Search

Background Phenotypic characteristics of patients with eosinophilic and noneosinophilic asthma are not well characterized in global, real-life severe asthma cohorts. Research Question What is the prevalence of eosinophilic and noneosinophilic phenotypes in the population with severe asthma, and can these phenotypes be differentiated by clinical and biomarker variables? Study Design and Methods This was an historical registry study. Adult patients with severe asthma and available blood eosinophil count (BEC) from 11 countries enrolled in the International Severe Asthma Registry (January 1, 2015-September 30, 2019) were categorized according to likelihood of eosinophilic phenotype using a predefined gradient eosinophilic algorithm based on highest BEC, long-term oral corticosteroid use, elevated fractional exhaled nitric oxide, nasal polyps, and adult-onset asthma. Demographic and clinical characteristics were defined at baseline (ie, 1 year before or closest to date of BEC). Results One thousand seven hundred sixteen patients with prospective data were included; 83.8% were identified as most likely (grade 3), 8.3% were identified as likely (grade 2), and 6.3% identified as least likely (grade 1) to have an eosinophilic phenotype, and 1.6% of patients showed a noneosinophilic phenotype (grade 0). Eosinophilic phenotype patients (ie, grades 2 or 3) showed later asthma onset (29.1 years vs 6.7 years; P Interpretation According to this multicomponent, consensus-driven, and evidence-based eosinophil gradient algorithm (using variables readily accessible in real life), the severe asthma eosinophilic phenotype was more prevalent than previously identified and was phenotypically distinct. This pragmatic gradient algorithm uses variables readily accessible in primary and specialist care, addressing inherent issues of phenotype heterogeneity and phenotype instability. Identification of treatable traits across phenotypes should improve therapeutic precision.

Trung N Tran,1 Marjan Kerkhof,2 Victoria Carter,3,4 David B Price3– 5 1Global Medicine Development, AstraZeneca, Gaithersburg, MD, USA; 2Mescio Research, Blauwestad, the Netherlands; 3Observational and Pragmatic Research Institute, Singapore; 4Optimum Patient Care, Cambridge, UK; 5Division of Applied Health Sciences, Centre of Academic Primary Care, University of Aberdeen, Aberdeen, UKCorrespondence: Trung N TranGlobal Medicine Development, AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USATel +1-301-398-5406Email trung.tran1@astrazeneca.comPurpose: Eosinophil count elevations are predictive of adverse outcomes in patients with asthma, yet little is known regarding longitudinal eosinophil patterns and their association with clinical outcomes. The goal of this study was to assess associations between longitudinal persistence of eosinophil elevations and both clinical outcomes and health care resource utilization (HCRU).Methods: Data were extracted from 2 databases in the United Kingdom. Patients included were aged ≥ 13 years, had active asthma, and had ≥ 3 blood eosinophil count (BEC) recordings. Patients were categorized by BEC as: never high (all BEC ≤ 300 cells/μL), intermittently high (≥ 1 BEC > 300 cells/μL but < 75% of BEC > 300 cells/μL), or persistently high (≥ 75% of BEC > 300 cells/μL). Asthma exacerbations, asthma control (risk domain, overall, and full), and HCRU were evaluated for 12 months after the last BEC.Results: The study population comprised 148,021 patients. Persistently high, intermittently high, and never high eosinophil patterns were detected in 13.6%, 40.5%, and 45.9% of patients, respectively. Patients with ≥ 1 elevated BEC were at greater risk for severe asthma exacerbations, regardless of whether the elevation was persistent (rate ratio [RR]: 1.28 [95% CI 1.24– 1.33]; P < 0.001) or intermittent (RR: 1.24 [95% CI 1.21– 1.27]; P < 0.001), compared with patients with no eosinophil elevations. Full asthma control was achieved by < 25% of patients across eosinophil pattern groups, and HCRU did not appreciably differ, although patients with persistently high BEC had the shortest hospital stay duration among the groups.Conclusion: These data suggest that elevated blood eosinophils, regardless of persistency, signify increased risk of severe asthma exacerbations.Keywords: asthma control, asthma exacerbation, biomarker, eosinophilia, phenotype, type 2 inflammation

Introduction Early identification of preventable risk factors of COPD progression is important. Whether exacerbations have a negative impact on disease progression is largely unknown. We investigated whether the long-term occurrence of exacerbations is associated with lung function decline at early stages of COPD. Methods Patients diagnosed with mild/moderate COPD (obstruction and FEV1% predicted 50-90%), aged ≥35 years, and a smoking history, who had ≥6 years of UK electronic medical records after initiation of maintenance therapy were studied. Multilevel mixed-effect linear regression was performed to determine the association between the count of any year in which the patient had ≥1 exacerbation over a 6-year period and FEV1 decline, adjusted for sex, age, anthropometrics and smoking habits. Exacerbations were defined as any prescription for an acute oral corticosteroid course and/or lower respiratory-related antibiotics and/or any COPD-related emergency or inpatient hospitalization. Results Of 11,337 patients included (mean age 65 years; 49% female) 31.6%, 23.3%, 16.6%, 11.6%, 8.1%, 5.3% and 3.4% had 0, 1, 2, 3, 4, 5 and 6 years with ≥1 exacerbation. The mean annual FEV1 decline accelerated by 1.50 mL/year (95% Confidence Interval 1.02; 1.98) with every additional year with ≥1 exacerbation from 31.0 mL/year in subjects without any exacerbation to 40.0 mL/year in patients experiencing ≥1 exacerbation every year. Patients with more years with ≥1 exacerbation had a lower mean FEV1 at first diagnosis: 14.7 mL (11.7; 17.8) lower with every additional year with exacerbations. When counting years with ≥2 exacerbations, greater effects were observed (2.19 [1.50; 2.88] mL/year excess decline per year with ≥2 exacerbations; 16.5 mL [12.1; 20.8] lower FEV1 at diagnosis). Conclusion Patients who experienced a greater exacerbation burden after initiation of maintenance therapy had worse lung function at diagnosis and a more rapid lung function decline thereafter, which emphasizes the need for better treatment strategies.

