Background: Subcutaneous immunotherapy has emerged as an effective option for treating allergic diseases. Here, we assessed the clinical impact of the mannan-conjugated birch pollen polallergoid T502 in birch pollen-induced allergic rhinoconjunctivitis. Methods: In this prospective, randomized, double-blind placebo-controlled phase III trial, 298 birch pollen–allergic adult patients were treated across 28 trial sites in Germany. Patients received either placebo or 23,000 mTU T502 subcutaneously over five pre-seasonal visits. Efficacy was assessed by comparing the combined symptom and medication score (CSMS) between placebo and T502 during the peak birch pollen season 2022. Safety, tolerability and immunologic effects were also analysed. Results: During the peak birch pollen season, the median CSMS of the T502 group was reduced by 33.00% (p=0.002) compared to placebo. The median daily symptom score and daily medication score were reduced by 30.43% (p<0.001) and 56.25% (p=0.045), respectively. Health related quality of life improved as reflected by reduction of RQLQ values by 31.54% (p<0.0001). Production of Bet v 1 sIgG4 and sIgG increased up to 6.2-fold and 3-fold respectively in the T502 group (p<0.0001). The sIgE/sIgG4 ratio was strongly reduced in the T502 group at V7 (-62.90%, p<0.0001). No fatalities nor serious adverse events were reported. In total, 16 systemic allergic reactions occurred (Grade I/II). Conclusions: Treatment with T502 significantly reduced symptoms and medication need in rhinoconjunctivitis patients. The treatment is well tolerated and safe.

Inhaled corticosteroids in early COVID-19 – a tale of many facetsLudger Klimek1, Cezmi A. Akdis2, Marek Jutel3, Torsten Zuberbier4, Jean Bousquet5-71. Center for Rhinology and Allergology, Wiesbaden, Germany.2. Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich - Christine Kühne - Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.3. Department of Clinical Immunology, Medical University of Wroclaw, ALL-MED Medical Research Institute, Wrocław, Poland.4. Clinic for Dermatology, Venereology and Allergology, Charité - University Medicine Berlin, Berlin, Germany.5. Charité, Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Berlin, Germany6. Comprehensive Allergy Center, Department of Dermatology and Allergy, Berlin Institute of Health, Berlin, Germany7. Centre Hospitalier Universitaire, Montpellier, France

Background: The German Therapy Allergen Ordinance (TAO) triggered an ongoing upheaval in the market for house dust mite (HDM) allergen immunotherapy (AIT) products. Three HDM subcutaneous AIT (SCIT) products hold approval in Germany and therefore will be available after the scheduled completion of the TAO procedure in 2026. In general, data from clinical trials on the long-term effectiveness of HDM AIT are rare. We evaluated real-world data (RWD) in a retrospective, observational cohort study based on a longitudinal claims database including 60% of all German statutory healthcare prescriptions to show the long-term effectiveness of one of these products in daily life. Methods: Subjects between 5 to 70 years receiving their first (index) prescription of SCIT with a native HDM product (SCIT group) between 2009 and 2013 were included. The exactly 3:1 matched control group received prescriptions for only symptomatic AR medication (non-AIT group); the evaluation period for up to 6 years of follow-up ended in February 2017. Study endpoints were the progression of allergic rhinitis (AR) and asthma, asthma occurrence and time to the onset of asthma after at least 2 treatment years. Results: 892 subjects (608 adults, 284 children/adolescents) were included in the SCIT group and 2676 subjects (1824 adults, 852 children/adolescents) in the non-AIT group. During the follow-up period after at least two years of SCIT, the number of prescriptions in the SCIT group was reduced by 62.8% (p<0.0001) for AR medication and by 42.4% for asthma medication (p=0.0003). New‐onset asthma risk was significantly reduced in the SCIT vs non‐AIT group by 27.0% (p=0.0212). The asthma preventive effect of SCIT occurred 15 months after start of the treatment. In the SCIT group, the time to onset of asthma was reduced compared to the non-AIT group (p=0.0010). Conclusion: In this RWD analysis patients aged between 5 to 70 years benefited from SCIT with a native HDM product in terms of the reduced progression of AR and asthma after at least 2 years of treatment in the long term. The effects lasted for up to six years after treatment termination. A significantly reduced risk of asthma onset was observed, starting after 15 months of treatment.

