PREVALENCE, CHARACTERISTICS AND PROGNOSIS OF EARLY COPD: THE COPENHAGEN GENERAL POPULATION STUDY

Yunus Çolak, MD, PhD1,2,3; Shoaib Afzal, MD, PhD, DMSc1,2,3; Børge G. Nordestgaard, MD, DMSc1,2,3; Jørgen Vestbo, MD, DMSc4; and Peter Lange, MD, DMSc2,3,5,6

1Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

2The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

3Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

4Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Manchester Academic Health Science Centre, University of Manchester, and Manchester University NHS Foundation Trust, Manchester, United Kingdom.

5Department of Public Health, Section of Epidemiology, University of Copenhagen, Copenhagen, Denmark.

6Department of Internal Medicine, Section of Respiratory Medicine, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Correspondence: Peter Lange, MD, DMSc, Professor, Consultant in Respiratory Medicine, Department of Public Health, Section of Epidemiology, University of Copenhagen, Øster Farimagsgade 5, Postal Box 2099, DK-1015 Copenhagen K, Denmark, Phone: +45 26879020, E-mail: Peter.Lange@sund.ku.dk

Author Contributions: YÇ and PL had full access to all data in the study and had final responsibility for the decision to submit for publication. YÇ, SA, BGN, JV, and PL contributed to the study concept and design. YÇ, SA, BGN, JV, and PL collected, analysed, or interpreted the data. YÇ wrote the draft manuscript and did the statistical analyses. YÇ, SA, BGN, JV, and PL revised the manuscript for important intellectual content. BGN obtained funding. BGN provided administrative, technical, or material support. JV and PL supervised the study.

Conflict of Interest Disclosures: YÇ reports personal fees from Boehringer Ingelheim and AstraZeneca outside of the submitted work. JV reports personal fees from GlaxoSmithKline, Chiesi Pharmaceuticals, Boehringer Ingelheim, Novartis, and AstraZeneca outside of the submitted work. PL reports grants from AstraZeneca and GlaxoSmithKline and personal fees from Boehringer Ingelheim, AstraZeneca, Novartis, and GlaxoSmithKline outside of the submitted work. BGN and SA have nothing to disclose. The views expressed are those of the authors.

Funding/Support: Funded by the Lundbeck Foundation. JV is supported by the NIHR Manchester BRC.

Role of the Sponsor: 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.

Running Head: Early COPD in the general population

Descriptor Number: 9.6 [COPD: Epidemiology]

Manuscript Length: Abstract word count: 246 (max. 250), total word count: 3678 (max. 3500), references: 35 (max. 50), and tables/figures: 7 (no max.). This article has an online data supplement, which is accessible from this issue's table of content online at www.atsjournals.org

AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject: COPD develops gradually over many years. Identification of younger adults at high risk of developing COPD could lead to implementation of preventive measures before disease onset and halt progression. Recently, an operational definition of early COPD has been proposed by an international group of experts in individuals aged <50 years with ≥10 pack-years of tobacco consumption. This is the first study to investigate early COPD in the general population using the proposed operational definition.

What This Study Adds to the Field: Using a Danish contemporary population-based cohort with 105 630 randomly selected individuals and a follow-up time of up to 14.4 years, we investigated the prevalence, characteristics, and prognosis of individuals with early COPD in the general population. We estimated the prevalence of early COPD to be 15%, defined as FEV1/FVC

ABSTRACT

Rationale: Identification of younger adults at high risk of developing chronic obstructive pulmonary disease (COPD) could lead to implementation of preventive measures before disease onset and halt progression.

Objective: To investigate the prevalence, characteristics, and prognosis of individuals with early COPD in the general population.

