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Research Article| Volume 191, 106403, January 2022

Occupation, socioeconomic status and chronic obstructive respiratory diseases – The EpiLung study in Finland, Estonia and Sweden

Open AccessPublished:May 02, 2021DOI:https://doi.org/10.1016/j.rmed.2021.106403

      Highlights

      • Occupational classifications associated uniformly with COPD.
      • Occupational classifications associated non-uniformly with asthma.
      • East-west disparity of allergic diseases was seen between Estonia, Finland and Sweden.
      • Socioeconomic factors and environment may even protect from eosinophilic inflammation.
      • Control for tobacco smoking on occupational associations is important.

      Abstract

      Objective

      To study occupational groups and occupational exposure in association with chronic obstructive respiratory diseases.

      Methods

      In early 2000s, structured interviews on chronic respiratory diseases and measurements of lung function as well as fractional expiratory nitric oxide (FENO) were performed in adult random population samples of Finland, Sweden and Estonia. Occupations were categorized according to three classification systems. Occupational exposure to vapours, gases, dusts and fumes (VGDF) was assessed by a Job-Exposure Matrix (JEM). The data from the countries were combined.

      Results

      COPD, smoking and occupational exposure were most common in Estonia, while asthma and occupations requiring higher educational levels in Sweden and Finland. In an adjusted regression model, non-manual workers had a three-fold risk for physician-diagnosed asthma (OR 3.18, 95%CI 1.07–9.47) compared to professionals and executives, and the risk was two-fold for healthcare & social workers (OR 2.28, 95%CI 1.14–4.59) compared to administration and sales. An increased risk for physician-diagnosed COPD was seen in manual workers, regardless of classification system, but in contrast to asthma, the risk was mostly explained by smoking and less by occupational exposure to VGDF. For FENO, no associations with occupation were observed.

      Conclusions

      In this multicenter study from Finland, Sweden and Estonia, COPD was consistently associated with manual occupations with high smoking prevalence, highlighting the need to control for tobacco smoking in studies on occupational associations. In contrast, asthma tended to associate with non-manual occupations requiring higher educational levels. The occupational associations with asthma were not driven by eosinophilic inflammation presented by increased FENO.

      Keywords

      Abbreviations

      ARC
      Allergic rhinitis or conjunctivitis
      CI
      95% confidence interval
      COPD
      Chronic obstructive pulmonary disease
      FENO
      Fractional exhaled nitric oxide
      FEV1
      Forced expiratory volume in 1 s
      FinEsS
      Finland, Estonia and Sweden Nordic Epidemiological Study on Obstructive Lung Diseases
      ICS
      Inhaled corticosteroid
      ISCO88
      International Standard Classification of Occupations (1988 edition)
      IQR
      Interquartile range
      Nordic EpiLung
      A multidisciplinary research approach on obstructive airway diseases: socio-economical and life course perspectivesA multidisciplinary research approach on obstructive airway diseases: socio-economical and life course perspectives
      NYK
      Nordic Classification of Occupations
      OLIN
      Obstructive Lung Diseases in Northern Sweden
      OR
      Odds ratio
      SEI
      Swedish Socioeconomic Index
      SPT
      Skin pick test
      SSYK
      Swedish Standard Classification of Occupations (2012 edition)
      VGDF
      Exposure to vapours, gases, dusts and fumes

