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Andrew N Menzies-Gow,1 Claire McBrien,2 Bindhu Unni,3 Celeste M Porsbjerg,4 Mona Al-Ahmad,5 Christopher S Ambrose,6 Karin Dahl Assing,7 Anna von Bülow,4 John Busby,8 Borja G Cosio,9 J Mark FitzGerald,10 Esther Garcia Gil,11 Susanne Hansen,12 Liam G aHeaney,8 Mark Hew,13,14 David J Jackson,15,16 Maria Kallieri,17 Stelios Loukides,17 Njira L Lugogo,18 Andriana I Papaioannou,17 Désirée Larenas-Linnemann,19 Wendy C Moore,20 Luis A Perez-de-Llano,21 Linda M Rasmussen,22 Johannes M Schmid,23 Salman Siddiqui,24 Marianna Alacqua,25 Trung N Tran,6 Charlotte Suppli Ulrik,26 John W Upham,27 Eileen Wang,28,29 Lakmini Bulathsinhala,3,30 Victoria A Carter,3,30 Isha Chaudhry,3,30 Neva Eleangovan,3,30 Ruth B Murray,3,30 Chris A Price,3,30 David B Price3,30,31 1UK Severe Asthma Network and National Registry, Royal Brompton & Harefield Hospitals, London, UK; 2Kingston Hospital, London, UK; 3Observational and Pragmatic Research Institute, Singapore, Singapore; 4Respiratory Research Unit, Bispebjerg University Hospital, Copenhagen, Denmark; 5Al-Rashed Allergy Center, Ministry of Health, Microbiology Department, Faculty of Medicine, Kuwait University, Kuwait, Kuwait; 6AstraZeneca, Gaithersburg, MD, USA; 7Department of Respiratory Medicine, Aalborg University Hospital, Aalborg, Denmark; 8UK Severe Asthma Network and National Registry, Queen’s University Belfast, Belfast, Northern Ireland; 9Son Espases University Hospital-IdISBa-Ciberes, Mallorca, Spain; 10The Centre for Lung Health, Vancouver Coastal Health Research Institute, UBC, Vancouver, Canada; 11AstraZeneca, Barcelona, Spain; 12Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark; 13Allergy, Asthma & Clinical Immunology Service, Alfred Health, Melbourne, Australia; 14Public Health and Preventive Medicine, Monash University, Melbourne, Australia; 15UK Severe Asthma Network andNational Registry, Guy’s and St Thomas’ NHS Trust, London, UK; 16School of Immunology & Microbial Sciences, King’s College London, London, UK; 17 2nd Respiratory Medicine Department, National and Kapodistrian University of Athens Medical School, Attikon University Hospital, Athens, Greece; 18Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA; 19Directora Centro de Excelencia en Asma y Alergia, Hospital Médica Sur, Ciudad de México, Mexico; 20Pulmonary, Critical Care, Allergy, and Immunologic Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; 21Department of Respiratory Medicine, Hospital Universitario Lucus Augusti, Lugo, Spain; 22Allergy Clinic, Department of Dermato-Allergology, Gentofte Hospital, Copenhagen, Denmark; 23University Hospital of Aarhus, Aarhus, Denmark; 24University of Leicester, Department of Respiratory Sciences & NIHR Leicester Biomedical Research Centre (Respiratory Theme), Leicester, UK; 25AstraZeneca, Cambridge, UK; 26Department of Respiratory Medicine, Copenhagen University Hospital-Hvidovre, Hvidovre, Denmark; 27Diamantina Institute & PA-Southside Clinical Unit, The University of Queensland, Brisbane, Australia; 28Division of Allergy & Clinical Immunology, Department of Medicine, National Jewish Health, Denver, CO, USA; 29Division of Allergy & Clinical Immunology, Department of Internal Medicine, University of Colorado School of Medicine, Aurora, CO, USA; 30Optimum Patient Care, Cambridge, UK; 31Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UKCorrespondence: David B PriceObservational and Pragmatic Research Institute, 22 Sin Ming Lane, #06 Midview City, Singapore, 573969 Tel +65 3105 1489Email dprice@opri.sgIntroduction: International registries provide opportunities to describe use of biologics for treating severe asthma in current clinical practice. Our aims were to describe real-life global patterns of biologic use (continuation, switches, and discontinuations) for severe asthma, elucidate reasons underlying these patterns, and examine associated patient-level factors.Methods: This was a historical cohort study including adults with severe asthma enrolled into the International Severe Asthma Registry (ISAR; http://isaregistries.org, 2015– 2020) or the CHRONICLE Study (2018– 2020) and treated with a biologic. Eleven countries were included (Bulgaria, Canada, Denmark, Greece, Italy, Japan, Kuwait, South Korea, Spain, UK, and USA). Biologic utilization patterns were defined: 1) continuing initial biologic; 2) stopping biologic treatment; or 3) switching to another biologic. Reasons for discontinuation/switching were recorded and comparisons drawn between groups.Results: A total of 3531 patients were included. Omalizumab was the most common initial biologic in 2015 (88.2%) and benralizumab in 2019 (29.6%). Most patients (79%; 2791/3531) continued their first biologic; 10.2% (356/3531) stopped; 10.8% (384/3531) switched. The most frequent first switch was from omalizumab to an anti–IL-5/5R (49.6%; 187/377). The most common subsequent switch was from one anti–IL-5/5R to another (44.4%; 20/45). Insufficient efficacy and/or adverse effects were the most frequent reasons for stopping/switching. Patients who stopped/switched were more likely to have a higher baseline blood eosinophil count and exacerbation rate, lower lung function, and greater health care resource utilization.Conclusion: The description of real-life patterns of continuing, stopping, or switching biologics enhances our understanding of global biologic use. Prospective studies involving structured switching criteria could ascertain optimal strategies to identify patients who may benefit from switching.Keywords: severe asthma, biologics, prescribing, cohort study, management, international

