Recommendations on skin tests with Hymenoptera venoms. Strength of consensus15. If an unequivocal diagnosis is obtained by in-vitro diagnostics, a skin test can be omitted.Consensus16. The skin test can be performed as a titrated prick and/or intradermal test.Strong Box 7.Recommendation on sting provocation in adults. Strength of consensus17. Diagnostic sting provocations (before the start of VIT) or sting provocations after completion of VIT shall not be performed.Consensus Box 8.Recommendations on large local sting reactions. Strength of consensus18. Acute treatment can be symptomatic using non-sedating antihistamines, cooling compresses, topical and/or systemic glucocorticoids.Consensus19. Antibiotic therapy for the treatment of non-infectious lymphangitis or lymphadenopathy shall not be performed.Consensus Box 9.Recommendations for long-term care in patients with a history of a large local reaction. Strength of consensus20. VIT shall not be performed for large local reactions.Strong Table 9.Emergency medication for self-treatment in children and adults [43]. Adrenaline auto-injector for intramuscular application, weight-adapted:7.5 – 25 kg BW or 15 – 30 kg BW150 μg*25 – 50 kg BW or 30 – 50 kg BW300 μg*> 50 kg BW300 – 500# – 600# μg– H1 receptor-blocking antihistamine, according to patient age and preference, orally as liquid or (melting) tablet – The dose of the respective antihistamine can be increased off-label up to four times the single dose – For dimetinden drops, a weight-adapted dosage of the IV formulation can be recommended as an oral dose (Table 8)Glucocorticoid, according to patient age and preference, rectally or orally (as liquid or tablet) with 50 – 100 mg prednisolone equivalentIn case of known bronchial asthma or previous reaction with bronchospasm additionally β2-adrenoceptor agonist 2 puffsIf there is a history of laryngeal edema, additionally: inhaled adrenaline preparation with spray head for drug vial (to be specifically requested from pharmacist)Note: An emergency first aid kit should include an anaphylaxis passport with written instructions for use of the components. *According to the respective approval status for the prescribed autoinjector; BW = body weight; #not available in Austria; IV = intravenous. Table 11.Recommendations for prescribing AAIs in patients with insect venom allergy. Absolute indication– Children and adults with mastocytosis and/or elevated basal serum tryptase levels: before, during, and after completion of immunotherapy– Untreated children and adults with more than cutaneous/mucosal SAR (i.e., grade I anaphylaxis) and at high risk of re-exposure– During VIT: in children and adults with more than cutaneous/mucosal SARs (i.e., grade I anaphylaxis) when there are additional risk factors* for non-response to immunotherapy– After completion of regular VIT in children and adults presenting with more than cutaneous/mucosal SAR (i.e., grade I anaphylaxis) and if there are additional risk factors* for non-response to VIT.Relative indication– Long distance to medical care and/or high risk of exposure and/or impaired quality of life– After completion of regular VIT in children and adults with cutaneous/mucosal reactions (grade I) who are at increased risk of exposure and/or have had a short duration of immunotherapy (< 3 years)– Individual patient request*Risk factors in this context are severe insect venom anaphylaxis (grade III or IV), high risk of exposure (e.g., beekeeper), (repeated) systemic reaction under immunotherapy, mastocytosis, or elevated baseline serum tryptase above 20 µg/L . For adults, bee venom allergy is also considered a risk factor. Table 10.Patient information sheet “How to behave in the event of a sting”. – Keep calm! If attacked by bees or wasps, protect the head with arms or clothing. The retreat must not be hectic, but very slow. Insects release pheromones when stinging, which also motivate other insects to sting. Therefore, the sting site should be covered with the hand in the event of a sting.– Try to selectively inform bystanders about the sting event and its possible consequences.– Immediately remove any stinger remaining in the skin. When doing so, do not squeeze the sting apparatus with your fingers, but scrape it away to the side.Emergency medication in case of mild reactions limited to the skin:– If venom-specific immunotherapy has not yet been administered, oral medication is taken immediately after the sting, even in the absence of symptoms, according to the doctor‘s instructions: – Antihistamines – Steroids– After a successful allergen-specific immunotherapy*, medication should only be taken if, contrary to expectations, systemic symptoms do occur. For symptoms limited to the skin, oral medications are used first, and for more extensive reactions, the adrenaline auto-injector is used.Emergency measures in case of shortness of breath, swelling in the mouth/throat region or of circulatory problems:– Inject adrenaline laterally into the lateral thigh– In case of asthma, inhale 2 puffs of the emergency spray– Correct positioning (shortness of breath→ raised upper body, circulatory problems head-down position, unconsciousness→ stable side position)– Take oral medications only if swallowing is possible without problems– Alert an emergency doctor immediately!