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Background: The long-acting anticholinergic (LAMA) aclidinium was approved in Europe in 2012 to relieve symptoms in adults with chronic obstructive pulmonary disease (COPD). A Post-Authorisation Safety Study (PASS) was initiated to assess potential cardiovascular safety concerns for aclidinium., Objective: To estimate the adjusted incidence rate ratio (IRR) for hospitalisation for heart failure in patients with COPD who were new users of aclidinium, tiotropium, other LAMA, long-acting beta-agonists/inhaled corticosteroids (LABA/ICS), and LAMA/LABA were compared with initiators of LABA., Methods: This population-based cohort study included patients with COPD aged ≥40 years initiating COPD medications in the Clinical Practice Research Datalink (CPRD) GOLD in the United Kingdom from 2012 to 2017. Medications were identified via general practice prescriptions. The first-ever hospitalisations for heart failure were identified in the Hospital Episode Statistics, and general practitioner records from the CPRD. Poisson regression models were used to estimate the IRR for hospitalisation for heart failure in users of COPD medications versus LABA, adjusting for clinically relevant covariates., Results: The study included 4350 new users of aclidinium, 23,405 of tiotropium, 6977 of other LAMAs, 3122 of LAMA/LABA, 26,093 of LABA/ICS, and 5678 of LABA. Mean age was 69-70 years across medication groups. Aclidinium users had the highest proportion of severe COPD, and LABA users had the lowest (35% vs 19%, respectively). Crude incidence rates per 1000 person-years for the first-ever hospitalisation for heart failure ranged from 6.9 in LABA to 9.5 in aclidinium. Using LABA as reference, adjusted IRRs (95% confidence interval) for first-ever hospitalisation for heart failure were 0.90 (0.53-1.53) for aclidinium, 1.02 (0.69-1.51) for tiotropium, 0.86 (0.50-1.47) for other LAMAs, 1.09 (0.41-2.92) for LAMA/LABA, and 1.01 (0.69, 1.48) for LABA/ICS., Conclusion: The study did not find increased risks of hospitalisations for heart failure in new users of aclidinium, tiotropium, other LAMAs, LAMA/LABA, and LABA/ICS compared with LABA., Competing Interests: CR, EP, JA, NSM, SPG, and ERF are salaried employees of RTI Health Solutions, a nonprofit research organisation that conducts research with multiple pharmaceutical companies and has an independent right to publish the results of this study. AR is an employee of BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom. AL is an employee of BioPharmaceuticals R&D, AstraZeneca, Barcelona, Spain. SD is an employee of BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, United States. The authors report no other conflicts of interest in this work., (© 2021 Rebordosa et al.)

Purpose: To report and discuss estimated prevalence of potential off-label use and associated methodological challenges using a case study of dabigatran., Methods: Observational, cross-sectional study using 3 databases with different types of clinical information available: Cegedim Strategic Data Longitudinal Patient Database (CSD-LPD), France (cardiologist panel, n = 1706; general practitioner panel, n = 2813; primary care data); National Health Databases, Denmark (n = 28 619; hospital episodes and dispensed ambulatory medications); and Clinical Practice Research Datalink (CPRD), UK (linkable to Hospital Episode Statistics [HES], n = 2150; not linkable, n = 1285; primary care data plus hospital data for HES-linkable patients)., Study Period: August 2011 to August 2015. Two definitions were used to estimate potential off-label use: a broad definition of on-label prescribing using codes for disease indication (eg, atrial fibrillation [AF]), and a restrictive definition excluding patients with conditions for which dabigatran is not indicated (eg, valvular AF)., Results: Prevalence estimates under the broad definition ranged from 5.7% (CPRD-HES) to 34.0% (CSD-LPD) and, under the restrictive definition, from 17.4% (CPRD-HES) to 44.1% (CSD-LPD). For the majority of potential off-label users, no diagnosis potentially related to anticoagulant use was identified. Key methodological challenges were the limited availability of detailed clinical information, likely leading to overestimation of off-label use, and differences in the information available, which may explain the disparate prevalence estimates across data sources., Conclusions: Estimates of potential off-label use should be interpreted cautiously due to limitations in available information. In this context, CPRD HES-linkable estimates are likely to be the most accurate., (Copyright © 2018 John Wiley & Sons, Ltd.)

