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Allergic asthma is the predominant phenotype among asthmatics. Although conventional pharmacotherapy is a central component in the management of asthma, it does not enable control of asthma symptoms in all patients. In recent decades, some uncontrolled asthmatic patients, especially those with allergic asthma, have benefited from biological therapies. However, biologics do not address all the unmet needs left by conventional pharmacotherapy. Furthermore, it is noteworthy that neither conventional pharmacotherapy nor biological therapies have disease-modifying properties. In this context, allergen immunotherapy (AIT) represents an indispensable component of the therapeutic arsenal against allergic asthma, due to its disease-modifying immunological effects. In this review article, funded by an AIT manufacturer, we find clinical trials support AIT as the only treatment option able both to improve allergic asthma symptoms and to prevent the onset and worsening of the condition. For patients with severe asthma or other safety concerns, the combination of AIT and biologics offers very promising new treatment modalities for the management of allergic asthma. Trial Registration: clinicaltrials.gov identifier: NCT06027073., (© 2024 Stallergenes SAS and The Author(s). Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Background: During the COVID-19 pandemic, novel nanoparticle-based mRNA vaccines were developed. A small number of individuals developed allergic reactions to these vaccines although the mechanisms remain undefined., Methods: To understand COVID-19 vaccine-mediated allergic reactions, we enrolled 19 participants who developed allergic events within 2 h of vaccination and 13 controls, nonreactors. Using standard hemolysis assays, we demonstrated that sera from allergic participants induced stronger complement activation compared to nonallergic subjects following ex vivo vaccine exposure., Results: Vaccine-mediated complement activation correlated with anti-polyethelyne glycol (PEG) IgG (but not IgM) levels while anti-PEG IgE was undetectable in all subjects. Depletion of total IgG suppressed complement activation in select individuals. To investigate the effects of vaccine excipients on basophil function, we employed a validated indirect basophil activation test that stratified the allergic populations into high and low responders. Complement C3a and C5a receptor blockade in this system suppressed basophil response, providing strong evidence for complement involvement in vaccine-mediated basophil activation. Single-cell multiome analysis revealed differential expression of genes encoding the cytokine response and Toll-like receptor (TLR) pathways within the monocyte compartment. Differential chromatin accessibility for IL-13 and IL-1B genes was found in allergic and nonallergic participants, suggesting that in vivo, epigenetic modulation of mononuclear phagocyte immunophenotypes determines their subsequent functional responsiveness, contributing to the overall physiologic manifestation of vaccine reactions., Conclusion: These findings provide insights into the mechanisms underlying allergic reactions to COVID-19 mRNA vaccines, which may be used for future vaccine strategies in individuals with prior history of allergies or reactions and reduce vaccine hesitancy., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

In rhinitis and asthma, several mHealth apps have been developed but only a few have been validated. However, these apps have a high potential for improving person-centred care (PCC), especially in allergen immunotherapy (AIT). They can provide support in AIT initiation by selecting the appropriate patient and allergen shared decision-making. They can also help in (i) the evaluation of (early) efficacy, (ii) early and late stopping rules and (iii) the evaluation of (carried-over) efficacy after cessation of the treatment course. Future perspectives have been formulated in the first report of a joint task force (TF)-Allergic Rhinitis and Its Impact on Asthma (ARIA) and the European Academy of Allergy and Clinical Immunology (EAACI)-on digital biomarkers. The TF on AIT now aims to (i) outline the potential of the clinical applications of mHealth solutions, (ii) express their current limitations, (iii) make proposals regarding further developments for both clinical practice and scientific purpose and (iv) suggest which of the tools might best comply with the purpose of digitally-enabled PCC in AIT., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Local allergic rhinitis (LAR) is defined by chronic nasal symptoms, absence of atopy, positive nasal allergen challenge (NAC) and a good response to subcutaneous allergen immunotherapy (SCIT). We sought to investigate SCIT capacity to induce local and systemic blocking antibodies in LAR patients., Methods: A RDBPC study of grass SCIT was performed, with participants receiving either SCIT (Group A; n = 10) or placebo (Group B; n = 14) in the first 6 months. Both groups subsequently received SCIT for 12 months at Year 2. Nasal and serum antibodies (IgG 4 , IgA 1 and IgA 2 ) and their inhibitory capacity were measured at multiple timepoints., Results: The allergen concentration tolerated increased significantly at 6 months (Group A; p = .047) and 24 months (Group B; p = .049) compared with baseline and persisted until the end of the study. Induction of serum sIgA 1 to Phl p was seen in Groups A and B, albeit the former being induced earlier (1.71-fold, p = .027). A significant induction in sIgG 4 to Phl p 1 and 5 was observed in serum of Group A (p = .047 and p = .0039) and sIgA 2 to Phl p in Group B (p = .032 and p = .0098) at 18 and 24 months, respectively. Both local and systemic blocking antibodies can inhibit allergen-IgE complexes binding to CD23 on B cells, and this correlated with level of allergen tolerated intra-nasally in Group A (serum; 𝜌 = -.47, p = .0006, nasal; 𝜌 = -.38, p = .0294)., Conclusions: Grass pollen SCIT induced functional systemic blocking antibodies that correlate with the concentration of allergen tolerated following NAC, highlighting their potential as a biomarker of SCIT in LAR., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

