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Patients with concomitant features of asthma and chronic obstructive pulmonary disease (COPD) have a heavy disease burden.Using data collected prospectively in the European Community Respiratory Health Survey, we compared the risk factors, clinical history and lung function trajectories from early adulthood to late sixties of middle-aged subjects with asthma+COPD (n=179), past (n=263) or current (n=808) asthma alone, COPD alone (n=111) or none of these (n=3477).Interview data and pre-bronchodilator forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) were obtained during three clinical examinations in 1991-1993, 1999-2002 and 2010-2013. Disease status was classified in 2010-2013, when the subjects were aged 40-68 years, according to the presence of fixed airflow obstruction (post-bronchodilator FEV 1 /FVC below the lower limit of normal), a lifetime history of asthma and cumulative exposure to tobacco or occupational inhalants. Previous lung function trajectories, clinical characteristics and risk factors of these phenotypes were estimated.Subjects with asthma+COPD reported maternal smoking (28.2%) and respiratory infections in childhood (19.1%) more frequently than subjects with COPD alone (20.9% and 14.0%, respectively). Subjects with asthma+COPD had an impairment of lung function at age 20 years that tracked over adulthood, and more than half of them had asthma onset in childhood. Subjects with COPD alone had the highest lifelong exposure to tobacco smoking and occupational inhalants, and they showed accelerated lung function decline during adult life.The coexistence between asthma and COPD seems to have its origins earlier in life compared to COPD alone. These findings suggest that prevention of this severe condition, which is typical at older ages, should start in childhood., Competing Interests: Conflict of interest: A. Marcon has nothing to disclose. Conflict of interest: F. Locatelli has nothing to disclose. Conflict of interest: S.C. Dharmage has nothing to disclose. Conflict of interest: C. Svanes has nothing to disclose. Conflict of interest: J. Heinrich has nothing to disclose. Conflict of interest: B. Leynaert has nothing to disclose. Conflict of interest: P. Burney has nothing to disclose. Conflict of interest: A. Corsico has nothing to disclose. Conflict of interest: G. Caliskan has nothing to disclose. Conflict of interest: L. Calciano has nothing to disclose. Conflict of interest: T. Gislason has nothing to disclose. Conflict of interest: C. Janson has nothing to disclose. Conflict of interest: D. Jarvis has nothing to disclose. Conflict of interest: R. Jõgi received grants from the Estonian Research Council (Personal Research Grant n. 562), and personal fees for consultancy and lecturing from GSK, Boehringer and Novartis, and for travels/accommodation/meetings from GSK and Boehringer. Conflict of interest: T. Lytras has nothing to disclose. Conflict of interest: A. Malinovschi has nothing to disclose. Conflict of interest: N. Probst-Hensch has nothing to disclose. Conflict of interest: K. Toren has nothing to disclose. Conflict of interest: L. Casas has nothing to disclose. Conflict of interest: G. Verlato has nothing to disclose. Conflict of interest: J. Garcia-Aymerich has nothing to disclose. Conflict of interest: S. Accordini has nothing to disclose., (Copyright ©The authors 2021.)

