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Background: High-intensity interval training is an effective and popular training regime but its feasibility in untrained adults with asthma is insufficiently described. Objective: The randomized controlled trial ‘EFFORT Asthma’ explored the effects of behavioural interventions including high-intensity interval training on clinical outcomes in nonobese sedentary adults with asthma. In this article we present a sub analysis of data aiming to evaluate if patients’ pre-intervention levels of asthma control, FEV1, airway inflammation and airway hyperresponsiveness (AHR) predicted their training response to the high-intensity interval training program, measured as increase in maximal oxygen consumption (VO2max). Design: We used data from the EFFORT Asthma Study. Of the 36 patients randomized to the 8-week exercise intervention consisting of high-intensity training three times per week, 29 patients (45% females) completed the study and were included in this data analysis. Pre-intervention assessment included the asthma control questionnaire (ACQ), spirometry, fractional exhaled nitric oxide (FeNO) and AHR to mannitol. VO2 max was measured during an incremental cycle test. Results: The majority of included patients had partly or uncontrolled asthma reflected by a mean (SD) ACQ at 1.7 (0.6). Median (IQR) FeNO was 28.5 (23.8) ppb and 75% had a positive mannitol test indicating AHR. The association between patients’ training response measured as increase in VO2max and pre-intervention ACQ scores was not statistically significant (p = 0.49). Likewise, the association between patients’ increase in VO2max and FeNO as well as AHR was not statistically significant (p = 0.80 and p = 0.58). Conclusions: Included asthma patients could adhere to the high-intensity interval protocol and improve their VO2max regardless of pre-intervention levels of asthma control, airway inflammation and AHR.

Objective: Acute exacerbations (AEs) of asthma are heterogeneous in terms of triggers, outcomes, and treatment response. This study investigated biomarker defined infective and inflammatory AE phenotypes in hospitalized adult asthma patients, and their impact on clinical outcomes and phenotype stability at AE recurrence., Method: Patients with asthma admitted with an AE between January 2010 and December 2011 with a 3-year follow-up were retrospectively studied. AEs were categorized into infective (CRP >10 mg/L) vs non-infective, eosinophilic (blood eosinophils ≥ 0.2 × 10 9 cells/L) vs non-eosinophilic, and viral (CRP >10 to <40 mg/L) vs bacterial (CRP ≥40 mg/L) phenotypes. Clinical impact of the index AE, the risk and time to a second AE and AE phenotype stability were analyzed using Kaplan-Meier survival curves and McNamar's test., Result: 294 asthma patients were included: 47% had infective AE with a longer length of stay than non-infective AE (2.0 vs. 1.0 days, p  = 0.01). The proportion of patients with eosinophilic AEs was evenly distributed across infective and non-infective AE (40% vs. 46%), although more patients with viral had eosinophilia than bacterial AE (46% vs. 26%). During follow-up, 18% had recurrent AE; with a higher risk in viral AE than bacterial AE (25% vs. 8%, p  = 0.02). Both inflammatory and infective AE phenotype were stable at recurrent AE., Conclusion: AE phenotyping in hospitalized asthma patients, based on CRP and blood eosinophils, revealed prolonged hospital stay in infective AEs and a higher risk of recurrent AE requiring hospitalization in viral versus bacterial AEs. Moreover, infective, and inflammatory AE phenotypes were rather stable at recurrent AE. Our results suggest a role for biomarker guided phenotyping of AEs of asthma.

Background: We have previously developed Core Outcome Measures sets for Severe Asthma (COMSA) by multi-stakeholder consensus. There are no patient-centred tools to quantify response to biologics for severe asthma. We aimed to develop paediatric and adult CompOsite iNdexes For Response in asthMa (CONFiRM) incorporating clinical parameters and patient-reported quality of life (QoL)., Methods: International expert healthcare professionals (HCPs) and patients with severe asthma were invited to: 1) develop consensus levels of clinically relevant changes for each outcome measure within COMSA; 2) use multicriteria decision analysis to develop the CONFiRM scores and 3) assess their internal validity. A separate group of HCPs evaluated CONFiRM's external validity., Results: Five levels of change for each COMSA outcome were agreed. Severe exacerbations and maintenance oral corticosteroids use were rated as most important in determining both paediatric and adult CONFiRM scores. There was strong agreement between HCPs and patients, although patients assigned greater importance to QoL. The CONFiRM score quantified response to a biological from -31 (deterioration) to 69 (best possible response). Paediatric and adult CONFiRMs had good discriminative ability for a sufficient (AUC≥0.92) and a substantial (AUC≥0.95) response to biologics. Both CONFiRMs demonstrated excellent external validity (Spearman correlation coefficients 0.9 and 0.8 for paediatric and adult respectively (p<0.0001))., Conclusions: We have developed novel patient-centred paediatric and adult CONFiRMs which include QoL measures. CONFiRMs should allow a more holistic understanding of response for the patient and a standardised assessment of the effectiveness of biologics between studies. Further research is needed to prospectively validate CONFiRM scores., (Copyright ©The authors 2024.)

Chronic obstructive pulmonary disease (COPD) is a progressive, incurable disease associated with smoking and advanced age, ranking as the third leading cause of death worldwide. DNA damage and loss of the central metabolite nicotinamide adenine dinucleotide (NAD + ) may contribute to both aging and COPD, presenting a potential avenue for interventions. In this randomized, double-blind, placebo-controlled clinical trial, we treated patients with stable COPD (n = 40) with the NAD + precursor nicotinamide riboside (NR) for 6 weeks and followed-up 12 weeks later. The primary outcome was change in sputum interleukin-8 (IL-8) from baseline to week 6. The estimated treatment difference between NR and placebo in IL-8 after 6 weeks was -52.6% (95% confidence interval (CI): -75.7% to -7.6%; P = 0.030). This effect persisted until the follow-up 12 weeks after the end of treatment (-63.7%: 95% CI -85.7% to -7.8%; P = 0.034). For secondary outcomes, NR treatment increased NAD + levels by more than twofold in whole blood, whereas IL-6 levels in plasma remained unchanged. In exploratory analyses, treatment with NR showed indications of upregulated gene pathways related to genomic integrity in the airways and reduced epigenetic aging, possibly through a reduction in cellular senescence. These exploratory analyses need to be confirmed in future trials. ClinicalTrials.gov identifier: NCT04990869 ., Competing Interests: Competing interests D.S. and R.W.D. are employees of Elysium Health and own shares in the company. The other authors declare no competing interests., (© 2024. The Author(s).)