      1. Introduction

      Asthma and chronic obstructive pulmonary disease (COPD) cause significant burden to public healthcare. They are associated with many comorbidities, and especially COPD increases mortality [
      • Cruz A.A.
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      Global Surveillance, Prevention and Control of CHRONIC RESPIRATORY DISEASES: a Comprehensive Approach.
      ]. They may also appear together, today commonly labelled asthma-COPD overlap. Occupational exposure may be important in the development of adult asthma or asthma symptoms [
      • Karjalainen A.
      • Kurppa K.
      • Martikainen R.
      • Klaukka T.
      • Karjalainen J.
      Work is related to a substantial portion of adult-onset asthma incidence in the Finnish population.
      ,
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      • Menezes A.M.B.
      • Plana E.
      • Mannino D.M.
      • Hallal P.C.
      • Toren K.
      • et al.
      Occupational exposures and COPD: an ecological analysis of international data.
      ,
      • Schyllert C.
      • Rönmark E.
      • Andersson M.
      • Hedlund U.
      • Lundbäck B.
      • Hedman L.
      • et al.
      Occupational exposure to chemicals drives the increased risk of asthma and rhinitis observed for exposure to vapours, gas, dust and fumes: a cross-sectional population-based study.
      ,
      • Pallasaho P.
      • Kainu A.
      • Sovijärvi A.
      • Lindqvist A.
      • Piirilä P.L.
      Combined effect of smoking and occupational exposure to dusts, gases or fumes on the incidence of COPD.
      ]. Although smoking is the dominant cause of COPD, attention has also been given to occupational exposure to vapours, gases, dusts and fumes (VGDF) [
      • Schyllert C.
      • Rönmark E.
      • Andersson M.
      • Hedlund U.
      • Lundbäck B.
      • Hedman L.
      • et al.
      Occupational exposure to chemicals drives the increased risk of asthma and rhinitis observed for exposure to vapours, gas, dust and fumes: a cross-sectional population-based study.
      ,
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      • Annesi-Maesano I.
      • Balmes J.R.
      • Cummings K.J.
      • Fishwick D.
      • Miedinger D.
      • et al.
      The occupational burden of nonmalignant respiratory diseases. An official American thoracic society and European respiratory society statement.
      ,
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      • Miedinger D.
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      • Bettschart R.
      • Bircher A.
      • Bridevaux P.O.
      • et al.
      Occupational exposure to dusts, gases, and fumes and incidence of chronic obstructive pulmonary disease in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults.
      ,
      • Harber P.
      • Tashkin D.P.
      • Simmons M.
      • Crawford L.
      • Hnizdo E.
      • Connett J.
      • et al.
      Effect of occupational exposures on decline of lung function in early chronic obstructive pulmonary disease.
      ,
      • Ryu J.Y.
      • Sunwoo Y.E.
      • Lee S.
      • Lee C.
      • Kim J.
      • Lee J.
      • et al.
      Chronic obstructive pulmonary disease (COPD) and Vapors, gases, dusts, or fumes VGDF: a meta-analysis.
      ,
      • Tommola M.
      • Ilmarinen P.
      • Tuomisto L.E.
      • Lehtimäki L.
      • Kankaanranta H.
      Occupational exposures and asthma–COPD overlap in a clinical cohort of adult-onset asthma.
      ].
      The Nordic EpiLung study, concerning the socioeconomic differences in Nordic countries, started in 2017. It gathered data from the previous Northern European epidemiological study (FinEsS = Finland, Estonia and Sweden Study) on obstructive pulmonary disease [
      • Pallasaho P.
      • Lundbäck B.
      • Läspä S.-L.
      • Jönsson E.
      • Sovijärvi A.
      • Laitinen L.
      Increasing prevalence of asthma but not of chronic bronchitis in Finland - report from the FinEsS-Helsinki study.
      ]. In early 2000s, 1669 randomly selected subjects were interviewed and clinically examined with measurements of lung function and of fractional exhaled nitric oxide (FENO). For the present paper, the data was used to evaluate how occupation, socioeconomic status, and smoking relate to the occurrence of respiratory diseases and symptoms [
      • Pekkarinen P.T.
      • von Hertzen L.
      • Laatikainen T.
      • Makela M.J.
      • Jousilahti P.
      • Kosunen T.U.
      • et al.
      A disparity in the association of asthma, rhinitis, and eczema with allergen-specific IgE between Finnish and Russian Karelia.
      ,
      • Asher M.
      • Anderson H.
      • Stewart A.
      • Crane J.
      • Ait-Khaled N.
      • Anabwani G.
      • et al.
      Worldwide variations in the prevalence of asthma symptoms: the international study of asthma and allergies in childhood (ISAAC).
      ,
      Variations in the prevalence of respiratory symptoms, self-reported asthma attacks, and use of asthma medication in the European Community Respiratory Health Survey (ECRHS).
      ,
      • Sunyer J.
      • Jarvis D.
      • Pekkanen J.
      • Chinn S.
      • Janson C.
      • Leynaert B.
      • et al.
      Geographic variations in the effect of atopy on asthma in the European community respiratory health study.
      ]. At the time of data collection, Estonia had just become independent and was socioeconomically at a lower level than Finland (Helsinki) and Sweden (Örebro and Stockholm).
      Assessment of occupational exposure has been diverse with postal questionnaire surveys, interviews on exposure at workplace [
      • Blanc P.D.
      • Menezes A.M.B.
      • Plana E.
      • Mannino D.M.
      • Hallal P.C.
      • Toren K.
      • et al.
      Occupational exposures and COPD: an ecological analysis of international data.
      ] or using Job-Exposure Matrixes (JEM). The latter comprises lists of exposure to a variety of potentially harmful agents for selected occupational titles [
      • de Vocht F.
      • Zock J.
      • Kromhout H.
      • Sunyer J.
      • Anto J.M.
      • Burney P.
      • et al.
      Comparison of self-reported occupational exposure with a job exposure matrix in an international community-based study on asthma.
      ,
      • Pralong J.A.
      • Cartier A.
      • Vandenplas O.
      • Labrecque M.
      Occupational asthma: new low-molecular-weight causal agents.
      ,
      • Rava M.
      • Ahmed I.
      • Kogevinas M.
      • Le Moual N.
      • Bouzigon E.
      • Curjuric I.
      • et al.
      Genes interacting with occupational exposures to low molecular weight Agents and irritants on adult-onset asthma in three European studies.
      ]. There is no consensus on the optimal way to evaluate occupational exposure in epidemiology [
      • Blanc P.D.
      • Menezes A.M.B.
      • Plana E.
      • Mannino D.M.
      • Hallal P.C.
      • Toren K.
      • et al.
      Occupational exposures and COPD: an ecological analysis of international data.
      ,
      • de Vocht F.
      • Zock J.
      • Kromhout H.
      • Sunyer J.
      • Anto J.M.
      • Burney P.
      • et al.
      Comparison of self-reported occupational exposure with a job exposure matrix in an international community-based study on asthma.
      ]. Furthermore, the classification of occupations has also an effect on the observed associations of occupation with respiratory diagnoses and symptoms [
      • Schyllert C.
      • Rönmark E.
      • Andersson M.
      • Hedlund U.
      • Lundbäck B.
      • Hedman L.
      • et al.
      Occupational exposure to chemicals drives the increased risk of asthma and rhinitis observed for exposure to vapours, gas, dust and fumes: a cross-sectional population-based study.
      ]. In Nordic countries, commonly used occupational classifications include Swedish Socioeconomic Classification (SEI, Socioeconomic Index), Nordic Classification of Occupations (NYK) based on the International Standard Classification of Occupations (ISCO) and Swedish Standard Classification of Occupations (SSYK).
      Fraction of exhaled nitric oxide (FENO) is used to assess bronchial eosinophilic inflammation [
      • Dweik R.A.
      • Boggs P.B.
      • Erzurum S.C.
      • Irvin C.G.
      • Leigh M.W.
      • Lundberg J.O.
      • et al.
      An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications.
      ,
      • Malinovschi A.
      • Janson C.
      • Holmkvist T.
      • Norback D.
      • Merilainen P.
      • Hogman M.
      Effect of smoking on exhaled nitric oxide and flow-independent nitric oxide exchange parameters.
      ]. In the recent Nordic EpiLung-study [
      • Lassmann-Klee P.G.
      • Piirilä P.L.
      • Brumpton B.
      • Larsson M.
      • Sundblad B.M.
      • Põlluste J.
      • Juusela M.
      • Rouhos A.
      • Meren M.
      • Lindqvist A.
      • Kankaanranta H.
      • Backman H.
      • Langhammer A.
      • Rönmark E.
      • Lundbäck B.
      • Sovijärvi A.R.A.
      Parallel gradients in FENO and in the prevalences of asthma and atopy in adult general populations of Sweden, Finland and Estonia - a Nordic EpiLung study.
      ], we found lower FENO levels in Estonia, compared to Finland and Sweden, indicating an east-west disparity in the prevalence of eosinophilic inflammation. The asthma risk was increased in Helsinki, Narva, and Stockholm, compared to Saaremaa in Estonia.
      In the present study, we asked whether occupation or socioeconomic status, assessed by job titles, associate with obstructive respiratory diseases and symptoms as well as indices of eosinophilic inflammation in the three countries.