Methods: We investigated 105 630 randomly chosen adults from a Danish contemporary population-based cohort. Early COPD was defined as forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC)

Measurements and Main Results: Among 8064 individuals aged <50 years with ≥10 pack-years of tobacco consumption, 1175 (15%) had early COPD, of whom 58% were current smokers. Individuals with early COPD more often had chronic respiratory symptoms, severe lung function impairment, asthma, and a history with bronchitis/pneumonia. During 14.4 years follow-up, we observed 117 acute hospitalisations with obstructive lung disease, 227 acute hospitalisations with pneumonia, and 185 deaths among the 8064 younger adults. Compared to individuals without COPD, those with early COPD had multivariable adjusted hazard ratios (HRs) of 6.42(95% confidence interval:3.39-12.2) for acute obstructive lung disease hospitalisations, 2.03(1.43-2.88) for acute pneumonia hospitalisations, and 1.79(1.28-2.52) for all-cause mortality.

Conclusions: Among individuals aged <50 years and ≥10 pack-years of tobacco consumption from the general population, 15% fulfil criteria of early COPD. Individuals with early COPD more often have chronic respiratory symptoms and severe lung function impairment, and an increased risk of acute respiratory hospitalisations and early death.

Abstract word count: 246

INTRODUCTION

Worldwide, chronic obstructive pulmonary disease (COPD) is a prevalent disease and one of the leading causes of morbidity and mortality, a scenario likely to persist for many years.1 One possible explanation for the poor prognosis may be that most COPD patients are diagnosed and only start treatment late in the disease course when a significant degree of airflow limitation is already present. Since COPD develops gradually over many years, identification of younger adults at high risk of developing COPD could lead to implementation of preventive measures before disease onset, and thereby halt progression to improve long-term prognosis.2-5

Recently, an operational definition of early COPD has been proposed by an international group of experts.6 Accordingly, early COPD should be defined in individuals aged <50 years with ≥10 pack-years of tobacco consumption with one or more of the following: (i) forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC)

In the present study, we investigated the prevalence, characteristics, and prognosis of individuals with early COPD in the general population. For this purpose, we used a Danish contemporary population-based cohort with 105 630 randomly selected individuals and a follow-up time of up to 14.4 years.

METHODS

Study Design and Population

We recruited individuals aged 20-100 years from the Copenhagen General Population Study, a Danish contemporary population-based cohort initiated in November 26, 2003 with ongoing enrolment.7,8 In the present study, we included 105 630 individuals with complete information on smoking and lung function recruited up to April 28, 2015. In Denmark, all individuals are assigned a unique identification number at birth or immigration in the national Danish Civil Registration System. Individuals living in the Capital Region of Denmark were randomly invited from the national Danish Civil Registration System to reflect the adult Danish population (response-rate 43%). All participants completed a questionnaire, underwent a physical examination, and provided blood for biochemical analyses. Questionnaires were reviewed at the day of attendance by a healthcare professional together with the participant. To avoid potential recall bias, questionnaires were completed and retrieved before the physical examination and blood analyses, and the participants were unaware of specific future studies and clinical outcomes. The study was approved by Herlev and Gentofte Hospital and the regional ethics committee (approval number:H-KF-01-144/01), and was conducted according to the Declaration of Helsinki. All participants provided written informed consent.

Early COPD

Date of birth and sex was obtained from the national Danish Civil Registration System. Information on smoking status and tobacco consumption was obtained from the questionnaire. Smoking status was defined as never, former, or current smoking. Cumulated tobacco consumption was calculated in pack-years based on information on age at smoking initiation and cessation (or for current smokers until age at baseline examination), duration of tobacco consumption, and amount of consumed tobacco in form of number of daily consumed cigarettes, cheroots, and cigars and grams of weekly consumed pipe tobacco (one cheroot=three grams of tobacco, one cigar=five grams of tobacco, and one gram of tobacco=one cigarette): a pack-year was defined as 20 cigarettes or equivalent smoked daily for a year. Thus, individuals not likely to have early COPD were excluded, i.e. aged 50 years or older and tobacco consumption less than 10 pack-years.