Background: Signal transducer and activator of transcription 6 (STAT6) is central to type 2 (T2) inflammation, and common noncoding variants at the STAT6 locus associate with various T2 inflammatory traits, including diseases, and its pathway is widely targeted in asthma treatment., Objective: We sought to test the association of a rare missense variant in STAT6, p.L406P, with T2 inflammatory traits, including the risk of asthma and allergic diseases, and to characterize its functional consequences in cell culture., Methods: The association of p.L406P with plasma protein levels, white blood cell counts, and the risk of asthma and allergic phenotypes was tested. Significant associations in other cohorts were also tested using a burden test. The effects of p.L406P on STAT6 protein function were examined in cell lines and by comparing CD4 + T-cell responses from carriers and noncarriers of the variant., Results: p.L406P associated with reduced plasma levels of STAT6 and IgE as well as with lower eosinophil and basophil counts in blood. It also protected against asthma, mostly driven by severe T2-high asthma. p.L406P led to lower IL-4-induced activation in luciferase reporter assays and lower levels of STAT6 in CD4 + T cells. We identified multiple genes with expression that was affected by the p.L406P genotype on IL-4 treatment of CD4 + T cells; the effect was consistent with a weaker IL-4 response in carriers than in noncarriers of p.L406P., Conclusions: A partial loss-of-function variant in STAT6 resulted in dampened IL-4 responses and protection from T2-high asthma, implicating STAT6 as an attractive therapeutic target., Competing Interests: Disclosure statement Disclosure of potential conflict of interest: K. Kristjansdottir, G. L. Norddahl, E. V. Ivarsdottir, G. H. Halldorsson, G. Einarsson, K. Bjarnadóttir, G. Rutsdottir, A. O. Arnthorsson, S. Gudmundsdottir, K. Gunnarsdottir, B. V. Halldorsson, H. Holm, S. Saevarsdottir, A. S. Snaebjarnarson, G. Sveinbjornsson, G. E. Thorlacius, G. Thorleifsson, V. Tragante, P. Sulem, D. F. Gudbjartsson, P. Melsted, I. Jonsdottir, T. A. Olafsdottir, and K. Stefansson are employees of deCODE genetics, a subsidiary of Amgen., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Long-term tezepelumab treatment in the DESTINATION study (NCT03706079) resulted in reduced asthma exacerbations, reduced biomarker levels, and improved lung function and symptom control in patients with severe, uncontrolled asthma., Objective: To explore the time course of changes in biomarkers and clinical manifestations after treatment cessation after 2 years of tezepelumab treatment., Methods: DESTINATION was a 2-year, phase 3, multicenter, randomized, placebo-controlled, double-blind study of tezepelumab treatment in patients (12-80 years old) with severe asthma. Patients received their last treatment doses at week 100 and could enroll in an extended follow-up period from weeks 104 to 140. Change over time in key biomarkers and clinical outcomes were assessed in tezepelumab vs placebo recipients for 40 weeks after stopping treatment., Results: Of 569 patients enrolled in the extended follow-up period, 426 were included in the analysis (289 received tezepelumab and 137 placebo). In the 40-week period after the last tezepelumab dose, blood eosinophil counts, fractional exhaled nitric oxide levels, and Asthma Control Questionnaire-6 scores gradually increased from weeks 4 to 10, with a gradual reduction in pre-bronchodilator forced expiratory volume in 1 second such that blood eosinophil counts, fractional exhaled nitric oxide levels, and clinical outcomes returned to placebo levels; however, none of these outcomes returned to baseline levels. Total IgE levels increased later from week 28 and remained well below placebo and baseline levels during the 40-week period after the last tezepelumab dose., Conclusion: This analysis reveals the benefits of continued tezepelumab treatment in the management of patients with severe, uncontrolled asthma, compared with stopping treatment after 2 years., Trial Registration: ClinicalTrials.gov Identifier: NCT03706079., Competing Interests: Disclosures Prof Brightling has received grants and consultancy fees from 4D Pharma, Areteia Therapeutics, AstraZeneca, Chiesi, Genentech, GSK, Global Access Diagnostics (formerly Mologic), Novartis, Regeneron Pharmaceuticals, Roche, and Sanofi. Dr Caminati has received fees from AstraZeneca for serving on advisory boards and has received speaker fees from GSK and Sanofi. Dr Llanos and Dr Caveney are employees of Amgen and own stock in Amgen. Dr Kotalik, Dr Lundahl, Ms Gołąbek, Dr Martin, and Dr Ponnarambil are employees of AstraZeneca and may own stock or stock options in AstraZeneca. Dr Griffiths was an employee of AstraZeneca at the time of the study. Prof Israel has served as a consultant to and received personal fees from 4D Pharma, AB Science, Amgen, AstraZeneca, Avillion, Biometry, Cowen, Equillium, Genentech, GSK, Merck, Novartis, Pneuma Respiratory, PPS Health, Regeneron Pharmaceuticals, Sanofi, Sienna Biopharmaceuticals, and Teva Pharmaceuticals; has received nonfinancial support from Circassia Pharmaceuticals, Teva Pharmaceuticals, and Vorso Corp; and has received clinical research grants from AstraZeneca, Avillion, Genentech, Gossamer Bio, Novartis, and Sanofi. Prof Pavord has received speaker fees from Aerocrine AB, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi, and Teva Pharmaceuticals; has received payments for organization of educational events from AstraZeneca, GSK, Regeneron Pharmaceuticals, Sanofi, and Teva Pharmaceuticals; has received consultancy fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia Pharmaceuticals, Dey Pharma, Genentech, GSK, Knopp Biosciences, Merck, MSD, Napp Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, RespiVert, Sanofi, Schering-Plough, and Teva Pharmaceuticals; has received international scientific meeting sponsorship from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Napp Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, and Teva Pharmaceuticals; and has received a research grant from Chiesi. Prof Wechsler has received consulting, advisory or speaker fees from Amgen, Areteia Therapeutics, AstraZeneca, Avalo Therapeutics, Boehringer Ingelheim, Celldex Therapeutics, Cellergy Pharma, Cerecor, CytoReason, Eli Lilly, Equillium, GSK, Incyte, Kinaset Therapeutics, Merck, Novartis, Om Pharma, Overtone Therapeutics/Foresite Labs, Phylaxis Bioscience, PULMATRiX, Rapt Therapeutics, Regeneron Pharmaceuticals, Roche/Genentech, Sanofi/Genzyme, Sentien Biotechnologies, Sound Biologics, Tetherex Pharmaceuticals, Teva Pharmaceuticals, Upstream Bio and Verona Pharma. Prof Porsbjerg has received grants and consultancy fees from ALK-Abelló, AstraZeneca, Chiesi, GSK, Novartis, Sanofi, and Teva Pharmaceuticals. Dr Corren has received grants and personal fees from AstraZeneca, Genentech, and Vectura; and has received grants from Optinose, Sanofi, and Teva Pharmaceuticals., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Anti-interleukin (IL)-5 biologics effectively reduce exacerbations and the need for maintenance oral corticosteroids (mOCS) in severe eosinophilic asthma. However, it is unknown how long anti-IL-5 treatment should be continued. Data from clinical trials indicate a gradual but variable loss of control after treatment cessation. In this pilot study of titration, we evaluated a dose-titration algorithm in patients who had achieved clinical control on an anti-IL-5 biologic., Methods: In this open-label randomised controlled trial conducted over 52 weeks, patients with clinical control (no exacerbations or mOCS) on anti-IL-5 treatment were randomised to continue with unchanged intervals or have dosing intervals adjusted according to a titration algorithm that gradually extended dosing intervals and reduced them again at signs of loss of disease control. The OPTIMAL algorithm was designed to down-titrate dosing until signs of loss of control, to enable assessment of the longest dosing interval possible., Results: Among 73 patients enrolled, 37 patients were randomised to the OPTIMAL titration arm; 78% of patients tolerated down-titration of treatment. Compared to the control arm, the OPTIMAL arm tended to have more exacerbations during the study (32% versus 17%; p=0.13). There were no severe adverse events related to titration, and lung function and symptoms scores remained stable and comparable in both study arms throughout., Conclusion: This study serves as a proof of concept for titration of anti-IL-5 biologics in patients with severe asthma with clinical control on treatment, and the OPTIMAL algorithm provides a potential framework for individualising dosing intervals in the future., Competing Interests: Conflict of interest: M.B. Soendergaard reports payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK and AstraZeneca, and participation on a data safety monitoring board or advisory board with AstraZeneca. A-S. Bjerrum reports payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK and AstraZeneca. L.M. Rasmussen reports payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, GSK, Teva and ALK, support for attending meetings from AstraZeneca and Chiesi, and participation on a data safety monitoring board or advisory board with AstraZeneca, GSK, Teva and Sanofi. A. von Bulow reports consultancy fees from Novartis, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Novartis and GSK, and participation on a data safety monitoring board or advisory board with AstraZeneca and Novartis. C. Porsbjerg reports grants paid to their institution from AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi and ALK, consultancy fees (paid both to institution and as personal honoraria) from AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi and ALK, payment or honoraria for lectures, presentations, manuscript writing or educational events (paid both to institution and as personal honoraria) from AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi and ALK, and participation on a data safety monitoring board or advisory board (fees paid both to institution and as personal honoraria) with AstraZeneca, Novartis, Teva, Sanofi and ALK. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Airway hyperresponsiveness (AHR) is a key clinical feature of asthma. The presence of AHR in people with asthma provides the substrate for bronchoconstriction in response to numerous diverse stimuli, contributing to airflow limitation and symptoms including breathlessness, wheeze, and chest tightness. Dysfunctional airway smooth muscle significantly contributes to AHR and is displayed as increased sensitivity to direct pharmacologic bronchoconstrictor stimuli, such as inhaled histamine and methacholine (direct AHR), or to endogenous mediators released by activated airway cells such as mast cells (indirect AHR). Research in in vivo human models has shown that the disrupted airway epithelium plays an important role in driving inflammation that mediates indirect AHR in asthma through the release of cytokines such as thymic stromal lymphopoietin and IL-33. These cytokines upregulate type 2 cytokines promoting airway eosinophilia and induce the release of bronchoconstrictor mediators from mast cells such as histamine, prostaglandin D 2 , and cysteinyl leukotrienes. While bronchoconstriction is largely due to airway smooth muscle contraction, airway structural changes known as remodeling, likely mediated in part by epithelial-derived mediators, also lead to airflow obstruction and may enhance AHR. In this review, we outline the current knowledge of the role of the airway epithelium in AHR in asthma and its implications on the wider disease. Increased understanding of airway epithelial biology may contribute to better treatment options, particularly in precision medicine., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Asthma is a disease of heterogeneous pathology, typically characterised by excessive inflammatory and bronchoconstrictor responses to the environment. The clinical expression of the disease is a consequence of the interaction between environmental factors and host factors over time, including genetic susceptibility, immune dysregulation and airway remodelling. As a critical interface between the host and the environment, the airway epithelium plays an important role in maintaining homeostasis in the face of environmental challenges. Disruption of epithelial integrity is a key factor contributing to multiple processes underlying asthma pathology. In this review, we first discuss the unmet need in asthma management and provide an overview of the structure and function of the airway epithelium. We then focus on key pathophysiological changes that occur in the airway epithelium, including epithelial barrier disruption, immune hyperreactivity, remodelling, mucus hypersecretion and mucus plugging, highlighting how these processes manifest clinically and how they might be targeted by current and novel therapeutics., Competing Interests: Conflict of interest: R.J. Russell has received support for conference registration fees and expenses from Chiesi. L-P. Boulet has received grants and/or consultancy fees from Amgen, AstraZeneca, BioHaven, Cipla, Covis, GSK, Merck, Novartis, Sanofi-Regeneron and Teva Pharmaceuticals. C.E. Brightling has received grants and consultancy fees from 4D Pharma, AstraZeneca, Chiesi, Genentech, GSK, Mologic, Novartis, Regeneron Pharmaceuticals, Roche and Sanofi. I.D. Pavord has received speaker fees from Aerocrine AB, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, payments for organisation of educational events from AstraZeneca, GSK, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, consultancy fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Dey Pharma, Genentech, GSK, Knopp Biosciences, Merck, MSD, Napp Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, RespiVert, Sanofi, Schering-Plough and Teva Pharmaceuticals, international scientific meeting sponsorship from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Napp Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, and a research grant from Chiesi. C. Porsbjerg has received grants and consultancy fees from ALK-Abelló, AstraZeneca, Chiesi, GSK, Novartis, Sanofi and Teva Pharmaceuticals. D. Dorscheid has received grants and clinical trial support from AstraZeneca, British Columbia Lung Association, Canadian Institutes of Health Research, Michael Smith Foundation for Health Research, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, and speaking and consultancy fees, travel grants, unrestricted project grants and writing fees from AstraZeneca, GSK, Novartis Canada, Regeneron Pharmaceuticals, Sanofi and Valeo Pharma. A. Sverrild has received grants and consultancy fees from Amgen, AstraZeneca, Chiesi, GSK and Sanofi., (Copyright ©The authors 2024.)

In the last 30 years, the treatment of obstructive lung diseases, such as asthma and COPD, has seen significant advancements. Introduction of inhaled corticosteroids (ICS) and, more recently, biological treatments has revolutionized care. Biological treatments are very successful in severe asthma and are expected to be approved for COPD soon. Systematic assessment and multidimensional treatment approaches are crucial in both conditions. Future care may involve specialized centres for severe obstructive lung diseases, focusing on personalized approaches and monitoring, as argued in this review., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Background: Thymic stromal lymphopoietin (TSLP) is released from the airway epithelium in response to various environmental triggers, inducing a type-2 inflammatory response, and is associated with airway inflammation, airway hyperresponsiveness (AHR), and exacerbations. TSLP may also induce AHR via a direct effect on airway smooth muscle and mast cells, independently of type-2 inflammation, although association between airway TSLP and AHR across asthma phenotypes has been described sparsely., Objectives: This study sought to investigate the association between AHR and levels of TSLP in serum, sputum, and bronchoalveolar lavage in patients with asthma with and without type-2 inflammation., Methods: A novel ultrasensitive assay was used to measure levels of TSLP in patients with asthma (serum, n = 182; sputum, n = 81; bronchoalveolar lavage, n = 85) and healthy controls (serum, n = 47). The distribution and association among airway and systemic TSLP, measures of AHR, type-2 inflammation, and severity of disease were assessed., Results: TSLP in sputum was associated with AHR independently of levels of eosinophils and fractional exhaled nitric oxide (ρ = 0.49, P = .005). Serum TSLP was higher in both eosinophil-high and eosinophil-low asthma compared to healthy controls: geometric mean: 1600 fg/mL (95% CI: 1468-1744 fg/mL) and 1294 fg/mL (95% CI: 1167-1435 fg/mL) versus 846 fg/mL (95% CI: 661-1082 fg/mL), but did not correlate with the level of AHR. Increasing age, male sex, and eosinophils in blood were associated with higher levels of TSLP in serum, whereas lung function, inhaled corticosteroid dose, and symptom score were not., Conclusions: The association between TSLP in sputum and AHR to mannitol irrespective of markers of type-2 inflammation further supports a role of TSLP in AHR that is partially independent of eosinophilic inflammation., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Respiratory virus infections are main triggers of asthma exacerbations. Tezepelumab, an anti-TSLP mAb, reduces exacerbations in patients with asthma, but the effect of blocking TSLP on host epithelial resistance and tolerance to virus infection is not known., Aim: To examine effects of blocking TSLP in patients with asthma on host resistance (IFNβ, IFNλ, and viral load) and on the airway epithelial inflammatory response to viral challenge., Methods: Bronchoalveolar lavage fluid (BALF, n = 39) and bronchial epithelial cells (BECs) were obtained from patients with uncontrolled asthma before and after 12 weeks of tezepelumab treatment (n = 13) or placebo (n = 13). BECs were cultured in vitro and exposed to the viral infection mimic poly(I:C) or infected by rhinovirus (RV). Alarmins, T2- and pro-inflammatory cytokines, IFNβ IFNλ, and viral load were analyzed by RT-qPCR and multiplex ELISA before and after stimulation., Results: IL-33 expression in unstimulated BECs and IL-33 protein levels in BALF were reduced after 12 weeks of tezepelumab. Further, IL-33 gene and protein levels decreased in BECs challenged with poly(I:C) after tezepelumab whereas TSLP gene expression remained unaffected. Poly(I:C)-induced IL-4, IL-13, and IL-17A release from BECs was also reduced with tezepelumab whereas IFNβ and IFNλ expression and viral load were unchanged., Conclusion: Blocking TSLP with tezepelumab in vivo in asthma reduced the airway epithelial inflammatory response including IL-33 and T2 cytokines to viral challenge without affecting anti-viral host resistance. Our results suggest that blocking TSLP stabilizes the bronchial epithelial immune response to respiratory viruses., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Rationale: Previous studies investigating the impact of comorbidities on the effectiveness of biologic agents have been relatively small and of short duration and have not compared classes of biologic agents. Objectives: To determine the association between type 2-related comorbidities and biologic agent effectiveness in adults with severe asthma (SA). Methods: This cohort study used International Severe Asthma Registry data from 21 countries (2017-2022) to quantify changes in four outcomes before and after biologic therapy-annual asthma exacerbation rate, FEV 1 % predicted, asthma control, and long-term oral corticosteroid daily dose-in patients with or without allergic rhinitis, chronic rhinosinusitis (CRS) with or without nasal polyps (NPs), NPs, or eczema/atopic dermatitis. Measurements and Main Results: Of 1,765 patients, 1,257, 421, and 87 initiated anti-IL-5/5 receptor, anti-IgE, and anti-IL-4/13 therapies, respectively. In general, pre- versus post-biologic therapy improvements were noted in all four asthma outcomes assessed, irrespective of comorbidity status. However, patients with comorbid CRS with or without NPs experienced 23% fewer exacerbations per year (95% CI, 10-35%; P  < 0.001) and had 59% higher odds of better post-biologic therapy asthma control (95% CI, 26-102%; P  < 0.001) than those without CRS with or without NPs. Similar estimates were noted for those with comorbid NPs: 22% fewer exacerbations and 56% higher odds of better post-biologic therapy control. Patients with SA and CRS with or without NPs had an additional FEV 1 % predicted improvement of 3.2% (95% CI, 1.0-5.3; P  = 0.004), a trend that was also noted in those with comorbid NPs. The presence of allergic rhinitis or atopic dermatitis was not associated with post-biologic therapy effect for any outcome assessed. Conclusions: These findings highlight the importance of systematic comorbidity evaluation. The presence of CRS with or without NPs or NPs alone may be considered a predictor of the effectiveness of biologic agents in patients with SA.