The fact that genetic and environmental factors could trigger disruption of the epithelial barrier and subsequently initiate a T H 2 inflammatory cascade conversely proposes that protecting the same barrier and promoting adequate interactions with other organs, such as the gut, may be crucial for lowering the risk and preventing atopic diseases, particularly, food allergies. In this review, we provide an overview of structural characteristics that support the epithelial barrier hypothesis in patients with atopic dermatitis, including the most relevant filaggrin gene mutations, the recent discovery of the role of the transient receptor potential vanilloid 1, and the role involvement of the microbiome in healthy and damaged skin. We present experimental and human studies that support the mechanisms of allergen penetration, particularly the dual allergen exposure and the outside-in, inside-out, and outside-inside-outside hypotheses. We discuss classic skin-targeted therapies for food allergy prevention, including moisturizers, steroids, and topical calcineurin inhibitors, along with pioneering trials proposed to change their current use (Prevention of Allergy via Cutaneous Intervention and Stopping Eczema and ALlergy). We provide an overview of the novel therapies that enhance the skin barrier, such as probiotics and prebiotics topical application, read-through drugs, direct and indirect FLG replacement, and interleukin and janus kinases inhibitors. Last, we discuss the newer strategies for preventing and treating food allergies in the form of epicutaneous immunotherapy and the experimental use of single-dose of adeno-associated virus vector gene immunotherapy., Competing Interests: Disclosures Dr Ciaccio receives research grant support from the National Institutes of Health (NIH), Food Allergy Research & Education (FARE), and Paul and Mary Yovovich and has served as a medical consultant/advisor for Genentech, Novartis, Siolta, Clostrabio, and FARE. Dr Chinthrajah reports receiving grants from National Institute of Allergy and Infectious Diseases (NIAID), CoFAR, Regeneron, Stanford Maternal and Child Health Research Institute, and FARE and is an advisory board member at Alladapt Therapeutics, Novartis, Genentech, Allergenis, Intrommune Therapeutics, and IgGenix. Dr Chan reports receiving grant from NIAID and NIH. Prof Leung reports receiving grants from Genentech, Incyte Corporation, and Sanofi-Genzyme; nonfinancial support from Aslan Pharmaceuticals; and personal fees from Leo Pharmaceuticals. Dr Marshall reports receiving research grant support from NIH. Prof Nadeau reports receiving grants from NIAID; National Heart, Lung, and Blood Institute (NHLBI); National Institute of Environmental Health Sciences (NIEHS); and FARE; receiving stock options from IgGenix, Seed Health, ClostraBio, Cour, and Alladapt; serving as an advisor at Cour Pharma; serving as a consultant for Excellergy, Red tree ventures, Before Brands, Alladapt, Cour, Latitude, Regeneron, and IgGenix; serving as a co-founder of Before Brands, Alladapt, Latitude, and IgGenix; serving as National Scientific Committee member at Immune Tolerance Network (ITN) and NIH clinical research centers; and having patents including, “Mixed allergen composition and methods for using the same,” “Granulocyte-based methods for detecting and monitoring immune system disorders,” and “Methods and Assays for Detecting and Quantifying Pure Subpopulations of White Blood Cells in Immune System Disorders.” Dr Radulovic reports receiving grant from NIAID and NIH. Prof Lack reports receiving grant from NIAID/NIH; having personal fees and stock options from DBV Technologies; having stock options from Mission MightyMe; and serving as a scientific consultant/advisor for Novartis, Sanofi-Genzyme, Regeneron, ALK-Abello, Reckitt Mead Johnson, and Lurie Children's Hospital. Dr Sindher receives research grant support from NIH, FARE, CoFAR, DBV, AIMMUNE, and Regeneron and has served as an advisor for Genentech. Prof Brough reports receiving grant from NIAID and NIH and receiving speaker honoraria from DBV Technologies, GlaxoSmithKline, and Sanofi. The remaining authors have no conflicts of interest to report., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale: It is unclear how each individual asthma symptom is associated with asthma diagnosis or control., Objectives: To assess the performance of individual asthma symptoms in the identification of patients with asthma and their association with asthma control., Methods: In this cross-sectional study, we assessed real-world data using the MASK-air ® app. We compared the frequency of occurrence of five asthma symptoms (dyspnea, wheezing, chest tightness, fatigue and night symptoms, as assessed by the Control of Allergic Rhinitis and Asthma Test [CARAT] questionnaire) in patients with probable, possible or no current asthma. We calculated the sensitivity, specificity and predictive values of each symptom, and assessed the association between each symptom and asthma control (measured using the e-DASTHMA score). Results were validated in a sample of patients with a physician-established diagnosis of asthma., Measurement and Main Results: We included 951 patients (2153 CARAT assessments), with 468 having probable asthma, 166 possible asthma and 317 no evidence of asthma. Wheezing displayed the highest specificity (90.5%) and positive predictive value (90.8%). In patients with probable asthma, dyspnea and chest tightness were more strongly associated with asthma control than other symptoms. Dyspnea was the symptom with the highest sensitivity (76.1%) and the one consistently associated with the control of asthma as assessed by e-DASTHMA. Consistent results were observed when assessing patients with a physician-made diagnosis of asthma., Conclusions: Wheezing and chest tightness were the asthma symptoms with the highest specificity for asthma diagnosis, while dyspnea displayed the highest sensitivity and strongest association with asthma control., (© 2024 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Background: There is still great need to develop new strategies to improve the efficacy of allergen immunotherapies