Mechanistic research suggests that lifestyle and environmental factors impact respiratory health across generations by epigenetic changes transmitted through male germ cells. Evidence from studies on humans is very limited.We investigated multigeneration causal associations to estimate the causal effects of tobacco smoking on lung function within the paternal line. We analysed data from 383 adult offspring (age 18-47 years; 52.0% female) and their 274 fathers, who had participated in the European Community Respiratory Health Survey (ECRHS)/Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) generation study and had provided valid measures of pre-bronchodilator lung function. Two counterfactual-based, multilevel mediation models were developed with: paternal grandmothers' smoking in pregnancy and fathers' smoking initiation in prepuberty as exposures; fathers' forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC), or FEV 1 /FVC z-scores as potential mediators (proxies of unobserved biological mechanisms that are true mediators); and offspring's FEV 1 and FVC, or FEV 1 /FVC z-scores as outcomes. All effects were summarised as differences (Δ) in expected z-scores related to fathers' and grandmothers' smoking history.Fathers' smoking initiation in prepuberty had a negative direct effect on both offspring's FEV 1 (Δz-score -0.36, 95% CI -0.63- -0.10) and FVC (-0.50, 95% CI -0.80- -0.20) compared with fathers' never smoking. Paternal grandmothers' smoking in pregnancy had a negative direct effect on fathers' FEV 1 /FVC (-0.57, 95% CI -1.09- -0.05) and a negative indirect effect on offspring's FEV 1 /FVC (-0.12, 95% CI -0.21- -0.03) compared with grandmothers' not smoking before fathers' birth nor during fathers' childhood.Fathers' smoking in prepuberty and paternal grandmothers' smoking in pregnancy may cause lower lung function in offspring. Our results support the concept that lifestyle-related exposures during these susceptibility periods influence the health of future generations., Competing Interests: Conflict of interest: S. Accordini has nothing to disclose. Conflict of interest: L. Calciano has nothing to disclose. Conflict of interest: A. Johannessen has nothing to disclose. Conflict of interest: B. Benediktsdóttir has nothing to disclose. Conflict of interest: R.J. Bertelsen has nothing to disclose. Conflict of interest: L. Bråbäck has nothing to disclose. Conflict of interest: S.C. Dharmage has nothing to disclose. Conflict of interest: B. Forsberg has nothing to disclose. Conflict of interest: F. Gómez Real has nothing to disclose. Conflict of interest: J.W. Holloway reports grants from the European Union's Horizon 2020 research and innovation programme, and from the Research Council of Norway, during the conduct of the study. Conflict of interest: M. Holm has nothing to disclose. Conflict of interest: C. Janson has nothing to disclose. Conflict of interest: N.O. Jõgi has nothing to disclose. Conflict of interest: R. Jõgi reports grants from the Estonian Research Council (personal research grant number 562), during the conduct of the study; personal fees for consultancy and lectures from GSK, Boehringer and Novartis, personal fees for travel/accommodation/meeting expenses from GSK and Boehringer, outside the submitted work. Conflict of interest: A. Malinovschi has nothing to disclose. Conflict of interest: A. Marcon has nothing to disclose. Conflict of interest: J. Martínez-Moratalla Rovira has nothing to disclose. Conflict of interest: J.L. Sánchez-Ramos has nothing to disclose. Conflict of interest: V. Schlünssen has nothing to disclose. Conflict of interest: K. Torén has nothing to disclose. Conflict of interest: D. Jarvis reports grants from the European Union, during the conduct of the study. Conflict of interest: C. Svanes has nothing to disclose., (Copyright ©The authors 2021.)

Bronchodilator response (BDR) testing is used as a diagnostic method in obstructive airway diseases. The aim of this investigation was to compare different methods for measuring BDR in participants with asthma and chronic obstructive pulmonary disease (COPD) and to study to the extent to which BDR was related to symptom burden and phenotypic characteristics.Forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) were measured before and 15 min after 200 μg of salbutamol in 35 628 subjects aged ≥16 years from three large international population studies. The subjects were categorised in three groups: current asthma (n=2833), COPD (n=1146) and no airway disease (n=31 649). Three definitions for flow-related reversibility (increase in FEV 1 ) and three for volume-related reversibility (increase in FVC) were used.The prevalence of bronchodilator reversibility expressed as increase FEV 1 ≥12% and 200 mL was 17.3% and 18.4% in participants with asthma and COPD, respectively, while the corresponding prevalence was 5.1% in those with no airway disease. In asthma, bronchodilator reversibility was associated with wheeze (OR 1.36, 95% CI 1.04-1.79), atopy (OR 1.36, 95% CI 1.04-1.79) and higher exhaled nitric oxide fraction, while in COPD neither flow- nor volume-related bronchodilator reversibility was associated with symptom burden, exacerbations or health status after adjusting for pre-bronchodilator FEV 1 Bronchodilator reversibility was at least as common in participants with COPD as those with asthma. This indicates that measures of reversibility are of limited value for distinguishing asthma from COPD in population studies. However, in asthma, bronchodilator reversibility may be a phenotypic marker., Competing Interests: Conflict of interest: C. Janson has nothing to disclose. Conflict of interest: A. Malinovschi has nothing to disclose. Conflict of interest: A.F.S. Amaral has nothing to disclose. Conflict of interest: S. Accordini has nothing to disclose. Conflict of interest: J. Bousquet reports personal fees and other funding from Chiesi, Cipla, Hikma, Menarini, Mundipharma, Mylan, Novartis, Sanofi-Aventis, Takeda, Teva and Uriach, and other funding from Kyomed, outside the submitted work. Conflict of interest: S.A. Buist has nothing to disclose. Conflict of interest: G.W. Canonica has nothing to disclose. Conflict of interest: B. Dahlen has received personal fees from TEVA, Sanofi, GSK and AstraZeneca, outside the submitted work. Conflict of interest: J. Garcia Aymerich has nothing to disclose. Conflict of interest: L. Gnatiuc has nothing to disclose. Conflict of interest: M.L. Kowalski has nothing to disclose. Conflict of interest: J. Patel has nothing to disclose. Conflict of interest: W. Tan has nothing to disclose. Conflict of interest: K. Torén has nothing to disclose. Conflict of interest: T. Zuberbier has received consultancy fees from Bayer Health Care, FAES, Novartis and Henkel; has received grants/has grants pensing form Novartis and Henkel, and has received lecture fees from AstraZeneca, AbbVie, ALK, Almirall, Astellas, Bayer HealthCare, Bencradm Berlin Chemie, FAES, HAL, Leti, Meda, Menarini, Merck, MSD, Novartis, Pfizer, Sanofi, Stallergenes, Takeda, TEVA, UCB, Henkel, Kryolan and L'Oreal, outside the submitted work. Conflict of interest: P. Burney has nothing to disclose. Conflict of interest: D. Jarvis has nothing to disclose., (Copyright ©ERS 2019.)