BackgroundLittle is known about the impact of exacerbations on COPD progression or whether inhaled corticosteroid (ICS) use and blood eosinophil count (BEC) affect progression. We aimed to assess this in a prospective observational study.MethodsThe study population included patients with mild to moderate COPD, aged ≥35 years, with a smoking history, who were followed up for ≥3 years from first to last spirometry recording using two large UK electronic medical record databases: Clinical Practice Research Datalink (CPRD) and Optimum Patient Care Research Database (OPCRD). Multilevel mixed-effects linear regression models were used to determine the relationship between annual exacerbation rate following initiation of therapy (ICS vs non-ICS) and FEV1decline. Effect modification by blood eosinophils was studied through interaction terms.ResultsOf 12178 patients included (mean age 66 years; 48% female), 8981 (74%) received ICS. In patients with BEC ≥350 cells/µL not on ICS, each exacerbation was associated with subsequent acceleration of FEV1decline of 19.4 mL/year (95% CI 12.0 to 26.7, pConclusionExacerbations are associated with a more rapid loss of lung function among COPD patients with elevated blood eosinophils, defined as ≥350 cells/µL, not treated with ICS. More aggressive prevention of exacerbations using ICS in such patients may prevent excess loss of lung function.

Background Although systemic corticosteroid (SCS) treatment, irrespective of duration or dosage, is associated with adverse outcomes for patients with asthma, the longitudinal effects of this treatment on adverse outcomes, healthcare resource utilization (HCRU), and healthcare costs are unknown. Methods We identified patients initiating intermittent or long‐term SCS who were diagnosed with active asthma from UK general practice with linked secondary care data. Control (non‐SCS) patients were matched by sex and index date with those initiating SCS. Minimum baseline period was 1 year prior to index date; minimum follow‐up duration was 2 years post–index date. Cumulative incidence of SCS‐associated adverse outcomes and associated HCRU and costs were compared between SCS and non‐SCS patient groups and among average SCS daily exposure categories. Associations between exposure and annualized HCRU and costs were assessed, adjusted for confounders. Results Analyses included 9413 matched pairs. Median (interquartile range) follow up was as follows: SCS group: 7.1 (4.1‐11.8) years; control group: 6.4 (3.8‐10.0) years. Greater SCS dosages were correlated with greater cumulative incidence. For example, patients with type 2 diabetes receiving an average daily dosage of ≥7.5 mg had a 15‐year cumulative incidence (37.5%) that was 1.5‐5 times greater than those receiving lower dosages. HCRU and costs increased annually for SCS patients but not for non‐SCS patients. Increases in all‐cause adverse outcome (excluding asthma)–associated HCRU and costs were dose‐dependent. Conclusions Over the long term, adverse outcomes associated with SCS initiation were relatively frequent and costly, with a positive dosage–response relationship with SCS exposure.

BackgroundWe developed an eosinophil phenotype gradient algorithm and applied it to a large severe asthma cohort (International Severe Asthma Registry).ObjectiveWe sought to reapply this algorithm in a UK primary care asthma cohort, quantify the eosinophilic phenotype, and assess the relationship between the likelihood of an eosinophilic phenotype and asthma severity/health care resource use (HCRU).MethodsPatients age 13 years and older with active asthma and blood eosinophil count or 1 or greater, who were included from the Optimum Patient Care Research Database and the Clinical Practice Research Datalink, were categorized according to the likelihood of eosinophilic phenotype using the International Severe Asthma Registry gradient eosinophilic algorithm. Patient demographic, clinical and HCRU characteristics were described for each phenotype.ResultsOf 241,006 patients, 50.3%, 22.2%, and 21.9% most likely (grade 3), likely (grade 2), and least likely (grade 1), respectively, had an eosinophilic phenotype, and 5.6% had a noneosinophilic phenotype (grade 0). Compared with patients with noneosinophilic asthma, those most likely to have an eosinophilic phenotype tended to have more comorbidities (percentage with Charlson comorbidity index of ≥2: 28.2% vs 6.9%) and experienced more asthma attacks (percentage with one or more attack: 24.8% vs 15.3%). These patients were also more likely to have asthma that was difficult to treat (31.1% vs 18.3%), to receive more intensive treatment (percentage on Global Initiative for Asthma 2020 step 4 or 5: 44.2% vs 27.5%), and greater HCRU (eg, 10.8 vs 7.9 general practitioner all-cause consultations per year).ConclusionsThe eosinophilic asthma phenotype predominates in primary care and is associated with greater asthma severity and HCRU. These patients may benefit from earlier and targeted asthma therapy.

