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Background: Some children with asthma experience exacerbations despite long-acting beta2-agonist (LABA) treatment. While this variability is partly caused by genetic variation, no genome-wide study until now has investigated which genetic factors associated with risk of exacerbations despite LABA use in children with asthma. We aimed to assess whether genetic variation was associated with exacerbations in children treated with LABA from a global consortium., Methods: A meta-analysis of genome-wide association studies (meta-GWAS) was performed in 1,425 children and young adults with asthma (age 6-21 years) with reported regular use of LABA from six studies within the PiCA consortium using a random effects model. The primary outcome of each study was defined as any exacerbation within the past 6 or 12 months, including at least one of the following: 1) hospital admissions for asthma, 2) a course of oral corticosteroids or 3) emergency room visits because of asthma., Results: Genome-wide association results for a total of 82 996 common single nucleotide polymorphisms (SNPs, MAF ≥1%) with high imputation quality were meta-analysed. Eight independent variants were suggestively (P-value threshold ≤5 × 10 -6 ) associated with exacerbations despite LABA use., Conclusion: No strong effects of single nucleotide polymorphisms (SNPs) on exacerbations during LABA use were identified. We identified two loci (TBX3 and EPHA7) that were previously implicated in the response to short-acting beta2-agonists (SABA). These loci merit further investigation in response to LABA and SABA use., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Real-world evidence is important to help unravel unanswered problems in severe asthma and is valuable to better understand the patient experience and common clinical practice. The Severe Heterogeneous Asthma Registry, Patient-centred (SHARP) Clinical Research Collaboration is created as a network of national registries and severe asthma centres that work together to perform registry based real-world research and clinical studies on a pan-European scale. Such collaboration requires a new, innovative design to overcome the many issues that arise with large-scale data collection across national borders. SHARP has developed a platform that offers a federated analysis approach where national registry data are transformed and integrated into a common data model (CDM). The CDM then allows a local analysis of de-identified patient data and subsequent aggregate (meta-)analysis. To facilitate an easily accessible way to set up new registries, SHARP enables new registries to take part in a central database, based on already proven technology. Next to being economical, this linkage ensures data from different SHARP central members to be comparable. Technological advancements lead to an ever-expanding rate of patient data that will be collected; with the collective effort of the pan-European severe asthma research community SHARP hopes to ensure that they are well equipped to enter a new era of medical research, with the ultimate goal to positively impact the lives of patients with severe asthma., Competing Interests: Conflict of interest: J.J.M.H. van Bragt has nothing to disclose. Conflict of interest: S. Hansen has nothing to disclose. Conflict of interest: R. Djukanovic reports receiving fees for lectures at symposia organised by Novartis, AstraZeneca and TEVA, consultation for TEVA and Novartis as member of advisory boards, and participation in a scientific discussion about asthma organised by GlaxoSmithKline. He is a co-founder and current consultant, and has shares in Synairgen, a University of Southampton spin out company. Conflict of interest: E.H.D. Bel reports grants and personal fees from GlaxoSmithKline, AstraZeneca, Novartis and Teva, and personal fees from Sanofi/Regeneron, Sterna and Chiesi, outside the submitted work. Conflict of interest: A. ten Brinke reports grants outside the submitted work from AstraZeneca, GSK and TEVA, institutional fees from Lectures from AstraZeneca, GSK, TEVA and Sanofi, and institutional fees from Research Advisory Boards from GSK, Sanofi, TEVA and AstraZeneca. Conflict of interest: S.S. Wagers reports consulting fees for work done on the SHARP project from the European Respiratory Society (ERS); and consulting fees from Kings College Hospital NHS Foundation Trust, Academic Medical Research, AMC Medical Research BV, Asthma UK, Athens Medical School, Boehringer Ingelheim International GmbH, CHU de Toulouse, CIRO, DS Biologicals Ltd, École Polytechnique Fédérale de Lausanne, ERS, FISEVI, Fluidic Analytics Ltd, Fraunhofer IGB, Fraunhofer ITEM, GlaxoSmithKline Research & Development Ltd, Holland & Knight, Karolinska Institutet Fakturor, KU Leuven, Longfonds, the National Heart & Lung Institute, Novartis Pharma AG, Owlstone Medical Limited, PExA AB, UCB Biopharma SPRL, UCB Biosciences GmbH, Umeå University, University Hospitals Southampton NHS Foundation Trust, Università Campus Bio-Medico di Roma, Universita Cattolica Del Sacro Cuore, Universität Ulm, the University of Bern, the University of Edinburgh, the University of Hull, the University of Leicester, the University of Loughborough, the University of Luxembourg, the University of Manchester, the University of Notthingham, Vlaams Brabant, Dienst Europa, Imperial College London, Boehringer Ingelheim, Breathomix, Gossamer Bio, AstraZeneca, CIBER, OncoRadiomics, the University of Leiden, the University of Wurzburg, Chiesi Pharmaceutical, the University of Liege, Teva Pharmacauticals and Sanofi, outside the submitted work. Conflict of interest: A.H. Maitland-van der Zee has received research grants outside the submitted work from GSK, 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, Smartfish, SODAQ, Thirona, TopMD and Novartis), and she has served in advisory boards for AstraZeneca, GSK and Boehringer Ingelheim with money paid to her institution. Conflict of interest: C. Porsbjerg has nothing to disclose., (Copyright ©The authors 2021.)