with optimal safety standards for patients. A new promising approach is to couple allergoids to mannan. The objective of this phase IIa/IIb study was to identify the optimal dose of mannan-conjugated birch pollen allergoids for the short-course treatment of birch pollen-induced allergic rhinoconjunctivitis., Methods: For this prospective, randomized, double-blind, placebo-controlled, dose-finding study, 246 birch pollen-allergic adults received 0.5 mL placebo or 1000, 3000 or 10,000 mTU/mL of mannan-conjugated birch pollen allergoids at five pre-seasonal visits. Efficacy was assessed by comparing allergic rhinoconjunctivitis symptoms and use of anti-allergic medication during the peak of the birch pollen season 2020. Immunologic, tolerability and safety effects were also analysed., Results: The highest dose of mannan-conjugated birch pollen allergoids reduced the combined symptom and medication score during the peak birch pollen season by a median of 24.7% compared to placebo. The production of Bet v 1 specific IgG4 significantly increased in a dose-dependent manner (3.6- and 4.5-fold) in the 3000 and 10,000 mTU/mL groups. The Bet v 1 specific IgE/IgG4 ratio was also strongly reduced (up to -70%). No fatalities nor serious adverse events were reported, and no adrenaline was used. In total, four systemic reactions occurred (two grade I and two grade II)., Conclusion: All doses of mannan-conjugated birch pollen allergoids can be considered as safe. Since the application of 10,000 mTU/mL resulted in the highest efficacy, this dose qualifies for further investigation., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

The importance of allergen immunotherapy (AIT) is multifaceted, encompassing both clinical and quality-of-life improvements and cost-effectiveness in the long term. Key mechanisms of allergen tolerance induced by AIT include changes in memory type allergen-specific T- and B-cell responses towards a regulatory phenotype with decreased Type 2 responses, suppression of allergen-specific IgE and increased IgG 1 and IgG 4 , decreased mast cell and eosinophil numbers in allergic tissues and increased activation thresholds. The potential of novel patient enrolment strategies for AIT is taking into account recent advances in biomarkers discoveries, molecular allergy diagnostics and mobile health applications contributing to a personalized approach enhancement that can increase AIT efficacy and compliance. Artificial intelligence can help manage and interpret complex and heterogeneous data, including big data from omics and non-omics research, potentially predict disease subtypes, identify biomarkers and monitor patient responses to AIT. Novel AIT preparations, such as synthetic compounds, innovative carrier systems and adjuvants, are also of great promise. Advances in clinical trial models, including adaptive, complex and hybrid designs as well as real-world evidence, allow more flexibility and cost reduction. The analyses of AIT cost-effectiveness show a clear long-term advantage compared to pharmacotherapy. Important research questions, such as defining clinical endpoints, biomarkers of patient selection and efficacy, mechanisms and the modulation of the placebo effect and alternatives to conventional field trials, including allergen exposure chamber studies are still to be elucidated. This review demonstrates that AIT is still in its growth phase and shows immense development prospects., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Hypersensitivity to house dust mite (HDM) allergens is a common cause of allergic asthma symptoms and can be effectively treated with allergy immunotherapy (AIT)., Objective: To investigate whether genetic and type 2 (T2) inflammatory biomarkers correlate with disease severity in subjects with allergic asthma, and whether this can be modified by AIT., Methods: MITRA (NCT01433523) was a phase III, randomised, double-blind, placebo-controlled trial of HDM sublingual immunotherapy (SLIT)-tablets in adults with HDM allergic asthma. Post hoc analyses of the study population (N=742) evaluated associations between T2 inflammatory (blood eosinophils, eosinophil cationic protein (ECP), total IgE and tryptase) and genetic (single-nucleotide polymorphisms, SNP) biomarkers (n=582) for the primary study endpoint (time to first moderate/severe asthma exacerbation). SNP associations were verified in HDM-positive subgroup from an independent 3-year Severe Asthma Research Programme (SARP3) subject cohort., Results: An increased asthma exacerbation risk in subjects homozygous for SNP rs7216389 (chromosomal locus 17q12-21) was reduced (p = 0.037) by treatment with HDM SLIT (HR=0.37 (95% CI 0.22 to 0.64), p<0.001). The associations between exacerbation risk and 17q12-21 SNPs were replicated in the SARP3 HDM-positive subgroup. High levels of T2 biomarkers were associated with increased risk of asthma exacerbations in the placebo group. HDM SLIT-tablet treatment reduced this risk (blood eosinophils: HR=0.50 (95% CI 0.30 to 0.85); ECP: HR=0.45 (95% CI 0.29 to 0.87); tryptase: HR=0.45 (95% CI 0.25 to 0.80)). The treatment effect was higher (p = 0.006) for subjects with a higher number of elevated T2 biomarkers., Conclusions: HDM SLIT-tablet AIT is efficacious in HDM-sensitised asthma subjects with a genetic asthma predisposition and/or an underlying T2 endotype., Trial Registration Number: NCT01433523., Competing Interests: Competing interests: IH is an employee of ALK-Abelló A/S. KB has acted as a paid consultant for ALK-Abelló A/S, AstraZeneca, Boehringer Ingelheim and Sanofi. TS is an employee of ALK-Abelló A/S. SB was an employee of ALK-Abelló A/S when data analysis took place. MHS receives grant support via Imperial College London from the Immune Tolerance Network, National Institute of Allergy and Infectious Diseases, Medical Research council, ALK-Abelló A/S, Regeneron, and serves as a consultant for Allergy Therapeutics, Angany, and UCB. EDB is a member of the Science Committee and Board of GINA. He reports personal fees from ALK-Abelló A/S in relation to the current submission, and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Menarini, Novartis, Orion, Regeneron and Sanofi Genzyme, outside the submitted