      2. Material and methods

      The respiratory data originate from the FinEsS Study of Finland, Estonia and Sweden with five participating research centres (Supplementary, Fig. 1). They performed similar questionnaire surveys and clinical examinations of random adult cohorts.
      Fig. 1
      Fig. 1The significantly increased risk for physician diagnosed COPD in Manual Workers (Industry and Service in SEI classification) compared with Non-manual Workers as a reference groups (combination of Professionals and Executives high, Non-Manual Workers intermediate and Non-Manual Workers low in SEI classification). A forest plot with values acquired from multinomial regression analysis.

      2.1 The study cohort (FinEsS, Nordic EpiLung)

      The FinEsS Study was started in 1995 to study the prevalence and symptoms of obstructive pulmonary disease in Finland, Estonia and Sweden [
      • Pallasaho P.
      • Lundbäck B.
      • Meren M.
      • Kiviloog J.
      • Loit H.M.
      • Larsson K.
      • et al.
      Prevalence and risk factors for asthma and chronic bronchitis in the capitals Helsinki, Stockholm, and Tallinn.
      ,
      • Meren M.
      • Jannus-Pruljan L.
      • Loit H.-M.
      • Polluste J.
      • Jönsson E.
      • Kiviloog J.
      • Luncbäck B.
      Asthma, chronic bronchitis and respiratory symptoms among adults in Estonia according to a postal questionnaire.
      ,
      • Lindström M.
      • Kotaniemi J.
      • Jonsson E.
      • Lundbäck B.
      Smoking, respiratory symptoms, and diseases: a comparative study between northern Sweden and northern Finland: report from the FinEsS study.
      ]. The study began as a questionnaire survey posted to 8000 subjects in Stockholm, Örebro and Helsinki each, to 5519 subjects in Narva and to 5432 in Saaremaa. Cohorts in each research center were formed by randomization into 10-year-age cohorts. The postal questionnaire was based on the OLIN (Obstructive Lung Diseases in Northern Sweden) research project [
      • Pallasaho P.
      • Lundbäck B.
      • Läspä S.-L.
      • Jönsson E.
      • Sovijärvi A.
      • Laitinen L.
      Increasing prevalence of asthma but not of chronic bronchitis in Finland - report from the FinEsS-Helsinki study.
      ,
      • Lundbäck B.
      • Nyström L.
      • Rosenhall L.
      • Stjernberg N.
      Obstructive lung disease in northern Sweden: respiratory symptoms assessed in a postal survey.
      ], which was developed mainly from the British Medical Research Council [
      Medical Research Council Committee on the aetiology of chronic bronchitis
      Standardised questionnaires on respiratory symptoms.
      ] and US Tucson [
      • Lebowitz M.
      • Knudson R.
      • Burrows B.
      The Tucson epidemiology study of chronic obstructive lung disease. I: methodology and prevalence of disease.
      ] questionnaires.
      The study continued in the early 2000s with structured interviews in 2658 randomly selected responders from the five centres. Of them 1669 were randomized for lung function testing including FENO measurements. Finally, 1498 subjects, aged 20–60 years with valid FENO measurements were included in the study cohort [
      • Lassmann-Klee P.G.
      • Piirilä P.L.
      • Brumpton B.
      • Larsson M.
      • Sundblad B.M.
      • Põlluste J.
      • Juusela M.
      • Rouhos A.
      • Meren M.
      • Lindqvist A.
      • Kankaanranta H.
      • Backman H.
      • Langhammer A.
      • Rönmark E.
      • Lundbäck B.
      • Sovijärvi A.R.A.
      Parallel gradients in FENO and in the prevalences of asthma and atopy in adult general populations of Sweden, Finland and Estonia - a Nordic EpiLung study.
      ]. In 2017, the Nordic EpiLung study commenced in Nordic countries to find out how socioeconomic differences affect chronic obstructive pulmonary diseases.

      2.2 Clinical examinations

      Structured interview. The structured interview and clinical tests were conducted in 1997–2003. The interview included 162 questions about respiratory diseases, medication, and risk factors for asthma and COPD. The interview, based on the former postal questionnaire, with some modifications, has been used in several Nordic studies [
      • Kotaniemi J.
      • Sovijärvi A.
      • Lundbäck B.
      Chronic obstructive pulmonary disease in Finland: prevalence and risk factors.
      ,
      • Pallasaho P.
      • Rönmark E.
      • Haahtela T.
      • Sovijärvi A.R.
      • Lundbäck B.
      Degree and clinical relevance of sensitization to common allergens among adults: a population study in Helsinki, Finland.
      ,
      • Lindberg A.
      • Larsson L.G.
      • Rönmark E.
      • Jonsson A.C.
      • Larsson K.
      • Lundbäck B.
      Decline in FEV1 in relation to incident chronic obstructive pulmonary disease in a cohort with respiratory symptoms.
      ,
      • Backman H.
      • Vanfleteren L.
      • Lindberg A.
      • Ekerljung L.
      • Stridsman C.
      • Axelsson M.
      • Nilsson U.
      • Nwaru B.I.
      • Sawalha S.
      • Eriksson B.
      • Hedman L.
      • Rådinger M.
      • Jansson S.A.
      • Ullman A.
      • Kankaanranta H.
      • Lötvall J.
      • Rönmark E.
      • Lundbäck B.
      Decreased COPD prevalence in Sweden after decades of decrease in smoking.
      ]. The questions used in the present study were the following.
      Allergic rhinitis or conjunctivitis (ARC). Have you had hay fever (allergic rhinitis) or allergic eye inflammation?”
      Asthma diagnosed by a physician. “Have you been diagnosed with asthma by a physician?”
      Asthma symptoms. “Have you had any symptoms of asthma during the last 12 months?”
      Asthma medication. “Have you used any asthma medicines in the last 12 months?” Furthermore, those who answered “yes” were asked about certain asthma medications.
      COPD diagnosed by a physician. “Have you been diagnosed with chronic bronchitis or emphysema by a physician?” Synonym for COPD at the time [
      • Biernacki W.
      • Gould G.A.
      • Whyte K.F.
      • Flenley D.C.
      Pulmonary hemodynamics, gas exchange, and the severity of emphysema as assessed by quantitative CT scan in chronic bronchitis and emphysema.
      ].
      Chronic cough or sputum. “Have you had longstanding cough during the last year?” or “Do you usually have phlegm when coughing or do you have phlegm on your chest, which is difficult to bring up?”
      Inhaled corticosteroids (ICS). “Have you used inhaled corticosteroids during the last 12 months?”
      Smoking. “Do you smoke?” Subjects who answered “yes” were classified as current smokers and “no” as not current smokers.
      Pack years were calculated from a question of “How many cigarettes per day have you been smoking on an average since you started smoking?” with options of “1–4, 5–14, 14–24 or >24”. Similar questions were asked about cigars and pipe smoking. Participants who were smokers or ex-smokers were also asked at what age they began or stopped smoking. The pack year values obtained from this were then divided into four categories. Further details can be found in the statistics section.

