Prognosis of asymptomatic and symptomatic undiagnosed

chronic obstructive pulmonary disease in the general

population: a prospective cohort study

Yunus Çolak, PhD; Shoaib Afzal, PhD; Børge G. Nordestgaard, DMSc; Jørgen Vestbo, DMSc; and

Peter Lange, DMSc

Department of Internal Medicine, Section of Respiratory Medicine, Herlev and Gentofte Hospital,

Copenhagen University Hospital, Herlev, Denmark (Dr. Çolak).

Department of Public Health, Section of Social Medicine, University of Copenhagen, Copenhagen,

Denmark (Dr. Çolak and Prof. Lange).

The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University

Hospital, Herlev, Denmark (Dr. Çolak, Dr. Afzal, Prof. Nordestgaard, and Prof. Lange).

Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (Dr.

Çolak, Dr. Afzal, Prof. Nordestgaard, and Prof. Lange).

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University

Hospital, Herlev, Denmark (Dr. Afzal and Prof. Nordestgaard).

Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences,

Manchester Academic Health Science Centre, University of Manchester, Manchester, United

Kingdom (Prof. Vestbo).

1

Medical Unit, Respiratory Section, Hvidovre Hospital, Copenhagen University Hospital, Hvidovre,

Denmark (Prof. Lange).

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: Peter.Lange@sund.ku.dk

Key words: emphysema; bronchitis, chronic; diagnosis; forced expiratory volume; spirometry;

smoking; asthma; airway obstruction.

Summary of total word count and other requirements:

Abstract word count: 313 (max. 300)

Total word count: 3401 (max. 3000)

References: 33 (max. 30)

Tables/Figures: 5 (no max.)

Supplement is available

2

Abstract

Background:Chronic obstructive pulmonary disease(COPD) can be detected early using

spirometry, but its use is only recommended in symptomatic smokers, although early stages of

COPD may be asymptomatic. We investigated the prognosis of asymptomatic and symptomatic

individuals with undiagnosed COPD in the general population.

Methods:Among 95 288 individuals aged 20-100years from the Copenhagen General Population

Study, 32 518 were assigned being at risk for COPD, defined as, age ≥40years, cumulative tobacco

consumption ≥10 pack-years, and no asthma. COPD was defined as a forced expiratory volume in 1

second(FEV1)/forced vital capacity(FVC)<0·70 and <lower limit of normal and FEV1<80% of the

predicted normal value. Individuals were considered undiagnosed if neither a previous COPD

hospital contact nor medical treatment for COPD was registered. Cox proportional hazard models

were used to assess risk of exacerbations, pneumonias, respiratory deaths, and deaths from all

causes from 2003 through 2014.

Results:In total, 3699 fulfilled the COPD criteria and 2903 (78%) were undiagnosed, of whom

2052 (71%) were symptomatic. We observed 800 exacerbations, 2038 pneumonias, and 2789

deaths including 152 deaths due to respiratory disease during a median follow-up of

6·1years(range:12days-11years). Compared to individuals without COPD, age and sex adjusted

hazard ratios(HRs) for exacerbations and pneumonias were 5·1(95% confidence interval:2·9-9·1)

and 1·7(1·3-2·2) for individuals with undiagnosed asymptomatic COPD and 16(11-22) and 2·8(2·4-

3·3) for individuals with undiagnosed symptomatic COPD. Corresponding HRs for respiratory

death and death from all causes were 0·7(0·2-3·0) and 1·3(1·1-1·6) for individuals with

undiagnosed asymptomatic COPD and 4·4(2·8-6·7) and 2·0(1·8-2·3) for individuals with

undiagnosed symptomatic COPD.

3

Interpretation:Individuals with undiagnosed symptomatic COPD had an increased risk of

exacerbations, pneumonias, and death. Individuals with undiagnosed asymptomatic COPD had an

increased risk of exacerbations and pneumonias. These findings suggest that there is a need for

better initiatives for early diagnosis and treatment of COPD.

Funding:The Danish Lung Association, the Danish Cancer Society, Herlev and Gentofte Hospital,

Copenhagen University Hospital, and University of Copenhagen.