*Your allergist has confirmed that success of an allergen-specific immunotherapy is highly likely based on a tolerated sting provocation or field sting. Box 10.Recommendations on the emergency kit. Strength of consensus21. In patients with a history of a severity grade I reaction, and in the absence of other risk factors, the prescription of an AAI is not required. However, the AAI can be prescribed in special situations (e.g., high risk of exposure, long distance to medical care, limitation of quality of life).Consensus22. In patients with a history of anaphylaxis (grade II – IV) or of a severity grade I reaction in combination with a high risk of re-exposure, an emergency kit including an AAI shall be prescribed until allergy diagnosis and assessment are complete.Consensus23. After successful initiation of VIT and reaching the maintenance dose at the maintenance interval, the prescription of an AAI can be waived in patients with a history of a systemic sting reaction (severity grade I – II) and in the absence of other risk factors for VIT failure.Consensus24. After successful completion of VIT, the prescription of an AAI can be waived in patients with a history of a systemic sting reaction (severity grade I – II) and in the absence of other risk factors for VIT failure.Consensus25. Patients with grade III or IV anaphylaxis or patients who present with other risk factors for VIT failure shall carry an emergency kit with an AAI during and after VIT. Risk factors include: high risk of exposure (e.g., beekeepers), repeated SAR on immunotherapy, mast cell disease, and/or elevated basal serum tryptase (> 20 µg/L). For adults, bee venom allergy is also considered a risk factor.Consensus Box 11.Recommendation on ACE inhibitors. Recommendation on ACE inhibitorsStrength of consensus26. If there is no firm need for the use of ACE inhibitors and if their switching is straightforward, the drug may be replaced by another medication.Consensus Box 12.Recommendations on the indication of Hymenoptera VIT. Strength of consensus27. VIT shall be performed in patients with a history of an anaphylactic reaction of severity grade ≥ II according to Ring and Messmer, and with evidence of IgE-mediated sensitization to the culprit venom.Strong28. If there is increased exposure, if there are relevant risk factors for a particularly severe anaphylaxis, and/or if quality of life would be significantly impaired without VIT, VIT shall be performed even if there is only a history of an exclusively cutaneous SAR.Strong Table 12.Contraindications of VIT. Uncontrolled asthmaActive malignant neoplastic diseasesSevere active systemic autoimmune diseases and severe immunodeficienciesInsufficient complianceUntreated, chronic infection (e.g., active HIV, viral hepatitis) Box 19.Recommendation on sting provocation. Strength of consensus43. Sting provocation can be performed on a case-by-case basis to verify the success of therapy. Provocation shall only be performed in patients who have reached the planned maintenance dose and tolerate VIT.Strong Table 16.Variables associated with treatment failure/success [59]. Risk factors or predictors of treatment failure– Bee venom > Vespula venom– Repeated systemic allergic reactions while being on VIT– Mastocytosis, increased bSTProtective factors– Higher treatment dose (also double VIT)– Extended treatment time Box 20.Recommendations on the management of systemic allergic sting reactions while being on maintenance therapy. Strength of consensus44. If treatment failure is evident during ACE inhibitor therapy, discontinuation of the ACE inhibitor should be considered.Strong45. If there is evidence of overt therapeutic failure, maintenance venom dose shall be increased in adults to up to 200 µg or above (maximum 400 µg), and in children to up to 200 µg.Strong46. If protection cannot be established by increasing the maintenance dose and if there are co-factors for severe anaphylaxis, co-medication with an IgE antibody (omalizumab; off-label use) should be considered during the relevant insect flight period.Strong Figure 1.Apis mellifera (honey bee).Figure 2.Vespula germanica on ivy.Figure 3.Vespula vulgaris on a plum.Figure 4.Dolichovespula media on the earth.Figure 5.Dolichovespula saxonica.Figure 6.Polistes dominulus while drinking.Figure 7.Vespa crabro (hornet) on a leaf.Figure 8.Bombus hortorum (bumblebee).Figure 9.Stepwise diagnosis using whole venoms (bee venom (BV) and Vespula venom (VV)) and allergen components of bee venom (Api m) and Vespula venom (Ves v).Figure 10.Algorithm for the diagnosis of suspected Hymenoptera venom allergy. Table 7.Allergologically significant components of bee and Vespula venom (http://www.allergome.org). Apis melliferaVespula speciesApi m 1Phospholipase A2a#Ves v 1Phospholipase A1a#Api m 2Hyaluronidasea,b#Ves v 2Hyaluronidasea,bApi m 3Acid phosphatasea#Ves v 3Dipeptidyl peptidasea,b#Api m 4Melittinc#Ves v 5Antigen 5aApi m 5Dipeptidyl peptidasea,b#Ves v 6VitellogeninbApi m 6Protease inhibitorApi m 7CUB Serine ProteaseApi m 8CarboxylesteraseApi m 9Serine carboxypeptidaseApi m 10Icarapinea#Api m 11Gellée royal proteinApi m 12VitellogeninbaMajor allergen: More than 50% of the patients tested show sensitization to the allergen in question; bcross-reacting venom allergens. The sIgE reactivity against bee venom hyaluronidase can be interpreted as a marker for bee venom-specific sensitization. In contrast, sIgE reactivity against Vespula venom hyaluronidase is mainly based on reactivity against cross-reactive carbohydrate determinants; cresearch purposes; #IgE detection kits for single detection are commercially available (singleplex). Table 8.Measures to prevent Hymenoptera stings. – Repellents (chemical insect repellents) do not provide protection.– When being outdoors, avoid eating or drinking food, picking fruits or flowers, staying near waste baskets, trash cans, animal enclosures, or fallen fruit, and using perfume or scented cosmetics. Wash hands and wipe mouth after eating.