      2.3 Other definitions

      Occupational exposure to vapours, gases, dusts and fumes (VGDF) was used both as a value acquired by summation from 4 separate Job-Exposure Matrix (JEM) components which was used to calculate a mean value for each group (VGDF mean), and as a cut-off variable (any VGDF). When the sum of the 4 VGDF components was least 1, the participant was considered having any VGDF. The component values were obtained from the list of occupations and have been explained earlier [
      • Pallasaho P.
      • Kainu A.
      • Sovijärvi A.
      • Lindqvist A.
      • Piirilä P.L.
      Combined effect of smoking and occupational exposure to dusts, gases or fumes on the incidence of COPD.
      ,
      • Mehta A.J.
      • Miedinger D.
      • Keidel D.
      • Bettschart R.
      • Bircher A.
      • Bridevaux P.O.
      • et al.
      Occupational exposure to dusts, gases, and fumes and incidence of chronic obstructive pulmonary disease in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults.
      ]. Determinants of this variable are further detailed in the supplementary section (Supplementary, Fig. 2a and b).
      Atopy is defined as a positive result (wheal diameter ≥ 3 mm) caused by any common allergen in the skin prick test (SPT).
      FENO ≥ 25 is defined as the group having standardized FENO (ppb) value of 25 ppb or higher. This is recommended as a cut-off value for a mild inflammation in risk analyses [
      • Dweik R.A.
      • Boggs P.B.
      • Erzurum S.C.
      • Irvin C.G.
      • Leigh M.W.
      • Lundberg J.O.
      • et al.
      An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications.
      ].
      FEV1% was acquired from the spirometry results [
      • Quanjer P.H.
      • Stanojevic S.
      • Cole T.J.
      • Baur X.
      • Hall G.L.
      • Culver B.H.
      • Enright P.L.
      • Hankinson J.L.
      • Ip M.S.M.
      • Zheng J.
      Stocks J and the ERS Global Lung Function Initiative. ERS TASK FORCE REPORT. The ERS Global Lung Function Initiative. Multi-ethnic reference values for spirometry for the 3-95 yr age range: the global lung function 2012 equations.
      ].

      2.4 Spirometry and FENO measurements

      Different spirometers were used in the participating centres (in Helsinki SensorMedix Vmax22; in Stockholm, Ohio spirometer; in Örebro, Volugraph 2000 and Vitalograph; in Narva and Saaremaa, Vicatest). We used only the values of forced expiratory volume in 1 s (FEV1) (Table 1), as the values of forced vital capacity (FVC) were not available from Estonia and Örebro in Sweden [
      • Kainu A.
      • Lindqvist A.
      • Sarna S.
      • Sovijarvi A.
      Intra-session repeatability of FET and FEV6 in the general population.
      ].
      Table 1Subject characteristics, respiratory diseases, symptoms, occupational exposure, and smoking.
      AllSwedenFinlandEstoniaPSexp
      FemaleMale
      n1498570295633824674
      Age (y)41 (18)41 (17)42 (18)41 (20)0.73441 (18)42 (19)0.226
      BMI categorized (kg/m2)0.0010.001
       <25 (%)515649475447
       25.0–29.9 (%)353436363041
       ≥30 (%)141015171612
      FEV1 (l)3.34 (1.14)3.32 (1.10)3.24 (1.27)3.45 (1.14)0.0013.00 (0.86)3.98 (1.09)0.001
      FEV1 (%)96 (18.3)92 (18)94 (15)100 (18)0.00197 (18.6)95 (18.1)0.042
      FENO (ppb)14.0 (10.5)15.5 (9.3)15.4 (13.7)12.5 (9.6)0.00113.6 (10.1)14.6 (10.8)0.643
      Skin prick test (SPT) (%)3634
      Lower amount skin prick test allergens were tested in Sweden.
      49310.00135360.643
      Allergic rhinitis (ARC) (%)323740240.00137270.001
      Asthma diagnosed by MD (%)69740.001770.481
      Asthma symptoms last year (%)8111340.001970.165
      Inhaled corticosteroid use (ICS) (%)46510.001430.692
      Currently smoking (%)312434370.00126370.001
      Any VGDF (%)443531590.00135550.001
      COPD diagnosed by MD (%)723130.001850.079
      Chronic cough or Sputum (%)513755610.00152500.442
      Age, FEV1 (l), FEV1 (%) and FENO are median values with Interquartile range (IQR).
      The highest occurrence of each value is bolded.
      BMI Body-mass index; FEV1 Forced expiratory volume in 1 s (liters/percent); FENO Fraction of exhaled nitric oxide; MD Doctor of Medicine; VGDF Vapours, gas, dusts and fumes; COPD Chronic obstructive pulmonary disease.
      a Lower amount skin prick test allergens were tested in Sweden.
      FENO was measured according to the ERS guidelines [
      ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide.
      ]. All participating centres employed a chemiluminescent nitric oxide (NO) analyzer (Sievers 270B, Boulder,Co, USA). In each centre, a standardization method was used to obtain FENO to correspond the same expiratory flow level. FENO flow at 50 m/s was chosen as the standard flow [
      ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide.
      ,
      • Lassmann-Klee P.G.
      • Lehtimäki L.
      • Lindholm T.
      • Malmberg L.P.
      • Sovijärvi A.
      • Piirilä P.
      Converting FENO by different flows to standard flow FENO.
      ].