work. EB has undertaken clinical trials through his employer, Wake Forest School of Medicine and University of Arizona, for AstraZeneca, MedImmune, Boehringer Ingelheim, Genentech, Novartis, Regeneron, and Sanofi Genzyme, and has served as a paid consultant for ALK-Abelló A/S, AstraZeneca, MedImmune, GlaxoSmithKline, Novartis, Regeneron, Sanofi Genzyme and TEVA, outside the submitted work. PSA is an employee of ALK-Abelló A/S., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Plant species vary under different climatic conditions and the distribution of pollen in the air. Trends in pollen distribution can be used to assess the impact of climate change on public health. In 2015, the Mobile Airways Sentinel networK for rhinitis and asthma (MASK-air®) was launched as a project of the European Innovation Partnership on Active and Healthy Ageing (EIP-on-AHA, DG Santé and DG CONNECT). This project aimed to develop a warning system to inform patients about the onset of the pollen season, namely, the System for Integrated modeLling of Atmospheric coMposition (SILAM). A global-to-meso-scale dispersion model was developed by the Finnish Meteorological Institute (FMI). It provides quantitative information on atmospheric pollution of anthropogenic and natural origins, particularly on allergenic pollens. Impact of Air Pollution on Asthma and Rhinitis (POLLAR, EIT Health) has combined MASK-air clinical data with SILAM forecasts. A new Horizon Europe grant (Climate Action to Advance HeaLthY Societies in Europe [CATALYSE]; grant agreement number 101057131), which came into force in September 2022, aims to improve our understanding of climate change and help us find ways to counteractit. One objective of this project is to develop early warning systems and predictive models to improve the effectiveness of strategies for adapting to climate change. One of the warning systems is focused on allergic rhinitis (CATALYSE Task 3.2), with a collaboration between the FMI (Finland), Porto University (Portugal), MASK-air SAS (France), ISGlobal (Spain), Hertie School (Germany), and the University of Zurich (Switzerland). It is to be implemented with the support of the European Academy of Allergy and Clinical Immunology. This paper reports the planning of CATALYSE Task 3.2.

Allergen immunotherapy (AIT) remains to be the only disease-modifying treatment for IgE-mediated allergic diseases such as allergic rhinitis. It can provide long-term clinical benefits when given for 3 years or longer. Mechanisms of immune tolerance induction by AIT are underscored by the modulation of several compartments within the immune system. These include repair of disruption in epithelial barrier integrity, modulation of the innate immune compartment that includes regulatory dendritic cells and innate lymphoid cells, and adaptive immune compartments such as induction of regulatory T and B cells. Altogether, these are also associated with the dampening of allergen-specific T H 2 and T follicular helper cell responses and subsequent generation of blocking antibodies. Although AIT is effective in modifying the immune response, there is a lack of validated and clinically relevant biomarkers that can be used to monitor desensitization, efficacy, and the likelihood of response, all of which can contribute to accelerating personalized medication and increasing patient care. Candidate biomarkers comprise humoral, cellular, metabolic, and in vivo biomarkers; however, these are primarily studied in small trials and require further validation. In this review, we evaluate the current candidates of biomarkers of AIT and how we can implement changes in future studies to help us identify clinically relevant biomarkers of safety, compliance, and efficacy., (Copyright © 2023. Published by Elsevier Inc.)

T and B cells are key components of the adaptive immune system. Through their immune properties and their interactions with other immune cells and cytokines around them, they build a complex network to achieve immune tolerance and maintain homeostasis of the body. This is achieved through mechanisms of central and peripheral tolerance, both of which are associated with advantages and disadvantages. For this reason, the immune system is tightly regulated and their dysregulation can result in the subsequent initiation of various diseases. In this review, we will summarize the roles played by T cells and B cells within immune tolerance with specific examples in the context of different diseases that include allergic disease. In addition, we will also provide an overview on their suitability as biomarkers of allergen-specific immunotherapy., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2023. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.)

Uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with elevated levels of type 2 inflammatory cytokines and raised immunoglobulin concentrations in nasal polyp tissue. By using single-cell RNA sequencing, transcriptomics, surface proteomics, and T cell and B cell receptor sequencing, we found the predominant cell types in nasal polyps were shifted from epithelial and mesenchymal cells to inflammatory cells compared to nasal mucosa from healthy controls. Broad expansions of CD4 T effector memory cells, CD4 tissue-resident memory T cells, CD8 T effector memory cells and all subtypes of B cells in nasal polyp tissues. The T and B cell receptor repertoires were skewed in NP. This study highlights the deviated immune response and remodeling mechanisms that contribute to the pathogenesis of uncontrolled severe CRSwNP. CLINICAL IMPLICATIONS: We identified differences in the cellular compositions, transcriptomes, proteomes, and deviations in the immune profiles of T cell and B cell receptors as well as alterations in the intercellular communications in uncontrolled severe CRSwNP patients versus healthy controls, which might help to define potential therapeutic targets in the future., Competing Interests: Declaration of Competing Interest Claus Bachert: Advisory Board member and speaker for Novartis, GSK, Astra-Zeneca, Sanofi, ALK, and Mylan. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2023 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.)