4

Research in context

Evidence before this study: Recently, an update from the US Preventive Services Task Force

(USPSTF) recommended against screening for COPD in asymptomatic smokers due to lack of

evidence. Before conducting the present study, we searched PubMed for clinical and

epidemiological studies published in English between January 1 2000 and November 1 2016, by

using the following medical subject heading terms: “chronic obstructive pulmonary disease”,

“airflow limitation”, “airway obstruction”, “undiagnosed”, “under-diagnosis”, and “mass

screening”. In general, the burden of under-diagnosis in COPD is substantial. Individuals with

undiagnosed COPD have a milder disease compared to those with diagnosed COPD, but they were

still experiencing exacerbations and premature death; however, no studies have described the long-

term prognosis of undiagnosed individuals while differentiating between those with and those

without respiratory symptoms.

Added value of this study: In a cohort of adult smokers from the general population, we

differentiate between individuals with asymptomatic and symptomatic undiagnosed COPD and

compare their prognosis to the prognosis of individuals without COPD. We found approximately

78% of individuals with COPD to be undiagnosed. Individuals with undiagnosed symptomatic

COPD had an increased risk of exacerbations, pneumonias, and death, whereas individuals with

undiagnosed asymptomatic COPD had an increased risk of exacerbations and pneumonias.

Implications of all the available evidence: Among individuals with undiagnosed COPD,

symptoms herald a poorer prognosis, but also asymptomatic individuals with COPD have a

substantial increased risk of respiratory complications compared to smokers without COPD. The

high prevalence of under-diagnosis in COPD, and the observed poor prognosis among individuals

5

with undiagnosed COPD highlights the importance of implementing better initiatives for early

diagnosis and treatment of COPD.

6

Introduction

Worldwide, chronic obstructive pulmonary disease (COPD) is one of the leading causes of

morbidity and mortality, and it is estimated that it will remain so for many years.1 Although there

are several risk factors for COPD, smoking is the single most important one, especially in Western

societies.2 The hallmark of COPD is airflow limitation that can be determined using spirometry.2

Due to slow progression of lung function impairment in most cases, spirometry can be used in high-

risk populations, e.g. smokers, to diagnose COPD early.3 Most guidelines as well as the Global

Initiative for Chronic Obstructive Lung Disease (GOLD) Strategy Document only recommend use

of spirometry for early detection in symptomatic smokers.2,4,5 Recently, an update on screening for

COPD from the US Preventive Services Task Force (USPSTF) recommended against screening for

COPD in asymptomatic smokers, mainly because such screening did not seem to result in higher

smoking cessation rates.6–8 Nevertheless, early stages of COPD can be asymptomatic resulting in

under-diagnosis even though significant airflow limitation may already be present3 and the burden

of under-diagnosis in COPD is substantial.9–12 Individuals with undiagnosed COPD were recently

found to have fewer symptoms and less impairment than those with diagnosed COPD, but they

were still a considerable burden to the healthcare system13 and had an increased risk of early death.14

Yet, the impact of symptoms on the long-term prognosis of individuals with undiagnosed COPD in

the general population is unknown.

In the present study, we investigated the prognosis of asymptomatic and symptomatic individuals

with undiagnosed COPD using a general population setting. For this purpose, we used a population-

based prospective cohort study in Copenhagen in Denmark including 95 288 participants. We

hypothesized that individuals with undiagnosed COPD would have a poor prognosis compared to

individuals without COPD, irrespective of presence of respiratory symptoms.

7

Methods

Study design and participants

We recruited 95 288 individuals aged 20-100 years from the Copenhagen General Population

Study, a Danish population-based prospective cohort study of the general population that was

initiated in November 2003 with ongoing enrollment.15 Individuals were randomly selected from the

National Danish Civil Registration System to reflect the adult white Danish population of Danish

descent based on age and sex, using the unique identification number provided to everyone at birth

or immigration. All participants completed a comprehensive questionnaire, underwent a physical

health examination, and provided blood for biochemical analyses. Questionnaires were reviewed at

the day of attendance by a healthcare professional together with the participant. The study was

conducted according to the Declaration of Helsinki and was approved by Herlev and Gentofte

Hospital and the regional ethics committee (H-KF-01-144/01). Written informed consent was

obtained from all participants.