      2.5 Skin prick tests

      Skin prick tests (SPT) were used to determine atopic disposition, which was defined as having at least one positive test result (skin wheal ≥3 mm) caused by a common allergen (15 allergens were tested in Finland and Estonia, 10 in Sweden). The test method and allergens used have been described previously [
      • Lassmann-Klee P.G.
      • Piirilä P.L.
      • Brumpton B.
      • Larsson M.
      • Sundblad B.M.
      • Põlluste J.
      • Juusela M.
      • Rouhos A.
      • Meren M.
      • Lindqvist A.
      • Kankaanranta H.
      • Backman H.
      • Langhammer A.
      • Rönmark E.
      • Lundbäck B.
      • Sovijärvi A.R.A.
      Parallel gradients in FENO and in the prevalences of asthma and atopy in adult general populations of Sweden, Finland and Estonia - a Nordic EpiLung study.
      ].
      Classifications of occupation by the current title.
      Three different classification systems were used and compared to the respiratory diseases and symptoms. These classifications were the Swedish Socio-economic Index (SEI) [
      ] Nordic Classification of Occupations (NYK) [
      ] and ISCO88 [

      International Labour Organization ILO: ISCO-88. Available at: https://www.ilo.org/public/english/bureau/stat/isco/isco88/index.htm. Accessed 4.11, 2019.

      ]. Their use and combinations are further explained in the Supplemental section (Supplementary, Fig. 3a–c).

      2.6 Statistics

      Multivariable logistic regression modelling was performed to calculate odds ratios (OR) with 95% confidence intervals (95%CI) for respiratory diseases and symptoms in association with the occupational categories according to the three classification systems (SEI, NYK and ISCO88). A separate model was estimated to calculate OR and 95%CI for any VGDF. The regression models were adjusted for age, atopy, sex and pack years. Reference categories were as follows: Professionals and Executives (high) for SEI, Administration and Sales for NYK, Professionals for ISCO88 and no exposure for any VGDF.
      FENO data consisted of both continuous and categorical variables. Kruskal‒Wallis and Wilcoxon's rank sum test were used to test the continuous variables (age, FEV1, FENO). For the categorical variables, the χ2 test was applied. Significance was set at p < 0.05 for all tests.
      To calculate the pack years, a yearly smoking amount in cigarette packs was evaluated. 1–4 cigarettes per day was considered as 1/3 of a pack, 5–14 as 2/3 of pack, 15–24 as a single cigarette pack and >24 as 4/3 of a pack. One cigar was equivalent to four cigarettes and 25 g of pipe tobacco weekly 50 cigarettes per week. Smoking parameters were summed to get daily amount of cigarette packs for an average year, which was multiplied by the years of smoking. The individual pack year values were then categorized withing 4 categories: None, < 10 pack years, 10-<20 pack years and ≥20 pack years to be used in the multinomial regression analysis.
      All analyses were carried out using IBM SPSS Statistics version 25 (IBM Corp, New York, NY, USA).

      3. Results

      Subject characteristics are given in Table 1. Allergic rhinitis, atopic disposition, asthma and asthma symptoms were much more common in Sweden and Finland than in Estonia, while COPD, smoking and occupational exposure were more common in Estonia. Allergic rhinitis was more prevalent in women.
      Manual labor was more common in Estonia than in Sweden or Finland (Table 2). Finland had the highest prevalence of non-manual occupation titles.
      Table 2Distribution of occupations (%) in Sweden, Finland and Estonia according to the three classifications.
      AllSwedenFinlandEstonia
      SEI (n)1339524240575


       Professionals and Executives (high)


      11


      10


      18


      8


       Non-Manual Workers (intermediate)20253012
       Non-Manual Workers (low)18182115
       Manual Workers Service24301921
       Manual Workers Industry2615844
       Self-employed2250
      P0.001
      NYK (n)1426542278606


       Science & arts


      19
      222513
       Health care & social workers1319165
       Administration and Sales27303820
       Agriculture4208
       Transportation and Communication7649
       Manufacturing20141031
       Service107714
      P0.001
      ISCO88 Major Groups (n)1394510277607