Asthma often remains uncontrolled, despite the fact that the pharmacological treatment has undergone large changes. We studied changes in the treatment of asthma over a 20-year period and identified factors associated with the regular use of inhaled corticosteroid (ICS) treatment. Changes in the use of medication were determined in 4617 randomly selected subjects, while changes in adults with persistent asthma were analysed in 369 participants. The study compares data from three surveys in 24 centres in 11 countries. The use of ICSs increased from 1.7% to 5.9% in the general population and the regular use of ICSs increased from 19% to 34% among persistent asthmatic subjects. The proportion of asthmatic subjects reporting asthma attacks in the last 12 months decreased, while the proportion that had seen a doctor in the last 12 months remained unchanged (42%). Subjects with asthma who had experienced attacks or had seen a doctor were more likely to use ICSs on a regular basis. Although ICS use has increased, only one-third of subjects with persistent asthma take ICSs on a regular basis. Less than half had seen a doctor during the last year. This indicates that underuse of ICSs and lack of regular healthcare contacts remains a problem in the management of asthma., Competing Interests: Conflict of interest: J.A. Gullón has nothing to disclose. Conflict of interest: R. Jogi reports receiving Estonian Research Council Personal Research Grant 562 during the conduct of the study; consultancy and lecture fees from GSK, Boehringer and Novartis, and travel, accommodation and meeting expenses from GSK and Boehringer. Conflict of interest: A. Johannessen has nothing to disclose. Conflict of interest: V. Bellisario has nothing to disclose. Conflict of interest: C. Janson reports receiving personal fees for lectures and advisory boards from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis and Teva, and for advisory boards from GSK, outside the submitted work. Conflict of interest: D. Jarvis reports receiving grants from Medical Research Council, during the conduct of the study. Conflict of interest: D. Gislason has nothing to disclose. Conflict of interest: I. Pin reports receiving travel grants from MSD, presentation fees from Teva, and both from AstraZeneca, outside the submitted work. Conflict of interest: J.L. Sánchez-Ramos has nothing to disclose. Conflict of interest: Isa Cerveri has nothing to disclose. Conflict of interest: S. Accordini has nothing to disclose. Conflict of interest: J.J. Weyler has nothing to disclose. Conflict of interest: R. Nielsen reports receiving grants from Boehringer Ingelheim and Novartis, personal fees from AstraZeneca, and grants and personal fees from GSK, outside the submitted work. Conflict of interest: L. Cazzoletti has nothing to disclose. Conflict of interest: J. Garcia-Aymerich has nothing to disclose. Conflict of interest: M. Holm has nothing to disclose. Conflict of interest: J. Martinez-Moratalla Rovira has nothing to disclose. Conflict of interest: V. Siroux reports receiving speakers’ honoraria from AstraZeneca, Novartis and Teva, outside the submitted work. Conflict of interest: A. Corsico has nothing to disclose. Conflict of interest: A. Marcon has nothing to disclose. Conflict of interest: S. Chanoine reports personal fees for board membership from AstraZeneca, and travel, accommodation and meeting expenses from Boehringer Ingelheim, Actelion Pharmaceuticals and MSD, outside the submitted work. Conflict of interest: J. Quint reports receiving grants from The Health Foundation, the MRC, the British Lung Foundation and IQVIA, grants and advisory board fees from GSK, Boehringer Ingelheim and AstraZeneca, travel fees from Chiesi and Teva, grants and speaking fees from Insmed, grants and consultancy fees from Bayer, outside the submitted work. Conflict of interest: D.S. Ferreira reports receiving grants from the Asthma Foundation of Victoria, Allen and Hanburys, and the National Health and Medical Research Council during the conduct of the study. Conflict of interest: D. Nowak has nothing to disclose. Conflict of interest: A. Malinovschi has nothing to disclose. Conflict of interest: K.A. Franklin has nothing to disclose. Conflict of interest: J. Heinrich has nothing to disclose.