Definition of COPD and classification of the study population

Since the purpose of the study was to investigate consequences of undiagnosed COPD in the

general population, individuals less likely to have COPD were excluded based on low age, minimal

cumulative tobacco consumption, and/or asthma (Figure 1). Thus, the study population comprised

former and current smokers aged 40 years or more with a cumulated tobacco consumption

corresponding to 10 pack-years or above, and without asthma. Asthma was based on self-report or a

previous inpatient or outpatient hospital contact due to asthma (International Classification of

Diseases [ICD]-8:493 and ICD-10:J45-J46), obtained from the National Danish Patient Registry.

The National Danish Patient Registry covers all public and private Danish hospitals, recorded until

8

November 2014. Denmark used the ICD-8 until January 1994 and proceeded directly to ICD-10

hereafter. One pack-year was 20 cigarettes or equivalent, e.g. cigars, cheroots, pipe, smoked daily

for one year.

Lung function was determined using spirometry.16 Pre-bronchodilator measurements of forced

expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were available. Internally

developed reference values based on healthy asymptomatic never-smokers were used to calculate

predicted values.16 We used a conservative definition of airflow limitation defined as

FEV1/FVC<0·70 and <lower limit of normal (LLN) and FEV1<80% of predicted value.17 LLN was

calculated as mean value minus 1·645 standard deviations. Individuals were considered to be

undiagnosed with COPD if they had airflow limitation but no previous inpatient or outpatient

hospital contact due to COPD (ICD-8:491-492 and ICD-10:J41-J44), obtained from the National

Danish Patient Registry, and no treatment for COPD; i.e., daily or almost daily use of medication

for asthma/bronchitis. Individuals were considered to have respiratory symptoms if they reported

chronic mucus hypersecretion, dyspnoea, wheezing, and/or cough. A more detailed description of

the questions used for respiratory symptoms and other characteristics can be found in the

Supplement. Based on the obtained information, individuals were assigned into the following five

groups (Figure 1):

1) No COPD: former and current smokers aged ≥40 years, with cumulative tobacco

consumption ≥10 pack-years, without asthma, with a normal lung function, without a

previous hospital contact with COPD, and reporting not to be on treatment for COPD.

2-5) COPD: former and current smokers aged ≥40 years, with cumulative tobacco consumption

≥10 pack-years, without asthma, and with airflow limitation.

9

2) Undiagnosed asymptomatic COPD: asymptomatic individuals with airflow

limitation but without a previous hospital contact with COPD and reporting not to

be on treatment for COPD.

3) Undiagnosed symptomatic COPD: symptomatic individuals with airflow

limitation but without a previous hospital contact with COPD and reporting not to

be on treatment for COPD.

4) Diagnosed asymptomatic COPD: asymptomatic individuals with airflow

limitation with a previous hospital contact with COPD and/or reporting to be on

treatment for COPD.

5) Diagnosed symptomatic COPD: symptomatic individuals with airflow limitation

with a previous hospital contact with COPD and/or reporting to be on treatment

for COPD.

Endpoints

Exacerbations (ICD-8:491-492 and ICD-10:J41-J44) and pneumonias (ICD-8:480-486 and ICD-

10:J12-J18) were defined as emergency department visits or hospital admissions with the mentioned

primary discharge diagnosis. Information on vital status was obtained from the National Danish

Civil Registration System, recorded until November 2014. Information on cause of death was

obtained from the National Danish Causes of Death Registry, recorded until January 2013. Death

from respiratory disease (ICD-8:460-519 and ICD-10:J00-J99) was only based on the primary cause

of death. The National Danish Causes of Death Registry lags the Danish Civil Registration System

by one year, so not all deaths could be classified by cause. As follow-up was done using the above

register linkage based on the unique person registration number, no person was lost to follow-up,

and individuals who emigrated were censored at the date of emigration (n=376). All diagnoses

recorded in the registries are made by a doctor.