Jaco Voorham,1,2 Simonetta Baldi,3 Luigi Santoro,4 Marjan Kerkhof,1,5 Marco Contoli,6 Leonardo M Fabbri,6 Huib AM Kerstjens,7 Jose Luis López-Campos,8 Nicolas Roche,9 Dave Singh,10 Claus F Vogelmeier,11 David B Price1,12 1Observational & Pragmatic Research Institute Pte Ltd, Singapore, Singapore; 2Data to Insights Research Solutions, Lisbon, Portugal; 3Department of Global Clinical Development, Chiesi SAS, Bois Colombes Cedex, France; 4Department of Global Clinical Development, Chiesi Farmaceutici S.p.A, Parma, Italy; 5Mescio Research, Blauwestad, The Netherlands; 6Section of Respiratory Medicine, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy; 7Department of Pulmonary Diseases, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands; 8Respiratory Diseases Unit, University Hospital Virgen Del Rocío, Seville, Spain; 9Service de Pneumologie, Hôpital Cochin, APHP, Centre-Université de Paris, Paris, France; 10University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK; 11Department of Internal Medicine, Pulmonary and Critical Care Medicine, University of Marburg, Member of the German Centre for Lung Research (DZL), Marburg, Germany; 12Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UKCorrespondence: David B PriceAcademic Primary Care, Division of Applied Health Sciences University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD 198785, UKTel +65 6962 3627Email dprice@opri.sgPurpose: This study aimed to evaluate the non-inferiority of initiating extrafine beclometasone dipropionate/formoterol fumarate (BDP/FF) versus double bronchodilation (long-acting beta-agonists [LABA]/long-acting muscarinic antagonists [LAMA]) among patients with a history of chronic obstructive pulmonary disease (COPD) exacerbations.Patients and Methods: A historical cohort study was conducted using data from the UK’s Optimum Patient Care Research Database. Patients with COPD ≥ 40 years at diagnosis were included if they initiated extrafine BDP/FF or any LABA/LAMA double therapy as a step-up from no maintenance therapy or monotherapy with inhaled corticosteroids (ICS), LAMA, or LABA and a history of ≥ 2 moderate/severe exacerbations in the previous two years. The primary outcome was exacerbation rate from therapy initiation until a relevant therapy change or end of follow-up. Secondary outcomes included rate of acute respiratory events, acute oral corticosteroids (OCS) courses, and antibiotic prescriptions with lower respiratory indication, modified Medical Research Council score (mMRC) ≥ 2, and time to first pneumonia diagnosis. The non-inferiority boundary was set at a relative difference of 15% on the ratio scale. Five potential treatment effect modifiers were investigated.Results: A total of 1735 patients initiated extrafine BDP/FF and 2450 patients initiated LABA/LAMA. The mean age was 70 years, 51% were male, 41% current smokers, and 85% had FEV1 < 80% predicted. Extrafine BDP/FF showed non-inferiority to LABA/LAMA for rate of exacerbations (incidence rate ratio [IRR] = 1.01 [95% CI 0.94– 1.09]), acute respiratory events (IRR = 0.98 [0.92– 1.04]), acute OCS courses (IRR = 1.01 [0.91– 1.11]), and antibiotic prescriptions (IRR = 0.99 [0.90– 1.09]), but not for mMRC (OR = 0.93 [0.69– 1.27]) or risk of pneumonia (HR = 0.50 [0.14– 1.73]). None of the a priori defined effect modifier candidates affected the comparative effectiveness.Conclusion: This study found that stepping up to extrafine BDP/FF from no maintenance or monotherapy was not inferior to stepping up to double bronchodilation therapy in patients with a history of exacerbations.Keywords: real-world, electronic health records, observational, comparative effectiveness, heterogeneity, chronic obstructive pulmonary disease

Introduction: Asthma is clinically heterogeneous. Recognition of eosinophilic phenotypes within a real-world asthma population is important for moving towards more personalised management. Objectives: To determine the prevalence and clinical characteristics of eosinophilic asthma based on the presence of clinical features of the eosinophilic phenotype. Methods: Asthma patients aged ≥13 years with ≥1 blood eosinophil count (BEC) recorded in the Optimum Patient Care Research Database were classified using a pre-defined algorithm developed by an expert panel defining 4 grades of likelihood of eosinophilic asthma based on the highest BEC ever, presence of late onset asthma, nasal polyps ever, or treatment with anti–IL-5 or maintenance oral corticosteroids (OCS) (Figure). FeNO was omitted given its limited availability. Age-standardised characteristics in the last year were described. Results: Of 152,943 patients (mean age 54 years; 37% men), 53% were classified as “most likely”; 22% as “likely”; 21% as “less likely”, and 5% as “unlikely” eosinophilic. Of these 4 groups, the “most likely” group had the highest proportions with comorbidities, exacerbations, and “difficult-to-treat asthma” (31%; GINA 2019 Step 4/5). Results were similar within the subgroup with “difficult-to-treat asthma”. Conclusions: Based on the proposed algorithm, most asthma patients had a high likelihood of eosinophilic asthma, which was associated with more severe asthma than a lower likelihood.

We examined associations between blood eosinophil counts (BEC) and risk of treatment failure or hospital readmission following acute oral corticosteroid (OCS)-treated COPD exacerbations. We conducted studies from the Optimum Patient Care Research Database (OPCRD) (www.optimumpatientcare.org/opcrd) and Clinical Practice Research Datalink (CPRD) (www.cprd.com/home/), validated databases for medical research, with linked Hospital Episode Statistics (HES) data for ∼20 000 COPD patients aged ≥40 years. For patients with OCS-treated COPD exacerbations treated in primary care, with BECs recorded on first day of OCS treatment (Cohort 1), we assessed treatment failure (COPD-related hospitalisations and OCS prescriptions beyond index OCS course). For patients hospitalised for COPD exacerbations, with BEC measured over an exacerbation-free period during the year prior to admission (Cohort 2), we assessed readmission rate. Cox proportional hazards regression analysis was adjusted for confounders to estimate the association between BEC and treatment outcomes. Of patients treated with OCS for COPD exacerbations in primary care (Cohort 1), 44% experienced treatment failure following single OCS courses, and 10% (255/2482) were hospitalised for ≤6 weeks. Greater BEC was associated with reduced hospital-admission risk (hazard ratio [HR]=0.26; 95% CI: 0.12–0.56, per 100 cells·µL−1 increase). BEC increases of ≥200 cells·µL−1 from exacerbation-free periods to exacerbations were associated with least hospitalisation risk (HR=0.32; 95% CI: 0.15–0.71) versus no BEC change. For patients hospitalised for COPD exacerbations (Cohort 2), 4-week hospital readmission was 12% (1189/10 245). BEC increases during an exacerbation-free period within the past year were associated with reduced risk of short-term readmission (HR=0.78; 95% CI: 0.63–0.96). Greater BEC predicted better outcomes for patients with OCS-treated COPD exacerbations, whether community or hospital managed. Eosinopenia predicted worse outcomes., Patients who have greater blood eosinophil counts during #AECOPD in the last year have lesser hospitalisation risk, enhanced OCS response and better response to OCS upon hospitalisation, as reflected by reduced readmissions https://bit.ly/2ZQIV1n

