AJRCCM Articles in Press. Published on 27-April-2015 as 10.1164/rccm.201502-0302OC
Page 1 of 45
Characteristics and prognosis of never smokers and smokers with asthma in the Copenhagen General Population Study: a prospective cohort study
Yunus Çolak, MD1,2,3,4; Shoaib Afzal, MD, PhD3,4,5; Børge G. Nordestgaard, MD, DMSc3,4,5; and Peter Lange, MD, DMSc2,3,4,6
1
Department of Internal Medicine, Section of Respiratory Medicine, Herlev Hospital, Copenhagen
University Hospital, Herlev, Denmark. 2
Department of Public Health, Section of Social Medicine, University of Copenhagen, Copenhagen,
Denmark. 3
The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital,
Herlev, Denmark. 4
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
5
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev,
Denmark 6
Medical Unit, Respiratory Section, Hvidovre Hospital, Copenhagen University Hospital, Hvidovre,
Denmark
1
Copyright © 2015 by the American Thoracic Society
AJRCCM Articles in Press. Published on 27-April-2015 as 10.1164/rccm.201502-0302OC
Page 2 of 45
Author contributions: Drs. Çolak and Afzal had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analyses. Study concept and design: Drs. Çolak, Afzal, Lange, and Nordestgaard. Acquisition, analyses, or interpretation of data: Drs. Çolak, Afzal, Lange, and Nordestgaard. Drafting of the manuscript: Dr. Çolak. Critical revision of the manuscript for important intellectual content: Drs. Çolak, Afzal, Lange, and Nordestgaard. Statistical analyses: Drs. Çolak and Afzal. Obtained funding: Drs. Lange and Nordestgaard. Administrative, technical, or material support: Dr. Nordestgaard. Study supervision: Drs. Lange and Nordestgaard. Conflict of interest disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Funding/support: Funded by the Danish Lung Association, the Danish Cancer Society, Department of Clinical Biochemistry and Department of Internal Medicine, Herlev Hospital, Copenhagen University Hospital, and Department of Public Health, University of Copenhagen. Role of the sponsors: The sponsors did not participate in the design and conduct of the study; collection, management, analysis, or interpretation of the data; or in preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
2
Copyright © 2015 by the American Thoracic Society
AJRCCM Articles in Press. Published on 27-April-2015 as 10.1164/rccm.201502-0302OC
Page 3 of 45
Correspondence: Peter Lange, MD, DMSc Professor, Consultant in Respiratory Medicine Department of Public Health, Section of Social Medicine, University of Copenhagen Øster Farimagsgade 5, Postal Box 2099, DK-1015 Copenhagen K, Denmark Phone: +45 26879020 E-mail: [email protected]
At a Glance Commentary Scientific Knowledge on the Subject: Asthma is associated with complications, cardiovascular comorbidities, and higher mortality in some individuals. However, many individuals with asthma are also tobacco smokers. Since tobacco smoking is a strong risk factor for pulmonary and cardiovascular diseases, it is difficult to separate the roles of asthma per se and of tobacco smoking regarding prognosis in individuals with asthma. What This Study Adds to the Field: Never smokers with asthma experience an increased risk of asthma and COPD exacerbations, and possibly of pneumonias. Importantly, risk of lung cancer, cardiovascular comorbidities, and death were restricted to smokers with asthma. Thus, this study substantiates that tobacco smoking is the main explanation of poor prognosis in some individuals with asthma.