       Legislation, Senior Officials, Managers


      4
      514
       Professionals17192213
       Technicians and Associate Professionals21233712
       Clerks91287
       Service, Shop and Market Sales Workers17201814
       Skilled Agricultural and Fishery Workers3105
       Craft and Related Trades Workers139620
       Plant, Machine Operators and Assemblers107514
       Elementary Occupations75411
      P0.001
      The highest prevalence of occupational category in the three countries is bolded.
      SEI Swedish socioeconomic-index; NYK Nordic classification of occupations; ISCO88 International standard classification of occupations (1988 edition).
      The prevalence of current smoking in all subjects was 31% and peaked to 40–50% in manual workers in Industry (SEI), Transportation and Communications (NYK) and Plant and Machine Operators and Assemblers (ISCO88) (Supplementary Table 1). The amount of pack years was also higher in manual than in non-manual work. FENO was significantly lower in the current smoking group. Prevalence of atopic disposition (positive SPT) did not differ between occupations.
      Prevalence of asthma symptoms and asthma diagnosed by a physician were the highest in occupations classified as non-manual workers (SEI), healthcare & social work (NYK) and Legislation as well as in senior officials and managers (ISCO88) (Supplementary Table 2). COPD was most common in occupations classified as manual workers, the highest prevalence being in manual workers in Industry (SEI), Agriculture (NYK) and workers in Skilled Agricultural and Fishery (ISCO88).
      Occupational exposure was more common in older age groups than in younger age groups (Supplementary Table 3). In addition, socioeconomic differences between age groups were more pronounced in men than in women (Supplementary Table 3).
      In the adjusted multivariable logistic regression model (Table 3), there was a significant risk for asthma in the non-manual workers compared to professionals and executives in the SEI classification. Healthcare & social work and service work were shown to have a higher risk of asthma symptoms. There was no significant risk group for asthma or asthma symptoms in the ISCO88 classification.
      Table 3Multivariable risk analysis of diseases, symptoms and elevated FENO (FENO≥25 ppb).
      Asthma by MDAsthma symptomsCOPD by MDChr. cough or SputumFENO≥25
      OR(95%CI)OR(95%CI)OR(95%CI)OR(95%CI)OR(95%CI)
      SEI
       Professionals and Executives (high)1ref1ref1ref1ref1ref
       Non-Manual Workers (intermediate)3.18(1.079.47)1.08(0.502.31)0.86(0.292.61)1.07(0.691.65)0.64(0.361.15)
       Non-Manual Workers (low)1.11(0.333.81)0.57(0.241.35)1.01(0.333.04)0.97(0.621.52)0.47(0.250.88)
       Manual Workers Service2.46(0.817.41)1.25(0.602.62)1.43(0.513.99)1.11(0.721.70)0.76(0.431.33)
       Manual Workers Industry1.55(0.504.80)0.55(0.241.24)3.51(1.339.25)1.41(0.932.15)0.63(0.361.09)
       Self-employed2.60(0.4315.7)0.88(0.174.47)X
      Results that could not be calculated due to small group sizes are marked with an X.
      (X
      Results that could not be calculated due to small group sizes are marked with an X.
      X
      Results that could not be calculated due to small group sizes are marked with an X.
      )
      0.67(0.251.79)1.47(0.504.34)
      NYK
       Science & arts1.09(0.532.24)1.16(0.612.22)1.12(0.522.44)1.04(0.741.45)0.95(0.601.52)
       Healthcare & social workers2.28(1.144.59)2.24(1.184.24)0.22(0.050.98)1.05(0.721.54)1.18(0.692.02)
       Administration and Sales1ref1ref1ref1ref1ref
       Agriculture0.67(0.152.99)0.27(0.042.08)2.75(1.017.53)1.70(0.993.26)0.33(0.101.10)
       Transportation and Communication0.72(0.232.22)0.59(0.201.81)2.44(0.986.09)0.92(0.571.48)1.41(0.772.59)
       Manufacturing0.78(0.351.72)0.85(0.421.74)2.97(1.505.85)1.43(1.022.00)0.78(0.481.26)
       Service1.40(0.613.23)2.39(1.184.62)2.23(1.034.82)1.80(1.192.73)1.26(0.722.19)
      ISCO88 Major Groups
       Legislation, Senior officials, Managers2.42(0.787.45)1.56(0.534.55)0.50(0.064.04)1.59(0.842.99)0.46(0.151.37)
       Professionals1ref1ref1ref1ref1ref
       Technicians and Associate Professionals1.33(0.602.93)1.09(0.562.14)1.18(0.482.94)0.99(0.681.44)0.85(0.501.43)
       Clerks1.09(0.393.09)0.89(0.372.16)0.88(0.292.71)0.86(0.541.37)0.77(0.391.55)
       Service, Shop and Market Sales Workers1.37(0.603.15)1.20(0.602.40)0.69(0.251.90)1.24(0.841.83)1.50(0.892.51)
       Skilled Agricultural and Fishery Workers1.13(0.245.42)X
      Results that could not be calculated due to small group sizes are marked with an X.
      (X
      Results that could not be calculated due to small group sizes are marked with an X.
      X
      Results that could not be calculated due to small group sizes are marked with an X.
      )
      5.18(1.6915.9)1.52(0.743.12)0.51(0.151.79)
       Craft and Related Trades Workers0.85(0.312.30)0.81(0.351.88)3.71(1.568.80)1.37(0.902.09)0.88(0.491.59)
       Plant, Machine Operators and Assemblers0.68(0.202.26)0.55(0.191.60)3.76(1.469.71)1.29(0.812.06)1.14(0.612.12)
       Elementary Occupations2.12(0.845.37)1.71(0.763.87)4.32(1.7710.5)1.29(0.782.13)0.51(0.231.17)
      Any VGDF
       No exposure1ref1ref1ref1ref1ref
       Exposure1.11(0.701.77)1.09(0.721.65)1.70(1.082.66)1.37(1.091.71)0.96(0.701.31)
      Any VGDF (not current smoker)
       No exposure1ref1ref1ref1ref1ref
       Exposure1.35(0.802.27)1.01(0.631.63)1.58(0.902.78)1.13(0.861.48)1.14(0.811.61)
      Any VGDF (current smoker)
       No exposure1ref1ref1ref1ref1ref
       Exposure0.68(0.241.99)1.87(0.734.77)1.84(0.834.08)1.75(1.142.71)0.58(0.261.30)
      The calculations were adjusted for age, atopy, pack years and sex. Any VGDF in groups not current smoker and current smoker was adjusted similarly.
      Statistically significant results are bolded.
      Chr. Chronic; MD Doctor of medicine; VGDF Vapours, gas, dusts and fumes; COPD Chronic obstructive pulmonary disease; FENO Fraction of exhaled nitric oxide; Ref reference value; OR Odds ratio; CI Confidence interval SEI Swedish socioeconomic index; NYK Nordic classification of occupations; ISCO88 International standard classification of occupations (1988 edition).
      a Results that could not be calculated due to small group sizes are marked with an X.
      A risk for COPD was seen in the multivariable model, adjusted for age, atopy, sex and pack years, with the manual labor groups in all three classification systems (SEI, NYK, ISCO88) (Table 3). Healthcare & social workers seemed to be protected from COPD (NYK). Fig. 1 shows the major risk for COPD, but not for other conditions, in the manual workers compared with combined non-manual workers in the SEI classification.
      For the eosinophilic inflammation marker, FENO, the analysis did not reveal any significant risk group for elevated values. The lowest FENO values among the current smokers were found in Estonia compared to Finland and Sweden (p < 0.001), although the reported pack years were the lowest in Estonia (p = 0.006) (Supplementary Figure 4-5).