The prevalence of asthma increased worldwide until the 1990s, but since then there has been no clear temporal pattern. The present study aimed to assess time trends in the prevalence of current asthma, asthma-like symptoms and allergic rhinitis in Italian adults from 1990 to 2010. The same screening questionnaire was administered by mail or phone to random samples of the general population (age 20-44 yrs) in Italy, in the frame of three multicentre studies: the European Community Respiratory Health Survey (ECRHS) (1991-1993; n = 6,031); the Italian Study on Asthma in Young Adults (ISAYA) (1998-2000; n = 18,873); and the Gene Environment Interactions in Respiratory Diseases (GEIRD) study (2007-2010; n = 10,494). Time trends in prevalence were estimated using Poisson regression models in the centres that repeated the survey at different points in time. From 1991 to 2010, the median prevalence of current asthma, wheezing and allergic rhinitis increased from 4.1% to 6.6%, from 10.1% to 13.9% and from 16.8% to 25.8%, respectively. The prevalence of current asthma was stable during the 1990s and increased (relative risk 1.38, 95% CI 1.19-1.59) from 1998-2000 to 2007-2010, mainly in subjects who did not report allergic rhinitis. The prevalence of allergic rhinitis has increased continuously since 1991. The asthma epidemic is not over in Italy. During the past 20 yrs, asthma prevalence has increased by 38%, in parallel with a similar increase in asthma-like symptoms and allergic rhinitis.

Asthma guidelines from the Global Initiative for Asthma (GINA) and from the National Heart, Lung, and Blood Institute provide conflicting definitions of airflow obstruction, suggesting a fixed forced expiratory volume in 1 s (FEV(1))/forced vital capacity (FVC) cut-off point and the lower limit of normality (LLN), respectively. The LLN was recommended by the recent American Thoracic Society/European Respiratory Society guidelines on lung function testing. The problem in using fixed cut-off points is that they are set regardless of age and sex in an attempt to simplify diagnosis at the expense of misclassification. The sensitivity and specificity of fixed FEV(1)/FVC ratios of 0.70, 0.75 and 0.80 versus the LLN were evaluated in 815 subjects (aged 20-44 yrs) with a diagnosis of asthma within the framework of the European Community Respiratory Health Survey. In males, the 0.70 ratio showed 76.5% sensitivity and 100.0% specificity, the 0.75 ratio 100.0% sensitivity and 92.4% specificity, and the 0.80 ratio 100.0% sensitivity but 58.1% specificity. In females, the 0.70 ratio showed 57.3% sensitivity and 100.0% specificity, the 0.75 ratio 91.5% sensitivity and 95.9% specificity, and the 0.80 ratio 100.0% sensitivity but 72.9% specificity. The fixed cut-off points cause a lot of misidentification of airflow obstruction in young adults, with overestimation with the 0.80 ratio and underestimation with the 0.70 ratio. In conclusion, the GINA guidelines should change their criteria for defining airflow obstruction.

The aim of this study was to describe changes in pharmacotherapy for asthma since the early 1990s in an international cohort of young and middle-aged adults. A total of 28 centres from 14 countries participated in a longitudinal study. The study included 8,829 subjects with a mean follow-up time of 8.7 yrs. Change in the prevalence of use for medication was expressed as absolute net change (95% confidence interval) standardised to a 10-yr period. The use of anti-asthmatics was found to have increased by 3.1% (2.4-3.7%) and the prevalence of symptomatic asthma by 4.0% (3.5-4.5%). In the sample with asthma in both surveys (n=423), the use of inhaled corticosteroids increased by 12.2% (6.6-17.8%). Despite this, only 17.2% were using inhaled corticosteroids on a daily basis at follow-up. Females with continuous asthma were more likely, compared with males, and smokers with asthma, to have started using inhaled corticosteroids since the first survey. The use of anti-asthmatics has increased in a pattern consistent with current consensus on treatment. However, despite increased use of inhaled corticosteroids, a large majority of subjects with symptomatic asthma do not use this treatment on a daily basis, particularly males and smokers with asthma.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines underline that the presence of chronic cough and sputum production before airflow obstruction offers a unique opportunity to identify subjects at risk of chronic obstructive pulmonary disease for an early intervention. Current epidemiological data on these subjects are scant. Between 1998-2000, the authors evaluated the prevalence and characteristics of these symptoms by a multicentre cross-sectional survey of Italian people aged between 20-44 yrs from the general population (Italian Study on Asthma in Young Adults (ISAYA)). Besides the questions on asthma, more than 18,000 subjects answered the question: "Have you had cough and phlegm on most days for as much as 3 months per year and for at least two successive years?" The adjusted prevalence of subjects with chronic cough and phlegm was 11.9%, being 11.8% in males and 12.0% in females. From these subjects approximately 20% reported coexisting asthma and approximately 30%, predominately females, were nonsmokers. The survey showed that sex (female), smoking and low socioeconomic status were significantly and independently associated with chronic cough and phlegm, current smoking playing the major role. The prevalence of subjects with chronic cough and phlegm is startlingly high among young adults. Further follow-up studies are needed to establish how many of them will go on to develop chronic obstructive pulmonary disease.