Molecular profiling of exhaled breath by electronic nose (eNose) might be suitable as a noninvasive tool that can help in monitoring of clinically unstable COPD patients. However, supporting data are still lacking. Therefore, as a first step, this study aimed to determine the accuracy of exhaled breath analysis by eNose to identify COPD patients who recently exacerbated, defined as an exacerbation in the previous 3 months. Data for this exploratory, cross-sectional study were extracted from the multicentre BreathCloud cohort. Patients with a physician-reported diagnosis of COPD (n=364) on maintenance treatment were included in the analysis. Exacerbations were defined as a worsening of respiratory symptoms requiring treatment with oral corticosteroids, antibiotics or both. Data analysis involved eNose signal processing, ambient air correction and statistics based on principal component (PC) analysis followed by linear discriminant analysis (LDA). Before analysis, patients were randomly divided into a training (n=254) and validation (n=110) set. In the training set, LDA based on PCs 1-4 discriminated between patients with a recent exacerbation or no exacerbation with high accuracy (receiver operating characteristic (ROC)-area under the curve (AUC)=0.98, 95% CI 0.97-1.00). This high accuracy was confirmed in the validation set (AUC=0.98, 95% CI 0.94-1.00). Smoking, health status score, use of inhaled corticosteroids or vital capacity did not influence these results. Exhaled breath analysis by eNose can discriminate with high accuracy between COPD patients who experienced an exacerbation within 3 months prior to measurement and those who did not. This suggests that COPD patients who recently exacerbated have their own exhaled molecular fingerprint that could be valuable for monitoring purposes., Competing Interests: Conflict of interest: J.J.M.H. van Bragt reports an unrestricted research grant from Boehringer Ingelheim during the conduct of the study. Conflict of interest: P. Brinkman has nothing to disclose. Conflict of interest: R. de Vries is COO of and has a considerable interest in the start-up company Breathomix BV. Conflict of interest: S.J.H. Vijverberg has nothing to disclose. Conflict of interest: E.J.M. Weersink has nothing to disclose. Conflict of interest: E.G. Haarman has nothing to disclose. Conflict of interest: F.H.C. de Jongh has nothing to disclose. Conflict of interest: S. Kester has nothing to disclose. Conflict of interest: A. Lucas has nothing to disclose. Conflict of interest: J.C.C.M. in 't Veen reports faculty grants from Boehringer Ingelheim, Teva and Chiesi, and personal fees for an international advisory board from Sanofi, outside the submitted work. Conflict of interest: P.J. Sterk reports being scientific advisor to and having a formally inconsiderable interest in the start-up company Breathomix BV. Conflict of interest: E.H.D. Bel reports grants and personal fees from AstraZeneca, GSK, Novartis, and Teva, and personal fees from Sanofi/Regeneron, Boehringer Ingelheim, Vectura, and Sterna, outside the submitted work. Conflict of interest: A.H. Maitland-van der Zee reports personal fees for advisory boards from AstraZeneca and Boehringer Ingelheim, and unrestricted research grants from Boehringer Ingelheim and GSK, during the conduct of the study., (Copyright ©ERS 2020.)