Tables/Figures: 5 (NA); References: 36 (max. 50); Total word count: 3,490 (max. 3,500); Abstract: 250 (max. 250). This article has an online data supplement, which is accessible from this issue’s table of content online at www.atsjournals.org
3
Copyright © 2015 by the American Thoracic Society
AJRCCM Articles in Press. Published on 27-April-2015 as 10.1164/rccm.201502-0302OC
Page 4 of 45
Abstract Rationale:Asthma is associated with complications, cardiovascular comorbidities, and higher mortality in some individuals. Objectives:To test the hypothesis that in individuals with asthma, never-smokers have different characteristics and better prognosis than smokers. Methods:We recruited 94,079 individuals aged 20-100years from the Copenhagen General Population Study, a prospective cohort study: 5,691(6%) had self-reported asthma (2,304 neversmokers, 2,467 former-smokers, and 920 current-smokers). We examined respiratory symptoms, lung function, and levels of inflammatory and allergic biomarkers in the systemic circulation. Furthermore, we assessed prospectively risk of asthma or chronic obstructive pulmonary disease(COPD) exacerbations, pneumonias, lung cancer, ischemic heart disease, ischemic stroke, and all-cause mortality during 4.5years follow-up. Measurements and Main Results:Compared to never-smokers without asthma, individuals with asthma had more respiratory symptoms and airflow limitation and higher levels of inflammatory and allergic biomarkers, which was most pronounced in smokers. Among individuals with asthma compared to never-smokers without asthma, multivariable adjusted hazard ratios for asthma exacerbations were 11(95%CI:5.8-22) in never-smokers, 13(6.2-29) in former-smokers, and 18(8.2-39) in current-smokers. Corresponding values for COPD exacerbations were 8.9(2.1-38), 23(8.8-58), and 36(12-105), for pneumonias 1.5(0.9-2.2), 1.6(1.0-2.4), and 2.4(1.6-3.7), for lung cancer 0.6(0.1-5.1), 4.0(1.3-12), and 13(4.3-41), for ischemic heart disease 1.2(0.9-1.6), 1.5(1.22.0), and 2.0(1.4-2.9), for ischemic stroke 1.4(0.9-2.1), 1.2(0.8-1.9), and 3.0(1.7-5.3), and for allcause mortality 0.9(0.6-1.3), 1.5(1.1-2.0), and 2.7(1.9-3.7), respectively.
4
Copyright © 2015 by the American Thoracic Society
AJRCCM Articles in Press. Published on 27-April-2015 as 10.1164/rccm.201502-0302OC
Page 5 of 45
Conclusions:Never-smokers with asthma had increased risk of asthma and COPD exacerbations, and possibly of pneumonias. Importantly, risk of lung cancer, cardiovascular comorbidities, and death were restricted to smokers with asthma. Thus, tobacco smoking was the main explanation of poor prognosis in asthma.
Key words: asthma; smoking; pneumonia; chronic obstructive pulmonary disease; cardiovascular diseases.
5
Copyright © 2015 by the American Thoracic Society
AJRCCM Articles in Press. Published on 27-April-2015 as 10.1164/rccm.201502-0302OC
Page 6 of 45
Introduction Despite being a relatively benign disease, in some individuals asthma is associated with complications,1 cardiovascular comorbidities,2-7 and high mortality.8-11 However, many of the previous studies were cross-sectional or retrospective, did not include a representative sample of the general population, and had not adjusted for all relevant confounders. Importantly, many individuals with asthma are also tobacco smokers.12 Since tobacco smoking is a strong risk factor for pulmonary and cardiovascular diseases, it is difficult to separate the roles of asthma per se and of tobacco smoking regarding prognosis in individuals with asthma, that is, development of complications, cardiovascular comorbidities, and mortality. We tested the hypothesis that in individuals with asthma, never smokers have different characteristics and less severe prognosis of the disease than smokers. First, we examined baseline general characteristics, respiratory symptoms, lung function, and levels of inflammatory and allergic biomarkers in the systemic circulation. Second, we assessed prospectively risk of asthma or chronic obstructive pulmonary disease (COPD) exacerbations, pneumonias, lung cancer, cardiovascular comorbidities, including ischemic heart disease, myocardial infarction, and ischemic stroke, and all-cause mortality.
6
Copyright © 2015 by the American Thoracic Society
AJRCCM Articles in Press. Published on 27-April-2015 as 10.1164/rccm.201502-0302OC
Page 7 of 45
Methods Study design and participants We recruited 94,079 individuals aged 20-100 years from the Copenhagen General Population Study, a prospective cohort study initiated in 2003.13;14 Participants were randomly selected from the national Danish Civil Registration System to reflect the adult white Danish population of Danish descent. All participants completed a comprehensive questionnaire, underwent a physical examination, and gave blood for biochemical analyses. Questionnaires were reviewed at the day of attendance by an investigator. Response-rate was 45%. The study was approved by Herlev Hospital and a Danish ethical committee, and was conducted according to the Declaration of Helsinki. Written informed consent was obtained from all participants.
Asthma and smoking Asthma was defined as an affirmative response to the question: “Do you have asthma?” Smoking status was defined as never, former, or current smokers. Cumulative tobacco consumption was defined as tobacco consumed through smoking and measured in pack years based on information on duration of tobacco smoking and current amount of tobacco consumed: one pack year was 20 cigarettes or equivalent smoked daily for one year.