– Do not drink from bottles or beverage cans, cover drinking glasses, use straws.– Do not scare insects away from food sources, especially not with hectic movements.– Keep skin largely covered by clothing (at least when gardening). Do not walk barefoot, or use open foot wear. When riding a motorcycle, wear gloves and motorcycle clothing close to the skin. Open bicycle helmets are to be provided with a net.– Be especially careful on days with hot and humid weather, as insects are aggressive during such weather.– Avoid wearing loose-fitting, light garments, e.g., loose skirts or dresses with dark colors; try to wear dresses with light colors.– Keep apartment windows closed during the day or secure them with insect nets. No light in the evening when windows are open, as hornets are nocturnal and then prefer to fly towards light sources.– Watch for hidden insects (especially in bed or shoes).– Beehives must be avoided. Nests near a permanent residence must be removed (by beekeeper or fire department).– Wasp traps or repellent sprays can be helpful.– When approached by insects or being near the nest, avoid hectic or flapping movements, pull back slowly! Nests must not be shaken. Do not breathe into a flight hole. Box 4.Recommendations on IgE determination against Hymenoptera venoms and their components. Strength of consensus10. If HVA requiring absolutely necessary treatment is suspected, and if results from IgE detection methods for venom components and whole venom and from skin tests are not conclusive, cellular tests can be performed.Consensus11. Determination of specific IgG antibodies to Hymenoptera venom should not be used to assess the need for treatment of HVA.Consensus Table 13.Schemes* for updosing to 100 µg insect venom. PeriodHymenoptera venom dose in µgDayHourUltra-rushRush (3 days)Cluster100.010.020.020.50.10.04110.080.041.5100.22200.40.082.5400.838023.544.0820100822041004068030802100WeekHour100.210.4200.812404185106207408809100*There are numerous modifications to these updosing schemes in which the maintenance dose of 100 µg can be reached in a shorter or longer time, and which contain even more or fewer intermediate steps. Table 14.Updosing schemes with aqueous Hymenoptera venom [according to Ruëff (scheme 1) or Bauer (scheme 2)] to > 100 µg). Scheme 1Scheme 2DayMinutesDose (µg)Dose (µg)10100100+302040+30306020150100+3020100+30303200 Table 15.Management of repeated systemic allergic reactions to Hymenoptera VIT. 1. Identification (and, where possible, elimination) of risk factors for SARs in VIT.   Drugs    Concomitant inhalant or food allergy    Chronic infection, other general diseases    Physical exertion on the day of injection   Optimization of drug therapy at the reacting organ (for example, an anti-obstructive therapy for asthmatic reactions).2. Adjunctive therapy with H1-blocking antihistamine3. Continued administration of the highest tolerated dose of HV for 3 months, then starting updosing again4. Pretreatment with an anti-IgE antibody (300 mg omalizumab; off-label use): e.g., 5, 3, and 1 week before resuming updosing (> 100 µg maintenance dose if necessary) and subsequent continuation every 4 weeks for 4 – 6 months [134].SAR = systemic allergic reactions; VIT = venom immunotherapy; HV = hymenoptera venom Box 13.Recommendations on contraindications of Hymenoptera VIT. Strength of consensus29. The use of β-blockers and ACE inhibitors are no contraindication of VIT. Patients should be informed about possible interactions.Consensus30. The following contraindications to VIT shall be respected: uncontrolled bronchial asthma, active malignant neoplastic disease, severe active systemic autoimmune disease and severe immunodeficiency (terminal AIDS), inadequate compliance, untreated chronic infection (e.g., active HIV, hepatitis C), pregnancy (for re-initiation)Strong31. In individual cases, VIT may be applied despite the presence of contraindications. This concept shall include a thorough weighing of the benefits and risks. Autoimmune diseases, severe cardiovascular or pulmonary diseases, and malignant diseases shall be optimally treated, shall be in remission before initiation of VIT, and shall be closely monitored during the course of VIT.Strong Box 15.Recommendations on venom selection for Hymenoptera VIT. Strength of consensus34. For VIT, that venom shall be used, which was the culprit venom according patient history and to the results of the allergological work-up.Strong35. If there is double sensitization, if the history of the patient is uncertain with regard to the culprit venom, and if the culprit venom cannot be determined even by additional diagnostic procedures, VIT with both venoms shall be performed.Strong36. If allergy to the venoms of bumblebees or hornets is certain, VIT shall be performed with the related, partly cross-reacting venoms of bees or wasps.Consensus Box 14.Recommendations on the practical implementation of Hymenoptera VIT. Strength of consensus32. The standard maintenance dose of VIT shall be 100 µg of Hymenoptera venom.Strong33. In case of bee venom allergy and increased risk of sting or risk of particularly severe anaphylaxis, starting VIT with a maintenance dose of 200 µg may be considered.Consensus Box 16.Recommendation on the maintenance therapy of Hymenoptera VIT. Strength of consensus37. The maintenance dose should be administered at 4-week intervals in the 1st year and, taking into account the manufacturer’s information, can be administered every 5 – 6 weeks from the 2nd year onwards, depending on the preparation used, and every 8 weeks from the 3rd year onwards if a depot preparation is used.Consensus