Background: For patients with asthma, COPD, or asthma-COPD overlap syndrome (ACOS), inter-country comparisons of seasonal changes in drug prescriptions are scarce or missing. Hence, we aimed to compare seasonal changes in prescription rates of long-acting beta-2-agonist (LABA) in four European countries., Methods: A common study protocol was applied to six health care databases (Germany, Spain, the Netherlands (2), and the UK (2)) to calculate age- and sex-standardized point prevalence rates (PPRs) of LABA-containing prescriptions by the 1st of March, June, September, and December of each year during the study period 2002-2009. Seasonal variation of PPRs was quantified using seasonal indexes (SIs; based on the ratio-to-moving-average-method) and SIs averaged over the study period (aSI) stratified by sex, age, and indication (asthma, COPD, or ACOS)., Results: There was a moderate seasonal change in LABA-containing prescriptions which was more pronounced in asthma or COPD patients compared to ACOS patients. For asthma and ACOS patients, highest seasonal variation was found for patients living in Spain (aSI: 87.3-110.7, aSI: 93.2-103.1) whereas for COPD highest seasonal variation was revealed for the NPCRD database (the Netherlands) (aSI: 92.2-105.6). Regarding age and sex, highest seasonal variation was found in Spanish boys under 10 years of age having a diagnosis of asthma., Conclusions: By applying a common analysis in six databases, we could observe moderate overall seasonal changes in LABA-containing prescription rates in patients with asthma, COPD, or ACOS., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: To study new onset of adult asthma in relation to dampness and moulds in dwelling places., Methods: Totally, 7104 young adults from 13 countries who participated in the European Community Respiratory Health Survey (ECRHS I and II) who did not report respiratory symptoms or asthma at baseline were followed prospectively for 9 years. Asthma was assessed by questionnaire data on asthmatic symptoms and a positive metacholine challenge test at follow-up. Data on the current dwelling was collected at the beginning and at the end of the follow-up period by means of an interviewer-led questionnaire, and by inspection. Relative risks (RR) for new onset asthma were calculated with log-binomial models adjusted for age, sex, smoking and study centre., Results: There was an excess of new asthma in subjects in homes with reports on water damage (RR 1.46; 95% CI 1.09 to 1.94) and indoor moulds (RR=1.30; 95% CI 1.00 to 1.68) at baseline. A dose-response effect was observed. The effect was stronger in those with multisensitisation and in those sensitised to moulds. Observed damp spots were related to new asthma (RR=1.49; 95% CI 1.00 to 2.22). The population-attributable risk was 3-10% for reported, and 3-14% for observed dampness/moulds., Conclusions: Dampness and mould are common in dwellings, and contribute to asthma incidence in adults.

Background: There are few longitudinal studies that have examined the association of lung function decline with indoor mould and dampness. Lung function decline in relation to dampness and mould in the home has studied in adults over a 9 year period., Methods: Spirometry was performed twice in participants in the European Respiratory Health Survey (ECRHS I and II) who were initially examined aged 20-45 years, in 1990-1995 and 9 years later (n=6443). Information on their current home was collected twice by interview. Dampness (water damage or damp spots) and indoor mould, ever and in the last 12 months, were assessed. A dampness score and a mould score were calculated. In addition, 3118 homes at 22 centres were inspected directly at follow-up for the presence of dampness and mould., Results: Dampness and mould were common. Overall, 50.1% reported any dampness and 41.3% any indoor mould in either ECRHS I or ECRHS II. Women with dampness at home had an additional decline in forced expiratory volume in 1 s (FEV(1)) of -2.25 ml/year (95% CI -4.25 to -0.25), with a significant trend in increased lung function decline in relation to the dampness score (p=0.03). The association in women was significant when excluding those with asthma at baseline. Observed damp spots in the bedroom was associated with a significant additional decline in FEV(1) of -7.43 ml/year (95% CI -13.11 to 1.74) in women., Conclusion: Dampness and indoor mould growth is common in dwellings, and the presence of damp is a risk factor for lung function decline, especially in women.