Systemic allergic reactions to vaccines are very rare. In this study we assessed the management and outcome suspected SARS-CoV-2 vaccine hypersensitivity. We present data of 219 individuals, who experienced symptoms suspicious for an allergic reaction after the first (n=214) or the second vaccination (n=5). 195 reactions occurred after the first application of mRNA-based vaccines (157 Comirnaty®, and 38 Spikevax®) and eighteen reactions were reported after first application of a vector vaccine (Vaxzevria®). Of these 162 experienced immediate symptoms. Skin symptoms occurred in 91 cases. The most frequent cutaneous symptom was angioedema (n=45), followed by generalized urticaria (n=36) and generalized erythema/flush (n=20). 70 patients had cardiovascular symptoms, 45 showed respiratory symptoms and gastrointestinal symptoms were recorded in 14 patients. The allergological assessment of 334 individuals (219 with reactions after COVID vaccination and 115 with a history of vaccine related reactions) showed in 17% a suspicion of sensitization against the SARS-CoV-2 vaccine and/or their ingredients defined as one positive skin test and/or BAT. The majority of the SPT/IDT with the vaccines were negative. Of the 214 patients with suspected allergic symptoms after the first vaccination, 67/67 patients tolerated the re-vaccination. In this study, 334 individuals of a cohort resembling >2000 persons presenting for an allergy workup regarding SARS-CoV-2 vaccination only 45 were diagnosed in concordance with the anaphylaxis definition of the Brighton collaboration with anaphylactic immediate hypersensitivity reaction after SARS-CoV-2 vaccination. Identifiable characteristics of these patients with suspected, but also diagnosed SARS-CoV-2 vaccine hypersensitivity were female gender and the symptom angioedema. Overall, IgE-mediated hypersensitivity towards SARS-CoV-2 vaccines is extremely low and not increased in comparison to the reported hypersensitivity for other vaccines.

Background: Allergen immunotherapy (AIT) may have a long-term disease modifying effect. The aim of this study is to demonstrate the long-term benefit of MCT®-associated allergoid pollen SCIT (MCT®-associated -AIT) on allergic rhinitis (AR) and asthma in clinical practice. Methods: In this retrospective Real-World-Evidence (RWE) study the impact of AIT on the progression of AR and onset of need for asthma medication was analyzed using a German longitudinal database. Anonymized prescription data of AR patients and exactly matched control patients aged from 5-65 years were analyzed. Results: Significantly less patients treated with MCT®-associated-AIT did receive prescriptions for symptomatic AR medication in the follow up period vs. control group (OR: 0.27; p < 0.001). Further, significantly less asthmatic patients under MCT®-associated-AIT did receive prescriptions for asthma medications (OR: 0.48; p = 0.004). In addition, the prescriptions of AR and asthma medication for MCT®-associated-AIT patients were significantly reduced in the follow-up vs. baseline and control group (24.2% and 35.6%, respectively, p < 0.001).The probability of asthma medication onset in non-asthmatic patients during follow-up was significantly reduced for AIT patients compared to controls (OR: 0.77, p = 0.001). All endpoints were significant for children/adolescents and adults in the individual analyses. Conclusions: This study gives evidence for long-term benefits up to 9.5 years of MCT®-associated-AIT on the need for AR and new-onset asthma medication in AR patients and asthma medication in asthmatics in an RWE setting.