Background: DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma. Methods: We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4–5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4–16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2–56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1–79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting. Findings: 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p

BackgroundLittle is known about the prevalence of severe, uncontrolled eosinophilic asthma (SUEA) and associated costs.AimsWe sought to determine the prevalence of SUEA and compare asthma-related healthcare resource use (HCRU) and associated costs with overall means for a general asthma population.MethodsThis cohort study evaluated anonymised medical record data (December 1989 through June 2015) from the Clinical Practice Research Datalink and the Optimum Patient Care Research Database to study UK patients with active asthma (diagnostic code and one or more drug prescriptions in the baseline year), aged 5 years and older, without concomitant COPD, and with recorded eosinophil count. SUEA was defined as two or more asthma attacks during 1 baseline year preceding a high blood eosinophil count (≥0.3×109/L) for patients prescribed long-acting β2-agonist (LABA) and high-dosage inhaled corticosteroids (ICS) during baseline plus 1 follow-up year. We compared asthma-related HCRU and associated direct costs (2015 pounds sterling, £) during the follow-up year for SUEA versus the general asthma population.ResultsOf 363 558 patients with active asthma and recorded eosinophil count, 64% were women, mean (SD) age was 49 (21) years; 43% had high eosinophil counts, 7% had two or more attacks in the baseline year and 10% were prescribed high-dosage ICS/LABA for 2 study years. Overall, 2940 (0.81%; 95% CI 0.78% to 0.84%) patients had SUEA. Total mean per-patient HCRU and associated costs were four times greater for SUEA versus all patients (HCRU and cost ratios 3.9; 95% CI 3.7 to 4.1).ConclusionsLess than 1% of patients in a general asthma population had SUEA. These patients accounted for substantially greater asthma-related HCRU and costs than average patients with asthma.

Introduction: It is unknown whether exacerbations affect COPD progression under maintenance therapy. Objective: To study whether the association between COPD exacerbations and FEV1 decline depends on the therapy level and the blood eosinophil count (BEC) in a real-life setting. Methods: Patients diagnosed early with COPD (FEV1 % predicted 50-90), ≥35 years and a smoking history were followed for ≥3 years using data from the UK Optimum Patient Care Research Database and Clinical Practice Research Datalink. Multilevel linear regression models were used to analyse effects of the mean annual exacerbation rate after starting the highest maintenance therapy on FEV1 decline stratified by therapy level. Effect modification by BEC (± 2 years) was studied through interaction terms. Results: Of 12,178 patients included, 8,981 (74%) received inhaled corticosteroids (ICS). Overall, each exacerbation/year increase was associated with 5.6 ml/year extra decline (95%CI: 4.9;6.4). The largest effect was found in patients not receiving ICS with BEC ≥0.35x109/L (17%): 19.4 ml/year (12.0;26.7), significantly stronger than in patients with BEC 0.05-0.34x109/L (Figure). No effect of exacerbations under ICS therapy was found in those with BEC ≥0.45x109/L (11%): 1.0 ml/year (-2.5;4.5). Conclusion: Frequent exacerbators with high blood eosinophil counts show rapid COPD progression when not treated with ICS.

This real-world study compared the effectiveness of triple therapy (TT; long-acting muscarinic antagonists (LAMAs)/long-acting inhaled β-agonists (LABAs)/inhaled corticosteroids (ICSs)) versus dual bronchodilation (DB; LAMAs/LABAs) among patients with frequently exacerbating COPD. A matched historical cohort study was conducted using United Kingdom primary care data. Patients with COPD aged ≥40 years with a history of smoking were included if they initiated TT or DB from no maintenance/LAMA therapy and had two or more exacerbations in the preceding year. The primary outcome was time to first COPD exacerbation. Secondary outcomes included time to treatment failure, first acute respiratory event, and first acute oral corticosteroid (OCS) course. Potential treatment effect modifiers were investigated. In 1647 matched patients, initiation of TT reduced exacerbation risk (adjusted hazard ratio (HR) 0.87, 95% CI 0.76–0.99), risk of acute respiratory event (HR 0.74, 95% CI 0.66–0.84) and treatment failure (HR 0.83, 95% CI 0.73–0.95) compared with DB. Risk reduction for acute respiratory events was greater for patients with higher rates of previous exacerbations. At baseline blood eosinophil counts (BECs) ≥ 0.35×109 cells·L−1, TT was associated with lower risk of OCS prescriptions than DB. This study provides real-life evidence of TT being more effective in reducing exacerbation risk than DB, which became more accentuated with increasing BEC and previous exacerbation rate., In a real-world population of COPD patients with history of exacerbations, initiation of triple therapy was associated with a larger reduction in future risk of exacerbation, acute respiratory event, and treatment failure compared with dual bronchodilation http://bit.ly/2xA1Xut

