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This article discusses the clinical efficacy of tezepelumab, a monoclonal antibody, in non-type 2 (T2) asthma patients. Tezepelumab targets thymic stromal lymphopoietin (TLSP), a biomarker associated with airway inflammation in non-T2 asthma. Previous research has shown that tezepelumab can improve lung function, asthma control, and quality of life in uncontrolled asthma patients with low baseline blood eosinophil counts. This case series examines the effects of tezepelumab in pre-defined non-T2 asthma patients, demonstrating improvements in lung function, asthma control, and quality of life in the majority of patients. These findings are promising for this population. [Extracted from the article]

The article discusses the basophil activation test (BAT) as a diagnostic tool for managing patients with IgE-mediated allergies. The authors emphasize the need for standardization and external quality assurance (EQA) of laboratory protocols and results interpretation. A task force was created to develop a consensus protocol for BAT-EQA, and round robin tests were conducted to train participating laboratories. The article presents a proposed standard operating protocol for BAT and highlights the importance of EQA for routine implementation of the assay. The authors conclude that the consensus protocol provides acceptable inter- and intralaboratory variability and can be implemented across Europe. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

This document is a response to concerns raised by Cheng et al. regarding a previous paper on the short-term efficacy of pre-seasonal subcutaneous administration of PQ Grass for grass allergy. The authors acknowledge the importance of long-term efficacy and safety and state that separate Phase III studies will address these aspects. They also address concerns about adverse events (AEs) by highlighting the extensive safety monitoring procedures implemented during the study. Additionally, the authors mention that underlying immunological mechanisms were evaluated through biomarker analysis, with findings indicating immune tolerance induction by PQ Grass AIT. The document concludes by acknowledging the contributions of individuals involved in editing and publishing the manuscript and disclosing conflicts of interest. [Extracted from the article]

Abstract: Background: Immunotherapy with peptide hydrolysates from Lolium perenne (LPP) is an alternative treatment for seasonal allergic rhinitis with or without asthma. The aim of this study was to assess the clinical efficacy and safety of a cumulative dose of 170 μg LPP administered subcutaneously over 3 weeks. Methods: In a randomized, double‐blind, placebo‐controlled trial, 554 adults with grass pollen rhinoconjunctivitis were randomized (1:2 ratio) to receive 8 subcutaneous injections of placebo or 170 μg LPP administered in increasing doses in 4 visits over 3 weeks. The primary outcome was the combined symptom and medication score (CSMS) measured over the peak pollen season. Reactivity to conjunctival provocation test (CPT) and quality of life (QOL) was assessed as secondary endpoints. Results: The mean reduction in CSMS in the LPP vs placebo group was −15.5% (P = .041) during the peak period and −17.9% (P = .029) over the entire pollen season. LPP‐treated group had a reduced reactivity to CPT (P < .001) and, during the pollen season, a lower rhinoconjunctivitis QOL global score (P = .005) compared with placebo group. Mostly mild and WAO grade 1 early systemic reaction (ESR) were observed ≤30 minutes in 10.5% of LPP‐treated patients, whereas 3 patients with a medical history of asthma (<1%) experienced a serious ESR that resolved with rescue medication. Conclusion: Lolium perenne pollen peptides administered over 3 weeks before the grass pollen season significantly reduced seasonal symptoms and was generally safe and well‐tolerated. [ABSTRACT FROM AUTHOR]