Background: Randomized controlled trials (RCTs) are the gold-standard for benefit-risk assessments during drug approval processes. Real-word data (RWD) and the resulting real-world evidence (RWE) are becoming increasingly important for assessing the effectiveness of drug products after marketing authorization showing how RCT results are transferred into real life care. The effectiveness of allergen immunotherapy (AIT) has been assessed in several RWE studies based on large prescription databases. Methods: We performed a literature search for retrospective cohort assessments of prescription databases in Europe to provide an overview on the methodology, long-term effectiveness outcomes and adherence to AIT. Results: 13 respective publications were selected. AIT was more effective in reducing the progression of allergic rhinitis (AR) compared to a non-AIT control group receiving only symptomatic treatment for AR for up to 6 years. The development and progression of asthma was hampered for most endpoints in patients treated with most preparations compared to the non-AIT group, receiving only anti-asthmatic medication. The results for “time to onset” of asthma were inconsistent. Adherence to AIT decreased during the recommended 3-years treatment period, however in most studies higher adherence to subcutaneous than to sublingual AIT was shown. Conclusion: The analysis of long-term effectiveness outcomes of the RWE studies based on prescription databases confirms the long-term efficacy of AIT demonstrated in RCTs. Progression of rhinitis and asthma symptoms as well as delayed onset of asthma triggered by different allergens, real life adherence to the treatment shows differences in particular application routes.

Immune modulation is a key therapeutic tool for allergic diseases and asthma. It can be achieved in an antigen-specific way via allergen immunotherapy (AIT) or in endotype-driven approach using biologicals that target the major pathways of the type 2 (T2) immune response: IgE, IL-5 and IL-4/IL-13. COVID-19 vaccine provides an excellent opportunity to tackle the global pandemics and is currently being applied in an accelerated rhythm worldwide. It works as well through immune modulation. Thus, as there is an obvious interference between these treatment modalities recommendations on how they should be applied in sequence are expected. The European Academy of Allergy and Clinical Immunology (EAACI) gathered an outstanding expert panel under its Research and Outreach Committee (ROC). This expert panel was called to evaluate the evidence and formulate recommendation on the administration of COVID-19 vaccine in patients with allergic diseases and asthma receiving AIT or biologicals. The panel also formulated recommendations for COVID-19 vaccine in association with biologicals targeting the type 1 or type 3 immune response. In formulating recommendations, the panel evaluated the mechanisms of COVID-19 infection, of COVID-19 vaccine, of AIT and of biologicals and considered the data published for other anti-infectious vaccines administered concurrently with AIT or biologicals.

This systematic review evaluates the efficacy and safety of biologicals for chronic rhinosinusitis with nasal polyps (CRSwNP) compared to the standard of care. Pubmed, EMBASE and Cochrane Library were searched for RCTs. Critical and important CRSwNP-related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. RCTs evaluated (dupilumab-2, omalizumab-4, mepolizumab-2, reslizumab-1) included 1236 adults, with follow-up 20-64 weeks. Dupilumab reduces the need for surgery (NFS) and oral corticosteroid (OCS) use (RR 0.28; 95%CI 0.20-0.39, moderate certainty) and improves with high certainty smell (mean difference (MD) +10.54; 95%CI +9.24 to +11.84) and quality of life (QoL) (MD -19.14; 95%CI -22.80 to -15.47), with fewer treatment-related adverse events (TAEs) (RR 0.95; 95%CI 0.89-1.02, moderate certainty). Omalizumab reduces NFS (RR 0.85; 95%CI 0.78 to 0.92, high certainty), decreases OCS use (RR 0.38; 95%CI 0.10-1.38, moderate certainty), improves with high certainty smell (MD +3.84; 95%CI +3.64 to +4.04) and QoL (MD -15.65; 95%CI -16.16 to -15.13), with increased TAE (RR 1.73; 95%CI 0.60-5.03, moderate certainty). There is low certainty for mepolizumab reducing NFS (RR 0.78; 95%CI 0.64 to 0.94) and improving QoL (MD -13.3; 95% CI -23.93 to -2.67) and smell (MD +0.7; 95%CI -0.48 to +1.88), with increased TAEs (RR 1.64; 95%CI 0.41-6.50). The evidence for reslizumab is very uncertain.