Introduction and objectives Chronic obstructive pulmonary disease (COPD) is a costly condition. There is a need to identify patient characteristics associated with greater health care resource utilization and treatable traits. We compared COPD-related health care costs by treatment subgroups for UK patients with elevated blood eosinophil counts (BEC, defined as ≥0.45 ×109/L) who were at high risk of exacerbations (Global Initiative for Chronic Obstructive Lung Disease [GOLD] group C/D) with costs for low-risk patients (GOLD group A/B) with elevated BEC. Methods Data from the Clinical Practice Research Datalink with Hospital Episode Statistics linkage were used to evaluate the GOLD grade and therapy for patients in a year prior to stable disease and elevated BEC (defined in this study as ≥0.45 ×109/L). Mean total COPD-related costs for 2016 were compared during a follow-up year for four groups of patients with elevated BEC: GOLD group C/D receiving triple therapy (TT; inhaled corticosteroid [ICS]+long acting β2-agonist [LABA]+long acting muscarinic antagonist [LAMA]), dual therapy (DT; ICS +LABA, ICS +LAMA, or LABA +LAMA), or other therapy (single or no maintenance inhaler), and GOLD group A/B. Results Of 5046 patients with COPD and elevated BEC, 19% were GOLD group C/D receiving TT, 10% were GOLD group C/D receiving DT, 6% were GOLD group C/D receiving other therapy, and 64% were GOLD group A/B. Mean total COPD-related costs were three times as high for GOLD group C/D patients receiving TT as for GOLD group A/B patients, whereas costs for patients in GOLD group C/D in other therapy subgroups were not significantly greater than for those in GOLD group A/B (table 1). Conclusions Patients graded GOLD C/D with elevated BEC receiving TT accounted for three times greater COPD-related costs than patients with less severe disease. This points to an unmet need and potential opportunity for intervention to alleviate burden of disease for these patients. Please refer to page A267 for declarations of interest related to this abstract.

Introduction and objectives Elevated blood eosinophil count (BEC) is a proposed biomarker for risk of readmission for patients with COPD. We aimed to determine if preadmission BEC is an indicator of short-term hospital readmission for COPD exacerbation. Methods We analyzed 2 years of medical records data (Clinical Practice Research Datalink with Hospital Episode Statistics linkage historic database) from patients hospitalized for COPD exacerbation (ICD-10 codes J44.0 or J44.1). Patients were included if they had a BEC recorded during stable disease (no exacerbation 4 weeks prior to measurement) within 1 year prior to hospitalization discharge (index date). We analyzed the association between BEC and readmission risk within 4 weeks after index date, with adjustment for age, sex, smoking status, body mass index, and timing of BEC by Cox regression. We also assessed independent clinical predictors of short-term hospital readmission. Results Of 10 246 patients who met the inclusion criteria, 11.6% (n=1,189) were readmitted to hospital for COPD exacerbation within 4 weeks of discharge. Patients with very high BEC (≥0.65×109/L; 5.1%) had the lowest risk (figure 1), which was most accentuated in 53% of patients treated with oral corticosteroids in general practice in the baseline year (hazard ratio [95% confidence interval]=0.53 [0.34–0.81]). A very low BEC ( Conclusions Patients with BEC ≥0.65 × 109/L measured during stable disease state were at reduced risk of short-term readmission for COPD exacerbation, whereas those with eosinopenia were at increased risk, perhaps indicating poor treatment response. Clinical features beyond blood eosinophils may help identifying patients at risk of hospital readmission. Please refer to page A265 for declarations of interest related to this abstract.

MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10−16). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure. The BAMSE cohort was supported by The Swedish Research Council, The Swedish Heart-Lung Foundation, Freemason Child House Foundation in Stockholm, MeDALL (Mechanisms of the Development of ALLergy), a collaborative project conducted within the European Union (grant agreement No. 261357), Centre for Allergy Research, Stockholm County Council (ALF), Swedish foundation for strategic research (SSF, RBc08-0027, EpiGene project), the Strategic Research Programme (SFO) in Epidemiology at Karolinska Institutet, The Swedish Research Council Formas and the Swedish Environment Protection Agency.

David B Price,1,2 Frank Trudo,3 Jaco Voorham,1 Xiao Xu,4 Marjan Kerkhof,1 Joanna Ling Zhi Jie,1 Trung N Tran5 1Observational and Pragmatic Research Institute, Singapore, Singapore; 2Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 3Medical Affairs, AstraZeneca, Wilmington, DE, USA; 4Global Payer Evidence and Pricing, AstraZeneca, Gaithersburg, MD, USA; 5Medical Evidence and Observational Research, AstraZeneca, Gaithersburg, MD, USA Purpose: Prior work suggests a threshold of four courses/year of systemic corticosteroid (SCS) therapy is associated with adverse consequences. The objective of this study was to investigate the onset of adverse outcomes beginning at SCS initiation in a broad asthma population. Patients and methods: This historical matched cohort study utilized anonymized, longitudinal medical record data (1984–2017) of patients (≥18 years) with active asthma. Matched patients with first SCS prescription (SCS arm) and no SCS exposure (non-SCS arm) were followed until first outcome event. Associations between time-varying exposure measures and onset of 17 SCS-associated adverse outcomes were estimated using Cox proportional hazard regression, adjusting for confounders, in separate models. Results: We matched 24,117 pairs of patients with median record availability before SCS initiation of 9.9 and 8.7 years and median follow-up 7.4 and 6.4 years in SCS and non-SCS arms, respectively. Compared with patients in the non-SCS arm, patients prescribed SCS had significantly increased risk of osteoporosis/osteoporotic fracture (adjusted hazard ratio 3.11;95%CI1.87–5.19), pneumonia (2.68; 2.30–3.11), cardio-/cerebrovascular diseases (1.53;1.36–1.72), cataract (1.50;1.31–1.73), sleep apnea (1.40; 1.04–1.86), renal impairment (1.36; 1.26–1.47), depression/anxiety (1.31; 1.21–1.41), type 2 diabetes (1.26; 1.15–1.37), and weight gain (1.14; 1.10–1.18). A dose-response relationship for cumulative SCS exposure with most adverse outcomes began at cumulative exposures of 1.0–0&ndash