Background: The development of novel targeted biologic therapies for severe asthma has provided an opportunity to consider remission as a new treatment goal., Research Question: How many patients with severe asthma treated with biologic therapy achieve clinical remission, and what predicts response to treatment?, Study Design and Methods: The Danish Severe Asthma Register is a nationwide cohort including all adult patients receiving biologic therapy for severe asthma in Denmark. This observational cohort study defined "clinical response" to treatment following 12 months as a ≥ 50% reduction in exacerbations and/or a ≥ 50% reduction in maintenance oral corticosteroid dose, if required. "Clinical remission" was defined by cessation of exacerbations and maintenance oral corticosteroids, as well as a normalization of lung function (FEV 1 > 80%) and a six-question Asthma Control Questionnaire score ≤ 1.5 following 12 months of treatment., Results: Following 12 months of treatment, 104 (21%) of 501 biologic-naive patients had no response to treatment, and 397 (79%) had a clinical response. Among the latter, 97 (24%) fulfilled the study criteria of clinical remission, corresponding to 19% of the entire population. Remission was predicted by shorter duration of disease and lower BMI in the entire population of patients treated with biologic therapy., Interpretation: Clinical response was achieved in most adult patients initiating biologic therapy, and clinical remission was observed in 19% of the patients following 12 months of treatment. Further studies are required to assess the long-term outcome of achieving clinical remission with biologic therapy., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: S. H. reports speaker fees from AstraZeneca; M. B. S. reports speaker fees from GSK; A. v. B. reports consulting fees from Novartis, speaker fees from Novartis, GSK, and AstraZeneca, travel grants from AstraZeneca, and participation in advisory boards with AstraZeneca and Novartis; A.-S. B. reports lecture fees from AstraZeneca and GSK; L. M. R. has received lecture fees from AstraZeneca, GSK, and Teva, support for attending meetings and/or travel received from AstraZeneca and Chiesi, and participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, GSK, and Teva; K. E. J. H. reports grants from SanofiGenzyme and AstraZeneca, lecture fees from AstraZeneca, GSK, Chiesi, TEVA, and SanofiGenzyme; O. H. reports support attending meetings from Sanofi, and participation in advisory boards with GSK, MSD, Sanofi, AstraZeneca, TEVA, and ALK; C. U. reports grants from Sanofi, Boehringer Ingelheim, AstraZeneca, and Novartis, consulting fees from Chiesi, Orion Pharma, AstraZeneca, GSK, Teva, Menarini, and Takeda, lecture fees from Orion Pharma, AstraZeneca, and TEVA, and participation in advisory boards with Novartis, GSK, AstraZeneca, Pfizer, Sanofi, Chiesi, and Boehringer Ingelheim; C. P. reports grants from AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi, and ALK, consulting fees from AstraZeneca, GSK, Novartis, TEVA, Sanofi, Chiesi, and ALK, lecture fees from AstraZeneca, GSK, Novartis, TEVA, Sanofi, Chiesi, and ALK, participation in advisory boards with AstraZeneca, Novartis, TEVA, Sanofi, and ALK. None declared (J. S., C. R. J., T. I., S. L. J., M. B., K. D. A.)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Investigation for the presence of asthma comorbidities is recommended by the Global Initiative for Asthma because their presence can complicate asthma management., Objective: To understand the prevalence and pattern of comorbidities and multimorbidity in adults with severe asthma and their association with asthma-related outcomes., Methods: This was a cross-sectional study using data from the International Severe Asthma Registry from 22 countries. A total of 30 comorbidities were identified and categorized a priori as any of the following: (1) potentially type 2-related comorbidities, (2) potentially oral corticosteroid (OCS)-related comorbidities, or (3) comorbidities mimicking or aggravating asthma. The association between comorbidities and asthma-related outcomes was investigated using multivariable models adjusted for country, age at enrollment, and sex (ie male or female)., Results: Of the 11,821 patients, 69%, 67%, and 55% had at least 1 potentially type 2-related, potentially OCS-related, or mimicking or aggravating comorbidities, respectively; 57% had 3 or more comorbidities, and 33% had comorbidities in all 3 categories. Patients with allergic rhinitis, nasal polyposis, and chronic rhinosinusitis experienced 1.12 (P = .003), 1.16 (P < .001), and 1.29 times (P < .001) more exacerbations per year, respectively, than those without. Patients with nasal polyposis and chronic rhinosinusitis were 40% and 46% more likely (P < .001), respectively, to have received long-term (LT) OCS. All assessed potential OCS-related comorbidities (except obesity) were associated with a greater likelihood of LTOCS use (odds ratios [ORs]: 1.23-2.77) and, except for dyslipidemia, with a greater likelihood of uncontrolled asthma (ORs: 1.29-1.68). All mimicking or aggravating comorbidities assessed were associated with more exacerbations (1.24-1.68 times more), all (except bronchiectasis) with increased likelihood of uncontrolled asthma (ORs: 1.57-1.81), and all (except chronic obstructive pulmonary disease) with increased likelihood of LTOCS use (ORs: 1.37-1.57). A greater number of comorbidities was associated with worse outcomes., Conclusion: In a global study, comorbidity or multimorbidity is reported in most adults with severe asthma and is associated with poorer asthma-related outcomes., Clinical Trial Registration: The International Severe Asthma Registry database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization Studies (European Network Centres for Pharmacoepidemiology and Pharmacovigilance [ENCEPP]/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EMA 2014; EUPAS44024) and with all applicable local and international laws and regulations, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=48848). Governance was provided by ADEPT (registration number: ADEPT1121)., Competing Interests: Disclosures Dr Scelo and Dr Murray are consultants for the Observational and Pragmatic Research Institute (OPRI). Dr Torres-Duque has received fees as an advisory board participant and/or speaker from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi-Aventis; has taken part in clinical trials from AstraZeneca, Novartis, and Sanofi-Aventis; and has received unrestricted grants for investigator-initiated studies at Fundacion Neumologica Colombiana from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols, and Novartis. Dr Maspero reports receiving speaker fees, grants, or fees for serving on advisory boards for AstraZeneca, Sanofi, GlaxoSmithKline, Novartis, Inmunotek, Menarini, and Noucor. Dr Tran, Dr Menzies-Gow, and Dr Martin are employees of AstraZeneca and may own stock or stock options in AstraZeneca. Dr Hew reports receiving grants and other advisory board fees (made to his institutional employer) from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, Teva, and Seqirus for unrelated projects. Dr Peters reports receiving personal fees and nonfinancial support from AstraZeneca and GlaxoSmithKline. Dr Gibson has received speaking fees and grants to his institution from AstraZeneca, GlaxoSmithKline, and Novartis. Dr Popov reports receiving relevant research support from Novartis and Chiesi Pharma. Dr Côté reports receiving speaking fees and consultant fees from Sanofi, Regeneron, AstraZeneca, GlaxoSmithKline, and ValeoPharma and reports receiving unrestricted grant support from GlaxoSmithKline; Dr Bergeron reports advisory board participation in Sanofi, AstraZeneca, Takeda, and ValeoPharma and honorarium for presentations for GlaxoSmithKline, AstraZeneca, Amgen, Grifols, Sanofi, Regeneron, and ValeoPharma. Dr Dorscheid is on faculty at the University of British Columbia and is supported by grants from the Canadian Institutes of Health Research, British Columbia Lung Association, and Michael Smith Foundation for Health Research. In addition, he has received speaking fees, travel grants, unrestricted project grants, and writing fees and is a paid consultant for Sanofi-Regeneron, Novartis Canada, AstraZeneca, GlaxoSmithKline, and ValeoPharma and is an active member of the Canadian Thoracic Society, American Thoracic Society, European Respiratory Society, and the Allergen Research Network. Dr FitzGerald previously reported receiving grants from AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron, and Novartis paid directly to UBC and personal fees for lectures and attending advisory boards for AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron, and Teva. Dr Chapman reports receiving grants from AstraZeneca, Boehringer Ingelheim, Bellus, CSL Behring, GlaxoSmithKline, Grifols, Inhibrx, Novartis, Regeneron, Sanofi, Takeda, and Vertex and consulting fees from AstraZeneca, CSL Behring, GlaxoSmithKline, Grifols, Inhibrx, Novartis, Sanofi, and Takeda; he has a leadership or fiduciary role in Alpha-1 Canada, the Canadian Thoracic Society, and Alpha-1 Foundation. Dr Boulet has received grants for participation in clinical studies from Amgen, AstraZeneca, GlaxoSmithKline, Merck, Novartis, Sanofi-Regeneron, and BioHaven; for consulting and advisory boards from AstraZeneca, Novartis, GlaxoSmithKline, Merck, and Sanofi-Regeneron; and lecture fees from AstraZeneca, Covis, Cipla, GlaxoSmithKline, Novartis, Merck, and Sanofi. Dr Bhutani has received speaker and consultant fees for AstraZeneca, GlaxoSmithKline, Sanofi, Covis, Boehringer Ingelheim, and Valeo. Dr Sadatsafavi has received honoraria from AstraZeneca, Boehringer Ingelheim, Teva, and GlaxoSmithKline for purposes unrelated to the content of this manuscript; and has received research funding from AstraZeneca and Boehringer Ingelheim directly into his research account from AstraZeneca for unrelated projects. Dr Jiménez-Maldonado has received fees as an advisory board participant and/or speaker from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi-Aventis and has participated in clinical trials for AstraZeneca, Novartis, and GlaxoSmithKline. Dr Duran-Silva has received fees as an advisory board participant and/or speaker from Boehringer Ingelheim, Novartis, and Sanofi-Aventis and has taken part in clinical trials from AstraZeneca, Novartis, and Sanofi-Aventis. Dr Solarte received fees from GlaxoSmithKline for participation on advisory boards. Dr Fernandez-Sanchez is a part-time employee of GlaxoSmithKline and does not hold shares in the company. Dr Bülow reports receiving speakers fees and consultancy fees from AstraZeneca and Novartis outside the submitted work and has also attended the advisory board for Novartis and AstraZeneca. Dr Bjerrum has received lecture fees from AstraZeneca, GlaxoSmithKline, and Novartis. Dr Ulrik reports receiving personal fees for talks and participation in advisory boards, among others, from AstraZeneca, GlaxoSmithKline, Teva, Boehringer Ingelheim, Orion Pharma, Sanofi-Genzyme, TFF Pharmaceuticals, Covis Pharma, Berlin-Chemie, Takeda, Chiesi, and Pfizer outside the submitted work. Dr Rasmussen declares receiving speaker fees from AstraZeneca, Boehringer Ingelheim, Teva, ALK, and Mundipharma outside the submitted work and attended advisory board for AstraZeneca, Sanofi, and Teva. Dr Altraja has received lecture fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, MSD, Norameda, Novartis, Orion, Sanofi, and Zentiva; sponsorships from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, MSD, Norameda, Novartis, and Sanofi; and has participated in advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi, and Teva. Dr Bourdin has received industry-sponsored grants from AstraZeneca-MedImmune, Boehringer Ingelheim, Cephalon/Teva, GlaxoSmithKline, Novartis, and Sanofi-Regeneron and consultancies with AstraZeneca-MedImmune, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Regeneron-Sanofi, Med-in-Cell, Actelion, Merck, Roche, and Chiesi. Dr Taille has received lecture or advisory board fees and grants to her institution from AstraZeneca, Sanofi, GlaxoSmithKline, Chiesi, and Novartis for unrelated projects. Dr Charriot reports receiving advisory board and lecture fees from AstraZeneca, GlaxoSmithKline, Sanofi; consulting fees for Chiesi; and serving as a trial coinvestigator for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi. Dr Roche reports receiving grants and personal fees from Austral, Biosency, Boehringer Ingelheim, Novartis, and Pfizer and personal fees from MSD, GlaxoSmithKline, AstraZeneca, Chiesi, Sanofi, Menarini, and Zambon. Dr Papaioannou has received fees and honoraria from Menarini, GlaxoSmithKline, Novartis, Elpen, Boehringer Ingelheim, AstraZeneca, and Chiesi. Dr Kostikas received honoraria for presentations and consultancy fees from AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, ELPEN, GILEAD, GlaxoSmithKline, Menarini, Novartis, Sanofi, Specialty Therapeutics, and WebMD; and received funding and grants from AstraZeneca, Boehringer Ingelheim, Chiesi, Innovis, ELPEN, GlaxoSmithKline, Menarini, Novartis, and NuvoAir (paid to the University of Ioannina). Dr Papadopoulos has been a speaker and/or advisory board member for Abbott, AbbVie, ALK, Asit Biotech, AstraZeneca, Biomay, Boehringer Ingelheim, GlaxoSmithKline, HAL, Faes Farma, Medscape, Menarini, MSD, Novartis, Nutricia, OM Pharma, Regeneron, Sanofi, Takeda, and Viatris. Dr Salvi reports receiving research support and speaker fees from Cipla, Glenmark, and GlaxoSmithKline. Dr Mitchell has received speaker fees from GlaxoSmithKline, AstraZeneca, Teva, and Novartis and has received grants from AstraZeneca and Teva. Dr Costello has received honoraria for lectures from Aerogen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Teva; is a member of advisory boards for GlaxoSmithKline and Novartis; has received grant support from GlaxoSmithKline and Aerogen; and has patents in the use of acoustics in the diagnosis of lung disease, assessment of adherence, and prediction of exacerbations. Dr Heffler declares receiving personal fees from Sanofi, Regeneron, GlaxoSmithKline, Novartis, AstraZeneca, Stallergenes, and Circassia. Dr Puggioni reports having received lectures or advisory board fees from Menarini, Mundipharma, Chiesi, Alk Abello, AstraZeneca, Boehringer Ingelheim, Guidotti, Malesci, GlaxoSmithKline, HAL Allergy, Novartis, Sanofi, Regeneron, Stallergenes Greer, Valeas, and Almirall. Dr Canonica has received research grants and lecture or advisory board fees from A. Menarini, Alk-Albello, Allergy Therapeutics, Anallergo, AstraZeneca, MedImmune, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia, Danone, Faes, Genentech, Guidotti Malesci, GlaxoSmithKline, HAL Allergy, Merck, MSD, Mundipharma, Novartis, Orion, Sanofi-Aventis, Sanofi, Genzyme/Regeneron, Stallergenes, UCB Pharma, Uriach Pharma, Teva, Thermo Fisher, and Valeas. Dr Iwanaga received lecture fees from Kyorin, GlaxoSmithKline, Novartis, Boehringer Ingelheim, and AstraZeneca. Dr Mona Al-Ahmad has received advisory board and speaker fees from AstraZeneca, Sanofi, Novartis, and GlaxoSmithKline and received a grant from the Kuwait Foundation for the Advancement of Sciences (KFAS). Dr Linnemann reports receiving personal fees from ALK-Abelló, AstraZeneca national and global, Bayer, Chiesi, Grunenthal, Grin, GlaxoSmithKline national and global, Viatris, Menarini, MSD, Novartis, Pfizer, Sanofi, Siegfried, UCB, and Carnot and grants from AbbVie, Bayer, Lilly, Sanofi, AstraZeneca, Pfizer, Novartis, Circassia, UCB, and GlaxoSmithKline outside the submitted work. Dr Garcia Ramirez received fees as a speaker and advisory board participant from AstraZeneca, GlaxoSmithKline, Sanofi-Genzyme, Chiesi, and Novartis. Dr Kuna reports receiving personal fees from Adamed, AstraZeneca, Berlin-Chemie Menarini, FAES, Glenmark, Novartis, Polpharma, Boehringer Ingelheim, Teva, and Zentiva outside the submitted work. Dr Fonseca reports receiving grants from or has research agreements with AstraZeneca, Mundipharma, Sanofi-Regeneron, and Novartis and has received personal fees for lectures and attending advisory boards for AstraZeneca, GlaxoSmithKline, Mundipharma, Novartis, Sanofi-Regeneron, and Teva. Dr Lehebi has given lectures at meetings supported by AstraZeneca, Boehringer Ingelheim, Novartis, GlaxoSmithKline, and Sanofi and participated in advisory board fees from GlaxoSmithKline, AstraZeneca, Novartis, and Abbott. Dr Koh reports receiving grant support from AstraZeneca and honoraria for lectures and advisory board meetings paid to her hospital (Singapore General Hospital) from GlaxoSmithKline, AstraZeneca, Novartis, Sanofi, and Boehringer Ingelheim outside the submitted work. Dr Kook Rhee received consulting/lecture fees from MSD, AstraZeneca, GlaxoSmithKline, Novartis, Takeda, Mundipharma, Boehringer Ingelheim, Teva, Sanofi, and Bayer. Dr Cosio declares receiving grants from Chiesi and GlaxoSmithKline; personal fees for advisory board activities from Chiesi, GlaxoSmithKline, Novartis, Sanofi, Teva, and AstraZeneca; and payment for lectures/speaking engagements from Chiesi, Novartis, GlaxoSmithKline, Menarini, and AstraZeneca outside the submitted work. Dr de Llano reports receiving grants, personal fees and nonfinancial support from AstraZeneca, Teva, Faes, and Sanofi; personal fees and nonfinancial support from GlaxoSmithKline and Chiesi; personal fees from MSD, Techdow Pharma, GILEAD, and Leo Pharma; and grants and personal fees from GEBRO outside the submitted work. Dr Perng received sponsorship to attend or speak at international meetings, honoraria for lecturing or attending advisory boards, and research grants from the following companies: AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Daiichi Sankyo, Shionogi, and Orient Pharma. Dr Tsai has received grants from Boehringer Ingelheim and has received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Orient EuroPharma. Dr Jackson has received speaker fees and consultancy fees from AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron, and Boehringer Ingelheim and research funding from AstraZeneca. Dr Busby has received research grants from AstraZeneca and personnel fees from NuvoAir outside the submitted work. Dr Heaney has received grant funding, participated in advisory boards, and given lectures at meetings supported by Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Hoffmann la Roche, GlaxoSmithKline, Novartis, Theravance, Evelo Biosciences, Sanofi, and Teva; has received grants from MedImmune, Novartis UK, Roche/Genentech Inc, GlaxoSmithKline, Amgen, Genentech/Hoffman la Roche, AstraZeneca, Aerocrine, and Vitalograph; has received sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Napp Pharmaceuticals; has taken part in asthma clinical trials sponsored by AstraZeneca, Boehringer Ingelheim, Hoffmann la Roche, and GlaxoSmithKline, for which his institution received remuneration; and is the Academic Lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma, which involves industrial partnerships with a number of pharmaceutical companies including Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann la Roche, and Janssen. Dr Pfeffer has attended advisory boards for AstraZeneca, GlaxoSmithKline, and Sanofi; has given lectures at meetings supported by AstraZeneca and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, GlaxoSmithKline, Novartis, and Sanofi, for which his institution received remuneration; and has a current research grant funded by GlaxoSmithKline. Dr Goddard reports receiving lecture fees from Sanofi. Dr Wang has received honoraria from AstraZeneca, GlaxoSmithKline, and Genentech; and has been an investigator on studies sponsored by AstraZeneca, GlaxoSmithKline, Genentech, Sanofi, Novartis, and Teva, for which her institution has received funding. Dr Hoyte reports receiving honoraria from AstraZeneca and Genentech and has been an investigator on clinical trials sponsored by GlaxoSmithKline, Genentech, Teva, and Sanofi, for which her institution has received funding. Dr Wechsler reports receiving grants and/or personal fees from Novartis, Sanofi, Regeneron, Genentech, Sentien, resTORbio, Equillium, Genzyme, Cohero Health, Teva, Boehringer Ingelheim, AstraZeneca, Amgen, GlaxoSmithKline, Cytoreason, Cerecor, Sound biologic, Incyte, and Kinaset. Ms Carter is an employee of Optimum Patient Care (OPC) (OPC is a cofounder of the International Severe Asthma Registry and a cofounder of the APEX-COPD initiative). Ms Bulathsinhala is an employee of OPRI. Ms Eleangovan and Mr Ariti were employees of OPRI. Dr Lyu was an employee of OPC. Dr Price has advisory board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi-Genzyme, Teva Pharmaceuticals, Thermofisher; consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, Theravance; received grants and unrestricted funding for investigator-initiated studies (conducted through OPRI Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi-Genzyme, Teva Pharmaceuticals, Theravance, and the UK National Health Service; received payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi-Genzyme, Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma, Novartis; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; funding for patient enrollment or completion of research from Novartis; has stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals; owns 74% of the social enterprise OPC Ltd (Australia and UK) and 74% of OPRI Pte Ltd (Singapore); has 5% shareholding in Timestamp, which develops adherence monitoring technology; is a peer reviewer for grant committees of the Efficacy and Mechanism Evaluation program and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. Dr Porsbjerg has attended advisory boards for AstraZeneca, Novartis, Teva, and Sanofi-Genzyme; has given lectures at meetings supported by AstraZeneca, Novartis, Teva, Sanofi-Genzyme, and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, Novartis, MSD, Sanofi-Genzyme, GlaxoSmithKline, and Novartis; and has received educational and research grants from AstraZeneca, Novartis, Teva, GlaxoSmithKline, ALK, and Sanofi-Genzyme. The remaining authors have no conflicts of interest to report., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Randomized trials of biologics in severe, uncontrolled asthma have excluded patients with a cumulative tobacco exposure of more than 10 pack-years. Therefore, our knowledge of the impact of smoking exposure on the clinical effects of biologics in severe asthma remains incomplete. However, because many patients with asthma are current or former smokers, investigating the potential impacts of tobacco exposure on the effects of biologic treatment is clinically important., Objective: To investigate the impact of smoking history and tobacco exposure on the effectiveness of biologic therapy in real-life patients with severe asthma., Methods: We used data from a complete nationwide cohort of patients with severe asthma who were receiving biologics, the Danish Severe Asthma Register. We divided patients according to smoking history and cumulative tobacco exposure and analyzed data at baseline and after 12 months of biologic treatment., Results: A total of 724 bio-naive patients were identified in the Danish Severe Asthma Register, 398 of whom had never been smokers (55%), 316 were previous smokers (44%), and 10 were current smokers (1%). Within the group of current and former smokers, 37% had 1 to 9 pack-years of tobacco exposure, 26% had 10 to 19 pack-years, and 37% had 20 or more pack-years of tobacco exposure. Patients with tobacco exposure had similar reductions in the number of exacerbations, reductions in maintenance oral corticosteroid use, and improvements in asthma symptoms compared with patients with 0 pack-years., Conclusion: Former smoking history and lifetime tobacco exposure do not have an impact on the efficacy of biologics in patients with severe asthma., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Vaccination is vital for achieving population immunity to severe acute respiratory syndrome coronavirus 2, but vaccination hesitancy presents a threat to achieving widespread immunity. Vaccine acceptance in chronic potentially immunosuppressed patients is largely unclear, especially in patients with asthma. The aim of this study was to investigate the vaccination experience in people with severe asthma., Methods: Questionnaires about vaccination beliefs (including the Vaccination Attitudes Examination (VAX) scale, a measure of vaccination hesitancy-related beliefs), vaccination side-effects, asthma control and overall safety perceptions following coronavirus disease 2019 (COVID-19) vaccination were sent to patients with severe asthma in 12 European countries between May and June 2021., Results: 660 participants returned completed questionnaires (87.4% response rate). Of these, 88% stated that they had been, or intended to be, vaccinated, 9.5% were undecided/hesitant and 3% had refused vaccination. Patients who hesitated or refused vaccination had more negative beliefs towards vaccination. Most patients reported mild (48.2%) or no side-effects (43.8%). Patients reporting severe side-effects (5.7%) had more negative beliefs. Most patients (88.8%) reported no change in asthma symptoms after vaccination, while 2.4% reported an improvement, 5.3% a slight deterioration and 1.2% a considerable deterioration. Almost all vaccinated (98%) patients would recommend vaccination to other severe asthma patients., Conclusions: Uptake of vaccination in patients with severe asthma in Europe was high, with a small minority refusing vaccination. Beliefs predicted vaccination behaviour and side-effects. Vaccination had little impact on asthma control. Our findings in people with severe asthma support the broad message that COVID-19 vaccination is safe and well tolerated., Competing Interests: Conflict of interest: A. Bossios reports support from Novartis for attending meetings, outside the submitted work; participation on a data safety monitoring or advisory board for AstraZeneca, GSK, Novartis, Teva and Sanofi, outside the submitted work; and is a member of the Steering Committee of SHARP, Secretary of Assembly 5 (Airway Diseases, Asthma, COPD and Chronic Cough) of the European Respiratory Society and Vice-chair of the Nordic Severe Asthma Network, outside the submitted work. K. Katsoulis reports payment or honoraria for lectures presentations, speakers bureaus, manuscript writing or educational events from GSK, Novartis and AstraZeneca; and support received from Menarini and Novartis for attending meetings and/or travel, outside the submitted work. K. Kostikas reports grants or contracts from AstraZeneca, Boehringer Ingelheim, Chiesi, Innovis, ELPEN, GSK, Menarini, Novartis and NuvoAir, outside the submitted work; consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, ELPEN, GSK, Menarini, Novartis and Sanofi-Genzyme, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, GSK, Menarini, Novartis, Sanofi-Genzyme and WebMD, outside the submitted work; and is a member of the GOLD Assembly, disclosures made outside the submitted work. N. Rovina reports receiving honoraria for lectures and presentations from Chiesi, AstraZeneca, Menarini, Gilead and Baxter, outside the submitted work. K. Bieksienė reports receiving lecture honoraria from Berlin-Chemie, AstraZeneca and Norameda, outside the submitted work. A. ten Brinke reports grants from Teva and GSK, outside the submitted work; consulting fees from AstraZeneca, GSK, Novartis, Sanofi-Genzyme and Teva, outside the submitted work; and payment or honoraria for lectures received from AstraZeneca, GSK, Sanofi-Genzyme and Teva, outside the submitted work; and is Chair of the Dutch severe asthma registry RAPSODI, outside the submitted work, and ERS SHARP CRC national lead for the Netherlands. R. Chaudhuri reports grants or contracts from AstraZeneca, outside the submitted work; payment of honoraria for lectures from GSK, AstraZeneca, Teva, Chiesi, Sanofi and Novartis, outside the submitted work; support for attending meetings and/or travel from Chiesi, Sanofi and GSK, outside the submitted work; and participation in advisory board meetings for GSK, AstraZeneca, Teva, Chiesi and Novartis, outside the submitted work. H. Rupani reports grant funding from GSK and AstraZeneca, outside the submitted work; payments for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, GSK, Novartis and Teva, outside the submitted work; and is an associate editor of this journal. P. Howarth is an employee of GSK, disclosure made outside the submitted work. C. Porsbjerg reports grants or contracts from AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi and ALK, outside the submitted work; consulting fees from AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi and ALK, outside the submitted work; personal honoraria from AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi and ALK, outside the submitted work; participation on a data safety monitoring or advisory board for AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi and ALK, outside the submitted work. E.H. Bel reports research grants from GSK and Teva, outside the submitted work; and consulting fees from AstraZeneca, GSK, Sterna Biologicals, Chiesi Pharmaceuticals, Sanofi/Regeneron and Teva, outside the submitted work. M.E. Hyland reports grants or contracts from Teva outside the submitted work; and payment received from GSK for writing educational material for respiratory nurses, outside the submitted work. The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