The exponential growth of precision diagnostic tools, including omic technologies, molecular diagnostics, sophisticated genetic and epigenetic editing, imaging and nano-technologies and patient access to extensive health care, has resulted in vast amounts of unbiased data enabling in-depth disease characterization. New disease endotypes have been identified for various allergic diseases and triggered the gradual transition from a disease description focused on symptoms to identifying biomarkers and intricate pathogenetic and metabolic pathways. Consequently, the current disease taxonomy has to be revised for better categorization. This European Academy of Allergy and Clinical Immunology Position Paper responds to this challenge and provides a modern nomenclature for allergic diseases, which respects the earlier classifications back to the early 20th century. Hypersensitivity reactions originally described by Gell and Coombs have been extended into nine different types comprising antibody- (I-III), cell-mediated (IVa-c), tissue-driven mechanisms (V-VI) and direct response to chemicals (VII). Types I-III are linked to classical and newly described clinical conditions. Type IVa-c are specified and detailed according to the current understanding of T1, T2 and T3 responses. Types V-VI involve epithelial barrier defects and metabolic-induced immune dysregulation, while direct cellular and inflammatory responses to chemicals are covered in type VII. It is notable that several combinations of mixed types may appear in the clinical setting. The clinical relevance of the current approach for allergy practice will be conferred in another article that will follow this year, aiming at showing the relevance in clinical practice where various endotypes can overlap and evolve over the lifetime., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Allergen immunotherapy (AIT) is a well-established disease-modifying therapy for allergic rhinitis, yet the fundamental mechanisms underlying its clinical effect remain inadequately understood. Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy was a randomized, double-blind, placebo-controlled trial of individuals allergic to timothy grass who received 2 years of placebo (n = 30), subcutaneous immunotherapy (SCIT) (n = 27), or sublingual immunotherapy (SLIT) (n = 27) and were then followed for 1 additional year., Objective: We used yearly biospecimens from the Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy study to identify molecular mechanisms of response., Methods: We used longitudinal transcriptomic profiling of nasal brush and PBMC samples after allergen provocation to uncover airway and systemic expression pathways mediating responsiveness to AIT., Trial Registration: ClinicalTrials.gov Identifier: NCT01335139, EudraCT Number: 2010-023536-16., Results: SCIT and SLIT demonstrated similar changes in gene module expression over time. In nasal samples, alterations included downregulation of pathways of mucus hypersecretion, leukocyte migration/activation, and endoplasmic reticulum stress (log2 fold changes -0.133 to -0.640, false discovery rates [FDRs] <0.05). We observed upregulation of modules related to epithelial development, junction formation, and lipid metabolism (log2 fold changes 0.104 to 0.393, FDRs <0.05). In PBMCs, modules related to cellular stress response and type 2 cytokine signaling were reduced by immunotherapy (log2 fold changes -0.611 to -0.828, FDRs <0.05). Expression of these modules was also significantly associated with both Total Nasal Symptom Score and peak nasal inspiratory flow, indicating important links between treatment, module expression, and allergen response., Conclusions: Our results identify specific molecular responses of the nasal airway impacting barrier function, leukocyte migration activation, and mucus secretion that are affected by both SCIT and SLIT, offering potential targets to guide novel strategies for AIT., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: A modified grass allergen subcutaneous immunotherapy (SCIT) product with MicroCrystalline Tyrosine and monophosphoryl lipid-A as an adjuvant system (Grass MATA MPL [PQ Grass]) is being developed as short-course treatment of grass-pollen allergic rhinitis (SAR) and/or rhinoconjunctivitis. We sought to evaluate the combined symptom and medication score (CSMS) of the optimized cumulative dose of 27,600 standardized units (SU) PQ Grass in a field setting prior to embarking on a pivotal Phase III trial., Methods: In this exploratory, randomized, double-blind, placebo-controlled trial subjects were enrolled across 14 sites (Germany and the United States of America). Six pre-seasonal subcutaneous injections of PQ Grass (using conventional or extended regimens) or placebo were administered to 119 subjects (aged 18-65 years) with moderate-to-severe SAR with or without asthma that was well-controlled. The primary efficacy endpoint was CSMS during peak grass pollen season (GPS). Secondary endpoints included Rhinoconjunctivitis Quality of Life Questionnaire standardized (RQLQ-S) and allergen-specific IgG4 response., Results: The mean CSMS compared to placebo was 33.1% (p = .0325) and 39.5% (p = .0112) for the conventional and extended regimens, respectively. An increase in IgG4 was shown for both regimens (p < .01) as well as an improvement in total RQLQ-S for the extended regimen (mean change -0.72, p = .02). Both regimens were well-tolerated., Conclusions: This trial demonstrated a clinically relevant and statistically significant efficacy response to PQ Grass. Unprecedented effect sizes were reached for grass allergy of up to ≈40% compared to placebo for CSMS after only six PQ Grass injections. Both PQ Grass regimens were considered equally safe and well-tolerated. Based on enhanced efficacy profile extended regime will be progressed to the pivotal Phase III trial., (© 2023 Allergy Therapeutics Plc and The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Introduction: Adherence to controller medication is a major problem in asthma management, being difficult to assess and tackle. mHealth apps can be used to assess