Purpose Acute COPD exacerbations account for much of the rising disability and costs associated with COPD, but data on predictive risk factors are limited. The goal of the current study was to develop a robust, clinically based model to predict frequent exacerbation risk. Patients and methods Patients identified from the Optimum Patient Care Research Database (OPCRD) with a diagnostic code for COPD and a forced expiratory volume in 1 second/forced vital capacity ratio

Introduction: Patients with COPD with high blood eosinophil counts (BEC) have an increased risk of exacerbations (Am J Respir Crit Care Med. 2011;184:662–71). Aims and Objectives: We aimed to evaluate the association between high BEC and exacerbation rates for different subgroups of patients with COPD, defined by treatment regimen and smoking status. Methods: We analyzed 2 years of medical records data for 42,142 patients with COPD (aged ≥40 y) receiving stable therapy, from the Optimum Patient Care Research Database. Patients’ baseline data came from the year before their most recent blood eosinophil counts, recorded at the time of no recent (≤4 weeks) exacerbation. Number of exacerbations was counted in a follow-up year. Negative binomial regression was used to estimate associations between high BEC (≥0.45 x 109/L) and exacerbation rate. Results: Associations were found for ex-smokers across all treatment regimens analyzed (table). Associations were significantly weaker for current smokers receiving short-acting bronchodilators (BD; 36%) or ICS/LABA (26%). Exclusion of patients with overlapping asthma (22%), or patients with poor adherence to ICS (55%; Medication Possession Ratio Conclusions: Patients with COPD and high BEC who are not current smokers had a greater frequency of exacerbations, regardless of treatment regimen or adherence.

Introduction: A United Kingdom study (Lancet Respir Med. 2015;3:849–58) demonstrated a greater risk of asthma exacerbations with high blood eosinophil counts (BEC).Aims and Objectives: We aimed to determine if patients hospitalized for asthma exacerbations were more likely to be readmitted if they had high BEC before admission.Methods: We analyzed 2 years of medical records data (Clinical Practice Research Datalink with Hospital Episode Statistics Linkage) from patients (aged ≥5 years) hospitalized for asthma who had BECs recorded within 1 year before admission. Patients were characterized in a baseline year, prior to the most recent first hospitalization for asthma (index date) occurring within 1 year after a BEC recording. We analyzed the association between high BEC (≥0.35 x 109/L) and readmission risk during 1 year of follow-up after index date, with adjustment for age, sex, smoking, and timing of most recent BEC as confounders.Results: A total of 835 of 2,613 patients with asthma (32%) had high BEC. In addition, 130 (55 with high BEC) patients were rehospitalized for asthma during the follow-up year. Patients with prior high BEC had a greater risk (6.6% vs. 4.2%; p=0.009) and a greater hazard ratio (HR: 1.45; 95% CI: 1.02−2.08; p=0.040) of readmission than those without high BEC. The association was strongest for nonsmokers (HR: 1.95; 95% CI: 1.16−3.31; p=0.013), compared with ex-smokers (HR: 1.52; 95% CI: 0.74−3.10; p=0.253) and with current smokers (HR: 0.97; 95% CI: 0.48–1.97; p=0.936).Conclusions: Patients with asthma and preadmission high BEC have a greater risk of rehospitalization for exacerbations.

Introduction: Patients with high blood eosinophil counts (BEC) may be at increased risk of asthma exacerbations (Lancet Respir Med. 2015;3:849–58).Aims and Objectives: We studied whether high BEC were associated with more asthma exacerbations in patients receiving medium- or high-dosage ICS.Methods: We analyzed 2 years of medical records data for 189,031 patients with asthma (aged ≥13 years) receiving stable ICS therapy, from the Clinical Practice Research Datalink and the Optimum Patient Care Research Database. Patients’ baseline data came from the year before their most recent blood eosinophil count. Number of exacerbations was counted in a follow-up year. Negative binomial regression was used to estimate the adjusted association between high BEC (≥0.35 x 109/L) and exacerbation rate.Results: 62,476 (33%) and 32,728 (17%) patients were receiving medium- or high-dosage ICS, respectively, and 26% in each group had high BEC. Nonsmokers receiving medium- or high-dosage ICS with high BEC had significantly greater exacerbation rates than those without high BEC (rate ratio: 1.36; 95% CI: 1.30–1.43). Associations were comparable for nonsmokers with high BEC whether they received medium- (1.37; 95% CI: 1.29−1.45) or high-dosage (1.32; 95% CI: 1.23−1.41) ICS. The association was significantly weaker in current smokers (1.15; 95% CI: 1.07−1.23) and ex-smokers (1.24; 95% CI: 1.18−1.31). Similar associations were found in patients with good adherence (Medication Possession Ratio ≥80%).Conclusions: Patients with asthma and high BEC have an increased risk of exacerbations despite medium- and high-dosage ICS treatment and good adherence.