Background: Allergy immunotherapy (AIT) can be administered as subcutaneous immunotherapy (SCIT) injections in the clinic or as sublingual immunotherapy (SLIT) tablets at home after initiation under medical supervision. To achieve long-term, sustained effects, a 3-year treatment duration is recommended., Objective: Our aim was to assess the association of AIT (SCIT and SLIT tablets) with long-term health care resource use (HRU) and costs in subjects with allergic rhinitis., Methods: REACT was a retrospective propensity score-matched cohort study using claims data from a German health insurance database (2007-2017), with up to 9 years of follow-up after AIT initiation. HRU and costs were evaluated for hospitalizations, ambulatory care visits, and prescriptions, in subjects who received AIT versus in matched controls with allergic rhinitis who had not received AIT, as well as for SCIT and SLIT tablets., Results: Across all 9 years, the subjects who received AIT had a significantly lower incidence of hospitalization than the controls did. Generally, proportions of subjects with ambulatory care visits and hospitalizations were lower, and length of hospitalization was shorter, for those receiving SLIT tablets than those who received SCIT. Total costs were significantly higher with AIT versus for the controls during the treatment period (years 1 to 3), driven by prescriptions and ambulatory care visits, but they were lower in years 4 to 9. During years 1 to 3, prescription costs were generally higher for SLIT tablets than for SCIT, whereas ambulatory care costs were numerically lower. In most years, hospitalization costs were numerically lower for SLIT tablets than for SCIT., Conclusion: Initial higher HRU and costs of AIT during the expected treatment period are offset in the long term. At-home administration of SLIT tablets may further reduce ambulatory care costs., Competing Interests: Supported by ALK-Abelló. Disclosure of potential conflict of interest: This study was conducted and funded by ALK-Abelló. B. Fritzsching reports personal fees from ALK-Abelló and speaker honoraria from 10.13039/100004336Novartis and 10.13039/100009947Merck Sharp & Dohme. C. Porsbjerg reports grants from ALK-Abelló, as well as grants and personal fees from 10.13039/100004325AstraZeneca, 10.13039/100004330GlaxoSmithKline, Novartis, Chiesi, Sanofi, and TEVA. M. Contoli reports personal fees from ALK-Abelló; personal fees and nonfinancial support from 10.13039/100004325AstraZeneca, 10.13039/100008349Boehringer Ingelheim, Novartis, and Zambon; grants, personal fees, and nonfinancial support from Chiesi and GlaxoSmithKline; and grants from the University of Ferrara, Italy. S. Buchs and J. R. Larsen are employees of ALK-Abelló. N. Freemantle reports personal fees from AstraZeneca, Ipsen, Sanofi Aventis, Grifols, Novartis, Aimmune, Vertex, MSD, and Allergan., (© 2023 The Authors.)