Characteristics Allergy was defined according to the questionnaire if the participants reported asthma, hay fever, or eczema as a reaction to food, medication, grass, flower, animal hair, or other allergens. Familial pre-disposition for asthma was as at least one first degree relative (father, mother, and/or sibling) with asthma. Information on asthma, hay fever, or eczema in childhood was self-reported.
7
Copyright © 2015 by the American Thoracic Society
AJRCCM Articles in Press. Published on 27-April-2015 as 10.1164/rccm.201502-0302OC
Page 8 of 45
Use of asthma medication was taking any kind of medication for asthma/bronchitis (including sprays/dry powders) daily or almost daily. Wheezing was whistling or wheezing while breathing. Any dyspnea was defined as shortness of breath during different levels of activity, at night-time, and/or while seated/at rest. The modified Medical Research Council dyspnea scale was used to categorize levels of dyspnea according to different levels of activity. Chest pain or tightness was when hurrying or taking the stairs. Sputum was phlegm from the lungs in the morning and/or during the day as long as three consecutive months each year. Cough was exercise induced cough. Spirometry was performed with a Vitalograph (Maids Moreton, Buckinghamshire, UK) in the first 14,625 participants and with an EasyOne Spirometer (ndd Medical Technologies, Zurich, Switzerland) in the remaining participants; pre-bronchodilatatory forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were typically measured with at least three sets of values and had two measurements differing by less than 5% as a criterion for reproducibility. The highest measurements of FEV1 and FVC were used in the analyses. The Vitalograph was calibrated daily with a 1-L syringe, and the EasyOne Spirometer was calibrated regularly as recommended from the manufacturer. FEV1, FVC, and FEV1/FVC as percentage of predicted value were calculated using internally derived reference values based on a subsample of healthy asymptomatic (without wheezing, dyspnea, chest pain or tightness, sputum, cough, and asthma) never smokers with age and height as covariates separately for men and women. Predicted values were calculated separately for the two spirometers (Figure E1 in the online data supplement). Individuals with airflow limitation were defined according to 1) a fixed ratio defined as FEV1/FVC
Page 1 of 45
Characteristics and prognosis of never smokers and smokers with asthma in the Copenhagen General Population Study: a prospective cohort study
Yunus Çolak, MD1,2,3,4; Shoaib Afzal, MD, PhD3,4,5; Børge G. Nordestgaard, MD, DMSc3,4,5; and Peter Lange, MD, DMSc2,3,4,6
1
Department of Internal Medicine, Section of Respiratory Medicine, Herlev Hospital, Copenhagen
University Hospital, Herlev, Denmark. 2
Department of Public Health, Section of Social Medicine, University of Copenhagen, Copenhagen,
Denmark. 3
The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital,
Herlev, Denmark. 4
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
5
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev,
Denmark 6
Medical Unit, Respiratory Section, Hvidovre Hospital, Copenhagen University Hospital, Hvidovre,
Denmark
1
Copyright © 2015 by the American Thoracic Society
AJRCCM Articles in Press. Published on 27-April-2015 as 10.1164/rccm.201502-0302OC
Page 2 of 45
Author contributions: Drs. Çolak and Afzal had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analyses. Study concept and design: Drs. Çolak, Afzal, Lange, and Nordestgaard. Acquisition, analyses, or interpretation of data: Drs. Çolak, Afzal, Lange, and Nordestgaard. Drafting of the manuscript: Dr. Çolak. Critical revision of the manuscript for important intellectual content: Drs. Çolak, Afzal, Lange, and Nordestgaard. Statistical analyses: Drs. Çolak and Afzal. Obtained funding: Drs. Lange and Nordestgaard. Administrative, technical, or material support: Dr. Nordestgaard. Study supervision: Drs. Lange and Nordestgaard. Conflict of interest disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Funding/support: Funded by the Danish Lung Association, the Danish Cancer Society, Department of Clinical Biochemistry and Department of Internal Medicine, Herlev Hospital, Copenhagen University Hospital, and Department of Public Health, University of Copenhagen. Role of the sponsors: The sponsors did not participate in the design and conduct of the study; collection, management, analysis, or interpretation of the data; or in preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
2
Copyright © 2015 by the American Thoracic Society
AJRCCM Articles in Press. Published on 27-April-2015 as 10.1164/rccm.201502-0302OC
Page 3 of 45
Correspondence: Peter Lange, MD, DMSc Professor, Consultant in Respiratory Medicine Department of Public Health, Section of Social Medicine, University of Copenhagen Øster Farimagsgade 5, Postal Box 2099, DK-1015 Copenhagen K, Denmark Phone: +45 26879020 E-mail: [email protected]
At a Glance Commentary Scientific Knowledge on the Subject: Asthma is associated with complications, cardiovascular comorbidities, and higher mortality in some individuals. However, many individuals with asthma are also tobacco smokers. Since tobacco smoking is a strong risk factor for pulmonary and cardiovascular diseases, it is difficult to separate the roles of asthma per se and of tobacco smoking regarding prognosis in individuals with asthma. What This Study Adds to the Field: Never smokers with asthma experience an increased risk of asthma and COPD exacerbations, and possibly of pneumonias. Importantly, risk of lung cancer, cardiovascular comorbidities, and death were restricted to smokers with asthma. Thus, this study substantiates that tobacco smoking is the main explanation of poor prognosis in some individuals with asthma.