adherence. We aimed to assess the adherence to inhaled corticosteroids+long-acting β2-agonists (ICS+LABA) in users of the MASK-air® app, comparing the adherence to ICS+formoterol (ICS+F) with that to ICS+other LABA., Materials and Methods: We analysed complete weeks of MASK-air® data (2015-2022; 27 countries) from patients with self-reported asthma and ICS+LABA use. We compared patients reporting ICS+F versus ICS+other LABA on adherence levels, symptoms and symptom-medication scores. We built regression models to assess whether adherence to ICS+LABA was associated with asthma control or short-acting beta-agonist (SABA) use. Sensitivity analyses were performed considering the weeks with no more than one missing day., Results: In 2598 ICS+LABA users, 621 (23.9%) reported 4824 complete weeks and 866 (33.3%) reported weeks with at most one missing day. Higher adherence (use of medication ≥80% of weekly days) was observed for ICS+other LABA (75.1%) when compared to ICS+F (59.3%), despite both groups displaying similar asthma control and work productivity. The ICS+other LABA group was associated with more days of SABA use than the ICS+F group (median=71.4% versus 57.1% days). Each additional weekly day of ICS+F use was associated with a 4.1% less risk in weekly SABA use (95%CI=-6.5;-1.6%;p=0.001). For ICS+other LABA, the percentage was 8.2 (95%CI=-11.6;-5.0%;p<0.001)., Conclusions: In asthma patients adherent to the MASK-air app, adherence to ICS+LABA was high. ICS+F users reported lower adherence but also a lower SABA use and a similar level of control., Competing Interests: Conflicts of interest JS reports grants and personal fees from SANOFI, personal fees from GSK, personal fees from NOVARTIS, personal fees from ASTRA ZENECA, personal fees from MUNDIPHARMA, personal fees from FAES FARMA, outside the submitted work. BS reports personal fees from Polpharma, personal fees from Viatris, grants and personal fees from AstraZeneca, personal fees from TEVA, personal fees from patient ombudsman, personal fees from Polish Allergology Society, grants from GSK, outside the submitted work. SBA reports grants from TEVA, personal fees from TEVA, personal fees from TEVA, personal fees from AstraZeneca, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Boehringer Ingelheim, personal fees from GSK, personal fees from Sanofi, personal fees from Mylan, personal fees from Menarini, outside the submitted work. BG reports grants from Chiesi, grants from Sandoz, grants from GSK, grants from AstraZeneca, grants from Deva, grants from Abdi İbrahim, outside the submitted work. RL reports grants and personal fees from AZ, grants and personal fees from GSK, grants from Chiesi, outside the submitted work. MK reports personal fees from Astra Zeneca, personal fees from Chiesi, personal fees from GSK, personal fees from Novartis, personal fees from Berlin Chemie, personal fees from Zentiva, personal fees from Allergopharma, personal fees from LEK-AM, personal fees from Polpharma, personal fees from Teva, personal fees from Sanofi, personal fees from Adamed, personal fees from Sandoz, personal fees from EMMA, outside the submitted work. FDB reports other from NOVARTIS, other from ALK, other from STALLERGENES, other from REGENERON, other from DBV, other from SANOFI, other from BOEHRINGER, other from ASTRAZENECA, outside the submitted work. CSU reports grants and personal fees from AZ, personal fees from GSK, personal fees from TEVA, grants and personal fees from Sanofi, grants and personal fees from BI, personal fees from Novartis, personal fees and non-financial support from Orion Pharma, personal fees from Chiesi, personal fees from TFF Pharmaceuticals, personal fees from Takeda, personal fees from Pfizer, personal fees from Covis Pharma, outside the submitted work. NP reports grants from Capricare, personal fees from Nestle, personal fees from Numil, personal fees from Vianex, outside the submitted work. FR reports personal fees from Novartis, personal fees from Sanofi, personal fees from AstraZeneca, personal fees from GSK, personal fees from Medinfar, personal fees from Azentis, outside the submitted work. TZ reports grants and personal fees from Novartis, grants and personal fees from Henkel, personal fees from Bayer, personal fees from FAES, personal fees from Astra Zeneca, personal fees from AbbVie, personal fees from ALK, personal fees from Almirall, personal fees from Astellas, personal fees from Bayer, personal fees from Bencard, personal fees from Berlin Chemie, personal fees from FAES, personal fees from Hal, personal fees from Leti, personal fees from Mesa, personal fees from Menarini, personal fees from Merck, personal fees from MSD, personal fees from Novartis, personal fees from Pfizer, personal fees from Sanofi, personal fees from Stallergenes, personal fees from Takeda, personal fees from Teva, personal fees from UCB, personal fees from Henkel, personal fees from Kryolan, personal fees from L'Oreal, outside the submitted work; and Organizational affiliations: Commitee member: WHO-Initiative "Allergic Rhinitis and Its Impact on Asthma" (ARIA); Member of the Board: German Society for Allergy and Clinical Immunology (DGAKI); Head: European Centre for Allergy Research Foundation (ECARF); President: Global Allergy and Asthma European Network (GA2LEN); Member: Committee on Allergy Diagnosis and Molecular Allergology, World Allergy Organization (WAO). AP reports grants from CHIESI, ASTRAZENECA, GSK, SANOFI, personal fees from CHIESI, ASTRAZENECA, GSK, NOVARTIS, SANOFI, IQVIA, AVILLION, ELPEN PHARMACEUTICALS, personal fees from CHIESI, ASTRAZENECA, GSK, BI, MENARINI, NOVARTIS, ZAMBON, MUNDIPHARMA, TEVA, SANOFI, EDMOND PHARMA, IQVIA, MSD, AVILLION, ELPEN PHARMACEUTICALS, outside the submitted work. RB reports grants from Boehringer Ingelheim, GlaxoSmithKline, Novartis and Roche, personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Novartis, Sanofi, Roche and Teva, outside the submitted work. LTB reports personal fees from DIATER, personal fees from Novartis, personal fees from LETI, outside the submitted work. JF reports personal fees from Viatris/Mylan, personal fees from