Aim: The International Severe Asthma Registry (ISAR; http://isaregistries.org/) uses standardised variables to enable multi-country and adequately powered research in severe asthma. This study aims to look at the data countries within ISAR and non-ISAR countries reported collecting that enable global research that support individual country interests., Methods: Registries were identified by online searches and approaching severe asthma experts. Participating registries provided data collection specifications or confirmed variables collected. Core variables (results from ISAR's Delphi study), steroid-related comorbidity variables, biologic safety variables (serious infection, anaphylaxis, and cancer), COVID-19 variables and additional variables (not belonging to the aforementioned categories) that registries reported collecting were summarised., Results: Of the 37 registries identified, 26 were ISAR affiliates and 11 non-ISAR affiliates. Twenty-five ISAR-registries and 4 non-ISAR registries reported collecting >90% of the 65 core variables. Twenty-three registries reported collecting all optional steroid-related comorbidity variables. Twenty-nine registries reported collecting all optional safety variables. Ten registries reported collecting COVID-19 variables. Twenty-four registries reported collecting additional variables including data from asthma questionnaires (10 Asthma Control Questionnaire, 20 Asthma Control Test, 11 Asthma Quality of Life Questionnaire, and 4 EuroQol 5-dimension 5-level Questionnaire). Eight registries are linked to databases such as electronic medical records and national claims or disease databases., Conclusion: Standardised data collection has enabled individual severe asthma registries to collect unified data and increase statistical power for severe asthma research irrespective of ISAR affiliations., Competing Interests: Breda Cushen has received honoraria for lectures from AstraZeneca, Novartis and Boehringer Ingelheim. Mariko Siyue Koh reports grant support from AstraZeneca, and honoraria for lectures and advisory board meetings paid to her hospital (Singapore General Hospital) from GlaxoSmithKline, AstraZeneca, Novartis, Sanofi and Boehringer Ingelheim, outside the submitted work. Trung N. Tran is an employee of AstraZeneca, a co-funder of the International Severe Asthma Registry. Neil Martin is an employee of AstraZeneca, a co-funder of the International Severe Asthma Registry. Ruth Murray declares no relevant conflicts of interest in this work. Thendral Uthaman is an employee of the Observational and Pragmatic Research Institute (OPRI). OPRI conducted this study in collaboration with Optimum Patient Care and AstraZeneca. Celine Yun Yi Goh is an employee of Optimum Patient Care Global (OPCG), a co-funder of the International Severe Asthma Registry. Rebecca Vella is an employee of Optimum Patient Care, a co-funder of the International Severe Asthma Registry. Neva Eleangovan was an employee of the Observational and Pragmatic Research Institute (OPRI). OPRI conducted this study in collaboration with Optimum Patient Care and AstraZeneca. Lakmini Bulathsinhala is an employee of the Observational and Pragmatic Research Institute (OPRI). OPRI conducted this study in collaboration with Optimum Patient Care and AstraZeneca. Jorge F Maspero reports speaker fees, grants or advisory boards for AstraZeneca, Sanofi, GSK, Novartis, Inmunotek, Menarini, Noucor. Matthew J Peters declares personal fees and non-financial support from AstraZeneca and GlaxoSmithKline. Florence Schleich reports consultancy work for GSK, AstraZeneca, Sanofi - Advisory board, received speaker fees from GSK, AstraZeneca, Chiesi, Amgen, TEVA and research grants from GSK, AstraZeneca, Chiesi. Paulo Pitrez received fees as speaker or for consultations from GSK, AstraZeneca, Novartis, Sanofi, and Boehringer Ingelheim. George Christoff declares no relevant conflicts of interest in this work. Mohsen Sadatsafavi has received honoraria from AZ, BI, TEVA, and GSK for purposes unrelated to the content of this manuscript and has received research funding from AZ and BI directly into his research account from AZ for unrelated projects. Carlos A. Torres-Duque has received fees as advisory board participant and/or speaker from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis and Sanofi-Aventis; has taken part in clinical trials from AstraZeneca, Novartis and Sanofi-Aventis; has received unrestricted grants for investigator-initiated studies at Fundacion Neumologica Colombiana from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Grifols and Novartis. Celeste Porsbjerg has attended advisory boards for AstraZeneca, Novartis, TEVA, and Sanofi-Genzyme; has given lectures at meetings supported by AstraZeneca, Novartis, TEVA, Sanofi-Genzyme, and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, Novartis, MSD, Sanofi-Genzyme, GlaxoSmithKline, and Novartis; and has received educational and research grants from AstraZeneca, Novartis, TEVA, GlaxoSmithKline, ALK, and Sanofi-Genzyme. Alan Altraja has received lecture fees from AstraZeneca, Berlin-Chemie Menarini, Boehringer Ingelheim, GlaxoSmithKline, MSD, Norameda, Novartis, Orion, Sanofi, and Zentiva; sponsorships from AstraZeneca, Berlin-Chemie Menarini, Boehringer Ingelheim, GlaxoSmithKline, MSD, Norameda, Novartis, and Sanofi; and has participated in advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi, and Teva. Lauri Lehtimäki has received personal fees from ALK, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Menarini, Novartis, Orion Pharma and Sanofi. Arnaud Bourdin has received industry-sponsored grants from AstraZeneca-MedImmune, Boehringer-Ingelheim, Cephalon/Teva, GlaxoSmithKline, Novartis, Sanofi-Regeneron and consultancies with AstraZeneca-MedImmune, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, Regeneron-Sanofi, Med-in-Cell, Actelion, Merck, Roche, and Chiesi. Christian Taube declares no relevant conflicts of interest in this work. Nikolaos G. Papadopoulos has been a speaker and/or advisory board member for Abbott, Abbvie, ALK, Asit Biotech, AstraZeneca, Biomay, Boehringer Ingelheim, GSK, HAL, Faes Farma, Medscape, Menarini, MSD, Mylan, Novartis, Nutricia, OM Pharma, Regeneron, Sanofi, Takeda, Viatris. He also reports research support from Capricare, Nestle, Numil, Vianex, and REG, outside the submitted work. Zsuzsanna Csoma declares no relevant conflicts of interest in this work. Unnur Bjornsdottir receives gratuities for lectures/presentations from AstraZeneca, Sanofi and Novartis. Sundeep Salvi declares research support and speaker fees from Cipla, Glenmark, GSK. Enrico Heffler declares personal fees from: Sanofi, Regeneron, GSK, Novartis, Astrazeneca, Stallergenes, Circassia. Takashi Iwanaga received lecture fees from Kyorin, GlaxoSmithKline, Novartis, Boehringer Ingelheim and AstraZeneca. Mona Al-Ahmad has received advisory board and speaker fees from AstraZeneca, Sanofi, Novartis, and GlaxoSmithKline. Received a grant from Kuwait Foundation for the Advancement of Sciences (KFAS). Désirée Larenas Linnemann reports personal fees from Allakos, Amstrong, AstraZeneca, Bayer, Chiesi, DBV Technologies, Grunenthal, GSK, Mylan/Viatris, Menarini, MSD, Novartis, Sanofi, Siegfried, UCB, Carnot, grants from Sanofi, Lilly, Pfizer, Abbvie, AstraZeneca, Novartis, Circassia, UCB, GSK, Purina institute, outside the submitted work. She also reports speaker’s bureau, safety board, Advisory board for ALK, Allakos, Amstrong, Astrazeneca national and global, Bayer, Chiesi, Grunenthal, Grin, GSK national and global, Viatris, Menarini, MSD, Novartis, Pfizer, Sanofi, Siegfried, UCB, Carnot; support with congresses from Abbvie, Lilly, Sanofi, Astrazeneca, Pfizer, Novartis, GSK, Purina institute. Job F.M. Van Boven received grants and/or consultancy fees from AstraZeneca, Chiesi, European Commission COST (COST Action 19132), GSK, Lung Alliance Netherlands, Novartis, Teva, and Trudell Medical, outside the submitted work and all paid to his institution. Bernt Bøgvald Aarli reports grants from Boehringer Ingelheim during the conduct of the study and personal fees from Boehringer Ingelheim, AstraZeneca, GSK, Sanofi-Aventis Norway, Chiesi, Boehringer Ingelheim, and Novartis Norway, outside the submitted work. Piotr Kuna reports personal fees from Adamed, AstraZeneca, Berlin Chemie Menarini, Celon Pharma, Chiesi, FAES, Glenmark, GSK, Novartis, Polpharma, Boehringer Ingelheim, Sandoz, Teva, Zentiva, outside the submitted work. Cláudia Chaves Loureiro declares research Grant (P.I., collaborator or consultant: AstraZeneca, GSK; Speakers Bureau / Honoraria: AstraZeneca, GSK, Novartis, Teva, Sanofi; Consultant / advisory board: AstraZeneca, Bial, GSK, Jaba Recordatti, Novartis, Teva, Sanofi. Riyad Al-Lehebi has given lectures at meetings supported by AstraZeneca, Boehringer Ingelheim, Novartis, GlaxoSmithKline, and Sanofi, and participated in advisory board fees from GlaxoSmithKline, AstraZeneca, Novartis, Abbott. Jae Ha Lee declares no conflicts of interest in this work. Nuria Marina Malanda reports grants, personal fees and non-financial support from AstraZeneca, GSK, Teva, Novartis, Sanofi, and Pfizer, outside the submitted work. Leif Bjermer has (in the last three years) received lecture or advisory board fees from Alk-Abello, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mundipharma, Novartis, Sanofi, Genzyme/Regeneron, and Teva. Chau-Chyun Sheu has received speaker fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis and Pfizer, and has acted as an investigator for trials sponsored by AstraZeneca, Novartis, Roche, Sanofi-Regeneron, Galapagos, Shionogi, Aridis, Bristol Myers Squibb, Insmed and Horizon Therapeutics. Bassam Mahboub reports no conflicts of interest in this work. John Busby has received personnel from NurvAir. Andrew N. Menzies-Gow has attended advisory boards for AstraZeneca, GlaxoSmithKline, Novartis, Regeneron, Sanofi and Teva, and has received speaker fees from AstraZeneca, Novartis, Teva and Sanofi. He has participated in research with AstraZeneca for which his institution has been remunerated and has attended international conferences with Teva. He has had consultancy agreements with AstraZeneca and Sanofi. Eileen Wang has received honoraria from AstraZeneca, GlaxoSmithKline, Wefight, and Clinical Care Options. She has been an investigator on studies sponsored by AstraZeneca, GlaxoSmithKline, Genentech, Sanofi and Sema4, Novartis, and Teva, for which her institution has received funding. David B Price has advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, Teva Pharmaceuticals; consultancy agreements with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, Teva Pharmaceuticals; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Chiesi, Viatris, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Commute Digital, Medscape, Viatris, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma, Novartis; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Novartis, Medscape, Viatris, Teva Pharmaceuticals; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline., (© 2023 Cushen et al.)

