Response to Correspondence ALL-2023-01107 “Short-course subcutaneous treatment with PQ Grass strongly improves symptom and medication scores in grass allergy”P.J. de Kam1, S. Zielen2, J.A. Bernstein3, U. Berger4, M. Berger5, M. Cuevas6, D. Cypcar7, A. Fuhr-Horst8, W.A. Greisner9, M. Jandl10, S. Laßmann11, M. Worm12, J. Matz13, E. Sher14, C. Smith15, G.C. Steven16, R. Mösges17,18, M.H. Shamji19,20, L. DuBuske21, F. Borghese1, K. Oluwayi1, T. Zwingers1, M. Seybold1, O. Armfield1, M.D. Heath1, S.J. Hewings1, M.F. Kramer1, M.A. Skinner1Allergy Therapeutics plc, Worthing, United KingdomChildren and Adolescents Dept., Allergology, Pulmonology & Cystic fibrosis, Goethe University, Frankfurt, GermanyBernstein Clinical Research Center, LLC, Cincinnati, OH, United States of AmericaAerobiology and Pollen Research Unit, Dept. Oto-Rhino-Laryngology, Medical University Vienna, Vienna, Austria.Wiener Gesundheitsverbund, Hospital Hietzing, Department of Otorhinolaryngology, Vienna, AustriaClinic and Polyclinic of Otorhinolaryngology, University Clinic Carl Gustav Carus, TU Dresden, GermanyAllergy Partners of Western North Carolina, Asheville, NC, United States of AmericaENT Research- Institut für klinische Studien, Essen, GermanyBluegrass Allergy Research, Lexington, KY, United States of AmericaHamburger Institut für Therapieforschung GmbH, Hamburg, GermanyStudienzentrum Dr. Sabine Laßmann, Saalfeld, GermanyUniversitätsmedizin Berlin, Department of Dermatology and Allergy - Charite Campus Mitte, Berlin, GermanyChesapeake Clinical Research, Inc. White Marsh, MD, United States of AmericaAllergy Partners of New Jersey, Ocean, NJ, United States of AmericaCertified Research Associates, Cortland, NY, United States of AmericaAllergy Asthma & Sinus Center, S.C., Greenfield, WI, United States of AmericaIMSB (Institute of Computational Biology and Medical Statistics), University at Cologne, Cologne, GermanyClinCompetence, Cologne, GermanyImmunomodulation and Tolerance Group, Allergy and Clinical Immunology, Department of National Heart and Lung Institute, Imperial College London, London, United KingdomAsthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United KingdomDivision of Allergy and Immunology, Department of Internal Medicine, George Washington University Hospital, Washington, DC, United States of America

CORRIGENDUMDate: 09 Feb 2024Manuscript number: ALL-2023-01229.R1Title of Article: Response to Correspondence ALL-2023-01107 “Short-course subcutaneous treatment with PQ Grass strongly improves symptom and medication scores in grass allergy”Authors: P.J. de Kam1, S. Zielen2, J.A. Bernstein3, U. Berger4, M. Berger5, M. Cuevas6, D. Cypcar7, A. Fuhr-Horst8, W.A. Greisner9, M. Jandl10, S. Laßmann11, M. Worm12, J. Matz13, E. Sher14, C. Smith15, G.C. Steven16, R. Mösges17,18, M.H. Shamji19,20, L. DuBuske21, F. Borghese1, K. Oluwayi1, T. Zwingers1, M. Seybold1, O. Armfield1, M.D. Heath1, S.J. Hewings1, M.F. Kramer1, M.A. Skinner1Allergy Therapeutics plc, Worthing, United KingdomChildren and Adolescents Dept., Allergology, Pulmonology & Cystic fibrosis, Goethe University, Frankfurt, GermanyBernstein Clinical Research Center, LLC, Cincinnati, OH, United States of AmericaUniversity of Innsbruck, Department of Botany, Innsbruck, AustriaWiener Gesundheitsverbund, Hospital Hietzing, Department of Otorhinolaryngology, Vienna, AustriaClinic and Polyclinic of Otorhinolaryngology, University Clinic Carl Gustav Carus, TU Dresden, GermanyAllergy Partners of Western North Carolina, Asheville, NC, United States of AmericaENT Research- Institut für klinische Studien, Essen, GermanyBluegrass Allergy Research, Lexington, KY, United States of AmericaHamburger Institut für Therapieforschung GmbH, Hamburg, GermanyStudienzentrum Dr. Sabine Laßmann, Saalfeld, GermanyUniversitätsmedizin Berlin, Department of Dermatology and Allergy - Charite Campus Mitte, Berlin, GermanyChesapeake Clinical Research, Inc. White Marsh, MD, United States of AmericaAllergy Partners of New Jersey, Ocean, NJ, United States of AmericaCertified Research Associates, Cortland, NY, United States of AmericaAllergy Asthma & Sinus Center, S.C., Greenfield, WI, United States of AmericaIMSB (Institute of Computational Biology and Medical Statistics), University at Cologne, Cologne, GermanyClinCompetence, Cologne, GermanyImmunomodulation and Tolerance Group, Allergy and Clinical Immunology, Department of National Heart and Lung Institute, Imperial College London, London, United KingdomAsthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United KingdomDivision of Allergy and Immunology, Department of Internal Medicine, George Washington University Hospital, Washington, DC, United States of AmericaName of the Corresponding Author: Pieter-Jan De Kam