The present work aims to assess the international variation in the prevalence of chronic bronchitis and its main risk factor, smoking habits, in young adults of 35 centres from 16 countries. Respiratory symptoms and pulmonary function were assessed in 17,966 subjects (20-44 yrs), randomly selected from the general population, in the frame of the European Community Respiratory Health Survey. The median prevalence of chronic bronchitis was 2.6%, with wide variations across countries (p<0.001; 0.7-9.7%). The prevalence of current smokers ranged 20.1-56.9%, (p<0.001) with a median value of 40%. Current smoking was the major risk factor for chronic bronchitis, especially in males. Its effect increased according to number of pack-yrs: in males, the odds ratio of chronic bronchitis was 3.51 (95% confidence interval (CI) 2.31-5.32) in 1-14 pack-yrs smokers and increased to 17.32 (9.97-30.11) in > or = 45 pack-yrs smokers with respect to nonsmokers. Only 30% of the geographical variability in prevalence could be explained by differences in smoking habits, suggesting that other environmental and/or genetic factors may play an important role. In conclusion, chronic bronchitis is a substantial health problem even in young adults. The impressive prevalence in current smokers in most countries highlights the need to improve the quality of prevention.

In the early 1990s a multicentre survey on asthma was performed on the young adult population (European Community Respiratory Health Survey - ECRHS). This study is to be repeated in order to estimate changes in the prevalence of asthma-like symptoms during the last decade and to assess the social and economic costs of the disease and their variations among countries. The self-administered questionnaire devised for this purpose is a two-page questionnaire. The first page contains the same items as those used in the first survey with four additional questions related to: 1) the frequency and severity of asthma attacks; 2) the presence of chronic bronchitis; 3) smoking habits; and 4) a visual analogue scale assessing perception of outdoor pollution. The second page aims to collect information regarding the direct and indirect costs of asthma. The influence of the length of the questionnaire on the response rate was assessed in a pilot study in Italy. Two random samples of 150 subjects received either the one-page questionnaire (first page) or the two-page questionnaire. The response rate was compared with that obtained from the first postal wave in the 1991-1992 survey. Although the response rate was unchanged when using the one-page questionnaire (45% versus 45%), it decreased by 7% when the two-page questionnaire was used (38% versus 45%). On the basis of these results, no problem should arise if four more questions are added to the one-page questionnaire. The slight reduction in the response rate of the two-page questionnaire is worrying but could be corrected by the use of telephone interviews.

Noncompliance to medication is a major barrier to effective asthma management. Its real extent and geographical variation throughout the world are not yet known. The data on compliance, collected in the framework of the European Community Respiratory Health Survey (ECRHS) on 1771 subjects (aged 20-44 yrs) with current asthma identified in 14 countries, offer a unique opportunity to assess the extent of noncompliance and its variation across countries. The median percentage of current asthmatics who had received a medical prescription at least once was 95%. The compliance of those patients who had received a medical prescription was found to be low in all countries (median 67%) but with wide variations, the rate ranging from 40% (USA) to 78% (Iceland). During exacerbations patients' rate of compliance increased to 72%. Age was the only variable which influenced compliance to treatment. A significant, although weak, negative correlation was found between patients' compliance and rate of hospital casualty department or emergency room admissions. This study documents that compliance to the treatment of asthma is poor worldwide and that there are large variations between countries. These results emphasize the necessity for further efforts to improve patients' education and to promulgate the international guidelines.