BACKGROUND: Mucus plugs in asthmatic airways are associated with airway obstruction and the activity of inflammatory cytokines, specifically interleukin (IL)-5 and IL-13, and they may provide an opportunity for targeted therapy. This analysis of the CASCADE (Study to Evaluate Tezepelumab on Airway Inflammation in Adults With Uncontrolled Asthma) placebo-controlled trial used computed tomography (CT) imaging to assess mucus plugs in patients with moderate-to-severe, uncontrolled asthma who received tezepelumab or placebo. METHODS: CASCADE was an exploratory, double-blind, placebo-controlled trial examining the anti-inflammatory effect of tezepelumab. Patients (aged 18 to 75 years old) were randomly assigned 1:1 to 210 mg tezepelumab or placebo every 4 weeks subcutaneously for at least 28 weeks. An expert radiologist, blinded to treatment groups and time points, objectively scored 18 lung segments for the presence of mucus plugs in CT scans obtained before and after treatment; greater numbers of mucus plugs resulted in higher mucus plug scores. RESULTS: Absolute change from baseline (mean [±standard deviation]) in mucus plug score was −1.7±2.6 in patients receiving tezepelumab (n=37) and 0.0±1.4 in patients receiving placebo (n=45). At baseline, mucus plug scores correlated positively with levels of inflammatory biomarkers (blood eosinophils, eosinophil-derived neurotoxin, fractional exhaled nitric oxide, IL-5, and IL-13) and negatively with lung function measures (prebronchodilator forced expiratory volume in 1 second and forced mid-expiratory flow). In tezepelumab recipients, reductions in mucus plug scores were correlated with improvements in lung function and reductions in blood eosinophil count and levels of eosinophil-derived neurotoxin, a biomarker of eosinophilic degranulation. CONCLUSIONS: Tezepelumab was associated with a reduction in occlusive mucus plugs versus placebo in a randomized controlled trial in patients with moderate-to-severe, uncontrolled asthma. (Funded by AstraZeneca and Amgen Inc.; ClinicalTrials.gov number, NCT03688074.)

Background: There is limited evidence on the pathways leading to severe asthma and we are presently unable to effectively predict the progression of the disease. We aimed to describe the longitudinal trajectories leading to severe asthma and to describe clinical events preceding disease progression in a nationwide population of patients with severe asthma., Methods: We conducted an observational study based on Swedish data from the NORdic Dataset for aSThmA Research (NORDSTAR) research collaboration platform. We identified adult patients with severe asthma in 2018 according to the European Respiratory Society/American Thoracic Society definition and used latent class analysis to identify trajectories of asthma severity over a 10-year retrospective period from 2018., Results: Among 169 128 asthma patients, we identified 4543 severe asthma patients. We identified four trajectories of severe asthma that were labelled as: trajectory 1 "consistently severe asthma" (n=389 (8.6%)), trajectory 2 "gradual onset severe asthma" (n=942 (20.7%)), trajectory 3 "intermittent severe asthma" (n=1685 (37.1%)) and trajectory 4 "sudden onset severe asthma" (n=1527 (33.6%)). "Consistently severe asthma" had a higher daily inhaled corticosteroid dose and more prevalent osteoporosis compared with the other trajectories. Patients with "gradual onset severe asthma" and "sudden onset severe asthma" developed type 2-related comorbidities concomitantly with development of severe asthma. In the latter group, this primarily occurred within 1-3 years preceding onset of severe asthma., Conclusions: Four distinct trajectories of severe asthma were identified illustrating different patterns of progression of asthma severity. This may eventually enable the development of better preventive management strategies in severe asthma., Competing Interests: Conflict of interest: A. von Bülow reports consulting fees from Novartis, speaker fees from Novartis, GSK and AstraZeneca, travel grants from AstraZeneca, and participation in advisory boards with AstraZeneca and Novartis. S. Hansen reports speaker fees from AstraZeneca. P. Sandin reports no conflicts of interest. O. Ernstsson reports no conflicts of interest. C. Janson reports no conflicts of interest. L. Lehtimäki reports fees for lectures, consultations or advisory board meetings from ALK, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Menarini, Mundipharma, Novartis, Orion and Sanofi. H. Kankaanranta reports consulting fees from AstraZeneca, GSK, Chiesi, MSD, Orion Pharma, Novartis and Sanofi-Genzyme, and speaker fees from AstraZeneca, GSK, Orion Pharma and Boehringer Ingelheim. C. Ulrik reports grants from Sanofi, Boehringer Ingelheim, AstraZeneca and Novartis, consulting fees from Chiesi, Orion Pharma, Menarini, Takeda, AstraZeneca, Teva and GSK, lecture fees from Orion, Pharma, AstraZeneca and Teva, and participation in advisory boards with Novartis, GSK, Pfizer, AstraZeneca, Sanofi, Chiesi and Boehringer Ingelheim. B.B. Aarli reports grants from Novartis, consulting fees from AstraZeneca, lecture fees from GSK, AstraZeneca, Sanofi-Aventis, Novartis and Boehringer Ingelheim, and participation in advisory boards with GSK, AstraZeneca, Chiesi Pharma, Novartis and Sanofi. K. Geale is a board member of Quantify Research AB, Quantify Research ApS, Quantify Research AS and Quantify HEOR Private Limited, is CEO of Quantify Research AB, Quantify Research ApS and Quantify Research AS, and has stock and stock options in Quantify Research AB. S.T. Tang is an employee at Sanofi and holds stocks in Sanofi. M. Wolf is an employee at Novartis Finland. V. Backer reports no conflicts of interest. O. Hilberg reports consulting fees from Novartis, Sanofi, AstraZeneca, GSK, ALK, MSD and Teva, and travel grants from Sanofi. A. Altraja reports consulting fees from AstraZeneca, Boehringer Ingelheim, GSK and Sanofi, speaker fees from AstraZeneca, Berlin-Chemie Menarini, Boehringer Ingelheim, Norameda (Chiesi), GSK, Sanofi and Zentiva, expert testimony for AstraZeneca, Boehringer Ingelheim, GSK and Sanofi, travel grants from AstraZeneca, Berlin-Chemie Menarini, Boehringer Ingelheim and Norameda (Chiesi), participation in advisory boards with AstraZeneca, Boehringer Ingelheim, GSK and Sanofi, and receipt of equipment from Berlin-Chemie Menarini. H. Backman reports speaker fees from AstraZeneca, Boehringer Ingelheim and GSK. D. Lúdvíksdóttir reports speaker fees from GSK and Boehringer Ingelheim. U.S. Björnsdóttir reports speaker fees from Sanofi, AstraZeneca and Novartis, support for travel from Sanofi, and participation in advisory boards with Sanofi. P. Kauppi reports consulting fees from Sobi, speaker fees from GSK and AstraZeneca, and fee for PI for Theravance. T. Sandström reports no conflicts of interest. A. Sverrild reports grants from AstraZeneca, and speaker fees from AstraZeneca, Chiesi, GSK, Sanofi-Genzyme and Novartis. V. Yasinska reports lecture fees from GSK and Sanofi, and participation in advisory boards with AstraZeneca and GSK. M. Kilpeläinen reports no conflicts of interest. B. Dahlén reports grants from GSK and Novartis. A. Viinanen reports consulting fees from AstraZeneca and GSK, speaker fees from GSK and Chiesi, and travel grants from AstraZeneca and Sanofi. L. Bjermer reports speaker fees from AstraZeneca, GSK, Airsonette, Birc, Chiesi, Novartis and Sanofi, and participation in advisory boards with AstraZeneca, Chiesi, GSK, Birc and Sanofi. A. Bossios reports speaker fees from GSK, AstraZeneca, Teva and Novartis, travel grants from AstraZeneca and Novartis, participation in advisory boards with GSK, AstraZeneca, Teva, Novartis and Sanofi, is a member of the steering committee of SHARP, Secretary of Assembly 5 (Airway diseases, asthma, COPD and chronic cough) of the European Respiratory Society and is the vice-president of the Nordic Severe Asthma Network. C. Porsbjerg reports grants from AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi and ALK, consulting fees from AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi and ALK, lecture fees from AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi and ALK, and participation in advisory boards with AstraZeneca, Novartis, Teva, Sanofi and ALK., (Copyright ©The authors 2023.)