10

Statistical analyses

Wilcoxon rank-sum test, Pearson χ2 test, and Fisher’s exact test were used in the cross-sectional

analyses. Cox proportional hazard models with 95% confidence intervals (CIs) were used in the

prospective analyses, determining risk of exacerbations, pneumonias, respiratory mortality, and all-

cause mortality with individuals without COPD as the reference group. For exacerbations and

pneumonias, we carried out multiple failure-time analysis using the Andersen-Gill approach,

meaning that individuals were at risk of recurrent events.18 Otherwise, an approach with single

failure-time analysis was used. Since we were particularly interested in the roles of smoking history

as a potential confounder and of FEV1 % predicted as a potential mediator affecting the risk of the

investigated outcomes (Figure S1), we present the models including these covariates in the main

manuscript, whereas models including other covariates are shown in the Supplement. Kaplan-Meier

analyses were used with left truncation and age as the underlying time scale without further

adjustments.19 All statistical analyses were performed using STATA/SE 13·1 for Windows

(StataCorp, College Station, Texas, US) and a two-sided P-value<0·05 was considered significant.

Additional modelling approaches and sensitivity analyses can be found in the Supplement.

Role of the funding source

The funders had no role in the design and conduct of the study; collection, management, analysis, or

interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit

the manuscript for publication. YÇ and PL had full access to all of the data in the study and had

final responsibility for the decision to submit for publication.

11

Results

Among 95 288 individuals, 32 518 (34%) were at risk of having COPD (Figure 1). In this group,

3699 (11%) had COPD, of whom 2903 (78%) were undiagnosed. Among the individuals with

undiagnosed COPD, 2052 (71%) reported to have respiratory symptoms. Median follow-up was 6·1

years (range:12 days to 11 years).

Characteristics

Individuals with COPD were older, more often current smokers and had higher cumulative tobacco

consumption, poorer socioeconomic status, and higher levels of all inflammatory biomarkers

compared to those without COPD (Tables 1 and 2). The proportion of individuals with FEV1<50%

of predicted, corresponding to severe or very severe degree of airflow limitation, was 5% in

individuals with undiagnosed asymptomatic COPD and 13% in those with undiagnosed

symptomatic COPD. Compared to those without COPD, individuals with COPD reported more

often a history of respiratory infections and had a higher number of visits to a general practitioner;

however, the difference seemed to be small between individuals without COPD and individuals

with undiagnosed COPD. Dyspnoea was the most frequent respiratory symptom, and the pattern of

symptoms seemed to be similar for individuals with undiagnosed and diagnosed COPD. However,

the prevalence of each symptom was lower in those with undiagnosed COPD.

Exacerbations and pneumonias

During the observation period, we observed 800 exacerbations of COPD and 2038 pneumonias

(Table S1). Individuals with undiagnosed COPD, irrespective of respiratory symptoms, had an

12

increased risk of both recurrent exacerbations and pneumonias compared to individuals without

COPD (Figures 2 and 3). Age and sex adjusted hazard ratios (HRs) for exacerbations and

pneumonias were 5·1 (95% CI: 2·9-9·1) and 1·7 (1·3-2·2) for individuals with undiagnosed

asymptomatic COPD and 16 (11-22) and 2·8 (2·4-3·3) for individuals with undiagnosed

symptomatic COPD. Adjustment for smoking status and cumulative tobacco consumption did not

seem to affect the risk estimates (Figure 2, middle panels). After adjustment for FEV1 % of

predicted, individuals with undiagnosed asymptomatic COPD were no longer at risk of

exacerbations or pneumonias (Figure 2, right panels).

Respiratory and all-cause mortality

We observed 2789 deaths of which 152 were due to respiratory disease (Table S1). Compared to

individuals without COPD, individuals with undiagnosed symptomatic COPD had an increased risk

of death, including from respiratory disease, whereas individuals with undiagnosed asymptomatic

COPD only seemed to have an increased risk of death from all causes (Figures 2 and 3).

Furthermore, risk of death from respiratory disease seemed to be restricted to older individuals. Age

and sex adjusted HRs for death from respiratory disease and from all causes were 0·7 (0·2-3·0) and

1·3 (1·1-1·6) for individuals with undiagnosed asymptomatic COPD and 4·4 (2·8-6·7) and 2·0

(1·8-2·3) for individuals with undiagnosed symptomatic COPD. After adjustment for current

smoking status and cumulative tobacco consumption, individuals with undiagnosed asymptomatic

COPD were no longer at risk of death from all causes (Figure 2, middle panels). After adjustment

for FEV1 % of predicted, individuals with undiagnosed symptomatic COPD were no longer at

increased risk of death from respiratory disease or all causes compared to those without COPD

13

(Figure 2, right panels). Only two individuals with undiagnosed asymptomatic COPD died due to

respiratory disease and risk estimates in this group should therefore be interpreted with caution.