Pre-bronchodilator FEV1 and FVC were measured at the baseline examination. Spirometry use in the Copenhagen General Population Study has undergone a rigorous validation process.9 Predicted values were calculated according to national Danish lung function reference equations, which are based on 11 288 healthy asymptomatic never-smoking individuals with age and height as covariates separately for men and women.9 The LLN, defined as the bottom 5th percentile of the predicted value, was calculated as the mean value minus 1.645 standard deviations. Early COPD was defined as a FEV1/FVC

Outcomes

Information on outcomes was obtained from Danish nationwide health registries. Main outcomes included acute hospitalisations due to obstructive lung disease, i.e. COPD and asthma, and pneumonia and all-cause mortality. Acute hospitalisations due to obstructive lung disease (International Classification of Diseases [ICD]-10:J41-J46) and pneumonia (ICD-10:J12-J18) included all emergency department visits and hospital admissions with the mentioned primary discharge diagnosis. The information was available from the national Danish Patient Registry, which covers all public and private hospital contacts in Denmark, recorded from baseline until April 10, 2018. Information on vital status was available from the national Danish Civil Registration System, which contains date of death and emigration for all residents in Denmark, recorded from baseline until April 19, 2018.

Secondary outcomes included cause-specific mortality and comorbidities. Detailed description of secondary outcomes is provided in the online data supplement.

As follow-up was done by combining the nationwide health registries with the national Danish Civil Registration System through the unique identification number provided to everyone at birth or immigration, no person was lost to follow-up, and individuals who emigrated were censored at the date of emigration (n=452). All diagnoses recorded in the registries are made by a medical doctor according to national Danish laws using the World Health Organisations ICD codes.

Statistical Analyses

Wilcoxon's rank-sum, Pearson's χ2, and Fisher's exact tests were used for group comparison. Cumulative incidences for acute hospitalisation due to obstructive lung disease and pneumonia were determined with all-cause mortality and emigration as competing events using the method of Coviello & Boggess,10 and differences were assessed using the method of Pepe & Mori.11 Cumulative incidence for all-cause mortality was determined using the Kaplan-Meier estimator, and difference was assessed using a log-rank test. Cox proportional regression model with age as the underlying timescale (=age adjustment) and left truncation (=delayed entry) was used to determine risk of acute hospitalisations due to obstructive lung disease and pneumonia and of all-cause mortality. For acute hospitalisations, we carried out multiple failure-time analysis using the Andersen-Gill approach, i.e. individuals were at risk of recurrent events.12 To avoid counting a single event multiple times, we chose that hospitalised individuals during follow-up had to be clinically stable for at least 4 weeks after discharge before they were at risk for a subsequent event, in accordance with previous recommendations.13-16 Single failure-time analysis was used for all-cause and cause-specific mortality and for comorbidities. Analyses were adjusted for potential confounders, including age (as timescale), sex, smoking status, and pack-years of tobacco consumption. Stratified analyses in individuals with early COPD were undertaken to investigate potential prognostic predictors of acute hospitalisations and death; effect modification was assessed by using Wald's test for interaction. In sensitivity analyses, (i) LLN was defined by calculating predicted values according to the Global Lung Initiative lung function reference equations,17 (ii) individuals reporting asthma and/or treatment with airway medication were excluded, and (iii) individuals with known interstitial lung disease were excluded. Prognosis of individuals with early COPD was also investigated by adjusting for presence of chronic respiratory symptoms, as chronic respiratory symptoms have been associated with increased risk of respiratory hospitalisations and death in individuals with normal spirometry.18 In addition, in order to bring a perspective to the clinical significance of the findings in individuals with early COPD, we also determined the prognosis of older individuals with COPD, defined as FEV1/FVC

RESULTS

Prevalence

Among 105 630 individuals from the Copenhagen General Population Study, 8064 (8%) were aged <50 years with ≥10 pack-years of tobacco consumption, of whom 1175 (15%) had early COPD, defined as FEV1/FVC