Following the emergency use authorization of the vaccine mRNA-1273 on 18th December 2020 in the US and the vaccine BNT162b2 one week earlier, two mRNA vaccines are in currently used for the prevention of coronavirus disease 2019 (COVID-19). Phase 3 pivotal trials on both vaccines excluded individuals with a history of allergy to vaccine components. Immediately after the initiation of vaccination in the United Kingdom, Canada, and in the US, anaphylactic reactions have been reported. While the culprit trigger requires investigation, initial reports suggested the excipient polyethylene glycol 2000 (PEG-2000), which is contained in both vaccines as PEG-micellar carrier system as the potential culprit. Surface PEG chains form a hydrate shell to increase stability and prevent opsonization. Allergic reactions to such PEG-ylated lipids are rarely IgE-mediated, but may result from complement activation-related pseudoallergy (CARPA) that has been described to similar liposomes. In addition, mRNA-1273 also contains tromethamine (trometamol), which has been reported to cause anaphylaxis to e.g. gadolinium-based or iodinated contrast media. Skin prick-, intradermal-, epicutaneous- tests, in vitro sIgE assessment, evaluation of sIgG/IgM, as well as basophil activation test are in use to demonstrate allergic reactions to various components of the vaccines.

Although there is a considerable body of knowledge about allergen immunotherapy (AIT), there is a lack of data on the reliability of real-world evidence (RWE) in AIT and consequently, a lack of information on how AIT effectively works in real life. To address the current unmet need for an appraisal of the quality of RWE in AIT, the European Academy of Allergy and Clinical Immunology Methodology Committee recently initiated a systematic review of observational studies of AIT, which will use the RELEVANT tool and the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE) to rate the quality of the evidence base as a whole. The next step will be to develop a broadly applicable, pragmatic “real-world” database using systematic data collection. Based on the current RWE base, and perspectives and recommendations of authorities and scientific societies, a hierarchy of RWE in AIT is proposed, which places pragmatic trials and registry data at the positions of highest level of evidence. There is a need to establish more AIT registries that collect data in a cohesive way, using standardised protocols. This will provide an essential source of real-world data that can be easily shared, promoting evidence-based research and quality improvement in study design and clinical decision-making.

Coronavirus disease 2019 (COVID-19) vaccine BNT162b2 received approval and within the first few days of public vaccination several severe anaphylaxis cases occurred. An investigation is taking place to understand the cases and their triggers. The vaccine will be administered to a large number of individuals worldwide and concerns raised for severe adverse events might occur. With the current information, the European Academy of Allergy and Clinical Immunology (EAACI) states its position for the following preliminary recommendations that are to be revised as soon as more data emerges. To minimize the risk of severe allergic reactions in vaccinated individuals, it is urgently required to understand the specific nature of the reported severe allergic reactions, including the background medical history of the individuals affected and the mechanisms involved. To achieve this goal all clinical and laboratory information should be collected and reported. Mild and moderate allergic patients should not be excluded from the vaccine as the exclusion of all these patients from vaccination may have a significant impact on reaching the goal of population immunity. Health care practitioners vaccinating against COVID-19 are required to be sufficiently prepared to recognise and treat anaphylaxis properly with the ability to administer adrenaline. A mandatory observation period after vaccine administration of at least 15 minutes for all individuals should be followed. The current guidelines, which exclude patients with severe allergies from vaccination with BNT162b2, should be re-evaluated after more information and experience with the new vaccine develops.

Background: The practice of allergology varies widely between countries, and the costs and sales for the treatment of rhinitis differ depending on practices and health systems. To understand these differences and their implications, the rhinitis market was studied in some of the EU countries. Methods: We conducted a pharmaco-epidemiological database analysis to assess the medications that were prescribed for allergic rhinitis in the years 2016, 2017 and 2018. We used the IQVIA platforms for prescribed medicines (MIDAS® - Meaningful Integration of Data, Analytics and Services) and for OTC medicines (OTC International Market Tracking - OTCims). We selected the five most important markets in the EU (France, Germany, Italy, Poland and Spain). The UK was excluded due to a lack of data. Results: Intra-nasal decongestants were excluded from the analyses because they are not prescribed for allergic rhinitis. For both Standard Units (SU) and costs, France is leading the other countries. In terms of SU, the four other countries are similar. For costs, Poland is lower than the three others. However, medication use differs largely. For 2018, in SU, intra-nasal corticosteroid is the first treatment in Poland (70.0%), France (51.3%), Spain (51.1%) and Germany (50.3%) whereas the Italian market is dominated by systemic anti-histamines (41.4%) followed by intra-nasal corticosteroids (30.1%). Results of other years were similar. Discussion: There are major differences between countries in terms of rhino-conjunctivitis medication usage.