Abstract: Background: Systemic allergic reactions are a risk for allergen immunotherapy that utilizes intact allergen preparations. We evaluated the safety, efficacy and immune mechanisms of short‐course treatment with adjuvant‐free Lolium perenne peptides (LPP) following a 6‐week dose‐escalation protocol. Methods: In a prospective, dose‐escalation study, 61 grass pollen–allergic patients received 2 subcutaneous injections of LPP once weekly for 6 weeks. Safety was assessed evaluating local reactions, systemic reactions and adverse events. The clinical effect of LPP was determined by reactivity to the conjunctival provocation test (CPT). Specific IgE, IgG4 and blocking antibodies were measured at baseline (V1), during (V6) and after treatment (V8). Results: No fatality, serious adverse event or epinephrine use was reported. Mean wheal diameters after injections were <0.6 cm and mean redness diameters <2.5 cm, independent of dose. Transient and mostly mild adverse events were reported in 33 patients. Two patients experienced a grade I and 4 patients a grade II reaction (AWMF classification). At V8, 69.8% of patients became nonreactive to CPT. sIgG4 levels were higher at V6 (8.1‐fold, P < .001) and V8 (12.2‐fold, P < .001) than at V1. The sIgE:sIgG4 ratio decreased at V6 (−54.6%, P < .001) and V8 (−71.6%, P < .001) compared to V1. The absolute decrease in IgE‐facilitated allergen binding was 18% (P < .001) at V6 and 25% (P < .001) at V8. Conclusion: Increasing doses of subcutaneous LPP appeared safe, substantially diminished reactivity to CPT and induced blocking antibodies as early as 4 weeks after treatment initiation. The benefit/risk balance of LPP immunotherapy remains to be further evaluated in large studies. [ABSTRACT FROM AUTHOR]

Abstract: Background: A novel subcutaneous allergen immunotherapy formulation (gpASIT+™) containing Lolium perenne peptides (LPP) and having a short up‐dosing phase has been developed to treat grass pollen–induced seasonal allergic rhinoconjunctivitis. We investigated peptide immunotherapy containing the hydrolysate from perennial ryegrass allergens for the optimum dose in terms of clinical efficacy, immunogenicity and safety. Methods: This prospective, double‐blind, placebo‐controlled, phase IIb, parallel, four‐arm, dose‐finding study randomized 198 grass pollen–allergic adults to receive placebo or cumulative doses of 70, 170 or 370 μg LPP. All patients received weekly subcutaneous injections, with the active treatment groups reaching assigned doses within 2, 3 and 4 weeks, respectively. Efficacy was assessed by comparing conjunctival provocation test (CPT) reactions at baseline, after 4 weeks and after completion. Grass pollen–specific immunoglobulins were analysed before and after treatment. Results: Conjunctival provocation test (CPT) response thresholds improved from baseline to V7 by at least one concentration step in 51.2% (170 μg; P = .023), 46.3% (370 μg), and 38.6% (70 μg) of patients receiving LPP vs 25.6% of patients receiving placebo (modified per‐protocol set). Also, 39% of patients in the 170‐μg group became nonreactive to CPT vs 18% in the placebo group. Facilitated allergen‐binding assays revealed a highly significant (P < .001) dose‐dependent reduction in IgE allergen binding across all treatment groups (70 μg: 17.1%; 170 μg: 18.8%; 370 μg: 26.4%). Specific IgG4 levels increased to 1.6‐fold (70 μg), 3.1‐fold (170 μg) and 3.9‐fold (370 μg) (mPP). Conclusion: Three‐week immunotherapy with 170 μg LPP reduced CPT reactivity significantly and increased protective specific antibodies. [ABSTRACT FROM AUTHOR]

Abstract: Innate lymphoid cells (ILC) represent a group of lymphocytes that lack specific antigen receptors and are relatively rare as compared to adaptive lymphocytes. ILCs play important roles in allergic and nonallergic inflammatory diseases due to their location at barrier surfaces within the airways, gut, and skin, and they respond to cytokines produced by activated cells in their local environment. Innate lymphoid cells contribute to the immune response by the release of cytokines and other mediators, forming a link between innate and adaptive immunity. In recent years, these cells have been extensively characterized and their role in animal models of disease has been investigated. Data to translate the relevance of ILCs in human pathology, and the potential role of ILCs in diagnosis, as biomarkers and/or as future treatment targets are also emerging. This review, produced by a task force of the Immunology Section of the European Academy of Allergy and Clinical Immunology (EAACI), encompassing clinicians and researchers, highlights the role of ILCs in human allergic and nonallergic diseases in the airways, gastrointestinal tract, and skin, with a focus on new insights into clinical implications, therapeutic options, and future research opportunities. [ABSTRACT FROM AUTHOR]