Characteristics

Individuals with early COPD were more often current smokers (58% versus 46%) and had a higher tobacco consumption (22.5 pack-years versus 18.8 pack-years), compared to those at risk but without COPD (Table 1). A substantial proportion had lung function impairment with FEV1 <80% of predicted (40% versus 9%), FEV1 <50% of predicted (3% versus <1%), and FEV1/FVC <0.70 (75% versus <1%); the latter observation being in line with the LLN criterion included in the early COPD definition. Furthermore, individuals with early COPD more often reported chronic respiratory symptoms, asthma (15% versus 5%), treatment with airway medication (13% versus 4%), and a history with bronchitis/pneumonia episodes (35% versus 27%). Among individuals with early COPD, these characteristics were even more noticeable in the subgroup with FEV1 <80% of predicted (Table E1 in the online data supplement).

When individuals with and without early COPD were stratified according to presence of chronic respiratory symptoms, symptomatic individuals without COPD were comparable to symptomatic individuals with early COPD; however, the latter group had markedly lower lung function and a higher prevalence of asthma and treatment with airway medication (Table E2). Similarly, asymptomatic individuals with and without early COPD were comparable except for lung function parameters.

Prognosis

During up to 14.4 years of follow-up (median: 10.1 years), we observed 117 acute hospitalisations with obstructive lung disease, 227 acute hospitalisations with pneumonia, and 185 deaths among the 8064 younger adults at risk of early COPD. Already after a short follow-up time, individuals with early COPD displayed a higher incidence of acute hospitalisations with obstructive lung disease and pneumonia compared to those without COPD (Figure 3). No difference was observed during the first four years of follow-up with regard to incidence of all-cause mortality, followed by an increase in individuals with early COPD. Compared to individuals without COPD, individuals with early COPD had multivariable adjusted hazard ratios (HRs) of 6.42 (95% confidence interval [CI]:3.39-12.2) for acute obstructive lung disease hospitalisations, 2.03 (1.43-2.88) for acute pneumonia hospitalisations, and 1.79 (1.28-2.52) for all-cause mortality (Figure 4).

When individuals with and without early COPD were stratified according to presence of chronic respiratory symptoms, symptomatic individuals without COPD had an increased risk of acute hospitalisations but not of death, while symptomatic individuals with early COPD had an increased risk of all outcomes (Figure 5). Asymptomatic individuals with and without early COPD did not differ with regard to prognosis. Compared to asymptomatic individuals without COPD, multivariable adjusted HRs for acute obstructive lung disease hospitalisations were 4.96 (95% CI:1.24-19.9) in symptomatic individuals without COPD, 2.54 (0.40-16.2) in asymptomatic individuals with early COPD, and 29.5 (6.98-124) in symptomatic individuals with early COPD. Corresponding HRs were 1.59 (1.07-2.35), 0.85 (0.34-2.12), and 3.47 (2.19-5.50) for acute pneumonia hospitalisations and 1.13 (0.79-1.61), 1.66 (0.84-3.27), and 2.03 (1.30-3.18) for all-cause mortality, respectively. However, there was no clear statistical evidence of effect modification between early COPD and chronic respiratory symptoms on risk of acute obstructive lung disease hospitalisations (P-value for interaction=0.39), acute pneumonia hospitalisations (P-value for interaction=0.06), or of all-cause mortality (P-value for interaction=0.84) (Figure 6).

Stratified analyses in individuals with early COPD revealed that presence of FEV1 <80% of predicted, chronic respiratory symptoms, asthma, and a history with bronchitis/pneumonia were mainly associated with increased risk of acute hospitalisations and early death (Figure 6). Effect modification with early COPD was only observed for FEV1 <80% of predicted on risk of acute pneumonia hospitalisations (all other P-values for interaction ≥0.05).