Background: Biological therapies for severe asthma have been demonstrated to effectively reduce exacerbations, by approximately 50-60% in RCTs. From clinical experience, some patients may experience complete resolution of exacerbations. However, the proportion of complete responders in a real-life setting has not been reported. Methods: The Danish Severe Asthma Register (DSAR) is a nationwide register of all Danish patients commenced on biological therapy. We identified all patients who had received at least one year of treatment with either omalizumab, mepolizumab, benralizumab, or reslizumab, and assessed the proportion of patients without exacerbations during the first year of treatment. Results: There were 97 patients followed for at least one year treated with omalizumab (n=16), mepolizumab (n=69), benralizumab (n=8), or reslizumab (n=4). These patients experienced a median number of exacerbations of 3 (1-5) in the previous 12 months before start of biological treatment. After one year, 61 (63%) patients had had no exacerbations on biological therapy. The proportion of patients without exacerbations was 67%, 65%, 67%, and 25% for omalizumab, mepolizumab, benralizumab, and reslizumab, respectively. Conclusion: More than half of patients treated with biologics for severe asthma had no exacerbations during the first year of treatment. The potential for down-titration of treatment should be explored in this group.

Background Airway hyperresponsiveness (AHR) is an indicator of poor asthma control. Asthma patients with AHR to methacholine have been shown to have a poorer quality of life compared with asthma patients without AHR, but it is not clear to what degree this is a result of more severe disease in patients with AHR. Objectives To describe the relationship between AHR and quality of life in asthma patients and to determine the impact of the severity of asthma on this relationship. Methods Data from 691 asthma patients were analyzed to describe the relationship between the impact of AHR to methacholine (cumulative dose of methacholine required to provoke a 20% decrease in forced expiratory volume in 1 second, ≤8 μmol) on quality of life (measured by the Asthma Quality of Life Questionnaire) of asthma patients in relation to the severity of asthma (according to the Global Initiative for Asthma guidelines). Results Asthma patients with AHR had more severe asthma and a poorer quality of life compared with asthma patients without AHR. Furthermore, the quality of life decreased with increasing severity of asthma. However, regression analysis showed an independent association between both the presence of AHR and the severity of asthma and quality of life, as well as an interaction between the effects of these 2 factors. Finally, subgroup analysis showed that the impact of AHR on the quality of life was only clinically significant in moderate to severe asthma but not in mild asthma. Conclusions AHR is associated with a negative impact on the quality of life of asthma patients that is partly independent of the severity of asthma.