Discussion

In this large sample from the general population, 78% of individuals with COPD were undiagnosed,

of whom 71% were symptomatic. Compared to individuals without COPD but similar tobacco

exposure, individuals with undiagnosed symptomatic COPD had an increased risk of exacerbations,

pneumonias, and death, whereas individuals with undiagnosed asymptomatic COPD had an

increased risk of exacerbations and pneumonias. To our knowledge, this is the first study focusing

on importance of respiratory symptoms with regard to the prognosis of individuals with

undiagnosed COPD in the general population.

Under-diagnosis of COPD is very common.9–14 A large international survey with 44 sites estimated

the overall prevalence of under-diagnosis to be approximately 81%,12 which is equivalent to the

observed prevalence in the present study. Approximately four-fifth of undiagnosed individuals with

COPD in the present study had respiratory symptoms, and as the majority of these individuals

smoke and most likely will continue to do so, COPD will likely progress leading to clinically

significant lung function reduction and increased number of exacerbations, ultimately leading to

premature death in some of these individuals.2 Indeed, a recent study using the Canadian Cohort

Obstructive Lung Disease study showed that individuals with undiagnosed COPD often experience

exacerbations despite of being less symptomatic and impaired than those with diagnosed COPD.13

Similarly, another recent study using the National Health and Nutrition Examination Survey

showed that although individuals with undiagnosed COPD appear to be healthy, they are still at risk

of premature death.14 In the latter study, individuals with undiagnosed COPD were no longer at risk

14

of death after lung function was taken into account,14 like in the present study, indicating that the

increased risk may be mediated through low lung function. This is also in line with recent

observations that reduced lung function level in early adulthood and fast lung function decline are

the best indicators for development and progression of COPD.20,21

It is likely that underutilization of spirometry is the main reason for under-diagnosis of COPD.12

Indeed, measurements of lung function in clinical practice are not used as often as measurements of

blood pressure or blood cholesterol.22 Although it is well-known that COPD patients often

underreport the true burden of respiratory symptoms, the majority of undiagnosed individuals in the

present study were symptomatic. Thus, opportunities to diagnose COPD early are being missed,23

which is in keeping with present findings, as the number of visits to the general practitioners office

in the last 12 months did not differ substantially between individuals without COPD and individuals

with undiagnosed COPD. At one hand, it may be surprising that we found such a high prevalence of

undiagnosed COPD in Denmark, which has a relatively advanced health care system. Here, under-

diagnosis is likely reflecting a combination of individuals not seeking their general practitioners

despite presence of symptoms and underutilization of spirometry in general practice. A targeted

Danish case-finding study conducted among 241 general practices with over 4000 individuals at

risk of COPD showed that 22% had COPD.24 Due to a high prevalence of smoking in the past,

Denmark still suffers from a very high mortality from COPD,25 and both the Danish Health

Authority and the Danish Respiratory Society suggested use of routine spirometry among smokers

visiting their general practitioners. Yet, the Danish College of General Practitioners is against this

initiative – a statement which has been reinforced after the recent recommendations from the

USPSTF.7 Nevertheless, a recent study showed that one in four COPD patients in clinical practice

do not receive treatment at first diagnosis despite having clinically significant lung function

15

impairment.26 Thus, other unknown factors seem to affect clinicians understanding of COPD and

their decision to initiate treatment.

Approximately one-fifth of undiagnosed individuals with COPD were asymptomatic in the present

study and do not fulfil the criteria for a clinical diagnosis of COPD according to GOLD.2 An update

on screening for COPD from the USPSTF recommends against screening for COPD in

asymptomatic smokers.7 Individuals with undiagnosed asymptomatic COPD in the present study

had lung function impairment with higher levels of inflammatory biomarkers and an increased risk

of exacerbations and pneumonias. Thus, while considering survival, the recommendations against

screening for COPD in asymptomatic smokers from the USPSTF seem to be well-supported by the

present study, we would argue that the higher risk of exacerbations and pneumonias in this

subgroup warrants early detection. In any case, the USPSTF encourages clinicians to pursue active

case-finding strategies for COPD in ever-smokers with respiratory symptoms,7 which is well-

supported by the present study showing poorer prognosis in this group. Symptomatic and

asymptomatic undiagnosed cases with COPD present different challenges to the health care system.