      4. Discussion

      As several occupational classifications are used in Nordic countries, we chose to use three of them to get comprehensive analyses of the association between chronic lung diseases and occupational or socioeconomic status of the participants. The classifications differed from each other in some aspects. The Swedish Socioeconomic Index (SEI) and Nordic Yrkesklassificering (NYK) were superior for identifying associations between occupation and obstructive respiratory diseases and symptoms.
      The results showed that all the three classifications associated significantly with COPD in the manual workers. They also smoked more and were more exposed to vapours, gases, dusts or fumes (VGDF) at work. Smoking was by far the most important risk factor, but occupational exposure also increased slightly the risk for chronic cough and sputum production. In an earlier study of a Finnish population, COPD was associated with occupational exposure yielding an additive effect of smoking [
      • Pallasaho P.
      • Kainu A.
      • Sovijärvi A.
      • Lindqvist A.
      • Piirilä P.L.
      Combined effect of smoking and occupational exposure to dusts, gases or fumes on the incidence of COPD.
      ]. The present results are in line with that in terms of COPD and symptoms, but our study did not find any association between occupational exposure and asthma. In fact, the non-manual workers, not much exposed at work, had increased risk for asthma and asthma symptoms in two of the occupational classifications. Our results are similar with previous observations indicating the increased risk for asthma in healthcare & social workers [
      • Walters G.I.
      • Moore V.C.
      • McGrath E.E.
      • Burge P.S.
      • Henneberger P.K.
      Agents and trends in health care workers' occupational asthma.
      ]. Regarding age groups and differences in socioeconomic status between them and sexes, occupational exposure was more common in older than younger age groups and socioeconomic differences between the age groups were greater in men than in women. These both are reflective for COPD being more common in men than in women and changes in occupational structure in Nordic countries with the shift from manual occupations to non-manual during the latter part of 20th century.
      Elevated FENO levels are signs of eosinophilic inflammation [
      • Dweik R.A.
      • Boggs P.B.
      • Erzurum S.C.
      • Irvin C.G.
      • Leigh M.W.
      • Lundberg J.O.
      • et al.
      An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications.
      ] and were associated with occupations requiring higher education and with little occupational exposure. The FENO levels, the prevalence of allergic rhinitis and of atopic disposition were the lowest in Estonia, where manual professions and occupations not requiring high education were most common. FENO levels were the lowest in Estonian noncurrent smokers. Smoking is well known to lower FENO levels [
      • Dweik R.A.
      • Boggs P.B.
      • Erzurum S.C.
      • Irvin C.G.
      • Leigh M.W.
      • Lundberg J.O.
      • et al.
      An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications.
      ,
      • Malinovschi A.
      • Janson C.
      • Holmkvist T.
      • Norback D.
      • Merilainen P.
      • Hogman M.
      Effect of smoking on exhaled nitric oxide and flow-independent nitric oxide exchange parameters.
      ,
      • Lassmann-Klee P.G.
      • Piirilä P.L.
      • Brumpton B.
      • Larsson M.
      • Sundblad B.M.
      • Põlluste J.
      • Juusela M.
      • Rouhos A.
      • Meren M.
      • Lindqvist A.
      • Kankaanranta H.
      • Backman H.
      • Langhammer A.
      • Rönmark E.
      • Lundbäck B.
      • Sovijärvi A.R.A.
      Parallel gradients in FENO and in the prevalences of asthma and atopy in adult general populations of Sweden, Finland and Estonia - a Nordic EpiLung study.
      ], and this was seen also here in all three countries. Estonian current smokers had the lowest FENO levels but, surprisingly, the Estonians reported the lowest pack years.
      In earlier studies, the east-west disparity has been apparent in increase of sensitization to common allergens and allergic diseases. Most of the reports are from children, but the difference has pertained in adult populations as well [
      • Lassmann-Klee P.G.
      • Piirilä P.L.
      • Brumpton B.
      • Larsson M.
      • Sundblad B.M.
      • Põlluste J.
      • Juusela M.
      • Rouhos A.
      • Meren M.
      • Lindqvist A.
      • Kankaanranta H.
      • Backman H.
      • Langhammer A.
      • Rönmark E.
      • Lundbäck B.
      • Sovijärvi A.R.A.
      Parallel gradients in FENO and in the prevalences of asthma and atopy in adult general populations of Sweden, Finland and Estonia - a Nordic EpiLung study.
      ,
      • Nicolai T.
      • Bellach B.
      • Mutius E.V.
      • Thefeld W.
      • Hoffmeister H.
      Increased prevalence of sensitization against aeroallergens in adults in West compared with East Germany.
      ,

      Hanski I, von Hertzen L, Fyhrquist N, Koskinen K, Torppa K, Laatikainen T, Karisola P, Auvinen P, Paulin L, Mäkelä MJ, Vartiainen E, Kosunen TU, Alenius H, Haahtela T. Environmental biodiversity, human microbiota, and allergy are interrelated. Proc. Natl. Acad. Sci. U. S. A.. 2012 May 22;109(21):8334-8339. doi: 10.1073/pnas.1205624109.

      ], and also the level and pattern of allergic sensitization among adults is different in Estonia compared with Finland and Sweden, storage mites and cockroach being the most common sensitizers in Estonia (43). In earlier studies, the east-west disparity has been apparent in more common sensitization to common allergens and allergic diseases, including asthma in westernized countries. The disparity has been associated with reduced exposure to biodiverse natural environment with rich microbiota in westernized countries [
      • Lassmann-Klee P.G.
      • Piirilä P.L.
      • Brumpton B.
      • Larsson M.
      • Sundblad B.M.
      • Põlluste J.
      • Juusela M.
      • Rouhos A.
      • Meren M.
      • Lindqvist A.
      • Kankaanranta H.
      • Backman H.
      • Langhammer A.
      • Rönmark E.
      • Lundbäck B.
      • Sovijärvi A.R.A.
      Parallel gradients in FENO and in the prevalences of asthma and atopy in adult general populations of Sweden, Finland and Estonia - a Nordic EpiLung study.
      ,
      • Nicolai T.
      • Bellach B.
      • Mutius E.V.
      • Thefeld W.
      • Hoffmeister H.
      Increased prevalence of sensitization against aeroallergens in adults in West compared with East Germany.
      ,
      • Raukas-Kivioja A.
      • Raukas E.
      • Loit H.M.
      • Kiviloog J.
      • Rönmark E.
      • Larsson K.
      • Lundbäck B.
      Allergic sensitization among adults in Tallinn, Estonia.
      ,
      • von Mutius E.
      • Weiland S.K.
      • Fritzsch C.
      • Duhme H.
      • Keil U.
      Increasing prevalence of hay fever and atopy among children in Leipzig, East Germany.
      ,
      • Ruokolainen L.
      • Paalanen L.
      • Karkman A.
      • Laatikainen T.
      • von Hertzen L.
      • Vlasoff T.
      • Markelova O.
      • Masyuk V.
      • Auvinen P.
      • Paulin L.
      • Alenius H.
      • Fyhrquist N.
      • Hanski I.
      • Mäkelä M.J.
      • Zilber E.
      • Jousilahti P.
      • Vartiainen E.
      • Haahtela T.
      Significant disparities in allergy prevalence and microbiota between the young people in Finnish and Russian Karelia.
      ]. The participants from Finland and Sweden had higher levels of FENO and had more often atopic disposition than those from Estonia. Estonians from Saaremaa and Narva were less likely to show mild eosinophilic inflammation, which here was suggested by lower FENO levels in both noncurrent and current smoking Estonians compared to Finns and Swedes. Ambient air pollution is a major global health risk, but its effect on the prevalence of allergies and asthma is controversial [
      • Zhang Q.
      • Qiu Z.
      • Chung K.F.
      • Huang S.K.
      Link between environmental air pollution and allergic asthma: east meets West.
      ].
      Our study did not indicate any association of occupational exposure to eosinophilic inflammation. Consequently, we suggest that differences in lifestyle and environmental changes (urbanization) are more important determinants than occupation explaining disposition to atopy, allergic diseases and asthma at population level. However, in specific working environments exposure to allergens or irritants may cause occupational or work-related asthma and rhinitis.