The Future of the Allergists and Specific Immunotherapy ( FASIT) workshop provides a regular platform for global experts from academia, allergy clinics, regulatory authorities and industry to review developments in the field of allergen immunotherapy ( AIT). The most recent meeting, held in February 2017, had two main themes: advances in AIT and hot topics in AIT from the regulatory point of view. The first theme covered opportunities for personalized AIT, advances in adjuvants and delivery systems, and the development of new molecules and future vaccines for AIT. Key topics in the second part of the meeting were the effects of the enactment of European Directive 2001/83 on the availability of allergens for therapy and diagnosis across the EU, the challenges of conducting Phase 3 studies in the field, the future role of allergen exposure chambers in AIT studies and specific considerations in performing AIT studies in the paediatric population. Finally, the group highlighted the forthcoming EAACI guidelines and their particular importance for the standardization of practice in the treatment of allergies. This review presents a comprehensive insight into those panel discussions and highlights unmet needs and also possible solutions to them for the future. [ABSTRACT FROM AUTHOR]

Background Allergen immunotherapy ( AIT) is an effective treatment for allergic rhinoconjunctivitis ( AR) with or without asthma. It is important to note that due to the complex interaction between patient, allergy triggers, symptomatology and vaccines used for AIT, some patients do not respond optimally to the treatment. Furthermore, there are no validated or generally accepted candidate biomarkers that are predictive of the clinical response to AIT. Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers. Method The EAACI taskforce reviewed all candidate biomarkers used in clinical trials of AR patients with/without asthma in a literature review. Biomarkers were grouped into seven domains: (i) IgE (total IgE, specific IgE and sIgE/Total IgE ratio), (ii) IgG-subclasses ( sIgG1, sIgG4 including SIgE/IgG4 ratio), (iii) Serum inhibitory activity for IgE (IgE- FAB and IgE- BF), (iv) Basophil activation, (v) Cytokines and Chemokines, (vi) Cellular markers (T regulatory cells, B regulatory cells and dendritic cells) and (vii) In vivo biomarkers (including provocation tests?). Results All biomarkers were reviewed in the light of their potential advantages as well as their respective drawbacks. Unmet needs and specific recommendations on all seven domains were addressed. Conclusions It is recommended to explore the use of allergen-specific IgG4 as a biomarker for compliance. sIgE/ tIgE and IgE-FAB are considered as potential surrogate candidate biomarkers. Cytokine/chemokines and cellular reponses provided insight into the mechanisms of AIT. More studies for confirmation and interpretation of the possible association with the clinical response to AIT are needed. [ABSTRACT FROM AUTHOR]

Follicular helper T cells (Tfh) are located within germinal centers of lymph nodes. Cognate interaction between Tfh, B cells, and IL-21 drives B cells to proliferate and differentiate into plasma cells thereby leading to antibody production. Tfh cells and IL-21 are involved in infectious and autoimmune diseases, immunodeficiencies, vaccination, and cancer. Human peripheral blood CXCR5+ CD4+ T cells comprise different subsets of Tfh-like cells. Despite the importance of the IgE response in the pathogenesis of allergic disorders, little is known about the role of follicular and blood Tfh cells and IL-21 in human and experimental allergic disease. Here, we review recent advances regarding the phenotypic and functional characteristics of both follicular and blood Tfh cells and of the IL-21/ IL-21R system in the context of allergic disorders. [ABSTRACT FROM AUTHOR]