Rationale: hormonal and metabolic status appears to influence lung health in women, and there are findings suggesting that early menarche may be related to asthma, cardiovascular disease, diabetes, and breast cancer., Objectives: this study investigates whether age at menarche is related to adult lung function and asthma., Methods: among participants in the European Community Respiratory Health Survey II, 3,354 women aged 27-57 years from random population samples in 21 centers responded to a questionnaire concerning women's health (1998-2002). Of these women, 2,873 had lung function measurements, 2,136 had measurements of bronchial hyperreactivity, and 2,743 had IgE measurements. Logistic, linear, and negative binomial regression analyses included adjustment for age, height, body mass index, education, smoking, family size, and center., Measurements and Main Results: FEV(1) and FVC were lower and asthma was more common in women with early menarche. Women reporting menarche at age 10 years or less, as compared with women with menarche at age 13 years (reference category), had lower FEV(1) (adjusted difference, -113 ml; 95% confidence interval [CI], -196 to -33 ml) and FVC (-126 ml; 95% CI, -223 to -28 ml); also lower FEV(1) expressed as a percentage of the predicted value (-3.28%; 95% CI, -6.25 to -0.30%) and FVC expressed as a percentage of the predicted value (-3.63%; 95% CI, -6.64 to -0.62%). Women with early menarche more often had asthma symptoms (odds ratio, 1.80; 95% CI, 1.09-2.97), asthma with bronchial hyperreactivity (odds ratio, 2.79; 95% CI, 1.06-7.34), and higher asthma symptom score (mean ratio, 1.58; 95% CI, 1.12-2.21)., Conclusions: women with early menarche had lower lung function and more asthma in adulthood. This supports a role for metabolic and hormonal factors in women's respiratory health.

Background: Respiratory symptoms are common in the general population, and their presence is related to Health-related quality of life (HRQoL). The objective was to describe the association of respiratory symptoms with HRQoL in subjects with and without asthma or COPD and to investigate the role of atopy, bronchial hyperresponsiveness (BHR), and lung function in HRQoL., Methods: The European Community Respiratory Health Survey (ECRHS) I and II provided data on HRQoL, lung function, respiratory symptoms, asthma, atopy, and BHR from 6009 subjects. Generic HRQoL was assessed through the physical component summary (PCS) score and the mental component summary (MCS) score of the SF-36.Factor analyses and linear regressions adjusted for age, gender, smoking, occupation, BMI, comorbidity, and study centre were conducted., Results: Having breathlessness at rest in ECRHS II was associated with mean score (95% CI) impairment in PCS of -8.05 (-11.18, -4.93). Impairment in MCS score in subjects waking up with chest tightness was -4.02 (-5.51, -2.52). The magnitude of HRQoL impairment associated with respiratory symptoms was similar for subjects with and without asthma/COPD. Adjustments for atopy, BHR, and lung function did not explain the association of respiratory symptoms and HRQoL in subjects without asthma and/or COPD., Conclusion: Subjects with respiratory symptoms had poorer HRQoL; including subjects without a diagnosis of asthma or COPD. These findings suggest that respiratory symptoms in the absence of a medical diagnosis of asthma or COPD are by no means trivial, and that clarifying the nature and natural history of respiratory symptoms is a relevant challenge. Several community studies have estimated the prevalence of common respiratory symptoms like cough, dyspnoea, and wheeze in adults. Although the prevalence varies to a large degree between studies and geographical areas, respiratory symptoms are quite common. The prevalences of respiratory symptoms in the European Community Respiratory Health Study (ECRHS) varied from one percent to 35%. In fact, two studies have reported that more than half of the adult population suffers from one or more respiratory symptoms. Respiratory symptoms are important markers of the risk of having or developing disease. Respiratory symptoms have been shown to be predictors for lung function decline, asthma, and even all-cause mortality in a general population study . In patients with a known diagnosis of asthma or chronic obstructive pulmonary disease (COPD), respiratory symptoms are important determinants of reduced health related quality of life (HRQoL). The prevalence of respiratory symptoms exceeds the combined prevalences of asthma and COPD, and both asthma and COPD are frequently undiagnosed diseases. Thus, the high prevalence of respiratory symptoms may mirror undiagnosed and untreated disease.The common occurrence of respiratory symptoms calls for attention to how these symptoms affect health also in subjects with no diagnosis of obstructive airways disease. Impaired HRQoL in the presence of respiratory symptoms have been found in two population-based studies 619, but no study of respiratory symptoms and HRQoL have separate analyses for subjects with and without asthma and COPD, and no study provide information about extensive objective measurements of respiratory health. The ECRHS is a randomly sampled, multi-cultural, population based cohort study. The ECRHS included measurements of atopy, bronchial hyperresponsiveness (BHR), and lung function, and offers a unique opportunity to investigate how respiratory symptoms affect HRQoL among subjects both with and without obstructive lung disease.In the present paper we aimed to: 1) Describe the relationship between respiratory symptoms and HRQoL in an international adult general population and: 2) To assess whether this relationship varied with presence of asthma and/or COPD, or presence of objective functional markers like atopy and BHR.