Box 17.Recommendation on the reduction of side effects in Hymenoptera VIT. Strength of consensus38. A non-sedating antihistamine can be administered as a preventive measure during updosing, which can be continued in the further treatment if required. In case of reactions in the area of the injection site, local cooling measures shall be used.Consensus Box 18.Recommendations on the management of repeated systemic allergic adverse events in Hymenoptera VIT. Strength of consensus39. Possible risk factors of systemic side effects of VIT shall be identified and eliminated as appropriate.Majority40. Concomitant therapy with an H1-blocking antihistamine should be performed. The last tolerated dose should be continued for 3 months and, subsequently, a new updosing should be attempted.Consensus41. If risk factors for systemic side effects are present and cannot be eliminated, and if concomitant therapy with an H1-blocking antihistamine is not effective, concomitant treatment with an anti-IgE antibody (omalizumab; off-label use) should be performed.Majority42. If side effects continue to occur, the last maximum dose that was tolerated should be administered every 4 weeks for 5 years.Consensus Box 21.Recommendations on the duration of Hymenoptera VIT. Strength of consensus47. In the absence of risk factors described below (recommendations 48 and 49), VIT can be discontinued after 3 – 5 years, provided that maintenance therapy has been tolerated without recurrent anaphylactic side effects.Consensus48. Permanent VIT can be considered in patients with, among others, – established mastocytosis, – cardiovascular or respiratory arrest due to Hymenoptera stings – other specific individual constellations indicating an increased individual risk (e.g., hereditary α-tryptasemia)Strong49. If insect exposure time is greatly increased and unavoidable (e.g., occupational), VIT can be given to adults until the end of intensive contact.Consensus, (© Dustri-Verlag Dr. K. Feistle.)

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., (© 2023 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Background: Recently, criteria for evaluation of response to biologics have been proposed and the concept of clinical remission has gained attention as a possible goal even in severe asthma., Objective: To analyze the response and remission in the German Asthma Net severe asthma registry cohort., Methods: We included adults not using a biologic at baseline (V0) and compared patients treated between V0 and 1-year visit (V1) without using a biologic (group A) to patients starting with a biologic after V0 and continuing it up to V1 (group B). We applied the Biologics Asthma Response Score to quantify composite response in good, intermediate, or insufficient. We defined clinical remission (R) as absence of significant symptoms (Asthma Control Test score ≥ 20 at V1) in the absence of exacerbations and oral corticosteroid therapy., Results: Group A included 233 and group B 210 patients, the latter receiving omalizumab (n = 33), mepolizumab (n = 40), benralizumab (n = 81), reslizumab (n = 1), or dupilumab (n = 56). At baseline, group B had less often an allergic phenotype (35.2% vs 41.6%), lower Asthma Control Test score (median, 12 vs 14), more exacerbations in the past year (median, 3 vs 2), and more often high-dose inhaled corticosteroid treatment (71.4% vs 51.5%) than group A. After 1 year of treatment, rates of response (good: 61.4% vs 34.8%; intermediate: 26.7% vs 42.9%; insufficient: 11.9% vs. 22.3%) and/or clinical remission (37.6% vs 17.2%) were higher in group B than in group A., Conclusions: Despite more severe asthma at baseline, patients treated with biologics had a markedly higher probability of achieving good clinical response and/or remission than patients treated without biologics., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Biologics have proven efficacy for patients with severe asthma but there is lack of consensus on defining response. We systematically reviewed and appraised methodologically developed, defined and evaluated definitions of non-response and response to biologics for severe asthma., Methods: We searched four bibliographic databases from inception to 15 March 2021 . Two reviewers screened references, extracted data, and assessed methodological quality of development, measurement properties of outcome measures and definitions of response based on COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). A modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach and narrative synthesis were undertaken., Results: 13 studies reported three composite outcome measures, three asthma symptoms measures, one asthma control measure and one quality of life measure. Only four measures were developed with patient input; none were composite measures. Studies utilised 17 definitions of response: 10 out of 17 (58.8%) were based on minimal clinically important difference (MCID) or minimal important difference (MID) and 16 out of 17 (94.1%) had high-quality evidence. Results were limited by poor methodology for the development process and incomplete reporting of psychometric properties. Most measures rated "very low" to "low" for quality of measurement properties and none met all quality standards., Conclusions: This is the first review to synthesise evidence about definitions of response to biologics for severe asthma. While high-quality definitions are available, most are MCIDs or MIDs, which may be insufficient to justify continuation of biologics in terms of cost-effectiveness. There remains an unmet need for universally accepted, patient-centred, composite definitions to aid