AstraZeneca, outside the submitted work; and being co-founder of an SME that develops mHealth technologies, such as digital biomarkers and has the copyright of the CARAT anda CARATkids PROM. VK reports non-financial support from Norameda, non-financial support from Berlin CHemie Menarini, outside the submitted work. NR reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from Novartis, grants and personal fees from GSK, personal fees from AstraZeneca, personal fees from Chiesi, grants and personal fees from Pfizer, personal fees from Sanofi, personal fees from Zambon, personal fees from MSD, personal fees from Austral, outside the submitted work. SB reports personal fees from Sanofi Genzyme, personal fees from AstraZeneca, grants from Auris medical, personal fees from Allergopharma, personal fees from ALK Abello, grants, personal fees and non-financial support from Bencard Allergy, personal fees from Allergy Therapeutics, non-financial support from Smart Reporting, personal fees from Stryker, personal fees from MSD, personal fees from Mylan, personal fees from GSK, outside the submitted work. JB reports personal fees from Cipla, Menarini, Mylan, Novartis, Purina, Sanofi-Aventis, Teva, Uriach, other from KYomed-Innov, other from Mask-air-SAS, outside the submitted work. TH reports personal fees from Orion Pharma, outside the submitted work. LC reports personal fees from Thermofisher, personal fees from Novartis, personal fees from ALK, personal fees from Sanofi, personal fees from GSK, personal fees from Astra Zeneca, outside the submitted work. LPB reports grants from Time frame: past 36 months Amgen, AstraZeneca, GlaxoSmithKline, Merck, Novartis, Sanofi-Regeneron, personal fees from Astra Zeneca, Novartis, GlaxoSmithKline, Merck, Sanofi-Regeneron, personal fees from AstraZeneca, Covis, Cipla, GlaxoSmithKline, Novartis, Merck, Sanofi, outside the submitted work. SDG reports grants and personal fees from AstraZeneca, personal fees from Chiesi, grants and personal fees from GSK, grants and personal fees from Novartis, personal fees from Guidotti, personal fees from Sanofi, outside the submitted work. PK reports personal fees from Adamed, personal fees from Berlin Chemie Menarini, personal fees from Boehringer Ingelheim, personal fees from AstraZeneca, personal fees from Glenmark, personal fees from Novartis, personal fees from Polpharma, personal fees from GSK, personal fees from Sanofi, personal fees from Chiesi, personal fees from Celon Pharma, outside the submitted work. AC reports personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from GSK, personal fees from Eurofarma, personal fees from Novartis, personal fees from Sanofi, outside the submitted work. MS reports grants from Immune Tolerance Network, grants from Medical Research Council, grants and personal fees from Allergy Therapeutics, grants and personal fees from LETI Laboratorios, grants from Revolo biotherapeutics, grants from Angany Inc, personal fees from Bristol Myers Squibb, outside the submitted work. GB reports personal fees from Astra Zeneca, personal fees from Boehringer-Ingelheim, personal fees from Chiesi, personal fees from GlaxoSmithKline, personal fees from Novartis, personal fees from Sanofi, grants from MerckSharp&Dohme, outside the submitted work. MJ reports personal fees from ALK-Abello, personal fees from Allergopharma, personal fees from Stallergenes, personal fees from Anergis, personal fees from Allergy Therapeutics, personal fees from Leti, personal fees from HAL, during the conduct of the study; personal fees from GSK, personal fees from Novartis, personal fees from Teva, personal fees from Takeda, personal fees from Chiesi, outside the submitted work. DLL reports personal fees from ALK, Astrazeneca national and global, Bayer, Chiesi, Grunenthal, Grin, GSK national and global, Viatris, Menarini, MSD, Novartis, Pfizer, Sanofi, Siegfried, UCB, Carnot, grants from Abbvie, Bayer, Lilly, Sanofi, Astrazeneca, Lilly, Pfizer, Novartis, Circassia, UCB, GSK, Purina institute., outside the submitted work. OP reports grants and personal fees from ALK-Abelló, grants and personal fees from Allergopharma, grants and personal fees from Stallergenes Greer, grants and personal fees from HAL Allergy Holding B.V./HAL Allergie GmbH, grants from Bencard Allergie GmbH/Allergy Therapeutics, grants from Lofarma, grants and personal fees from ASIT Biotech Tools S.A., grants and personal fees from Laboratorios LETI/LETI Pharma, grants and personal fees from GlaxoSmithKline, personal fees from ROXALL Medizin, personal fees from Novartis, grants and personal fees from Sanofi-Aventis and Sanofi-Genzyme, personal fees from Med Update Europe GmbH, personal fees from streamedup! GmbH, grants from Pohl-Boskamp, grants from Inmunotek S.L., personal fees from John Wiley and Sons, AS, personal fees from Paul-Martini-Stiftung (PMS), personal fees from Regeneron Pharmaceuticals Inc., personal fees from RG Aerztefortbildung, personal fees from Institut für Disease Management, personal fees from Springer GmbH, grants and personal fees from AstraZeneca, personal fees from IQVIA Commercial, personal fees from Ingress Health, personal fees from Wort&Bild Verlag, personal fees from Verlag ME, personal fees from Procter&Gamble, personal fees from ALTAMIRA, personal fees from Meinhardt Congress GmbH, personal fees from Deutsche Forschungsgemeinschaft, personal fees from Thieme, grants from Deutsche AllergieLiga e.V., personal fees from AeDA, personal fees from Alfried-Krupp Krankenhaus, personal fees from Red Maple Trials Inc., personal fees from TU Dresden, outside the submitted work. YO reports personal fees from Torii pharmaceutical Co., LTD., personal fees from Tanabe-Mitsubishi Pharmaceutical Co., Ltd., personal fees from Kirin Holdings Co., Ltd., personal fees from Novartis Co., Ltd., personal fees from Allergologisk Laboratorium København, personal fees from Shionogi Co., Ltd., outside the submitted work. JCI reports personal fees and non-financial support from Laboratorios Casasco, personal fees from Abbott Ecuador, personal fees from Laboratorios Bago Bolvia, personal fees from Faes Farma, outside the submitted