      4.1 Strengths and limitations

      The present material is large and includes data from three countries and five study centres. The participants represent variable socioeconomic status, lifestyle, environment and east-west location. The Estonians were recruited shortly after independency of the country. We also used the same structured interview for each center, and the cohorts were selected similarly randomized and stratified for age and sex. Therefore, the material is ideal for comparison of the risk factors of chronic respiratory diseases and symptoms.
      One limitation was that the occupational exposure was not inquired from the subjects but assessed from the reported occupations with JEM-based occupational exposure levels. However, in earlier applications the used exposure assessment has given valid results [
      • Pallasaho P.
      • Kainu A.
      • Sovijärvi A.
      • Lindqvist A.
      • Piirilä P.L.
      Combined effect of smoking and occupational exposure to dusts, gases or fumes on the incidence of COPD.
      ]. The association with FENO and exposure in the occupational categories were logical although FENO levels remained usually low. ISCO88 was approximated from NYK and SEI as it was not used in the original FinEsS-study. It should also be noted that the classifications were done based on the title of the occupation. This approach does not always reflect the actual working conditions, which may differ with the same occupational title. There is also another problem in the assignment of occupation category from the current occupation title, as it does not take in to account the healthy worker effect [
      • Radon K.
      • Goldberg M.
      • Becklake M.
      Healthy worker effect in cohort studies on chronic bronchitis.
      ] in which people change their occupation due to symptoms that have begun during their work. This effect could in some part explain the poor correlation between occupational exposure and asthma diagnose and symptoms. Further, the use of self-reported COPD diagnoses by a physician instead of spirometry-verified COPD is another weakness due to the known under-diagnosis and misclassification of COPD.

      5. Conclusions

      In summary, the three occupational classifications gave similar results on associations with COPD but non-uniform ones with asthma. COPD was associated with manual labour where the smoking prevalence was high. This combination was especially seen in Estonia, where also COPD was more common. In contrast to this asthma was more common in non-manual occupations requiring higher educational levels which were more common in Finland and Sweden.
      Occupational exposure to vapours, gases, dusts or fumes was associated with symptoms common in bronchitis, but not with asthma. The FENO levels were higher in Sweden and Finland than in Estonia, and tended to be higher in non-manual occupations requiring high education, but significant occupational associations were lacking. Thus, occupational associations with asthma seem at least not mainly be driven by eosinophilic inflammation with elevated FENO levels, although lower FENO levels suggested on more favorable biodiversity in Estonia compared to Finland and Sweden. The results further highlight the importance of controlling for tobacco smoking in studies on occupational exposures and obstructive respiratory diseases, especially regarding COPD.

      Ethics approval

      The study was approved by the ethics committee of the Department of Medicine, Helsinki University Central Hospital and Tallinn Ethics Committee, Estonia and Swedish Ethical Review Authority. The subjects filled in a written informed consent form.

      Consent for publication

      Not applicable.

      Data availability

      The datasets used are not publicly available due to the laws of the study countries.

      Funding

      This work was supported by The Nordic Council of Ministers: NordForsk Foundation (Nordic EpiLung Study). Paul-Lassman-Klee received funding from the following sources; Foundation of the Finnish Anti-Tuberculosis Association, Finland; HES The Research Foundation of the Pulmonary Diseases, Finland; Tampere Tuberculosis Foundation, Finland; Väinö and Laina Kivi Foundation, Finland. Päivi Piirilä received funding from Nummela Sanatorium Foundation. In addition the original FinEsS-project was funded by the Helsinki University Central Hospital special governmental subsidy for health sciences research project.

      CRediT authorship contribution statement

      Juuso Jalasto: Formal analysis, Writing – original draft, Writing – review & editing, Visualization. Paul Lassmann-Klee: Formal analysis, Writing – original draft. Christian Schyllert: Writing – original draft. Ritva Luukkonen: Writing – original draft, Writing – review & editing. Mari Meren: Investigation. Matz Larsson: Investigation. Jaak Põlluste: Investigation. Britt-Marie Sundblad: Investigation. Ari Lindqvist: Resources, Writing – review & editing. Steinar Krokstad: Writing – original draft, Writing – review & editing. Hannu Kankaanranta: Writing – original draft, Writing – review & editing. Paula Kauppi: Writing – original draft, Writing – review & editing. Anssi Sovijärvi: Conceptualization, Writing – review & editing, Resources. Tari Haahtela: Writing – original draft. Helena Backman: Writing – original draft. Bo Lundbäck: Conceptualization, Writing – original draft. Päivi Piirilä: Conceptualization, Supervision.

      Declaration of competing interest

      The authors declare that they have no competing interests.

      Acknowledgements

      We thank the research nurses and assistants in Helsinki, Stockholm, Örebro, Saaremaa, Narva and Tallinn for the epidemiologic field work. Further we thank Professor Eva Rönmark, Umeå/Luleå, Sweden, for heading the coordination of the FinEsS-data and heading the work with creating the Nordic common database. We would like to offer our thanks to Nordforsk for the funding of Nordic EpiLung and enabling these studies.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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