Tables/Figures: 5 (NA); References: 36 (max. 50); Total word count: 3,490 (max. 3,500); Abstract: 250 (max. 250). This article has an online data supplement, which is accessible from this issue’s table of content online at www.atsjournals.org
3
Copyright © 2015 by the American Thoracic Society
AJRCCM Articles in Press. Published on 27-April-2015 as 10.1164/rccm.201502-0302OC
Page 4 of 45
Abstract Rationale:Asthma is associated with complications, cardiovascular comorbidities, and higher mortality in some individuals. Objectives:To test the hypothesis that in individuals with asthma, never-smokers have different characteristics and better prognosis than smokers. Methods:We recruited 94,079 individuals aged 20-100years from the Copenhagen General Population Study, a prospective cohort study: 5,691(6%) had self-reported asthma (2,304 neversmokers, 2,467 former-smokers, and 920 current-smokers). We examined respiratory symptoms, lung function, and levels of inflammatory and allergic biomarkers in the systemic circulation. Furthermore, we assessed prospectively risk of asthma or chronic obstructive pulmonary disease(COPD) exacerbations, pneumonias, lung cancer, ischemic heart disease, ischemic stroke, and all-cause mortality during 4.5years follow-up. Measurements and Main Results:Compared to never-smokers without asthma, individuals with asthma had more respiratory symptoms and airflow limitation and higher levels of inflammatory and allergic biomarkers, which was most pronounced in smokers. Among individuals with asthma compared to never-smokers without asthma, multivariable adjusted hazard ratios for asthma exacerbations were 11(95%CI:5.8-22) in never-smokers, 13(6.2-29) in former-smokers, and 18(8.2-39) in current-smokers. Corresponding values for COPD exacerbations were 8.9(2.1-38), 23(8.8-58), and 36(12-105), for pneumonias 1.5(0.9-2.2), 1.6(1.0-2.4), and 2.4(1.6-3.7), for lung cancer 0.6(0.1-5.1), 4.0(1.3-12), and 13(4.3-41), for ischemic heart disease 1.2(0.9-1.6), 1.5(1.22.0), and 2.0(1.4-2.9), for ischemic stroke 1.4(0.9-2.1), 1.2(0.8-1.9), and 3.0(1.7-5.3), and for allcause mortality 0.9(0.6-1.3), 1.5(1.1-2.0), and 2.7(1.9-3.7), respectively.
4
Copyright © 2015 by the American Thoracic Society
AJRCCM Articles in Press. Published on 27-April-2015 as 10.1164/rccm.201502-0302OC
Page 5 of 45
Conclusions:Never-smokers with asthma had increased risk of asthma and COPD exacerbations, and possibly of pneumonias. Importantly, risk of lung cancer, cardiovascular comorbidities, and death were restricted to smokers with asthma. Thus, tobacco smoking was the main explanation of poor prognosis in asthma.
Key words: asthma; smoking; pneumonia; chronic obstructive pulmonary disease; cardiovascular diseases.