Background : Studies have shown a relationship between asthma, serum YKL-40, and the single nucleotide polymorphism (SNP) (−131 C/G, rs4950928) in the CHI3L1 gene that codes for YKL-40. However, the findings differ. We studied the relationship between clinical asthma phenotypes, serum YKL-40, and SNP (−131 C/G, rs4950928). Methods : In this study, 1,137 patients with asthma, 415 with rhinitis only, and 275 non-asthmatic controls were included. Assessment included a clinical interview concerning the diagnosis of asthma, severity of asthma, and asthma treatment as well as clinical tests to assess asthma and rhinitis. Serum YKL-40 was measured, and genotyping for the SNP (−131 C/G) was conducted. Results : No significant difference in the serum concentration of YKL-40 was found between patients with asthma, patients with rhinitis, and non-asthmatic controls; however, YKL-40 was increased in patients with severe asthma. No association was found between the SNP (−131 C/G rs4950982) and the risk of having asthma (odds ratio = 0.90, p =0.4). Higher levels of serum YKL-40 were found in all subjects when comparing CC genotype to CG and GG genotypes (45 µg/L vs. 32 µg/L and 19 µg/L, p

Experience from other fields of internal medicine shows that Internet-based technology can be used to monitor various diseases. The new technology handles complex calculation programs easily, and it is a unique way of communicating. These advantages might be used in optimizing the treatment for asthmatic subjects because undertreatment is a common problem found in European asthmatic subjects.We sought to investigate the outcome of monitoring and treatment using a physician-managed online interactive asthma monitoring tool and to assess whether the outcome differs from that of monitoring and treatment in an outpatient respiratory clinic or in primary care.Three hundred asthmatic subjects were randomized to 3 parallel groups in a 6-month prospective study: (1) Internet-based monitoring (n = 100); (2) specialist monitoring (n = 100); and (3) general practitioner (GP) monitoring (n = 100). All the patients were examined on entry into the study and after 6 months of treatment.The treatment and monitoring with the Internet-based management tool lead to significantly better improvement in the Internet group than in the other 2 groups regarding asthma symptoms (Internet vs specialist: odds ratio of 2.64, P = .002; Internet vs GP: odds ratio of 3.26; P.001), quality of life (Internet vs specialist: odds ratio of 2.21, P = .03; Internet vs GP: odds ratio of 2.10, P = .04), lung function (Internet vs specialist: odds ratio of 3.26, P = .002; Internet vs GP: odds ratio of 4.86, P.001), and airway responsiveness (Internet vs GP: odds ratio of 3.06, P = .02).When physicians and patients used an interactive Internet-based asthma monitoring tool, better asthma control was achieved.

The frequency of smokers among asthma patients often mirrors the frequency of smokers among healthy individuals. Smoking has been shown to increase the lung function decline in adult asthma patients and change the composition of the bronchial inflammation.To examine the consequences of smoking in a large cohort of young asthma patients.Seven hundred ninety-three asthma patients, aged 14 to 44, were examined using lung function measurements, bronchial provocations, clinical interviews, and questionnaires.Forty-five percent of participants were smokers; smokers had significantly lower forced expiratory volume in one second (FEV(1)), FEV(1) in percent of predicted value (FEV(1)% pred), and FEV(1)/forced vital capacity (FVC) values compared with nonsmokers, and there was a dose-response relationship between tobacco exposure and these lung function measures. Smoking seemingly affected the FEV(1) growth already in adolescence, and before the age of 45, significantly more smokers than nonsmokers had signs of airflow limitation, with FEV(1)/FVC ratios below 0.70. Smokers had more asthma symptoms despite receiving inhaled corticosteroid (ICS) treatment as frequently as did nonsmokers.The additive effect of smoking on lung function decline in asthma patients is detectable at early ages and leads to signs of airflow limitation before the age of 45 years.

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

Summary Background Bronchial provocation using methacholine, a cholinergic agonist, causes airway narrowing directly by contraction of bronchial smooth muscle. While methacholine has a high sensitivity for identifying airway hyper-responsiveness (AHR), it does not have a high specificity to diagnose asthma and false-positive responses may be observed in non-asthmatics. Mannitol is an osmotic stimulus that acts indirectly to cause airway narrowing by release of endogenous bronchoconstricting mediators. Objectives We tested the hypothesis that subjects with asymptomatic AHR to methacholine would not have AHR to mannitol. Methods Sixteen subjects with a methacholine PD20