Background: Randomized controlled trials have demonstrated the efficacy of allergy immunotherapy (AIT) in allergic rhinitis (AR) and the disease-modifying effects of the SQ grass sublingual immunotherapy (SLIT) tablet., Objective: We sought to assess real-world, long-term effectiveness and safety across AIT subgroups: route of administration, therapeutic allergen, persistence to AIT, and SQ grass SLIT tablet., Methods: The primary outcome of AR prescriptions from a retrospective cohort study (REAl-world effeCtiveness in allergy immunoTherapy; 2007-2017) was assessed across prespecified AIT subgroups in subjects with AR with and without AIT prescriptions (controls). Safety was assessed as anaphylaxis for 2 days or less of the first AIT prescription. Subgroup follow-up continued until samples were fewer than 200 subjects., Results: Subcutaneous immunotherapy (SCIT) and SLIT tablets showed similarly greater reductions in AR prescriptions than controls (SCIT vs SLIT tablets: year 3, P = .15; year 5, P = .43). Comparably greater reductions in AR prescriptions were observed for grass- and house dust mite-specific AIT than for controls, but significantly smaller reductions were observed for tree-specific AIT (tree vs house dust mite, and vs grass: years 3 and 5, P < .0001). Persistence to AIT was associated with greater reductions in AR prescriptions versus nonpersistence (persistence vs nonpersistence: year 3, P = .09; year 5, P = .006). SQ grass SLIT tablet showed sustained reductions versus controls for up to 7 years (year 3, P = .002; year 5, P = .03). Rates of anaphylactic shock were low (0.000%-0.092%), with no events for SQ SLIT tablets., Conclusions: These results demonstrate real-world, long-term effectiveness of AIT, complement disease-modifying effects observed in SQ grass SLIT-tablet randomized controlled trials, and highlight the importance of using newer evidence-based AIT products for tree pollen AR., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Airway hyperresponsiveness is a hallmark of asthma across asthma phenotypes. Airway hyperresponsiveness to mannitol specifically relates to mast cell infiltration of the airways, suggesting inhaled corticosteroids to be effective in reducing the response to mannitol, despite low levels of type 2 inflammation., Objective: We sought to investigate the relationship between airway hyperresponsiveness and infiltrating mast cells, and the response to inhaled corticosteroid treatment., Methods: In 50 corticosteroid-free patients with airway hyperresponsiveness to mannitol, mucosal cryobiopsies were obtained before and after 6 weeks of daily treatment with 1600 μg of budesonide. Patients were stratified according to baseline fractional exhaled nitric oxide (Feno) with a cutoff of 25 parts per billion., Results: Airway hyperresponsiveness was comparable at baseline and improved equally with treatment in both patients with Feno-high and Feno-low asthma: doubling dose, 3.98 (95% CI, 2.49-6.38; P < .001) and 3.85 (95% CI, 2.51-5.91; P < .001), respectively. However, phenotypes and distribution of mast cells differed between the 2 groups. In patients with Feno-high asthma, airway hyperresponsiveness correlated with the density of chymase-high mast cells infiltrating the epithelial layer (ρ, -0.42; P = .04), and in those with Feno-low asthma, it correlated with the density in the airway smooth muscle (ρ, -0.51; P = .02). The improvement in airway hyperresponsiveness after inhaled corticosteroid treatment correlated with a reduction in mast cells, as well as in airway thymic stromal lymphopoietin and IL-33., Conclusions: Airway hyperresponsiveness to mannitol is related to mast cell infiltration across asthma phenotypes, correlating with epithelial mast cells in patients with Feno-high asthma and with airway smooth muscle mast cells in patients with Feno-low asthma. Treatment with inhaled corticosteroids was effective in reducing airway hyperresponsiveness in both groups., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Severe asthma is a complex, multidimensional disease. Optimal treatment, adherence and outcomes require shared decision-making, rooted in mutual understanding between patient and clinician. This study used a novel, patient-centred approach to examine the most bothersome aspects of severe asthma to patients, as seen from both perspectives in asthma registries., Methods: Across seven countries, 126 patients with severe asthma completed an open-ended survey regarding most the bothersome aspect(s) of their asthma. Patients' responses were linked with their treating clinician who also completed a free-text survey about each patient's most bothersome aspect(s). Responses were coded using content analysis, and patient and clinician responses were compared. Finally, asthma registries that are part of the SHARP (Severe Heterogeneous Asthma Research collaboration, Patient-centred) Clinical Research Collaboration were examined to see the extent to which they reflected the most bothersome aspects reported by patients., Results: 88 codes and 10 themes were identified. Clinicians were more focused on direct physical symptoms and were less focused on "holistic" aspects such as the effort required to self-manage the disease. Clinicians accurately identified a most bothersome symptom for 29% of patients. Agreement was particularly low with younger patients and those using oral corticosteroids infrequently. In asthma registries, patient aspects were predominantly represented in questionnaires., Conclusions: Results demonstrated different perspectives and priorities between patients and clinicians, with clinicians more focused on physical aspects. These differences must be considered when treating individual patients, and within multidisciplinary treatment teams. The use of questionnaires that include multifaceted aspects of disease may result in improved asthma research., Competing Interests: Conflict of interest: B. Ainsworth is a member of the UK Taskforce for Lung Health, has received honoraria for educational talks from AstraZeneca, and sits on advisory boards for the Medito Foundation and earGym. Conflict of interest: C. Coleman is an employee of the European Lung Foundation. Conflict of interest: M. Hyland has received grant income from Teva, GSK and AstraZeneca. Conflict of interest: L. Heaney has received grant funding, participated in advisory boards and given lectures at meetings supported by Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Hoffmann la Roche, GlaxoSmithKline, Novartis, Theravance, Evelo Biosciences, Sanofi and Teva; he has received grants from MedImmune, Novartis UK, Roche/Genentech Inc., GlaxoSmithKline, Amgen, Genentech/Hoffman la Roche, AstraZeneca, MedImmune, Aerocrine and Vitalograph; he has received sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK and Napp Pharmaceuticals; he has also taken part in asthma clinical trials sponsored by AstraZeneca, Boehringer Ingelheim, Hoffmann la Roche and GlaxoSmithKline for which his institution received remuneration; he is the Academic Lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma, which involves industrial partnerships with a number of pharmaceutical companies including Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann la Roche, and Janssen. Conflict of interest: V. Sedlák has received honoraria for educational talks and advisory boards from AstraZeneca, GSK, Novartis, TEVA, Chiesi and Boehringer Ingelheim. Conflict of interest: N. Edelbaher has received honoraria for educational talks and advisory boards from AstraZeneca, Sanofi, Novartis, GSK, Amgen, Boherringer Ingelheim, Chiesi and Berlin Chemie. Conflict of interest: A. ten Brinke has received honoraria for educational talks and advisory board from AstraZeneca, GSK, Novartis, Sanofi and TEVA, and grant income from AstraZeneca, GSK and TEVA. Conflict of interest: C. Loureiro has received honoraria for educational talks and advisory boards from AstraZeneca, GSK, Jaba-Recordati, Novartis, Sanofi and TEVA. Conflict of interest: R. Djukanovic has received honoraria for education talks and advisory board from AZ, GSK, Teva, Novartis and Sanofi. Conflict of interest: N. Kwon is a GSK employee and held stocks in GSK at the time of manuscript writing. Conflict of interest: All other authors have no competing interests., (Copyright ©The authors 2023.)

Bronchial and alveolar remodeling and impaired epithelial function are characteristics of chronic respiratory diseases. In these patients, an increased number of mast cells (MCs) positive for serine proteases, tryptase and chymase, infiltrate the epithelium and alveolar parenchyma. However, little is known regarding the implication of intraepithelial MCs on the local environment, such as epithelial cell function and properties. In this study, we investigated whether MC tryptase is involved in bronchial and alveolar remodeling and the mechanisms of regulation during inflammation. Using novel holographic live cell imaging, we found that MC tryptase enhanced human bronchial and alveolar epithelial cell growth and shortened the cell division intervals. The elevated cell growth induced by tryptase remained in a pro-inflammatory state. Tryptase also increased the expression of the anti-apoptotic protein BIRC3, as well as growth factor release in epithelial cells. Thus, our data imply that the intraepithelial and alveolar MC release of tryptase may play a critical role in disturbing bronchial epithelial and alveolar homeostasis by altering cell growth-death regulation.

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

Background: The use of anti-interleukin-5 (IL5) for severe asthma is based on criteria from randomised controlled trials (RCTs), but in real-life patients might not fulfil the eligibility criteria but may benefit from biologics. We aimed to characterise patients starting anti-IL5(R) in Europe and evaluate the discrepancies between initiation of anti-IL5(R) in real life and in RCTs., Materials and Methods: We performed a cross-sectional analysis with data from the severe asthma patients at the start of anti-IL5(R) in the Severe Heterogeneous Asthma Research collaboration Patient-centred (SHARP Central) registry. We compared the baseline characteristics of the patients starting anti-IL5(R) from 11 European countries within SHARP with the baseline characteristics of the severe asthma patients from 10 RCTs (four for mepolizumab, three for benralizumab and three for reslizumab). Patients were evaluated following eligibility criteria from the RCTs of anti-IL5 therapies., Results: Patients starting anti-IL5(R) in Europe (n=1231) differed in terms of smoking history, clinical characteristics and medication use. The characteristics of severe asthma patients in the SHARP registry differed from the characteristics of patients in RCTs. Only 327 (26.56%) patients fulfilled eligibility criteria of all the RCTs; 24 patients were eligible for mepolizumab, 100 for benralizumab and 52 reslizumab. The main characteristics of ineligibility were: ≥10 pack-years, respiratory diseases other than asthma, Asthma Control Questionnaire score ≤1.5 and low-dose inhaled corticosteroids., Conclusion: A large proportion of patients in the SHARP registry would not have been eligible for anti-IL5(R) treatment in RCTs, demonstrating the importance of real-life cohorts in describing the efficacy of biologics in a broader population of patients with severe asthma., Competing Interests: Conflict of interest: S. Principe is an employee of the University of Palermo with co-EU research funds EU-REACT FESR o FSE, PON Ricerca e Innovazione 2014–2020 - DM 1062/2021. Conflict of interest: A. Ten Brinke reports grants from AstraZeneca, GSK and TEVA, fees for advisory boards and lectures from AstraZeneca, GSK, Novartis, TEVA and Sanofi Genzyme. Conflict of interest: I. Grisle declares honoraria for lectures from AZ, Novartis, GSK, Berlin Chemie, Boehringer Ingelheim and Norameda. Conflict of interest: P. Kuna declares honoraria for lectures/presentations from AstraZeneca, GSK, Boehringer Ingelheim, Berlin Chemie, Menarini, FAES, Adamed, Polpharma, Glenmark, Novartis and Teva, and support for attending meetings from AstraZeneca, Berlin Chemie and Menarini. Conflict of interest: S. Popović-Grle declares consulting fees from AZ, GSK, Novartis, Pliva Teva, Sanofi and ALK, and honoraria for lectures from AZ, GSK, Novartis, Pliva TEVA, Sanofi and ALK. Conflict of interest: S. Škgrat declares, in the past 36 months, honoraria for lectures and educational events from AstraZeneca (AZ), Pliva Teva, Berlin Chemie, Chiesi and Medis, and participation on advisory boards for AZ and Berlin Chemie. Conflict of interest: C. Porsbjerg declares, in the past 36 months, grants from AZ, GSK, Novartis, TEVA, Sanofi, Chiesi and ALK, consulting fees from AZ, GSK, Novartis, TEVA, Sanofi, Chiesi and ALK, honoraria for lectures from AZ, GSK, Novartis, TEVA, Sanofi, Chiesi and ALK, participation for advisory boards AZ, GSK, Novartis, TEVA, Sanofi, Chiesi and ALK. Conflict of interest: All the other authors declare that they have no conflicts of interest., (Copyright ©The authors 2023.)

Rationale: Allergic asthma is linked to impaired bronchial epithelial secretion of IFNs, which may be causally linked to the increased risk of viral exacerbations. We have previously shown that allergen immunotherapy (AIT) effectively reduces asthma exacerbations and prevents respiratory infections requiring antibiotics; however, whether AIT alters antiviral immunity is still unknown. Objectives: To investigate the effect of house dust mite sublingual AIT (HDM-SLIT) on bronchial epithelial antiviral and inflammatory responses in patients with allergic asthma. Methods: In this double-blind, randomized controlled trial (VITAL [The Effect of Allergen Immunotherapy on Anti-viral Immunity in Patients with Allergic Asthma]), adult patients with HDM allergic asthma received HDM-SLIT 12-SQ or placebo for 24 weeks. Bronchoscopy was performed at baseline and at Week 24, which included sampling for human bronchial epithelial cells. Human bronchial epithelial cells were cultured at baseline and at Week 24 and stimulated with the viral mimic polyinosinic:polycytidylic acid (poly(I:C)). mRNA expression was quantified using qRT-PCR, and protein concentrations were measured using multiplex ELISA. Measurements and Main Results: Thirty-nine patients were randomized to HDM-SLIT ( n  = 20) or placebo ( n  = 19). HDM-SLIT resulted in increased polyinosinic:polycytidylic acid-induced expression of IFN-β at both the gene ( P  = 0.009) and protein ( P  = 0.02) levels. IFN-λ gene expression was also increased ( P  = 0.03), whereas IL-33 tended to be decreased ( P  = 0.09). On the other hand, proinflammatory cytokines IL-6 ( P  = 0.009) and TNF-α (tumor necrosis factor-α) ( P  = 0.08) increased compared with baseline in the HDM-SLIT group. There were no significant changes in TSLP (thymic stromal lymphopoietin), IL-4, IL-13, and IL-10. Conclusions: HDM-SLIT improves bronchial epithelial antiviral resistance to viral infection. These results potentially explain the efficacy of HDM-SLIT in reducing exacerbations in allergic asthma. Clinical trial registered with www.clinicaltrials.gov (NCT04100902).