Since we recorded a relatively low number of deaths in this young population, we were limited in investigating cause-specific mortality. We observed that individuals with early COPD had an increased risk of deaths from other causes than respiratory disease, cardiovascular disease, or cancer compared to those without COPD (Figure E1). Nonetheless, symptomatic individuals with early COPD had an increased risk of respiratory mortality compared to asymptomatic individuals without COPD with a multivariable adjusted HR of 11.4 (95% CI:1.13-116) (Figure E2). We observed no differences between individuals with versus without early COPD, regardless of presence of symptoms, with regard to risk of ischaemic heart disease, heart failure, lung cancer, or any cancer (Figures E3 and E4).

Sensitivity Analyses and Comparison with Older Individuals with COPD

Results were similar after redefining LLN by calculating predicted values according to the Global Lung Initiative lung function reference equations (compare Figures 4 and 5 with Figures E5 and E6). Results were also largely similar after exclusion of individuals reporting asthma and/or treatment with airway medication (compare Figures 4 and 5 with Figures E7 and E8); however, results for symptomatic individuals without COPD were attenuated and no longer associated with risk of acute hospitalisations. Results were likewise similar after exclusion of individuals with interstitial lung disease (compare Figures 4 and 5 with Figures E9 and E10). Finally, results were similar after adjusting for presence of chronic respiratory symptoms (compare Figure 4 with Figure E11). Interestingly, after adjusting for FEV1/FVC

Lastly, prognosis for main outcomes was compared between younger individuals with early COPD and older individuals with COPD. While the prevalence of early COPD was 15%, the prevalence of COPD was 25%, defined as FEV1/FVC

DISCUSSION

By using a Danish contemporary population-based cohort with 105 630 randomly selected individuals, we estimated the prevalence of early COPD to be 15%, defined as FEV1/FVC

More than half of individuals with early COPD were active smokers and thus at high risk of progression of lung function impairment leading to development of clinical disease with accompanying reduced life-expectancy. Early detection and intervention in form of smoking cessation could potentially halt progression and change the disease course accordingly.19 It is important to note that a substantial proportion of individuals with early COPD already had clinical signs of disease onset at baseline examination in the form of chronic respiratory symptoms and lung function impairment with FEV1 <80% of predicted. Furthermore, an increased risk of acute hospitalisations due to obstructive lung disease and pneumonia was already observed after a very short follow-up time. These observations suggest that the newly proposed operational definition of early COPD may capture not only mild but also moderate cases of COPD.6 Perhaps, we need to refine the definition so the very early phases of disease development can be captured in order to implement prevention before a substantial lung damage has taken place.

Since chronic respiratory symptoms may precede the development of COPD,18,20-24 we chose to stratify individuals with and without early COPD accordingly. Interestingly, half of individuals without COPD reported chronic respiratory symptoms. It seemed that symptomatic individuals with and without early COPD had several clinical features in common at baseline examination and shared a similar poor prognosis besides risk of all-cause mortality. It is possible that some of these symptomatic individuals with FEV1/FVC ≥LLN may have early COPD despite of a normal spirometry, e.g. evidenced by CT abnormalities and/or increased FEV1 decline. Individuals with normal spirometry and chronic respiratory symptoms have been observed with increased airway wall thickness, pulmonary emphysema, gas trapping, and abnormal diffusing capacity and a prognosis resembling that of COPD.18,25,26 However, it is remarkable that upon exclusion of individuals with asthma from the analyses, symptomatic individuals without COPD did no longer have an increased risk of acute hospitalisations due to obstructive lung disease or pneumonia, suggesting that asthma may have driven the poor prognosis in this group (compare Figure 5 with Figure E8). In contrast, symptomatic individuals with early COPD still had an increased risk of acute hospitalisations and early death. Nonetheless, it is noticeable that despite of only using one of the three criteria of the proposed operational definition, i.e. FEV1/FVC