Background: Patients with severe asthma not meeting the strict trial eligibility criteria for mepolizumab are now routinely treated with this biological in clinical practice, but it remains unclear whether these ineligible patients respond differently to mepolizumab treatment., Objective: This study investigated the extent and reasons for trial ineligibility of real-life, mepolizumab-treated patients with severe asthma and compared the characteristics of these patients with trial populations. Subsequently, therapeutic response in ineligible patients was assessed on the basis of oral corticosteroid (OCS) reduction., Methods: Trial eligibility, population differences, and therapeutic response were assessed using the baseline characteristics of mepolizumab-receiving patients with severe asthma treated in the Amsterdam University Medical Centres and OCS dose at 6 months for OCS-dependent patients extracted from patients' electronic health records. Eligibility criteria and population characteristics from trials investigating mepolizumab were extracted from their original publications., Results: A total of 82.4% of 119 mepolizumab-receiving, real-life patients with severe asthma were ineligible for trial inclusion, wherein 42.9% and 39.5% were excluded on the basis of inclusion and exclusion criteria, respectively. The clinical care population was older, more often male and demonstrating a better lung function under lower OCS maintenance dosages in comparison with trial populations. A total of 50% of 66 ineligible, OCS-dependent mepolizumab-treated patients were able to reduce their maintenance OCS dosage to ≤5 mg prednisone/day., Conclusions: A large proportion of the real-life, mepolizumab-treated population with severe asthma would be excluded from trial participation, and significant differences in population characteristics exist. Regardless, a large fraction of ineligible patients in clinical care can reduce maintenance OCS dosage under mepolizumab therapy., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m -2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day -1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day -1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries., Competing Interests: Conflict of interest: J.J.M.H. van Bragt has nothing to disclose. Conflict of interest: I.M. Adcock has nothing to disclose. Conflict of interest: E.H.D. Bel reports grants and personal fees from AstraZeneca, GSK and Novartis, grants from Teva, and personal fees from Boehringer Ingelheim, Sanofi/Regeneron, Vectura and Sterna, outside the submitted work. Conflict of interest: G-J. Braunstahl reports grants from GSK, Novartis, AstraZeneca and Chiesi, outside the submitted work. Conflict of interest: A. Ten Brinke reports institutional fees for research advisory boards and lectures from GSK, Teva and AstraZeneca, institutional fees for research advisory boards from Sanofi, Novartis and Boehringer Ingelheim, outside the submitted work. Conflict of interest: J. Busby has nothing to disclose. Conflict of interest: G.W. Canonica reports personal fees from A. Menarini, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia, GSK, MSD, Novartis, Roche, Sanofi-Aventis and Teva, during the conduct of the study. Conflict of interest: H. Cao is an employee of Novartis, which is one of the funding pharmaceutical companies of SHARP. Conflict of interest: K.F. Chung has received honoraria for participating in advisory board meetings from GSK, AstraZeneca, Novartis, Merck, Boehringer Ingelheim and Teva regarding treatments for asthma and chronic obstructive pulmonary disease and has also been remunerated for speaking engagements. Conflict of interest: Z. Csoma has nothing to disclose. Conflict of interest: B. Dahlén reports advisory board membership for Teva, GSK and Sanofi, personal fees for lectures from AstraZeneca, outside the submitted work. Conflict of interest: E. Davin has nothing to disclose. Conflict of interest: S. Hansen has nothing to disclose. Conflict of interest: E. Heffler reports personal fees from AstraZeneca, Sanofi Genzyme, Teva, Novartis, GSK, Circassia and Nestle Purina, outside the submitted work. Conflict of interest: I. Horvath reports personal fees from AstraZeneca, Boehringer Ingelheim, GSK, Chiesi, Berlin-Chemie, Roche, MSD, CSL and Sager Pharma, outside the submitted work. Conflict of interest: S. Korn reports personal fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Teva and Roche, grants and personal fees from GSK and Novartis, during the conduct of the study. Conflict of interest: M. Kots is a full time Chiesi Famaceutici SpA employee, Global clinical development department. Conflict of interest: P. Kuna reports personal fees for lectures and advisory board work from AstraZeneca and Novartis, personal fees for lectures and nonfinancial support for meeting attendance from Berlin-Chemie, Menarini and Boehringer Ingelheim, outside the submitted work. Conflict of interest: N. Kwon is an employee of GSK. Conflict of interest: R. Louis reports grants and personal fees for advisory board work from GSK, AstraZeneca and Novartis, grants from Chiesi, outside the submitted work. Conflict of interest: V. Plaza reports grants, personal fees and nonfinancial support from Chiesi, grants and personal fees from AstraZeneca, personal fees from ALK, Mundipharma and Sanofi, grants from Menarini, outside the submitted work. Conflict of interest: C. Porsbjerg has nothing to disclose. Conflict of interest: D. Ramos-Barbon has nothing to disclose. Conflict of interest: L.B. Richards has nothing to disclose. Conflict of interest: S. Škrgat reports personal fees for lectures and scientific discussion at symposia from Teva and Boehringer, personal fees for lectures and advisory boards from AstraZeneca, Glaxo, Berlin-Chemie and Chiesi, outside the submitted work. Conflict of interest: J.K. Sont has nothing to disclose. Conflict of interest: S.J.H. Vijverberg has nothing to disclose. Conflict of interest: E.J. Weersink has nothing to disclose. Conflict of interest: V. Yasinska has nothing to disclose. Conflict of interest: S.S. Wagers reports consultancy fees from the European Respiratory Society, during the conduct of the study; consultancy fees from King's College Hospital NHS Foundation Trust, Academic Medical Research, AMC Medical Research BV, Asthma UK, Athens Medical School, Boehringer Ingelheim International GmbH, CHU de Toulouse, CIRO, DS Biologicals Ltd, École Polytechnique Fédérale de Lausanne, European Respiratory Society, FISEVI, Fluidic Analytics Ltd, Fraunhofer IGB, Fraunhofer ITEM, GSK R&D Ltd, Holland and Knight, Karolinska Institutet Fakturor, KU Leuven, Longfonds, National Heart and Lung Institute, Novartis Pharma AG, Owlstone Medical Ltd, PExA AB, UCB Biopharma SPRL, UCB Biosciences GmbH, Umeå University, University Hospital Southampton NHS Foundation Trust, Università Campus Bio-Medico di Roma, Universita Cattolica Del Sacro Cuore, Universität Ulm, University of Bern, University of Edinburgh, University of Hull, University of Leicester, University of Loughborough, University of Luxembourg, University of Manchester, University of Nottingham, Vlaams Brabant, Dienst Europa, Imperial College London, Boehringer Ingelheim, Breathomix, Gossamer Bio, AstraZeneca and CIBER, outside the submitted work. Conflict of interest: R. Djukanovic reports receiving fees for lectures at symposia organised by Novartis, AstraZeneca and Teva, consultation for Teva and Novartis as member of advisory boards, and participation in a scientific discussion about asthma organised by GSK; and is a co-founder and current consultant, and has shares in Synairgen, a University of Southampton spin out company. Conflict of interest: A.H. Maitland-van der Zee reports personal fees for participating in an advisory board from AstraZeneca and Boehringer Ingelheim, unrestricted research grants from Boehringer Ingelheim and GSK., (Copyright ©ERS 2020.)