clinical decision making and comparability of responses to biologics., Competing Interests: Conflict of interests: E. Khaleva and A. Rattu declare funding for the present manuscript from the 3TR European Union Innovative Medicines Initiative 2 paid to the university. C. Brightling declares grants from GlaxoSmithKline, AstraZeneca, Novartis, Chiesi, Boehringer Ingelheim, Genentech, Roche, Sanofi, Mologic and 4DPharma, consulting fees from GlaxoSmithKline, AstraZeneca, Novartis, Chiesi, Boehringer Ingelheim, Genentech, Roche, Sanofi, Mologic, 4DPharma and Teva, and support from the 3TR project. A. Bourdin reports being an investigator for clinical trials promoted by AstraZeneca, Chieisi, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Regeneron and Sanofi; having received fees for lectures, attendance of meeting and consultancy from AstraZeneca, Chieisi, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Regeneron and Sanofi; having received research grants from AstraZeneca and Boehringer Ingelheim; and participation on a data safety monitoring or advisory board of AB Science. A. Bossios has received lecture fees from GlaxoSmithKline, AstraZeneca, Teva and Novartis; honoraria for advisory board meetings from GlaxoSmithKline, AstraZeneca, Teva, Novartis and Sanofi; and received support for attending meetings from AstraZeneca and Novartis, all outside the present work; reports being a member of the Steering Committee of SHARP, Secretary of Assembly 5 (Airway Diseases, Asthma, COPD and Chronic Cough) of the European Respiratory Society and Vice-chair of the Nordic Severe Asthma Network (NSAN). K.F. Chung has received honoraria for participating in advisory board meetings of GlaxoSmithKline, AstraZeneca, Roche, Novartis, Merck and Shionogi regarding treatments for asthma, COPD and chronic cough, and has also been renumerated for speaking engagements for Novartis and AstraZeneca. R. Chaudhuri has received lecture fees from GlaxoSmithKline, AstraZeneca, Teva, Chiesi, Sanofi and Novartis; honoraria for advisory board meetings from GlaxoSmithKline, AstraZeneca, Teva, Chiesi and Novartis; sponsorship to attend international scientific meetings from Chiesi, Napp, Sanofi, Boehringer, GlaxoSmithKline and AstraZeneca, and a research grant to her Institute from AstraZeneca for a UK multicentre study. C. Coleman declares funding received to support this work by the European Lung Foundation (ELF) from the European Commission's Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement number 831434 (3TR), and is an employee of the ELF. R. Djukanovic declares funding from European Respiratory Society, Teva, GlaxoSmithKline, Novartis, Sanofi and Chiesi for the SHARP CRC, consulting fees for Synairgen; honorarium for a lecture from GlaxoSmithKline, participation on a data safety monitoring board or advisory board for Kymab (Cambridge) and shares in Synairgen, outside the submitted work. S-E. Dahlen declares funding from 3TR IMI Grant; consulting fees from AstraZeneca, Cayman Co., GlaxoSmithKline, Novartis, Regeneron, Sanofi and Teva; honoraria for lectures from AstraZeneca and Sanofi. A. Exley declares being a minority shareholder in GlaxoSmithKline PLC. L. Fleming declares participation in advisory boards and honoraria for lectures from Sanofi, Respiri UK, AstraZeneca, Novartis and Teva, outside the scope of this publication. All payments were made to her institution. A. Gupta received speaker and advisory board fees from GlaxoSmithKline, Novartis, AstraZeneca and Boehringer Ingelheim. A. Gupta's institution had received research grants from GlaxoSmithKline, Novartis, AstraZeneca and Boehringer Ingelheim. E. Hamelmann declares support from the German Ministry of Education and Research (BMBF) and German Asthma Net (GAN) e.V.; funding for research in severe asthma in children (CHAMP-01GL1742D) and for Severe Asthma Register. G.H. Koppelman reports receiving research grants from the Lung Foundation of the Netherlands, Ubbo Emmius Foundation, H2020 European Union, Teva, GlaxoSmithKline and Vertex, outside this work (money to institution); he reports memberships of advisory boards to GlaxoSmithKline and PURE-IMS, outside this work (money to institution). E. Melen has received consulting fees from AstraZeneca, Chiesi, Novartis and Sanofi outside the submitted work. V. Mahler has no conflict of interest but declares that the views expressed in this review are the personal views of the author and may not be understood or quoted as being made on behalf of or reflecting the position of the respective national competent authority, the European Medicines Agency, or one of its committees or working parties. F. Singer reports being an investigator for clinical trials promoted by Vertex and having received fees for lectures from Vertex and Novartis, outside the submitted work. C. Porsbjerg declares grants, consulting fees and honoraria from AstraZeneca, GlaxoSmithKline, Novartis, Teva, Sanofi, Chiesi and ALK (paid to institution and personal honoraria); participation in the advisory board for AstraZeneca, Novartis, Teva, Sanofi and ALK, outside the submitted work. V. Ramiconi reports grants paid to EFA from Pfizer, Novartis, AstraZeneca, Sanofi, Chiesi Farmaceutici, Regeneron, DBV Technologies, MSD, GlaxoSmithKline, Aimmune, LeoPharma, AbbVie, Boehringer Ingelheim, OM Pharma and Roche; payment for expert testimony from Novartis Global Respiratory Patient Council 2021 and Novartis EPIS Steering Committee to EFA. G. Roberts declares EU IMI funding and consulting fees from AstraZeneca paid to his institution. No other author has any conflict of interest to declare., (Copyright ©The authors 2023.)