5
Copyright © 2015 by the American Thoracic Society
AJRCCM Articles in Press. Published on 27-April-2015 as 10.1164/rccm.201502-0302OC
Page 6 of 45
Introduction Despite being a relatively benign disease, in some individuals asthma is associated with complications,1 cardiovascular comorbidities,2-7 and high mortality.8-11 However, many of the previous studies were cross-sectional or retrospective, did not include a representative sample of the general population, and had not adjusted for all relevant confounders. Importantly, many individuals with asthma are also tobacco smokers.12 Since tobacco smoking is a strong risk factor for pulmonary and cardiovascular diseases, it is difficult to separate the roles of asthma per se and of tobacco smoking regarding prognosis in individuals with asthma, that is, development of complications, cardiovascular comorbidities, and mortality. We tested the hypothesis that in individuals with asthma, never smokers have different characteristics and less severe prognosis of the disease than smokers. First, we examined baseline general characteristics, respiratory symptoms, lung function, and levels of inflammatory and allergic biomarkers in the systemic circulation. Second, we assessed prospectively risk of asthma or chronic obstructive pulmonary disease (COPD) exacerbations, pneumonias, lung cancer, cardiovascular comorbidities, including ischemic heart disease, myocardial infarction, and ischemic stroke, and all-cause mortality.
6
Copyright © 2015 by the American Thoracic Society
AJRCCM Articles in Press. Published on 27-April-2015 as 10.1164/rccm.201502-0302OC
Page 7 of 45
Methods Study design and participants We recruited 94,079 individuals aged 20-100 years from the Copenhagen General Population Study, a prospective cohort study initiated in 2003.13;14 Participants were randomly selected from the national Danish Civil Registration System to reflect the adult white Danish population of Danish descent. All participants completed a comprehensive questionnaire, underwent a physical examination, and gave blood for biochemical analyses. Questionnaires were reviewed at the day of attendance by an investigator. Response-rate was 45%. The study was approved by Herlev Hospital and a Danish ethical committee, and was conducted according to the Declaration of Helsinki. Written informed consent was obtained from all participants.
Asthma and smoking Asthma was defined as an affirmative response to the question: “Do you have asthma?” Smoking status was defined as never, former, or current smokers. Cumulative tobacco consumption was defined as tobacco consumed through smoking and measured in pack years based on information on duration of tobacco smoking and current amount of tobacco consumed: one pack year was 20 cigarettes or equivalent smoked daily for one year.
Characteristics Allergy was defined according to the questionnaire if the participants reported asthma, hay fever, or eczema as a reaction to food, medication, grass, flower, animal hair, or other allergens. Familial pre-disposition for asthma was as at least one first degree relative (father, mother, and/or sibling) with asthma. Information on asthma, hay fever, or eczema in childhood was self-reported.
7
Copyright © 2015 by the American Thoracic Society
AJRCCM Articles in Press. Published on 27-April-2015 as 10.1164/rccm.201502-0302OC
Page 8 of 45
Use of asthma medication was taking any kind of medication for asthma/bronchitis (including sprays/dry powders) daily or almost daily. Wheezing was whistling or wheezing while breathing. Any dyspnea was defined as shortness of breath during different levels of activity, at night-time, and/or while seated/at rest. The modified Medical Research Council dyspnea scale was used to categorize levels of dyspnea according to different levels of activity. Chest pain or tightness was when hurrying or taking the stairs. Sputum was phlegm from the lungs in the morning and/or during the day as long as three consecutive months each year. Cough was exercise induced cough. Spirometry was performed with a Vitalograph (Maids Moreton, Buckinghamshire, UK) in the first 14,625 participants and with an EasyOne Spirometer (ndd Medical Technologies, Zurich, Switzerland) in the remaining participants; pre-bronchodilatatory forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were typically measured with at least three sets of values and had two measurements differing by less than 5% as a criterion for reproducibility. The highest measurements of FEV1 and FVC were used in the analyses. The Vitalograph was calibrated daily with a 1-L syringe, and the EasyOne Spirometer was calibrated regularly as recommended from the manufacturer. FEV1, FVC, and FEV1/FVC as percentage of predicted value were calculated using internally derived reference values based on a subsample of healthy asymptomatic (without wheezing, dyspnea, chest pain or tightness, sputum, cough, and asthma) never smokers with age and height as covariates separately for men and women. Predicted values were calculated separately for the two spirometers (Figure E1 in the online data supplement). Individuals with airflow limitation were defined according to 1) a fixed ratio defined as FEV1/FVC