Background: Identification of biomarkers is required for a systems medicine approach and personalized treatment in AD. These biomarkers may not only aid in diagnosing but also might be suitable to predict the effectiveness of targeted treatment. Objective: We aimed to identify proteomic, microbial, and miRNA biomarkers in atopic dermatitis patients and investigated their course in relation to the clinical response upon anti-IL-4Rα therapy. Methods: Proteomic and miRNA screening was performed in AD patients in comparison to healthy controls. Differentially regulated serum proteins, miRNA, and selected skin microbiota were measured consecutively in 50 AD patients before and upon systemic dupilumab treatment. A random forest classifier was used to predict the outcome of dupilumab therapy based on the initial biomarker patterns. Results: We identified 27 proteomic candidates, miRNA, and 3 microbial strains to be dysregulated in AD. Besides the well-known chemokine CCL17 other proteins i.e., CCL13, CCL22, E-selectin and BDNF were differently regulated and significantly associated with treatment response. By contrast neither the microbial changes nor the miRNA pattern were found to be associated with treatment response upon dupilumab treatment. Conclusion: AD patients display defined dysregulations regarding their systemic proteomic serum profile, miRNA patterns, and their skin microbiome. The proteomic profile and selekted skin bacteria changed profoundly upon anti-IL-4Rα therapy which was associated with an overall clinical response. This was not seen in miRNA-related biomarkers. Our findings support the hypothesis that biomarker profiles reflect treatment responses and may in the future be used to develop a personalized medicine approach for the treatment of atopic dermatitis patients.

Introduction and objective Drugs are a frequent cause of severe anaphylactic reactions. Clinical epidemiology of drug-induced anaphylaxis (DIA) supports the identification of the most frequent eliciting drug groups, risk factors, symptoms and treatment procedures. Our aim was to analyze data to promote better recognition and long-term management of affected individuals. Methods Data from the European Anaphylaxis Registry (2007-2019) with 1,815 cases of drug-induced anaphylaxis were analyzed regarding demographics, elicitors, symptoms, comorbidities, and treatment. Results The most frequent eliciting groups of drugs were analgesics (41.27%) – with non-steroidal anti-inflammatory drugs (NSAIDs) being the most common subgroup (65.42%) – antibiotics (33.17%), local anesthetics (7.38%) and radiocontrast media (5.18%). Adrenaline was used more often in patients with DIA (23.20%) than in anaphylaxis due to other causes (17.82%). The majority of events occurred in female patients (65.34%), although they were admitted to hospital (29.01%) or an intensive care unit (ICU) (9.61%) less often. Skin symptoms were most common (84.02%), while gastrointestinal symptoms were reported less frequently (30.25%). Compared to other anaphylactic reactions in the registry (food/insects) severe reactions occurred significantly more often in DIA (5.62% vs. 1.67%). Hospitalization (31.63%) and ICU admission rates (11.85%) were significantly higher in DIA than anaphylactic reactions to other elicitors (27.58% and 5.45%). Conclusions DIA affects middle aged females more frequently and is more severe in elderly males in the sample observed. Analgesics and antibiotics are the leading causes of DIA. Adrenaline was rarely administered to patients, even though it is recommended by guidelines.