Background: The calcium-binding 2EF-hand protein Phl p 7 from timothy grass pollen is a highly cross-reactive pollen pan-allergen that can induce severe clinical symptoms in allergic patients. Recently, a human monoclonal Phl p 7-specific IgG4 antibody (mAb102.1F10) was isolated from a patient who had received grass pollen-specific immunotherapy (SIT). Methods: We studied epitope specificity, cross-reactivity, affinity and cross-protection of mAb102.1F10 towards homologous calcium-binding pollen allergens. Sequence comparisons and molecular modelling studies were performed with ClustalW and SPADE, respectively. Surface plasmon resonance measurements were made with purified recombinant allergens. Binding and cross-reactivity of patients' IgE and mAb102.1F10 to calcium-binding allergens and peptides thereof were studied with quantitative RAST-based methods, in ELISA, basophil activation and IgE-facilitated allergen presentation experiments. Results: Allergens from timothy grass (Phl p 7), alder (Aln g 4), birch (Bet v 4), turnip rape (Bra r 1), lamb's quarter (Che a 3) and olive (Ole e 3, Ole e 8) showed high sequence similarity and cross-reacted with allergic patients' IgE. mAb102.1F10 bound the C-terminal portion of Phl p 7 in a calcium-dependent manner. It cross-reacted with high affinity with Ole e 3, whereas binding and affinity to the other allergens were low. mAb102.1F10 showed limited cross-inhibition of patients' IgE binding and basophil activation. Sequence comparison and surface exposure calculations identified three amino acids likely to be responsible for limited cross-reactivity. Conclusions: Our results demonstrate that a small number of amino acid differences among cross-reactive allergens can reduce the affinity of binding by a SITinduced IgG and thus limit cross-protection. [ABSTRACT FROM AUTHOR]

Objectives The relationship between exposure to rodent allergens and laboratory animal allergy is complex; at highest allergen exposures there is an attenuation of sensitisation and symptoms which are associated with increased levels of rat-specific immunoglobulin (Ig)G and IgG4 antibodies. We set out to examine whether the increased levels of rat-specific IgG and IgG4 antibodies that we have previously observed at high allergen exposure in our cohort of laboratory animal workers play a functional role through blockage of the binding of IgE-allergen complex binding to CD23 receptors on B cells. Methods Cross-sectional survey of laboratory animal workers (n=776) in six UK pharmaceutical companies were surveyed. IgE-allergen complex binding to B cells was measured in 703 (97.9%) eligible employees; their exposure was categorised by either job group or number of rats handled daily. Results We observed a significant decrease in IgE-allergen complex binding to B cells with increasing quartiles of both rat-specific IgG and IgG4 antibodies (p<0.001). IgE-allergen complex binding to B cells was lower in workers with high allergen exposure, and significantly so (p=0.033) in the subgroup with highest exposures but no work-related chest symptoms. Conclusions These findings demonstrate a functional role for rat-specific IgG/G4 antibodies in laboratory animal workers, similar to that observed in patients treated with high dose immunotherapy who become clinically tolerant, suggesting a potential explanation for the attenuation of risk at highest allergen exposures. [ABSTRACT FROM AUTHOR]

To cite this article: Shamji MH, Ljørring C, Francis JN, Calderon MA, Larché M, Kimber I, Frew AJ, Ipsen H, Lund K, Würtzen PA, Durham SR. Functional rather than immunoreactive levels of IgG4 correlate closely with clinical response to grass pollen immunotherapy. Allergy 2012; 67: 217-226. Abstract Background: Induction of allergen-specific IgG4 antibodies is the most consistent immunological finding in immunotherapy trials. However, quantitative assessments of IgG4 antibodies have not proven beneficial in evaluating clinical changes during or after immunotherapy. In the current study, we investigated the relationship between clinical outcome and allergen-specific IgG4 titres or functional antibody responses following immunotherapy. We hypothesized that functional assays of serum IgG-associated inhibitory activity such as inhibition of IgE-allergen interactions (IgE-blocking factor) and inhibition of CD23-dependent IgE-facilitated allergen binding (IgE-FAB) correlate more closely with clinical outcome and may be biomarkers of clinical response. Methods: In an 8-month dose-response randomized double-blind placebo-controlled study, 221 polysensitized subjects with severe seasonal rhinitis received Alutard SQ, Phleum pratense 100 000 SQ-U, 10 000 SQ-U or placebo injections. Serum specimens were collected before treatment, after up-dosing, during the peak season and at the end of the study. Allergen-specific IgG4 titres and IgG-associated inhibitory activity were evaluated. Results: A time- and dose-dependent increase in serum inhibitory activity for both the IgE-blocking factor and IgE-FAB was observed, which paralleled increases in grass pollen-specific IgG4 antibodies. A modest but significant inverse relationship was demonstrated between postimmunotherapy serum inhibitory activity and combined symptom-rescue medication scores (IgE-FAB: r = −0.25, P = 0.0002; IgE-blocking factor: r = −0.28, P < 0.0001), whereas this was not observed for immunoreactive IgG4 levels ( r = −0.11, P = 0.12). Conclusions: Functional assays of inhibitory IgG4 and IgE-blocking factor may be more useful surrogates of clinical response than IgG4. Whether these antibody effects may serve as predictive biomarkers of clinical efficacy in individual patients requires further investigation. [ABSTRACT FROM AUTHOR]

