Roberto de Marco, Simone Accordini, Alessandro Marcon, Isa Cerveri Josep M. Anto, Thorarinn Gislason,Joachim Heinrich,Christer Janson, Deborah Jarvis, Nino Kuenzli, Be´ne´dicte Leynaert, Jordi Sunyer, Cecilie Svanes, Matthias Wjst, and Peter Burney for the European Community Respiratory Health Survey (ECRHS) AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 183 Risk Factors for Chronic Obstructive Pulmonary Disease in a European Cohort of Young Adults R1. 엄유진

Introduction Chronic obstructive pulmonary disease (COPD) progressive airflow obstruction and the destruction of lung parenchyma. progressive airflow obstruction and the destruction of lung parenchyma. Risk factor Tobacco smoking age a previous history of asthma genes early respiratory infections environmental determinants. occupational exposures occupational exposures exposure to biomass smoke exposure to biomass smoke sex, socioeconomic status, body mass index (BMI)

Introduction risk factors for the early inception of COPD are not well known aims of the present analysis to assess the main risk factors of COPD incidence in an international European cohort of young adults to evaluate whether the identification of the risk factors may depend on the definition used for COPD. to evaluate whether the identification of the risk factors may depend on the definition used for COPD. the data from the European Community Respiratory Health Survey (ECRHS) were used.

Method Design of the Study ECRHS I :international multicenter study on respiratory diseases ECRHS I :international multicenter study on respiratory diseases performed in 1991 to 1993 on random samples of young adults (20–44 yr) from the general population performed in 1991 to 1993 on random samples of young adults (20–44 yr) from the general population stage 1: brief screening questionnaire stage 1: brief screening questionnaire stage 2: from those who responded a random sample was selected to undergo a more detailed clinical examination stage 2: from those who responded a random sample was selected to undergo a more detailed clinical examination ECRHS II follow-up study of the participants in the ECRHS I stage 2 follow-up study of the participants in the ECRHS I stage 2 performed between 1999 and 2002 performed between 1999 and 2002

Method Subjects and Definitions 9,511 subjects 9,511 subjects 6,019 (63.3%) 6,019 (63.3%) attended the second survey attended the second survey the cohort consisted of 4,636 subjects. the cohort consisted of 4,636 subjects. 6,019 (63.3%) attended the second survey 24 centers in 10 European countries participated in the ECRHS I stage 2 (1991–1993: baseline), Valid lung function measurements (prebronchodilator values of FEV1 and FVC) FVC) did not report having had asthma during lifetime as defined by a positive answer to the question ‘‘Have you ever had asthma?’’ the cohort consisted of 4,636 subjects. :After excluding the subjects with no valid spirometry and the subjects who reported asthma during the follow-up,

Method Incident COPD cases were defined according to the following three ‘‘modified’’ diagnostic criteria (1) Global Initiative for Chronic Obstructive Lung Disease (GOLD) (1) Global Initiative for Chronic Obstructive Lung Disease (GOLD) if they had a prebronchodilator FEV1/FVC ratio if they had a prebronchodilator FEV1/FVC ratio less than 0.7 at follow-up (but not at baseline); less than 0.7 at follow-up (but not at baseline); (2) lower limit of normal (LLN) (Quanjer) (2) lower limit of normal (LLN) (Quanjer) (3) LLN (LuftiBus) (3) LLN (LuftiBus) if they had a prebronchodilator FEV1/FVC ratio less than or equal to if they had a prebronchodilator FEV1/FVC ratio less than or equal to the LLN at follow-up (but not at baseline), where the LLN was the LLN at follow-up (but not at baseline), where the LLN was computed using the Quanjer and colleagues or the LuftiBus equations computed using the Quanjer and colleagues or the LuftiBus equations

Method Statistical Analysis Incidence rates of COPD were estimated as the ratio between the number of new cases and the number of person-years at risk (per 1,000) Incidence rates of COPD were estimated as the ratio between the number of new cases and the number of person-years at risk (per 1,000) Sensitivity Analysis Due to the lack of post-bronchodilator lung function measurements, some subjects with asthma could have been misclassified as COPD. Due to the lack of post-bronchodilator lung function measurements, some subjects with asthma could have been misclassified as COPD. Therefore, the main analyses (IRRs) were repeated after the exclusion Therefore, the main analyses (IRRs) were repeated after the exclusion of all the subjects who had reported having had ‘‘wheezing or whistling of all the subjects who had reported having had ‘‘wheezing or whistling in the chest at any time in the last 12 months’’ at baseline. in the chest at any time in the last 12 months’’ at baseline.

Results

Classification and Main Characteristics of the Studied Sample None of the new cases of COPD had a FEV1 less than 50% predicted, whereas 12.8% (GOLD), 21.3% (LLN [Quanjer]) and 16.7% (LLN [LuftiBus]) had FEV1 greater than or equal to 50% predicted and less than 80% predicted. With respect to subjects with normal lung function, COPD cases (with any definition) had a poorer lung function both at baseline and at follow-up, and a steeper decline in FEV1

Incidence of COPD

The GOLD-COPD incidence was higher in males than in females A strong positive association was found between age and GOLD COPD incidence (P, 0.001) no age trend was observed for the LLN incidence rates

Risk Factors for COPD increased the risk of the occurrence of COPD Active smoking AHR occurrence of respiratory infections in childhood Family history of asthma varied according to the definition used BMI and past smoking not associated with the incidence of COPD Low socioeconomic class environmental tobacco smoke (ETS) biomass and occupational exposures IgE sensitization Risk of developing COPD was significantly increased only when The GOLD definition was used

PAF(population-attributable fraction) Smoking explained the higher percentage of new COPD cases in our cohort the PAF ranged from 29 to 39%, according to the definition used. AHR, a family history of asthma, and respiratory infection in childhood Accounted for a relevant percentage of incident cases (about 15, 10, and 8%, respectively).