Background: Diseases of the skin are important and often preventable conditions occurring among workers with dermal exposures to irritant and sensitizing agents., Objective: We conducted this analysis to assess the associations between metalworking exposures and current and persistent skin symptoms among male and female participants in two population-based epidemiologic studies., Methods: We pooled data from the European Community Respiratory Health Survey II (ECRHS II) and the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults 2 (SAPALDIA 2), two prospective cohort studies in Europe. Each participant completed interviewer-administered questionnaires to provide information about symptoms and exposures related to selected occupations, including metalworking, during the follow-up periods. We assessed associations between skin symptoms and the frequency of metalworking exposures among 676 ECRHS II/SAPALDIA 2 respondents., Results: Current skin symptoms were reported by 10% of metalworkers and were associated with frequent use, defined as four or more days per week, of oil-based metalworking fluids [prevalence ratio (PR): 1.76, 95% confidence interval (CI): 1.25-2.49)] and organic solvent/degreasing agents (PR: 2.06, 95% CI: 1.21-3.50)., Conclusions: Skin symptom prevalence is associated with increasing frequency of oil-based metalworking fluid and degreasing agent use. Our findings justify assessing strategies for reducing the frequency of metal-related exposures.

Unlabelled: Investigation of long-term effects of childhood pet exposure is usually based on retrospective information provided by adults, while there is little knowledge about the reliability in adult reporting of childhood events. We analyzed 8287 adults interviewed about childhood pets twice, on average nine years apart, in the European Community Respiratory Health Survey. Agreement between the surveys in reporting of childhood cats, dogs and birds were investigated with kappa statistics, and potential effects of disease status on agreement were analyzed with kappa statistics and multiple logistic regressions. Cats, dogs and birds in childhood were reported by 44, 41 and 38%, respectively. Cohen's kappa for agreement in adult reporting of childhood pets was 0.714 (95% CI=0.698-0.729) for cat, 0.709 (0.691-0.722) for dog, and 0.606 (0.591-0.626) for bird. Thus, agreement was significantly higher for reporting of cat and dog than for bird. Adult wheeze, asthma or atopy did not influence agreement. Neither did adult cat sensitization influence agreement in adult reporting of childhood cat. Childhood factors such as moving house <5 years, or growing up as a single child, in a large family or in a rural area, were associated with poorer agreement, while adult factors were unrelated to agreement., Practical Implications: Long-term reliability in adult reporting of childhood pets was substantial, and not influenced by disease status. Thus, collection of information about childhood pets from adults appears to be reliable for the purpose of studying adult allergic disease. Future studies should consider that the reliability was higher for a more important childhood event and influenced by childhood rather than adult characteristics. Imperfect reliability contributed to underestimation of the effects of pets on adult allergy; i.e. with a kappa of 0.71, a true odds ratio (OR) of 0.80 would be attenuated to 0.86. Future studies should account for non-differential misclassification error.