The symptomatic cases appear to show underestimation of symptoms by the patient or misdiagnosis

at some level of the health care system, whereas the asymptomatic cases are not attributable to

underestimation of symptoms or misdiagnosis, but could imply the need of screening programmes

in at-risk population, as the clinical consequences appear to be important. However, we do agree on

the need of additional intervention studies in individuals with undiagnosed COPD, including those

who are asymptomatic, to better characterize the natural history of disease before reassessing

present recommendations.6,8

Individuals with diagnosed COPD, irrespective of respiratory symptoms, seemed to have significant

disease, especially based on the higher risk estimates for exacerbations, pneumonias, and death. The

subgroup with symptoms had the most severe lung function impairment. These observations are

16

keeping with our expectations that patients with severe symptoms and advanced disease would be

more likely to be diagnosed than patients with a less obvious clinical presentation and early stages

of the disease.

Strengths of the present study include a large sample randomly selected from the general population

with a substantial number of individuals with COPD, and a long and complete follow-up time.

Also, we had information on several clinical attributes as well as on many important endpoints.

A limitation of our study is that we use lack of medical treatment in the identification of

undiagnosed individuals with COPD, which may have introduced potential misclassification, as

some individuals with COPD have poor compliance and this could result in poor prognosis. We also

cannot exclude potential admixture of asthma cases in to the group that we label as COPD using a

definition based on use of medication. Nevertheless, we also used previous hospital contacts with

COPD in order to ensure a correct diagnostic status. Furthermore, the observed under-diagnosis in

the present study is in accordance with a recent large international survey.12

Another important limitation of our study was lack of post-bronchodilator spirometry to diagnose

COPD.2 However, by using two different criteria for defining airflow limitation in a high-risk

population with the potential of developing COPD and excluding all cases with a FEV1 % of

predicted higher than 80, we believe to have identified a vast majority of COPD cases correctly.17 In

fact, the prevalence of COPD among adults aged ≥40 years has been reported to be 9-10% in a

meta-analysis,27 which corresponds well to the present study. However, never-smokers with COPD

were not included to enable more precise case definition.28,29

Another limitation may be the use of self-report in the exclusion of individuals with asthma.

However, self-reported asthma has been evaluated before and is useful in an epidemiological setting

by displaying high specificity and sensitivity.30 In addition, previous hospital contacts due to asthma

17

were also included in the exclusion process. Furthermore, by not taking the presence of asthma-

COPD overlap into account, we may have underestimated the true burden of undiagnosed COPD.31

Another limitation is that lung function, respiratory symptoms, and medical treatment of the

participating individuals were only assessed once. With regard to persistence of respiratory

symptoms, previous findings from the Copenhagen City Heart Study have shown considerable

fluctuations, particularly if smoking cessation is achieved.32,33 In fact, almost 40% of individuals

with chronic phlegm at baseline reported absence of chronic phlegm after 5 years of follow-up.33

We believe that if we were able to identify smokers with persistent respiratory symptoms at more

than a single occasion, this group would have an even higher risk of respiratory complications

during follow-up. Furthermore, although variations in lung function, respiratory symptoms, and

medical treatment during follow-up would bias our risk estimates, these potential sources of error

would attenuate the risk estimates and are not likely explanations for our positive findings.

Although common potential confounders were taken into account, residual confounding will

inevitably be present. Yet, by observing the well-known complications of COPD, including the

increased risks for exacerbations, pneumonias, and premature death, and by observing no large

discrepancies between crude and adjusted risk estimates, we believe the degree of residual

confounding to be small.

Lastly, we have precluded individuals with a mild degree of airflow limitation as potential COPD

cases. Often, there will be diagnostic challenges related to this group and most of them will not

qualify for a clinical diagnosis of COPD. Whether diagnosis and treatment for COPD is indicated

among these individuals is unknown. We chose a conservative definition for the diagnosis of COPD

in order to obtain a high specificity and identify vast majority of cases correctly.