As many as one-third of individuals with early COPD were asymptomatic. Asymptomatic individuals with early COPD had the same risk of investigated outcomes as asymptomatic individuals without COPD. Although this could easily be due to insufficient statistical power, they shared similar characteristics at baseline examination except for lung function parameters, which were markedly lower in those with early COPD. Yet, asymptomatic individuals with early COPD differed substantially from symptomatic individuals with early COPD. Presence of chronic respiratory symptoms may be a prognostic marker of disease progression in early COPD, which is also in accordance with previous observations.18,20-24 An intervention in symptomatic individuals with early COPD would probably have greater impact than in asymptomatic individuals. Despite lung function impairment, asymptomatic individuals with early COPD may not develop clinical disease. Nonetheless, investigating progression of early COPD in those with and without chronic respiratory symptoms seems warranted.

A few previous studies have investigated clinical characteristics and prognosis in young patients with COPD. In a clinical study comprising 1708 patients with COPD, severity distribution and progression of disease in those aged ≤55 years were like those aged ≥65 years, suggesting that COPD has its origin of disease components already in young age.27 This is in keeping with the present findings of younger individuals with early COPD having similar distribution of clinical characteristics and prognosis like older individuals with COPD. In a pre-specified post hoc analysis of the UPLIFT trial comprising 356 patients with moderate to severe COPD aged 40-50 years, those treated with tiotropium had improved quality of life and decreased exacerbation rate compared to those treated with placebo, suggesting that early treatment with a long-acting bronchodilator may benefit long-term prognosis in early COPD.28

Strengths of the present study include a large contemporary population-based cohort study with randomly selected individuals with a long and complete follow-up, and with information on COPD related characteristics and outcomes.

A major limitation is that only pre-bronchodilator and not post-bronchodilator spirometric indices were available, precluding characterisation of airflow limitation into reversible or irreversible type. Although using pre-bronchodilator instead of post-bronchodilator values has been shown to overestimate prevalence of COPD,29,30 there seems to be no difference in diagnostic accuracy for COPD between them.31 Nonetheless, as early COPD was defined in a high-risk population with substantial cumulated tobacco consumption, which is usually an inclusion criterion in clinical trials with COPD and an exclusion criterion in clinical trials with asthma,32 we believe to have identified most cases of early COPD correctly. In accordance with the proposed operational definition of early COPD,6 we have deliberately not excluded individuals with asthma from the present study, as asthma may precede and contribute to the risk of developing COPD later in life.33,34 Nonetheless, results were similar in sensitivity analyses after exclusion of individuals reporting asthma and/or treatment with airway medication.

Another potential limitation is that we did not have information on lung imaging with CT. Thus, some individuals with a normal spirometry may have CT abnormalities suggesting presence of early COPD. However, this would bias results towards the null, and therefore cannot explain our findings.

Lastly, although we used the proposed operational definition of early COPD requiring tobacco exposure, we cannot ignore the fact that some never-smokers with relevant risk factors will develop COPD and could also be identified early in the disease course.35

Clinical implications of the present study relate to early detection and intervention in COPD to influence disease course. Early COPD seems to be prevalent among young and middle-aged adults with tobacco exposure, and these individuals had a relatively similar poor prognosis as older individuals with COPD. Since more than half of them were active smokers, smoking cessation is the most obvious intervention. Nonetheless, we need trials investigating whether treatment intervention in these young susceptible smokers will halt progression and improve long-term prognosis. Our results suggest that especially presence of chronic respiratory symptoms, asthma, and a history with bronchitis/pneumonia were all important characteristics that could be used to identify subgroups with the highest risk of progression of early COPD.

In conclusion, among individuals aged <50 years and ≥10 pack-years of tobacco consumption from the general population, 15% fulfil criteria of early COPD. Individuals with early COPD more often have chronic respiratory symptoms and severe lung function impairment, and an increased risk of acute respiratory hospitalisations and early death.

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1

Table 1. Baseline characteristics according to presence of early COPD among individuals aged <50 years with ≥10 pack-years of tobacco consumption in the Copenhagen General Population Study.