As cholinergic innervation is a major contributor to increased vagal tone and mucus secretion, inhaled long-acting muscarinic antagonists (LAMA) are a pillar for the treatment of chronic obstructive pulmonary disease and asthma. By blocking the muscarinic receptors expressed in the lung, LAMA improve lung function and reduce exacerbations in asthma patients who remained poorly controlled despite treatment with inhaled corticosteroids and long-acting β2 agonists. Asthma guidelines recommend LAMA as a third controller to be added on before the initiation of biologicals. In addition to bronchodilation, LAMA also exert anti-inflammatory and anti-fibrotic effects by inhibiting muscarinic receptors present in neutrophils, macrophages, fibroblasts and airway smooth muscle cells. Thus, besides bronchodilation, LAMA might provide additional therapeutic effects, thereby supporting an endotype-driven approach to asthma management. The Position Paper, developed by the Asthma Section of the European Academy of Allergy and Clinical Immunology, discusses the main cholinergic pathways in the lung, reviews the findings of significant clinical trials and real-life studies on LAMA use in asthma, examines the placement of these drugs in asthma clinical guidelines, and considers the potential for personalised medicine with LAMA in both adult and paediatric asthma patients., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

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.

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.)

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.)

Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

A significant proportion of rhinitis patients without systemic IgE-sensitisation tested by skin prick test and serum allergen-specific IgE (sIgE) display nasal reactivity upon nasal allergen provocation test (NAPT). This disease phenotype has been termed local allergic rhinitis (LAR). LAR is an underdiagnosed entity affecting children and adults from different parts of the world, with moderate-to-severe symptoms, impairment of quality of life and rapid progression to symptom worsening. LAR is a stable phenotype and not merely an initial state of AR. Allergic rhinitis and LAR share many clinical features including a positive NAPT response, markers of type 2 nasal inflammation including sIgE in nasal secretions and a significant rate of asthma development. LAR should be considered as a differential diagnosis in those subjects of any age with symptoms suggestive of AR but no evidence of systemic atopy. Although LAR pathophysiology is partially unknown, in some patients sIgE can be demonstrated directly in the nasal secretions and/or indirectly via positive responses in basophil activation test (BAT). LAR can coexist with other rhinitis phenotypes, especially AR. The diagnosis currently relies on the positivity of NAPT to a single or multiple allergens. NAPT has high sensitivity, specificity and reproducibility, and it is considered the gold standard. BAT and the measurement of nasal sIgE can also contribute to LAR diagnosis. LAR patients benefit from the same therapeutic strategies than AR individuals, including the avoidance of allergen exposure and the pharmacotherapy. Moreover, several recent studies support the effectiveness and safety of allergen immunotherapy for LAR, which opens a window of treatment opportunity in these patients., (© 2018 John Wiley & Sons Ltd.)

Allergic diseases often occur early in life and persist throughout life. This life-course perspective should be considered in allergen immunotherapy. In particular it is essential to understand whether this al treatment may be used in old age adults. The current paper was developed by a working group of AIRWAYS integrated care pathways for airways diseases, the model of chronic respiratory diseases of the European Innovation Partnership on active and healthy ageing (DG CONNECT and DG Santé). It considered (1) the political background, (2) the rationale for allergen immunotherapy across the life cycle, (3) the unmet needs for the treatment, in particular in preschool children and old age adults, (4) the strategic framework and the practical approach to synergize current initiatives in allergen immunotherapy, its mechanisms and the concept of active and healthy ageing.