work. HK reports personal fees from Mylan/Viatris, personal fees from Sanofi, outside the submitted work. MO reports personal fees from Hycor Diagnostics, outside the submitted work; and Scientific Co-Founder, Tolerogenics SARL, Luxembourg. The other authors have no COIs to disclose, outside the submitted work., (Copyright © 2023 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Heat waves are increasing in intensity, frequency, and duration causing significant heat stress in all living organisms. Heat stress has multiple negative effects on plants affecting photosynthesis, respiration, growth, development, and reproduction. It also impacts animals leading to physiological and behavioral alterations, such as reduced caloric intake, increased water intake, and decreased reproduction and growth. In humans, epidemiological studies have shown that heat waves are associated with increased morbidity and mortality. There are many biological effects of heat stress (structural changes, enzyme function disruption, damage through reactive oxygen or nitrogen species). While plants and animals can mitigate some of these effects through adaptive mechanisms such as the generation of heat shock proteins, antioxidants, stress granules, and others, these mechanisms may likely be inadequate with further global warming. This review summarizes the effects of heat stress on plants and animals and the adaptative mechanisms that have evolved to counteract this stress., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Biomarkers for the diagnosis, treatment and follow-up of patients with rhinitis and/or asthma are urgently needed. Although some biologic biomarkers exist in specialist care for asthma, they cannot be largely used in primary care. There are no validated biomarkers in rhinitis or allergen immunotherapy (AIT) that can be used in clinical practice. The digital transformation of health and health care (including mHealth) places the patient at the center of the health system and is likely to optimize the practice of allergy. Allergic Rhinitis and its Impact on Asthma (ARIA) and EAACI (European Academy of Allergy and Clinical Immunology) developed a Task Force aimed at proposing patient-reported outcome measures (PROMs) as digital biomarkers that can be easily used for different purposes in rhinitis and asthma. It first defined control digital biomarkers that should make a bridge between clinical practice, randomized controlled trials, observational real-life studies and allergen challenges. Using the MASK-air app as a model, a daily electronic combined symptom-medication score for allergic diseases (CSMS) or for asthma (e-DASTHMA), combined with a monthly control questionnaire, was embedded in a strategy similar to the diabetes approach for disease control. To mimic real-life, it secondly proposed quality-of-life digital biomarkers including daily EQ-5D visual analogue scales and the bi-weekly RhinAsthma Patient Perspective (RAAP). The potential implications for the management of allergic respiratory diseases were proposed., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: The self-reporting of asthma frequently leads to patient misidentification in epidemiological studies. Strategies combining the triangulation of data sources may help to improve the identification of people with asthma. We aimed to combine information from the self-reporting of asthma, medication use and symptoms to identify asthma patterns in the users of an mHealth app., Methods: We studied MASK-air® users who reported their daily asthma symptoms (assessed by a 0-100 visual analogue scale - "VAS Asthma") at least three times (either in three different months or in any period). K-means cluster analysis methods were applied to identify asthma patterns based on: (i) whether the user self-reported asthma; (ii) whether the user reported asthma medication use and (iii) VAS asthma. Clusters were compared by the number of medications used, VAS asthma levels and Control of Asthma and Allergic Rhinitis Test (CARAT) levels., Findings: We assessed a total of 8,075 MASK-air® users. The main clustering approach resulted in the identification of seven groups. These groups were interpreted as probable: (i) severe/uncontrolled asthma despite treatment (11.9-16.1% of MASK-air® users); (ii) treated and partly-controlled asthma (6.3-9.7%); (iii) treated and controlled asthma (4.6-5.5%); (iv) untreated uncontrolled asthma (18.2-20.5%); (v) untreated partly-controlled asthma (10.1-10.7%); (vi) untreated controlled asthma (6.7-8.5%) and (vii) no evidence of asthma (33.0-40.2%). This classification was validated in a study of 192 patients enrolled by physicians., Interpretation: We identified seven profiles based on the probability of having asthma and on its level of control. mHealth tools are hypothesis-generating and complement classical epidemiological approaches in identifying patients with asthma., (Copyright © 2022 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Allergic diseases and asthma are intrinsically linked to the environment we live in and to patterns of exposure. The integrated approach to understanding the effects of exposures on the immune system includes the ongoing collection of large-scale and complex data. This requires sophisticated methods to take full advantage of what this data can offer. Here we discuss the progress and further promise of applying artificial intelligence and machine-learning approaches to help unlock the power of complex environmental data sets toward providing causality models of exposure and intervention. We discuss a range of relevant machine-learning paradigms and models including the way such models are trained and validated together with examples of machine learning applied to allergic disease in the context of specific environmental exposures as well as attempts to tie these environmental data streams to the full representative exposome. We also discuss the promise of artificial intelligence in personalized medicine and the methodological approaches to healthcare with the final AI to improve public health., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)