Background\ud \ud Asthma attacks are common, serious, and costly. Individual factors associated with attacks, such as poor symptom control, are not robust predictors.\ud \ud Objective\ud \ud We investigated whether the rich data available in UK electronic medical records could identify patients at risk of recurrent attacks.\ud \ud Methods\ud \ud We analyzed anonymized, longitudinal medical records of 118,981 patients with actively treated asthma (ages 12-80 years) and 3 or more years of data. Potential risk factors during 1 baseline year were evaluated using univariable (simple) logistic regression for outcomes of 2 or more and 4 or more attacks during the following 2-year period. Predictors with significant univariable association (P < .05) were entered into multiple logistic regression analysis with backward stepwise selection of the model including all significant independent predictors. The predictive accuracy of the multivariable models was assessed.\ud \ud Results\ud \ud Independent predictors associated with future attacks included baseline-year markers of attacks (acute oral corticosteroid courses, emergency visits), more frequent reliever use and health care utilization, worse lung function, current smoking, blood eosinophilia, rhinitis, nasal polyps, eczema, gastroesophageal reflux disease, obesity, older age, and being female. The number of oral corticosteroid courses had the strongest association. The final cross-validated models incorporated 19 and 16 risk factors for 2 or more and 4 or more attacks over 2 years, respectively, with areas under the curve of 0.785 (95% CI, 0.780-0.789) and 0.867 (95% CI, 0.860-0.873), respectively.\ud \ud Conclusions\ud \ud Routinely collected data could be used proactively via automated searches to identify individuals at risk of recurrent asthma attacks. Further research is needed to assess the impact of such knowledge on clinical prognosis.

Blood eosinophil counts are a promising biomarker to guide therapy for chronic obstructive pulmonary disease (COPD). We examined the association between blood eosinophil counts in stable COPD and exacerbations in the following year in real-life patients, and assessed whether the relationship differs in specific patient subgroups. We conducted a historical follow-up study using anonymized medical records for patients ≥40 years with spirometrically confirmed COPD and a smoking history. We estimated the association between eosinophil counts and the number of exacerbations during 1 follow-up year, adjusted for confounders assessed in the preceding year. Of 8,318 patients with COPD (56% male; mean [SD] age 70 [10] years), 87.7% had eosinophil counts ranging from 0.05 to Elevated blood eosinophil counts may potentially serve as a biomarker of COPD exacerbation risk, yet only in some subgroups of COPD.

BACKGROUND: Childhood wheeze is an important, well-known risk factor for asthma, yet little is known about the contribution of nocturnal dry cough. We investigated the association of nocturnal dry cough at ages 1-7 years with doctor-diagnosed asthma at 8 years of age, both in the presence and absence of wheeze. METHODS: Data of 3,252 children from the PIAMA birth cohort were studied. Parents reported the presence of nocturnal dry cough, wheeze, and doctor-diagnosed asthma in the past 12 months yearly, from birth up to the age of 8 years. RESULTS: Nocturnal dry cough without wheeze was significantly associated with doctor-diagnosed asthma at age 8, except for age 1 (range of Relative Risks (RR) at ages 2-7: 1.8 (age 5) - 7.1 (age 7), all P-values

PurposeWe investigated the use of asthma medication by children and the association of use as recommended by guidelines with modifiable risk factors: parental attitudes, knowledge of asthma medication and information provided by health care providers. MethodsQuestionnaire data were obtained from parents of 229 8-year-old children participating in the prevention and incidence of asthma and mite allergy birth cohort who used asthma medication in the past 12months. They reported on their child's medication use, their own knowledge and attitudes towards the medication and their satisfaction with the information they received from health care providers. ResultsIrregular use of inhaled corticosteroids (ICS) was common: 40% of the parents only gave their child ICS when the child felt breathless and 52% only when the child needed it'; 15% of the parents tried to avoid giving medication, and about 25% of the parents sometimes discontinued medication. Parental knowledge of how asthma medication should be given was a major determinant of guideline-recommended use: Of the parents who knew that anti-inflammatory drugs should be taken everyday (53% of all parents), 84% reported that they actually gave their child the medicines everyday as compared with 25% of the parents who did not know this. Guideline-recommended use was also significantly associated with parental satisfaction with the amount of information received from health care providers. These associations were independent of maternal school education. ConclusionsOur findings suggest that substantial improvements in the use of asthma medication are feasible, and this could considerably improve the effectiveness of current asthma treatment. Copyright (c) 2014 John Wiley & Sons, Ltd.