Background: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) Working Group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies., Methods: COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult and paediatric clinicians, pharmaceutical representatives, and health regulators from across Europe. Evidence included a systematic review of development, validity and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients' and carers' views about outcome measures. It was discussed using a modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria., Results: Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV 1 ) as z-scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire and Asthma Control Test or Childhood Asthma Control Test, while the adult COM set includes the Severe Asthma Questionnaire and Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately)., Conclusions: This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma., Competing Interests: Conflict of interest: E. Khaleva and A. Rattu declare funding from 3TR European Union Innovative Medicines Initiative 2 to their institution for the present manuscript. C. Brightling declares grants from GlaxoSmithKline, AstraZeneca, Novartis, Chiesi, Boehringer Ingelheim, Genentech, Roche, Sanofi, Mologic and 4DPharma; consulting fees from GlaxoSmithKline, AstraZeneca, Novartis, Chiesi, Boehringer Ingelheim, Genentech, Roche, Sanofi, Mologic, 4DPharma and Teva; and support from the 3TR project. G.W. Clarke declares that he is an employee of AstraZeneca; and that he holds stock or stock options in AstraZeneca. M. van den Berge declares grants from GlaxoSmithKline, AstraZeneca, Roche, Genentech and Novartis paid to the university. A. Bossios declares honoraria for lectures from GlaxoSmithKline, AstraZeneca, Teva and Novartis; support for attending meetings from AstraZeneca and Novartis; honoraria for advisory board meetings from GlaxoSmithKline, AstraZeneca, Teva, Novartis and Sanofi; being a member of the Steering Committee of SHARP, Secretary of Assembly 5 (Airway Diseases, Asthma, COPD and Chronic Cough) of the European Respiratory Society; Vice-chair of the Nordic Severe Asthma Network (NSAN). V. Ramiconi and S. Romagosa Vilarnau declare unrestricted educational grants paid to the organisation from Novartis, Pfizer, AstraZeneca, Chiesi Farmaceutici, GlaxoSmithKline, AbbVie, LeoPharma, Boehringer Ingelheim, Sanofi, Regeneron, OM Pharma, MSD, Roche and DBV Technologies; support for attending meetings from Novartis. S-E. Dahlén declares a 3TR Innovative Medicines Initiative grant; consulting fees for AstraZeneca, Cayman Co., GlaxoSmithKline, Novartis, Regeneron, Sanofi and Teva; payment for lectures from AstraZeneca and Sanofi. S. Principe declares support for provision of study materials and medical writing. G. Hedlin declares participation in advisory boards of AstraZeneca and Sanofi. F. Singer reports grants from Lung League Bern, grants from the Swiss Cystic Fibrosis Society (CFCH), personal fees from Vertex Pharmaceuticals, personal fees from Novartis, outside the submitted work. A. Deschildre reports personal consulting fees from Sanofi-Regeneron, ALK, Novartis and GlaxoSmithKline; honoraria for lectures from ALK, Boehringer Ingelheim and Novartis; support for attending meetings from AstraZeneca, Stallergènes-Greer, MEDA, Nutricia, Sanofi and Novartis, outside the submitted work; and being on the scientific committee of SFA (Société Française d'Allergologie). L.J. Fleming declares participation in advisory boards and honoraria for lectures from Sanofi, Respiri UK, AstraZeneca, Novartis and Teva, outside of the scope of this publication; all payments were made to her institution. H. Staudinger reports that he is a salaried employee of Sanofi Genzyme and owns company stock of Sanofi and Merck & Co. K.C. Pike declares consultancy fees from Novartis, Adherium and Respiri, and honoraria for a lecture from Novartis. J. Grigg declares payments from GlaxoSmithKline, OM Pharma, Omron and Novartis (advisory boards), Sanofi (for lectures) and AstraZeneca (CI clinical trial). N. Rutjes reports personal fees for advisory board work from Sanofi. G.H. Koppelman reports receiving research grants from the Lung Foundation of the Netherlands, Ubbo Emmius Foundation, H2020 European Union, Teva, GlaxoSmithKline and Vertex, outside this work (money to institution); he reports memberships of advisory boards to GlaxoSmithKline and PURE-IMS, outside this work (money to institution). D. Cunoosamy holds shares in AstraZeneca and Sanofi. A.H. Maitland-van der Zee has received research grants outside the submitted work from GlaxoSmithKline, Boehringer Ingelheim and Vertex, she is the PI of a P4O2 (Precision Medicine for more Oxygen) public private partnership sponsored by Health Holland involving many private partners that contribute in cash and/or in kind (Boehringer Ingelheim, Breathomix, Fluidda, Ortec Logiqcare, Philips, Quantib-U, Roche, Smartfish, SODAQ, Thirona, TopMD and Novartis), and she has served in advisory boards for AstraZeneca, GlaxoSmithKline and Boehringer Ingelheim with money paid to her institution. K.F. Chung has received honoraria for participating in advisory board meetings of GlaxoSmithKline, AstraZeneca, Roche, Novartis, Merck and Shionogi, regarding treatments for asthma, COPD and chronic cough, and has also been remunerated for speaking engagements for Novartis and AstraZeneca; received a MRC grant on Precision Medicine for severe asthma, EPSRC grant on air pollution and asthma, and a GlaxoSmithKline grant on mepolizumab and eosinophils in asthma. P. Nagakumar received speaker fees for talks on severe asthma from GlaxoSmithKline and Novartis. G. Brusselle declares payments from AstraZeneca, Novartis, Boehringer Ingelheim, Chiesi, Sanofi, GlaxoSmithKline and MSD, outside the submitted work. E. Hamelmann declares support from the German Ministry of Education and Research (BMBF) and German Asthma Net (GAN) eV; funding for research in severe asthma in children (CHAMP-01GL1742D) and for Severe Asthma Register. S. Vijverberg is PI of the PERMEABLE consortium. The