No COPD

(n=6889)

Early COPD

(n=1175)

General characteristics

Age – years

45.0 (42.0-47.6)

45.9 (42.8-48.1)*

Male sex – no. (%)

3181 (46)

490 (42)*

BMI – kg/m2

25.7 (23.4-28.7)

24.6 (22.5-27.3)*

FEV1 predicted – %

97 (88-105)

83 (74-92)*

FVC predicted – %

99 (90-107)

101 (90-111)*

FEV1/FVC

0.79 (0.76-0.83)

0.68 (0.65-0.70)*

Current smokers – no. (%)

3167 (46)

678 (58)*

Tobacco consumption – pack-years

18.8 (13.5-26.0)

22.5 (15.0-30.0)*

Age at smoking initiation – years

15.0 (14.0-17.0)

15.0 (14.0-17.0)*

Poor socioeconomic status – no. (%)

1123 (16)

233 (20)*

Clinical characteristics

FEV1

638 (9)

492 (42)*

FEV1 <80% of predicted – no. (%)

596 (9)

471 (40)*

FEV1 <50% of predicted – no. (%)

2 (<1)

32 (3)*

FEV1/FVC <0.70 – no. (%)

2 (<1)

879 (75)*

Chronic mucus hypersecretion – no. (%)

722 (10)

234 (20)*

Dyspnoea – no. (%)

2307 (33)

538 (46)*

mMRC ≥2 – no. (%)

454 (7)

124 (11)*

Night-time dyspnoea – no. (%)

293 (4)

108 (9)*

Wheezing – no. (%)

1867 (27)

543 (46)*

Cough – no. (%)

1339 (19)

378 (32)*

1st degree relative with asthma – no. (%)

1347 (20)

336 (29)*

Childhood asthma/allergy – no. (%)

1259 (18)

280 (24)*

Asthma – no. (%)

354 (5)

180 (15)*

Treatment with airway medication – no. (%)

245 (4)

155 (13)*

Physically inactive – no. (%)

763 (11)

162 (14)*

Bronchitis/pneumonia episodes in the last 10 years – no. (%)

1868 (27)

414 (35)*

General practitioner visits in the last 12 months – no. (%)

5280 (77)

947 (81)*

α1-antitrypsin <1 g/L – no. (%)

648 (9)

107 (9)

Blood eosinophils ≥300 cells/µL – no (%)

1304 (19)

254 (22)*

Data presented as median (25th and 75th percentiles), or number (percent). Early COPD was defined as FEV1/FVC

*P<0.05 for comparison with individuals without COPD, obtained from Wilcoxon's rank-sum, Pearson's χ2 tests, or Fischer's exact test.

FIGURE LEGENDS

Figure 1. Study population. Symptoms included chronic mucus hypersecretion, dyspnoea, wheezing, and/or cough. COPD=chronic obstructive pulmonary disease. FEV1=forced expiratory volume in 1 second. FVC=forced vital capacity. LLN=the lower limit of normal.

Figure 2. Prevalence of FEV1/FVC

Figure 3. Cumulative incidence of acute hospitalisations due to obstructive lung disease and pneumonia and of death in individuals with and without early COPD. Included individuals are aged <50 years with ≥10 pack-years of tobacco consumption. Early COPD was defined as FEV1/FVC

Figure 4. Risk of acute hospitalisations due to obstructive lung disease and pneumonia and of death in individuals with and without early COPD. Included individuals are aged <50 years with ≥10 pack-years of tobacco consumption. Early COPD was defined as FEV1/FVC

Figure 5. Risk of acute hospitalisations due to obstructive lung disease and pneumonia and of death in symptomatic and asymptomatic individuals with and without early COPD. Included individuals are aged <50 years with ≥10 pack-years of tobacco consumption. Early COPD was defined as FEV1/FVC

Figure 6. Risk of acute hospitalisations due to obstructive lung disease and pneumonia and of death in individuals with early COPD. Early COPD was defined as FEV1/FVC

Figures

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