Summary Background Eczema, rhinitis, and asthma often coexist (comorbidity) in children, but the proportion of comorbidity not attributable to either chance or the role of IgE sensitisation is unknown. We assessed these factors in children aged 4–8 years. Methods In this prospective cohort study, we assessed children from 12 ongoing European birth cohort studies participating in MeDALL (Mechanisms of the Development of ALLergy). We recorded current eczema, rhinitis, and asthma from questionnaires and serum-specific IgE to six allergens. Comorbidity of eczema, rhinitis, and asthma was defined as coexistence of two or three diseases in the same child. We estimated relative and absolute excess comorbidity by comparing observed and expected occurrence of diseases at 4 years and 8 years. We did a longitudinal analysis using log-linear models of the relation between disease at age 4 years and comorbidity at age 8 years. Findings We assessed 16 147 children aged 4 years and 11 080 aged 8 years in cross-sectional analyses. The absolute excess of any comorbidity was 1·6% for children aged 4 years and 2·2% for children aged 8 years; 44% of the observed comorbidity at age 4 years and 50·0% at age 8 years was not a result of chance. Children with comorbidities at 4 years had an increased risk of having comorbidity at 8 years. The relative risk of any cormorbidity at age 8 years ranged from 36·2 (95% CI 26·8–48·8) for children with rhinitis and eczema at age 4 years to 63·5 (95% CI 51·7–78·1) for children with asthma, rhinitis, and eczema at age 4 years. We did longitudinal assessment of 10 107 children with data at both ages. Children with comorbidities at 4 years without IgE sensitisation had higher relative risks of comorbidity at 8 years than did children who were sensitised to IgE. For children without comorbidity at age 4 years, 38% of the comorbidity at age 8 years was attributable to the presence of IgE sensitisation at age 4 years. Interpretation Coexistence of eczema, rhinitis, and asthma in the same child is more common than expected by chance alone—both in the presence and absence of IgE sensitisation—suggesting that these diseases share causal mechanisms. Although IgE sensitisation is independently associated with excess comorbidity of eczema, rhinitis, and asthma, its presence accounted only for 38% of comorbidity, suggesting that IgE sensitisation can no longer be considered the dominant causal mechanism of comorbidity for these diseases. Funding EU Seventh Framework Programme.

BackgroundGenomewide association studies (GWASs) of asthma have identified single-nucleotide polymorphisms (SNPs) that modestly increase the risk for asthma. This could be due to phenotypic heterogeneity of asthma. Bronchial hyperresponsiveness (BHR) is a phenotypic hallmark of asthma. We aim to identify susceptibility genes for asthma combined with BHR and analyse the presence of cis-eQTLs among replicated SNPs. Secondly, we compare the genetic association of SNPs previously associated with (doctor's diagnosed) asthma to our GWAS of asthma with BHR.MethodsA GWAS was performed in 920 asthmatics with BHR and 980 controls. Top SNPs of our GWAS were analysed in four replication cohorts, and lung cis-eQTL analysis was performed on replicated SNPs. We investigated association of SNPs previously associated with asthma in our data.ResultsA total of 368 SNPs were followed up for replication. Six SNPs in genes encoding ABI3BP, NAF1, MICA and the 17q21 locus replicated in one or more cohorts, with one locus (17q21) achieving genomewide significance after meta-analysis. Five of 6 replicated SNPs regulated 35 gene transcripts in whole lung. Eight of 20 asthma-associated SNPs from previous GWAS were significantly associated with asthma and BHR. Three SNPs, in IL-33 and GSDMB, showed larger effect sizes in our data compared to published literature.ConclusionsCombining GWAS with subsequent lung eQTL analysis revealed disease-associated SNPs regulating lung mRNA expression levels of potential new asthma genes. Adding BHR to the asthma definition does not lead to an overall larger genetic effect size than analysing (doctor's diagnosed) asthma.

Background A novel data-driven approach was used to identify wheezing phenotypes in pre-schoolchildren aged 0-8 years, in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort. Five phenotypes were identified: never/infrequent wheeze, transient early wheeze, intermediate onset wheeze, persistent wheeze and late onset wheeze. It is unknown which perinatal risk factors drive development of these phenotypes.Objective The objective of the study was to assess associations of perinatal factors with wheezing phenotypes and to identify possible targets for prevention.Methods In the PIAMA study (n = 3963), perinatal factors were collected at 3 months, and wheezing was assessed annually until the age of 8 years. Associations between perinatal risk factors and the five wheezing phenotypes were assessed using weighted multi-nomial logistic regression models. Odds ratios were adjusted for confounding variables and calculated with 'never/infrequent wheeze' as reference category.Results Complete data were available for 2728 children. Risk factors for transient early wheeze (n = 455) were male gender, maternal and paternal allergy, low maternal age, high maternal body mass index, short pregnancy duration, smoking during pregnancy, presence of older siblings and day-care attendance. Risk factors for persistent wheeze (n = 83) were male gender, maternal and paternal allergy, and not receiving breastfeeding for at least 12 weeks. Intermediate onset wheeze (n = 98) was associated with a lower birth weight and late onset wheeze (n = 45) with maternal allergy.Conclusion and Clinical Relevance We identified different risk factors for specific childhood wheezing phenotypes. Some of these are modifiable, such as maternal age and body mass index, smoking, day-care attendance and breastfeeding, and may be important targets for prevention programmes.

Background: Atopic dermatitis (AD) and food allergy frequently co-exist in children. Both immediate and late reactions have been reported after oral food challenge. The aim of this study was to investigate the reactions occurring in children with AD during double blind, placebo-controlled food challenges (DBPCFC). Also, the frequency of positive DBPCFCs in children reporting exacerbations of eczema as their only symptom to foods was studied. Method: Between 2001 and 2011, children underwent DBPCFCs for one or more suspected food allergies as part of regular care. The history relating to the suspected food was obtained. Children and/or parents were questioned about current AD. Immediate symptoms were defined as symptoms occurring during the challenge, or within 2 h after the last dose. Symptoms were considered 'intermediate' when they occurred between 2 and 6 h and 'late' between 6 and 48 h after the last challenge dose. McNemar's test was used to test for statistical differences between frequencies on verum and placebo days. Results: Of the 682 children undergoing DBPCFC, 381 children (55.9%) had a current history of AD, of which 317 had a history of reactions to foods and 64 had no known ingestion of the food previously. Immediate reactions consisting of exacerbations of AD only occurred rarely [two patients out of 326 (0.6%) on verum days vs one patient on a placebo day (0.3%), not significant (n.s.)]. Comparing verum to placebo days, immediate symptoms other than AD were seen more frequently (39.6% vs 8.0% respectively, P