PERMEABLE consortium is a research consortium focused on severe asthma and allergy and supported by ZonMW (456008004), the Swedish Research Council (2018-05619), the Ministry of Education, Science and Sport of the Republic of Slovenia (C3330-19-252012), and the German Ministry of Education and Research (BMBF) FKZ01KU1909A), under the frame of the ERA PerMed JTC 2018 Call. In addition, S. Vijverberg has received research funding for a project on severe paediatric asthma from the Lung Foundation Netherlands (6.2.18.244JO). A-M.M. Schoos has participated on an advisory board for ALK. B. Dahlén reports personal fees for lectures from AstraZeneca, Novartis and Sanofi; and grants from Novartis and GlaxoSmithKline, outside the submitted work; participation on an advisory board for AstraZeneca and Sanofi. A. Exley declares being a minority shareholder in GlaxoSmithKline Plc. E.A. Gaillard reports consultancy work for Boehringer Ingelheim with money paid to the institution (University of Leicester); investigator-led research grants from Circassia Group, Gilead Sciences, Chiesi Limited and Propeller Health; and has a research collaboration with Medimmune. M. Pijnenburg declares payments to her institution from Sanofi Genzyme (advisory work) and Novartis (speakers fee). E. Melén declares consulting fees from AstraZeneca, Chiesi, Novartis and Sanofi, outside the submitted work. R. Chaudhuri has received lecture fees from GlaxoSmithKline, AstraZeneca, Teva, Chiesi, Sanofi and Novartis; honoraria for advisory board meetings from GlaxoSmithKline, AstraZeneca, Teva, Chiesi and Novartis; sponsorship to attend international scientific meetings from Chiesi, Napp, Sanofi and GlaxoSmithKline, and a research grant to her institute from AstraZeneca for a UK multi-centre study. C. Pilette declares grants, consulting fees and honoraria for lectures (paid to institution) from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, Mundipharma, Teva, Sanofi and ALK. C. Porsbjerg declares grants (paid to institution), consulting fees (paid to institution and personal honoraria) and honoraria for lectures (paid to institution and personal honoraria) from AstraZeneca, GlaxoSmithKline, Novartis, Teva, Sanofi, Chiesi and ALK; participation on an advisory board (paid to institution and personal honoraria) for AstraZeneca, Novartis, Teva, Sanofi and ALK. C. Coleman and C. Williams declare funding received to support this work by the European Lung Foundation (ELF) from the European Commission's Innovative Medicines Initiative 2 Joint Undertaking under grant agreement number 831434 (3TR), and are employees of the ELF. B. Ahrens, S. Kaul, D. Hartenstein and V. Mahler declare no conflict of interest for this article and state that the views expressed in this review are the personal views of the author and may not be understood or quoted as being made on behalf of or reflecting the position of the respective national competent authorities, the European Medicines Agency or one of its committees or working parties. L.G. Heaney declares support from the 3TR; grants from industrial pharma partners Amgen, AstraZeneca, Medimmune, Janssen, Novartis, Roche/Genentech, GlaxoSmithKline and Boehringer Ingelheim; project grant funding from Medimmune, Novartis UK, Roche/Genentech and GlaxoSmithKline, outside the submitted work; payments for lectures by AstraZeneca, Novartis, Roche/Genentech, GlaxoSmithKline, Chiesi and Teva, outside the submitted work; travel funding support to international respiratory meetings by AstraZeneca, Chiesi, Novartis, Boehringer Ingelheim, Teva and GlaxoSmithKline, outside the submitted work; advisory boards for AstraZeneca, Novartis, GlaxoSmithKline, Chiesi, Teva, Theravance and Vectura, outside the submitted work. R. Djukanovic declares funding from the European Respiratory Society, Teva, GlaxoSmithKline, Novartis, Sanofi and Chiesi for the SHARP Clinical Research Collaboration; consulting fees for Synairgen; honorarium for a lecture from GlaxoSmithKline; participation on a data safety monitoring board or advisory board for Kymab (Cambridge) and shares in Synairgen outside of the submitted work. A. Bourdin declares grants from Boehringer and AstraZeneca; consulting fees and payments from Boehringer, AstraZeneca, GlaxoSmithKline, Novartis, Chiesi, Regeneron, Sanofi and Amgen outside of the submitted work. B. Karadag declares participation in a trial conducted by Sanofi (payment to institution) and attending advisory board meetings for GlaxoSmithKline (personal fees). K. Blumchen declares grants from Aimmune Therapeutics, DBV Technologies and Hipp GmbH; consulting fees from Aimmune Therapeutics, DBV Technologies and Allergy Therapeutics; payments for lectures from Aimmune Therapeutics, DBV Technologies, Novartis, Allergy Therapeutics, HAL, ALK, Allergopharma, Nutricia, Thermo Fisher Scientific, and Bausch and Lomb; personal fees for expert discussions from Novartis and Nestle; fees for attending meetings from Aimmune Therapeutics and DBV Technologies; being on data safety monitoring board of Charité, IIT. A. Gupta received speaker/advisory board fees from GlaxoSmithKline, Novartis, AstraZeneca and Boehringer Ingelheim; received research grants from GlaxoSmithKline, Novartis, AstraZeneca and Boehringer Ingelheim, paid to institution. L. Giovannini-Chami declares consulting fees from ALK, AstraZeneca and Novartis; honoraria for lectures, presentations from Novartis, ALK, Stallergènes, Sanofi and AstraZeneca; support for attending meetings from Stallergènes; participation on a data safety monitoring board or advisory board for Sanofi; being head of the Scientific Committee of the French Pediatric Pulmonology and Allergology Society. C.S. Murray has received lecture fees from GlaxoSmithKline and Novartis; received grants from Asthma UK and National Institute for Health Research; and has participated on an advisory board for Boehringer Ingelheim. G. Roberts declares European Union Innovative Medicines Initiative funding and AstraZeneca paid to the institution. Other co-authors declare no conflicts of interest for this article., (Copyright ©The authors 2023.)