Objectives: Reported associations of self-employment with occupational injury and cerebrovascular disease suggest that worker safety and health precautions may vary by occupational status. The authors assessed the extent to which use of respiratory protection and ventilation equipment is associated with self-employed versus employee status among adults in an international study., Methods: The European Community Respiratory Health Survey II (ECRHS II) is a follow-up study conducted in a population-based random sample of adult ECRHS I participants. Men and women enrolled in the ECRHS II completed interviewer-administered questionnaires to provide information about their occupational status and job history during the 9-year ECRHS follow-up period. Respondents in selected occupational groups completed supplemental questionnaires about their jobs and use of respiratory protection and ventilation equipment on-the-job. The authors assessed self-reported use of respiratory and ventilation equipment among 72 self-employed and 371 employed adults in metalworking, soldering and welding occupations., Results: Local exhaust ventilation (fixed extraction: OR 0.37, 95% CI 0.17 to 0.80; mobile extraction: OR 0.23, 95% CI 0.09 to 0.60; on-tool extraction: OR 0.39, 95% CI 0.18 to 0.88) was reported less frequently among self-employed respondents than among employed respondents. The magnitude of the negative association between self-employment status and any of the three types of local exhaust ventilation was not attenuated by adjustment for duration of work per day or week or asthma and/or wheezing symptoms. Respiratory protection was not associated with employment status in these data., Conclusions: More limited use of local exhaust ventilation among self-employed workers compared to employees suggests the need to promote occupational safety among self-employed workers.

Objective: The rise in the prevalence of asthma in the second half of the 20th century has not been evenly distributed according to recent surveys. We assessed changes in the prevalence of asthma after a period of 9 to 10 years in a cohort of young adults in the Spanish arm of the European Community Respiratory Health Survey (ECRHS)., Material and Methods: The ECRHS-II is a multicenter cohort study taking place in 27 centers around Europe, with Spanish centers located in Albacete, Barcelona, Galdakao, Huelva, and Oviedo. The ECRHS questionnaire was administered to individuals who had participated in the first phase of the survey; spirometry and methacholine challenge tests were also performed according to the published protocol., Results: Among new smokers, the prevalence of wheezing in the last 12 months increased from 10% to 33%, while the frequency of phlegm production rose from 8% to 22% (P< .05). In ex-smokers, the prevalences of wheezing and phlegm production decreased from 21% to 12% and from 15% to 8%, respectively (P< .05). Symptom prevalences remained similar for never smokers, although the frequency of diagnosed asthma rose from 4% to 7% (P< .05). After adjusting for smoking, age, sex, and center, we found no significant differences in the frequency of symptoms or asthma, even when the phrase bronchial hyperreactivity was included in the definition. However, the rate of reported asthma rose annually by 0.34% (95% confidence interval [CI], 0.20%-0.48%), while diagnosed asthma rose by 0.26% (95% CI, 0.13%-0.39%) and treated asthma by 0.16% (95% CI, 0.07%-0.25%)., Conclusions: Increased prevalence rates of asthma diagnosis and treatment have been detected, but the rates of reported symptoms have remained similar, consistent with the assumption that more persons are being classified as asthmatics.

Objective: The authors examined the relations between self-reported work tasks, use of cleaning products and latex glove use with new-onset asthma among nurses and other healthcare workers in the European Community Respiratory Health Survey (ECRHS II)., Methods: In a random population sample of adults from 22 European sites, 332 participants reported working in nursing and other related healthcare jobs during the nine-year ECRHS II follow-up period and responded to a supplemental questionnaire about their principal work settings, occupational tasks, products used at work and respiratory symptoms. Poisson regression models with robust error variances were used to compare the risk of new-onset asthma among healthcare workers with each exposure to that of respondents who reported professional or administrative occupations during the entire follow-up period (n = 2481)., Results: Twenty (6%) healthcare workers and 131 (5%) members of the referent population reported new-onset asthma. Compared to the referent group, the authors observed increased risks among hospital technicians (RR 4.63; 95% CI 1.87 to 11.5) and among those using ammonia and/or bleach at work (RR 2.16; 95% CI 1.03 to 4.53)., Conclusions: In the ECRHS II cohort, hospital technicians and other healthcare workers experience increased risks of new-onset current asthma, possibly due to specific products used at work.