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

Background: Valid outcome measures are imperative to evaluate treatment response, yet the suitability of existing end-points for severe asthma is unclear. This review aimed to identify outcome measures for severe asthma and appraise the quality of their measurement properties., Methods: A literature search was performed to identify "candidate" outcome measures published between 2018 and 2020. A modified Delphi exercise was conducted to select "key" outcome measures within healthcare professional, patient, pharmaceutical and regulatory stakeholder groups. Initial validation studies for "key" measures were rated against modified quality criteria from COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). The evidence was discussed at multi-stakeholder meetings to ratify "priority" outcome measures. Subsequently, four bibliographic databases were searched from inception to 20 July 2020 to identify development and validation studies for these end-points. Two reviewers screened records, extracted data, assessed their methodological quality and graded the evidence according to COSMIN., Results: 96 outcome measures were identified as "candidates", 55 as "key" and 24 as "priority" for severe asthma, including clinical, healthcare utilisation, quality of life, asthma control and composite. 32 studies reported measurement properties of 17 "priority" end-points from the latter three domains. Only the Severe Asthma Questionnaire and Childhood Asthma Control Test were developed with input from severe asthma patients. The certainty of evidence was "low" to "very low" for most "priority" end-points across all measurement properties and none fulfilled all quality standards., Conclusions: Only two outcome measures had robust developmental data for severe asthma. This review informed development of core outcome measures sets for severe asthma., Competing Interests: Conflict of interest: A. Rattu and E. Khaleva declare funding from the European Commission's Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement number 831434 (3TR) for this manuscript. C. Brightling declares grants from GlaxoSmithKline, AstraZeneca, Novartis, Chiesi, Boehringer Ingelheim, Genentech, Roche, Sanofi, Mologic and 4DPharma, consulting fees from GlaxoSmithKline, AstraZeneca, Novartis, Chiesi, Boehringer Ingelheim, Genentech, Roche, Sanofi, Mologic, 4DPharma and Teva, and support from the 3TR project. S-E. Dahlén declares a 3TR IMI grant, consulting fees from AstraZeneca, Cayman Co., GlaxoSmithKline, Novartis, Regeneron, Sanofi and Teva, and payment for lectures from AstraZeneca and Sanofi. A. Bossios declares honoraria for lectures from GlaxoSmithKline, AstraZeneca, Teva and Novartis, support for attending meetings from AstraZeneca and Novartis, honoraria for advisory board meetings from GlaxoSmithKline, AstraZeneca, Teva, Novartis and Sanofi, and being a member of the Steering Committee of SHARP, Secretary of Assembly 5 (Airway Diseases, Asthma, COPD and Chronic Cough) of the European Respiratory Society, and Vice-chair of the Nordic Severe Asthma Network (NSAN). L. Fleming declares participation in advisory boards and honoraria for lectures from Sanofi, Respiri UK, AstraZeneca, Novartis and Teva, outside the submitted work; all payments were made to her institution. K.F. Chung has received honoraria for participating in advisory board meetings of GlaxoSmithKline, AstraZeneca, Roche, Novartis, Merck and Shionogi regarding treatments for asthma, COPD and chronic cough, and has also been remunerated for speaking engagements for Novartis and AstraZeneca; has received an MRC grant on precision medicine for severe asthma, an EPSRC grant on air pollution and asthma, and a GlaxoSmithKline grant on mepolizumab and eosinophils in asthma. E. Melén declares consulting fees from AstraZeneca, Chiesi, Novartis and Sanofi, outside the submitted work. R. Chaudhuri has received lecture fees from GlaxoSmithKline, AstraZeneca, Teva, Chiesi, Sanofi and Novartis, honoraria for advisory board meetings from GlaxoSmithKline, AstraZeneca, Teva, Chiesi and Novartis, sponsorship to attend international scientific meetings from Chiesi, Napp, Sanofi and GlaxoSmithKline, and a research grant to her institute from AstraZeneca for a UK multicentre study. R. Djukanovic declares funding from the European Respiratory Society, Teva, GlaxoSmithKline, Novartis, Sanofi and Chiesi for the SHARP CRC, consulting fees for Synairgen, honorarium for a lecture from GlaxoSmithKline, participation on a data safety monitoring board or advisory board for Kymab (Cambridge), and shares in Synairgen, outside the submitted work. A. Exley declares being a minority shareholder in GlaxoSmithKline PLC. G.H. Koppelman reports receiving research grants from the Lung Foundation of the Netherlands, Ubbo Emmius Foundation, H2020 European Union, Teva, GlaxoSmithKline and Vertex, outside this work (money to institution); he reports memberships of advisory boards to GlaxoSmithKline and PURE-IMS, outside this work (money to institution). A. Bourdin declares unrestricted grants from AstraZeneca and Boehringer Ingelheim to his institute; consulting fees, honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, and support for attending meetings and travel from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis and Sanofi; participation on a data safety monitoring board or advisory board for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi and Abs science. C. Porsbjerg declares grants (paid to institution), consulting fees (paid to institution and personal honoraria) and honoraria for lectures (paid to institution and personal honoraria) from AstraZeneca, GlaxoSmithKline, Novartis, Teva, Sanofi, Chiesi and ALK; participation on an advisory board (paid to institution and personal honoraria) for AstraZeneca, Novartis, Teva, Sanofi and ALK. C. Coleman and C. Williams declare funding received to support this work by the European Lung Foundation (ELF) from the European Commission's Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement number 831434 (3TR), and are employees of the ELF. E. Davin bought and sold shares on the public market during 2021–2022 in Regeneron, Roche and ICON Plc, and declares no current holdings. P. Taverner declares honorarium for being a lay member of Asthma and Lung UK's research funding panel, and chairing a Patient and Community Oversight Group for two NIHR health protection research units on environmental and chemical hazards; and payment for chairing a NICE guideline committee on advocacy services. S. Romagosa Vilarnau declares unrestricted educational grants paid to the organisation from Novartis, Pfizer, AstraZeneca, Chiesi Farmaceutici, GlaxoSmithKline, AbbVie, LeoPharma, Boehringer Ingelheim, Sanofi, Regeneron, OM Pharma, MSD, Roche and DBV Technologies. G. Roberts declares EU IMI funding and consulting fees from AstraZeneca paid to his institution. No other author has any conflict of interest to declare., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Real-life evidence on prevalence and management of severe asthma is limited. Nationwide population registries across the Nordic countries provide unique opportunities to describe prevalence and management patterns of severe asthma at population level. In nationwide register data from Sweden, Norway and Finland, we examined the prevalence of severe asthma and the proportion of severe asthma patients being managed in specialist care., Methods: This is a cross-sectional study based on the Nordic Dataset for Asthma Research (NORDSTAR) research collaboration platform. We identified patients with severe asthma in adults (aged ≥18 years) and in children (aged 6-17 years) in 2018 according to the European Respiratory Society/American Thoracic Society definition. Patients managed in specialist care were those with an asthma-related specialist outpatient contact (only available in Sweden and Finland)., Results: Overall, we identified 598 242 patients with current asthma in Sweden, Norway and Finland in 2018. Among those, the prevalence of severe asthma was 3.5%, 5.4% and 5.2% in adults and 0.4%, 1.0%, and 0.3% in children in Sweden, Norway and Finland, respectively. In Sweden and Finland, 37% and 40% of adult patients with severe asthma and two or more exacerbations, respectively, were managed in specialist care; in children the numbers were 56% and 41%, respectively., Conclusion: In three Nordic countries, population-based nationwide data demonstrated similar prevalence of severe asthma. In children, severe asthma was a rare condition. Notably, a large proportion of patients with severe asthma were not managed by a respiratory specialist, suggesting the need for increased recognition of severe asthma in primary care., Competing Interests: Conflict of interest: The work was financially supported by Novartis and Sanofi & Regeneron Pharmaceuticals. S. Hansen reports no conflicts of interest. A. von Bülow reports consulting fees from Novartis, speaker fees from Novartis, GSK and AstraZeneca, travel grants from AstraZeneca, and participation in advisory boards with AstraZeneca and Novartis. P. Sandin has no conflicts of interest. O. Ernstsson has no conflicts of interest. C. Janson reports speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Orion Pharma and Sanofi, and expert testimony payments from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Orion Pharma and Sanofi. L. Lehtimäki reports consulting fees from AstraZeneca and GSK, and speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Orion Pharma and Sanofi. H. Kankaanranta reports consulting fees from AstraZeneca, GSK, Chiesi, MSD, Orion Pharma, Novartis and Sanofi Genzyme, and speaker fees from AstraZeneca, GSK, Chiesi, Mundipharma, Orion Pharma and Sanofi Genzyme. C. Ulrik reports grants from Sanofi, Boehringer Ingelheim, AstraZeneca and Novartis, consulting fees from Orion Pharma, AstraZeneca and Teva, and participation in advisory boards with Novartis, GSK, AstraZeneca, Sanofi, Chiesi and Boehringer Ingelheim. B.B. Aarli reports consulting fees from GSK and AstraZeneca, lecture fees from GSK, AstraZeneca, Sanofi-Aventis Norge, Novartis and Boehringer Ingelheim, and participation in advisory boards with GSK, Astra Zeneca and Sanofi-Aventis Norge. H. Fues Wahl has no conflicts of interest. K. Geale is a board member of Quantify Research AB, Quantify Research ApS, Quantify Research AS and Quantify HEOR Private Limited, is CEO of Quantify Research AB, Quantify Research ApS and Quantify Research AS, and has stock and stock options in Quantify Research AB. S.T. Tang is an employee at Sanofi and holds stocks in Sanofi. M. Wolf is an employee at Novartis Finland. T. Larsen is an employee at Novartis Norway. A. Altraja reports consulting fees from AstraZeneca, Boehringer Ingelheim, GSK and Sanofi, speaker fees from AstraZeneca, Berlin-Chemie Menarini, Boehringer Ingelheim, Norameda (Chiesi), GSK, Sanofi, Teva and Zentiva, expert testimony for AstraZeneca, Boehringer Ingelheim, GSK and Sanofi, travel grants from AstraZeneca, Berlin-Chemie Menarini, Boehringer Ingelheim and Norameda (Chiesi), participation in advisory boards with AstraZeneca, Boehringer Ingelheim, GSK and Sanofi, and receipt of equipment from Berlin-Chemie Menarini. H. Backman reports speaker fees from AstraZeneca, Boehringer Ingelheim, GSK and Sanofi. M. Kilpeläinen reports no conflicts of interest. A. Viinanen reports consulting fees from GSK, speaker fees from AstraZeneca, ALK, GSK, Boehringer Ingelheim and Chiesi, and travel grants from AstraZeneca, Sanofi and Boehringer Ingelheim. D. Ludviksdottir reports travel grants from GSK and AstraZeneca. P. Kauppi reports no conflicts of interest. A. Sverrild reports grants from AstraZeneca, consulting fees from Novartis, speaker fees from AstraZeneca and Chiesi, travel grants from Teva, and participation in advisory boards with Chiesi and Sanofi-Genzyme. S. Lehmann reports no conflicts of interest. V. Backer reports no conflicts of interest. V. Yasinska reports lecture fees from GSK and Sanofi, and participation in advisory boards with AstraZeneca, Chiesi and GSK. T. Skjold reports no conflicts of interest. J. Karjalainen reports consulting fees from AstraZeneca, GSK, MSD and Novartis, and lecture fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, MSD, MundiPharma, Novartis and Orion Pharma. A. Bossios reports lecture fees from GSK, AstraZeneca, Teva and Novartis, travel grants from AstraZeneca and Novartis, and participation in advisory boards with GSK, AstraZeneca, Teva, Novartis and Sanofi, and is a member of the steering committee of SHARP, Secretary of Assembly 5 (Airway diseases, asthma, COPD and chronic cough) of the European Respiratory Society and the vice-president of the Nordic Severe Asthma Network. C. Porsbjerg reports grants from AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi and ALK, consulting fees from AZ, GSK, Novartis, TEVA, Sanofi, Chiesi and ALK, lecture fees from AZ, GSK, Novartis, TEVA, Sanofi, Chiesi and ALK, and participation in advisory boards with AstraZeneca, Novartis, TEVA, Sanofi and ALK., (Copyright ©The authors 2023.)