Discussion The main results of our study of an international cohort of young adults point out that 1. Cigarette smoke is the main cause of COPD also in young people. 1. Cigarette smoke is the main cause of COPD also in young people. 2. The same host factors that increase the risk of asthma 2. The same host factors that increase the risk of asthma : play an important role in the inception of COPD in young adults. : play an important role in the inception of COPD in young adults. 3. The role of sex, age, former smoking, and BMI 3. The role of sex, age, former smoking, and BMI : largely depends on the criterion used to define COPD. : largely depends on the criterion used to define COPD. family history of asthma AHR respiratory infections in childhood,

Discussion Tobacco Smoke Exposure and COPD Incidence in Young Adults Tobacco smoke is the major risk factor for COPD Tobacco smoke is the major risk factor for COPD for COPD also among young adults, and that smoking prevention could reduce the incidence of COPD in the young population by 29 to 39%. for COPD also among young adults, and that smoking prevention could reduce the incidence of COPD in the young population by 29 to 39%. smoking and the incidence of COPD early interaction of the tobacco exposure with some genetic or early interaction of the tobacco exposure with some genetic or immunologic host characteristics immunologic host characteristics rather than the effect of the cumulative exposure to cigarette smoke rather than the effect of the cumulative exposure to cigarette smoke The risk of developing COPD has been reported to be higher in former smokers than in nonsmokers years after they quit

Discussion Factors That Increase the Risk of Asthma Also Increase the Risk of COPD Dutch hypothesis : both asthma and COPD share common origins : both asthma and COPD share common origins with differences in the phenotypic Presentation with differences in the phenotypic Presentation our analysis clearly show that well-known risk factors for asthma are relevant risk factors also for COPD are relevant risk factors also for COPD AHR Familiarity respiratory infection in childhood

Discussion Factors That Increase the Risk of Asthma Also Increase the Risk of COPD AHR : cardinal feature of asthma AHR : cardinal feature of asthma hyperresponsive subjects without asthma hyperresponsive subjects without asthma :fourfold greater risk of developing COPD :fourfold greater risk of developing COPD respiratory infections in their childhood : risk of developing COPD is doubled : risk of developing COPD is doubled Virus infections may lead to permanent changes in the airways Virus infections may lead to permanent changes in the airways Some viruses may persist as a latent infection in the airways Some viruses may persist as a latent infection in the airways → increasing the susceptibility to COPD. → increasing the susceptibility to COPD.

Discussion Are Sex, Age, and BMI Associated with the Risk of Developing COPD in Young Adults? Empirically conclude that, because of the contrasting results, aging, sex, and low BMI play only a minor role in the early development of COPD. GOLD COPD criterionmale Underweight older subjects significantly increased risk of developing COPD sex-age–based definition was used (LLN criteria) age, sex, BMI reverse association. lost their statistical significance regardless of the diagnostic criteria used older than 40 years of age COPD prevalence is higher

Discussion Environmental Exposure, Socioeconomic Class, and the Risk of Developing COPD Previous studies (8, 9) found an association between ETS, occupational and biomass exposures, socioeconomic class, and the incidence of COPD. However, we were not able to confirm these findings. young age of our cohort ->implied a relatively low cumulative exposure to environmental factors factors have been measured using simple questions during a clinical interview, and exposures could have thus been misclassified. due to the relatively low number of subjects with COPD in young adults, the power of our study might not have been enough to detect small effects

Discussion COPD Incidence and the Performance of Different Diagnostic Criteria COPD incidence was slightly lower than the incidence measured in other older populations in Europe only 34.4% were simultaneously diagnosed as having COPD by all three criteria. potential risk factors and the incidence of COPD showed a wide variation

Discussion Limitations and Strengths of the Study main limitation of our study : use of prebronchodilator spirometric values for defining COPD : use of prebronchodilator spirometric values for defining COPD → subjects with asthma with fully reversible obstruction could have been falsely classified as having COPD. → subjects with asthma with fully reversible obstruction could have been falsely classified as having COPD. Due to the lack of post-bronchodilator measurements : cannot rule out that some cases of undiagnosed asthma with transient airflow obstruction at the end of the follow-up could have been erroneously classified as COPD. : cannot rule out that some cases of undiagnosed asthma with transient airflow obstruction at the end of the follow-up could have been erroneously classified as COPD. the misclassification bias, if present, could have affected our results only to a minor extent. ← probability for a subject with asthma to report neither the label of asthma nor wheezing in the last year is very low,

Conclusion considerable problem for young adults and the most important risk factor for developing COPD cigarette smoke. cigarette smoke. Smoking prevention : To reduce the occurrence of the disease. : To reduce the occurrence of the disease. AHR, a family history of asthma, and respiratory infections in childhood different diagnostic criteria of COPD → variation in incidence estimates and identification of risk factors → variation in incidence estimates and identification of risk factors → suggests the need for an epidemiological definition of the disease that is not exclusively based on spirometry. → suggests the need for an epidemiological definition of the disease that is not exclusively based on spirometry.