The present study investigated the relationship between socioeconomic status, using measures of occupational class and education level, and the prevalence and incidence of asthma (with and without atopy) and chronic bronchitis using data from the European Community Respiratory Health Survey (ECRHS). Asthma and chronic bronchitis were studied prospectively within the ECRHS (n = 9,023). Incidence analyses comprised subjects with no history of asthma or bronchitis at baseline. Asthma symptoms were also assessed as a continuous score. Bronchitis risk was associated with low educational level (prevalence odds ratio (POR) 1.9; 95% confidence interval (CI) 1.4-2.8) and occupational class (1.8; 1.2-2.7). Incident bronchitis also increased with low educational level (risk ratio (RR) 2.8; 95%CI 1.5-5.4). Prevalent and incident asthma with no atopy were associated with low educational level. Subjects in the low occupational class (incident risk ratio (IRR) 1.4; 95%CI 1.2-1.7) and education group (IRR 1.3; 95% CI 1.1-1.6) had higher mean asthma scores than those in higher socioeconomic groups. Lower educational level was associated with increased risk of prevalent and incident chronic bronchitis and asthma with no atopy. Lower socioeconomic groups tended to have a higher prevalence and incidence of asthma, particularly higher mean asthma scores. Adjustment for variables associated with asthma and bronchitis explained little of the observed health differences by socioeconomic status.

Background: Several studies in European homes have described allergen levels from the house dust mite species Dermatophagoides pteronyssinus and to a lesser extent Dermatophagoides farinae, but geographic comparisons of exposure levels and risk factors have been hampered by a lack of standardized methods., Objective: To study the distribution and determinants of the major house dust mite allergens Der p 1 and Der f 1 in 10 European countries using a common protocol., Methods: During home visits with 3580 participants of the European Community Respiratory Health Survey II from 22 study centers, mattress dust was sampled and analyzed for Der p 1, Der f 1, and Der 2 allergen. Information on housing characteristics was obtained by both observations and interview., Results: Der 1 and Der 2 allergens were detectable (>/=0.1 mug/g) in 68% and 53% of the samples, respectively. Large differences in allergen levels between study centers were observed, and geographic patterns for Der p 1 and Der f 1 were different. Low winter temperatures reduced Der p 1 rather than Der f 1. Important risk factors for high allergen levels included an older mattress, a lower floor level of the bedroom, limited ventilation of the bedroom, and dampness for Der p 1 but not for Der f 1., Conclusion: There are large qualitative and quantitative differences of house dust mite allergen levels in Europe, which can partly be explained by geographic and housing characteristics., Clinical Implications: Mite allergen exposure may be reduced by replacing the mattress regularly and increasing ventilation of the bedroom, particularly in winter.

Background: Asthma and allergy might influence the choice of keeping pets, leading to apparent protective effects of pets on allergic disease., Objective: We investigated the effects of asthma and allergy on subsequent pet keeping in childhood and adulthood., Methods: Information about asthma and pet keeping at ages 0 to 4, 5 to 15, 20 to 44, and 26 to 56 years was provided by 9812 subjects participating in the 9-year follow-up of the European Community Respiratory Health Survey., Results: In childhood asthma debut at younger than 5 years was associated with less cat keeping at 5 to 15 years (odds ratio [OR], 0.60; 95% CI, 0.44-0.82), an effect only observed when the parents did not have asthma or allergy (P(interaction) = .045). Childhood asthma did not influence adult pet ownership, unless there were adult symptoms. Adults less often acquired cats at follow-up if they had 3 or more asthma symptoms (OR, 0.78; 95% CI, 0.64-0.95), were taking asthma medication (OR, 0.48; 95% CI, 0.31-0.74), had hay fever (OR, 0.75; 95% CI, 0.62-0.91), had atopy (OR, 0.75; 95% CI, 0.61-0.91), or had specific IgE to cat (OR, 0.57; 95% CI, 0.39-0.82) at baseline. Adults who already had pets usually continued keeping the same type of pet, except that the presence of 3 or more asthma symptoms was associated with less subsequent dog keeping (OR, 0.69; 95% CI, 0.53-0.89). Pet removal between surveys to reduce allergen was reported by 4.7%., Conclusion: Selective avoidance subsequent to asthma or allergy was observed for childhood cat keeping and adult cat acquisition. Avoidance would produce an apparent protective effect of cats on childhood asthma (large OR, 0.83). Avoidance was generally not observed for dogs or birds., Clinical Implications: A part of the protective effects of childhood cats on asthma and allergy can be attributed to selective avoidance.