This publication is the second part of the German-language S3 guideline on urticaria. It covers the management of urticaria and should be used together with Part 1 of the guideline on classification and diagnosis. This publication was prepared according to the criteria of the AWMF on the basis of the international English-language S3 guideline with special consideration of health system conditions in German-speaking countries. Chronic urticaria has a high impact on the quality of life and daily activities of patients. Therefore, if causal factors cannot be eliminated, effective symptomatic treatment is necessary. The recommended first-line treatment is to administer new generation, non-sedating H1 antihistamines. If the standard dose is not sufficiently effective, the dose should be increased up to fourfold. For patients who do not respond to this treatment, the second-line treatment in addition to antihistamines in the treatment algorithm is omalizumab and, if this treatment fails, ciclosporin. Other low-evidence therapeutic agents should only be used if all treatments in the treatment algorithm agreed upon by the guideline group fail. Both the benefit-risk profile and cost should be considered. Corticosteroids are not recommended for long-term treatment due to their inevitable severe side effects., (© 2023 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

The lifetime prevalence of urticaria, a severe allergic disease, is almost 20%. It not only limits the quality of life of those affected, but also their general performance at work and in their daily activities. This publication is the first section of the Urticaria Guideline. It covers the classification and diagnosis of urticaria, taking into account the major advances in research into its causes, triggering factors and pathomechanisms. It also addresses strategies for the efficient diagnosis of the different subtypes of urticaria. This is crucial for individual, patient-oriented treatment, which is covered in the second part of the guideline, published separately. This German-language guideline was developed according to the criteria of the AWMF on the basis of the international English-language S3 guideline with special consideration of health system characteristics in the German-speaking countries. This first part of the guideline describes the classification of urticaria, distinguishing spontaneously occurring wheals (hives) and angioedema from forms of urticaria with inducible symptoms. Urticaria is defined as sudden onset of wheals, angioedema, or both, but is to be distinguished from conditions in which wheals occur as a short-term symptom, such as anaphylaxis. The diagnosis is based on (a limited number of) laboratory tests, but especially on medical history. In addition, validated instruments are available to measure the severity, activity and course of the disease., (© 2023 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

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., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Allergen immunotherapy (AIT) represents the only possibility of causal therapy for allergic respiratory diseases. Although the prevailing high prevalence of allergic diseases and restrictions in the daily lives of patients, AIT is offered to a suboptimal number of patients in Germany., Methods: Insured patients with documented allergic respiratory disease of one of the largest statutory health insurances in Germany, 'DAK-Gesundheit', were contacted by postal mail and asked to participate in the study. In case of written consent, primary and secondary data of patients were collected and analysed. Patient characteristics, predictors of being offered AIT, predictors of performing AIT and guideline-compliant care were analysed., Results: 2505 subjects were included in the VerSITA study. Allergy to tree pollen and native speaking were identified as predictors, which increase the probability of being offered AIT. The probability was significantly decreased by the characteristics allergic rhinitis only, allergic asthma only, age in years, non-German citizenship, no graduation and lower secondary qualification. Significant positive predictors for an AIT to be actually performed were: Allergy to tree pollen and male sex. Predictors that decrease the likelihood that AIT is performed were: only allergic asthma, current smoker, former smoker, age and non-German citizenship. Furthermore, it was possible to identify characteristics in which guideline-compliant patients differed significantly from the rest of the study population., Conclusions: Based on statutory health insurance data and patient survey data, the VerSITA study provides a broad and in-depth overview of the care situation with regard to AIT in Germany and identifies deficits., (© 2022 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Not available., (© Dustri-Verlag Dr. K. Feistle.)