Little is known about adult-onset asthma in different ethnic groups. The aim of this study was to examine ethnic differences in the prevalence of adult-onset asthma and factors associated with this phenotype. Cross-sectional data of 23,356 participants of the HELIUS study were used, including Dutch, South-Asian Surinamese, African Surinamese, Moroccan, Turkish and Ghanaian origin participants. Adult-onset asthma was defined as: self-reported asthma symptoms or start of asthma-medication at age ≥18 years combined with a smoking history <10 pack years. The prevalence of adult-onset asthma and its association with potential risk factors were assessed by logistic regression analyses. The adjusted prevalence of adult-onset asthma was higher in the Turkish, Moroccan and South-Asian Surinamese groups (4.9-6.0%) compared to the Dutch, Ghanaian and African Surinamese origin groups (2.4-2.6%). In addition to ethnicity, age, female sex, BMI, and doctors' diagnosis of nasal allergy/hay fever and chronic sinusitis/polyps were independently associated with adult-onset asthma. There are significant differences in the adjusted prevalence of adult-onset asthma among six ethnic groups., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: The complexity and heterogeneous nature of asthma and chronic obstructive pulmonary disease (COPD) results in difficulties in diagnosing and treating patients. Biomarkers that can identify underlying mechanisms, identify patient phenotypes and to predict treatment response could be of great value for adequate treatment. Areas covered: Biomarkers play an important role for the development of novel targeted therapies in airways disease. Blood biomarkers are relatively non-invasive, easy to obtain and easy to apply in routine care. Several blood biomarkers are being used to diagnose and monitor chronic airways diseases, as well as to predict response to treatment and long-term prognosis. Blood eosinophils are the best studied biomarker, the most applied in clinical practice, and until now the most promising of all blood biomarkers. Other blood biomarkers, including serum periostin, IgE and ECP and plasma fibrinogen are less studied and less relevant in clinical practice. Recent developments include the use of antibody assays of many different cytokines at the same time, and 'omics' techniques and systems medicine. Expert commentary: With the exception of blood eosinophils, the use of blood biomarkers in asthma and COPD has been rather disappointing. Future research using new technologies like big-data analysis of blood samples from real-life patient cohorts will probably gain better insight into underlying mechanisms of different disease phenotypes. Identification of specific molecular pathways and associated biomarkers will then allow the development of new targets for precision medicine.

Purpose of Review: Asthma features a high degree of heterogeneity in both pathophysiology and therapeutic response, resulting in many asthma patients being treated inadequately. Biomarkers indicative of underlying pathological processes could be used to identify disease subtypes, determine prognosis and to predict or monitor treatment response. However, the newly identified as well as more established biomarkers have different applications and limitations., Recent Findings: Conventional markers for type 2-high asthma, such as blood eosinophils, fraction of exhaled nitric oxide, serum IgE and periostin, feature limited sensitivity and specificity despite their significant correlations. More distinctive models have been developed by combining biomarkers and/or using omics techniques. Recently, a model with a positive predictive value of 100% for identification of type 2-high asthma based on a combination of minimally invasive biomarkers was developed., Summary: Individualisation of asthma treatment regimens on the basis of biomarkers is necessary to improve asthma control. However, the suboptimal properties of currently available conventional biomarkers limit its clinical utility. Newly identified biomarkers and models based on combinations and/or omics analysis must be validated and standardised before they can be routinely applied in clinical practice. The development of robust biomarkers will allow development of more efficacious precision medicine-based treatment approaches for asthma.

Introduction: Chronic inflammatory diseases predispose for development of a first pulmonary embolism (PE). Previous studies showed that corticosteroids, which are the mainstay of treatment for inflammatory diseases, enhance the risk of a first venous thromboembolism. Yet, it is unknown whether corticosteroids also predispose for recurrent events. Therefore, we investigated the association between oral and/or inhaled corticosteroid use and the risk of recurrent PE., Methods: We performed a nested case-control study using the PHARMO Database. Adult patients who had suffered from a first PE for which vitamin K antagonists were prescribed, were eligible. Of these, 384 patients with recurrent PE were matched to 1030 patients without recurrent PE., Results: We showed that oral or inhaled corticosteroids was ever used by 22.7% and 20.6% of patients with recurrent PE, and 23.5% and 21.5% of the patients without recurrent PE. There was an overall association between oral corticosteroid use and the risk of recurrent PE (p=0.02). Current use of oral corticosteroids increased the risk of recurrent PE (OR 3.74; 95% CI 2.04-6.87), whereas past use reduced the risk (OR 0.46; 95% CI 0.28-0.74). A similar pattern was observed for inhaled corticosteroids, although less strong (p=0.10)., Conclusions: Current use of oral corticosteroids is associated with increased risk of recurrent PE. Whether this increased risk is caused by oral corticosteroids themselves, or by the underlying disease, or both, needs further investigation. Nevertheless, given the frequent use of corticosteroids in clinical practice, clinicians should be aware of this risk., (Copyright © 2016 Elsevier Ltd. All rights reserved.)