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.

Recent reports indiciate that the prevelance of food allergy is increasing, but accurate estimates remain a challenge due to cross-reactivity and limited use of precise diagnostic methods. Component-resolved diagnostics (CRD), in which sensitization to individual molecular components of whole food allergen extracts is measured, is emerging as a promising tool for evaluation of sensitization profiles. In this systematic review, we summarized estimates of prevalence of sensitization to food allergen components in the general population in Europe. We searched seven databases with no restrictions on publication date or language. Two reviewers independently screened the literature and appraised the risk of bias in the included studies. From 4,776 de-duplicated records, five studies, with low to moderate overall risk of bias, were included and narratively synthesized. Forty-six components from 18 foods were investigated. Overall, the prevalence of sensitization was low, particularly for major allergens, and non-existent for 10 components (0% [95% CI 0-0.8]). The highest prevalence was seen for PR-10 proteins, such as Cor a 1.04 (13.6% [95% CI 10.9-16.9]). There were not enough studies to discern regional differences or perfom meta-analysis, highlighting the need for more population-representative studies in order to elucidate patterns of sensitization to food allergen components in Europe.

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.

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: Peanut allergy has a rising prevalence in high-income countries, affecting 0.5–1.4% of children. This study aimed to better understand peanut anaphylaxis in comparison to anaphylaxis to other food triggers in European children and adolescents. Methods: Data was sourced from the European Anaphylaxis Registry via an online questionnaire, after in-depth review of food induced anaphylaxis cases in a tertiary paediatric allergy centre. Results: 3514 cases of food anaphylaxis were reported between July 2007 - March 2018, 56% in patients younger than 18 years. Peanut anaphylaxis was recorded in 459 children and adolescents (85% of all peanut anaphylaxis cases). Previous reactions (42% vs 38%; p=0.001), asthma comorbidity (47% vs 35%; p<0.001), relevant co-factors (29% vs 22%; p=0.004) and biphasic reactions (10% vs 4%; p=0.001) were more commonly reported in peanut anaphylaxis. Most cases were labelled as severe anaphylaxis (Ring&Messmer grade III 65% vs 56% and grade IV 1.1% vs 0.9%; p=0.001). Self-administration of intramuscular adrenaline was low (17% vs 15%), professional adrenaline administration was higher in non-peanut food anaphylaxis (34% vs 26%; p=0.003). Hospitalisation was higher for peanut anaphylaxis (67% vs 54%; p=0.004). Conclusions: The European Anaphylaxis Registry data confirmed peanut as one of the major causes of severe, potentially life-threatening allergic reactions in European children, with some characteristic features e.g. presence of asthma comorbidity and increased rate of biphasic reactions. Usage of intramuscular adrenaline as first line treatment is low and needs to be improved. The Registry, designed as the largest database on anaphylaxis, allows continuous assessment of this condition.

Background This systematic review used the GRADE approach to compile evidence to inform an anaphylaxis guideline from the European Academy of Allergy and Clinical Immunology (EAACI). Methods We searched five bibliographic databases from 1946 to 20 April 2020 for studies about the diagnosis, management and prevention of anaphylaxis. We included 50 studies with 18,449 participants: 29 randomised controlled trials, seven controlled clinical trials, seven consecutive case series and seven case-control studies. Findings were summarised narratively because studies were too heterogeneous to conduct meta-analysis. Results It is unclear whether the NIAID/FAAN criteria or Brighton case definition are valid for immediately diagnosing anaphylaxis due to the very low certainty of evidence. Adrenaline is the cornerstone of first-line emergency management of anaphylaxis but, due to ethical constraints, little robust research has assessed its effectiveness . Newer models of adrenaline autoinjectors may slightly increase the proportion of people correctly using the devices and reduce time to administration. Face-to-face training for laypeople may slightly improve anaphylaxis knowledge and competence in using autoinjectors. Adrenaline prophylaxis prior to snake bite anti-venom may reduce anaphylaxis but the impact of prophylactic corticosteroids and antihistamines is uncertain. There was insufficient evidence about the impact of other anaphylaxis management strategies. Conclusions Anaphylaxis is a potentially life-threatening condition but, due to practical and ethical challenges, there is a paucity of robust evidence about how to diagnose and manage it.