18

In conclusion, individuals with undiagnosed symptomatic COPD had an increased risk of

exacerbations, pneumonias, and death, whereas individuals with undiagnosed asymptomatic COPD

had an increased risk of exacerbations and pneumonias. These findings suggest that there is a need

for better initiatives for early diagnosis and treatment of COPD.

19

Acknowledgments

Contributors: Study concept and design: YÇ, SA, BGN, JV, and PL. Acquisition, analyses, or

interpretation of data: YÇ, SA, BGN, JV, and PL. Drafting of the manuscript: YÇ. Critical

revision of the manuscript for important intellectual content: YÇ, SA, BGN, JV, and PL. Statistical

analyses: YÇ. Obtained funding: BGN and PL. Administrative, technical, or material support:

BGN. Study supervision: PL.

Declaration of interests: YÇ reports personal fees from Boehringer Ingelheim outside of the

submitted work. JV reports personal fees from GlaxoSmithKline, Chiesi Pharmaceuticals,

Boehringer Ingelheim, Novartis, Almirall, AstraZeneca, Bioxydyn, and Ferring 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.

SA and BGN have nothing to disclose.

20

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Table 1: General characteristics of 31 636 individuals with and without COPD in the Copenhagen General Population Study

No COPD

(n=27 937)

COPD

(n=3699)

Undiagnosed asymptomatic COPD

(n=851)

Undiagnosed symptomatic COPD

(n=2052)

Diagnosed asymptomatic COPD

(n=47)

Diagnosed symptomatic COPD

(n=749)

Age – years 60 (52-68) 65 (59-72)* 65 (58-73)* 69 (60-74)* 70 (63-77)*

Men – no. (%) 15 492 (55) 485 (57) 1185 (58)† 28 (60) 373 (50)†

BMI – kg/m2 26 (24-29) 25 (23-28)* 26 (23-29)* 26 (21-27)† 26 (23-29)*

FEV1 predicted – % 94 (85-104) 71 (64-76)* 66 (57-74)* 68 (59-73)* 57 (44-67)*

FVC predicted – % 98 (88-108) 89 (82-95)* 84 (75-92)* 89 (80-94)* 79 (67-90)*

FEV1/FVC – % 77 (73-81) 63 (58-66)* 62 (57-66)* 60 (53-64)* 57 (48-63)*

Current smokers – no. (%) 10 358/27 937 (37) 385/851 (45)* 1217/2052 (59)* 13/47 (28) 321/749 (43)†

Cumulative tobacco consumption – pack-years 24 (16-36) 30 (21-44)* 38 (26-51)* 33 (23-49)* 40/749 (27-54)*

Familial predisposition for asthma – no. (%) 4431/29 937 (16) 139/851 (16) 409/2052 (20)* 10/47 (21) 166/749 (22)*

Childhood asthma, hay fever, or eczema – no. (%) 2571/27 937 (9) 55/851 (6)† 165/2052 (8) 0/47 (0)† 60/749 (8)

Occupational exposure to dust/fumes – no. (%) 4109/27 937 (15) 103/851 (12)† 461/2052 (22)* 6/47 (13) 189/749 (23)*

Daily exposure to passive smoking – no. (%) 5814/27 937 (21) 162/851 (19) 471/2052 (23)† 10/47 (21) 149/749 (20)

Poor socioeconomic status – no. (%) 2508/27 937 (9) 101/851 (12)† 376/2052 (18)* 7/47 (15) 178/749 (24)*

Physical inactivity – no. (%) 2098/27 937 (8) 50/851 (6) 268/2052 (13)* 2/47 (4) 116/749 (15)*

Data presented as median (25th and 75th percentiles) or number (%). BMI = body mass index. COPD = chronic obstructive pulmonary disease. FEV1 = forced expiratory volume in 1 second. FVC = forced vital capacity.*P<0·001 or †P<0·05 for comparison with individuals without COPD, calculated using Wilcoxons rank-sum test, Pearsons χ2 test, or Fischers exact test.

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Table 2: Clinical characteristics of 31 636 individuals with and without COPD in the Copenhagen General Population Study

No COPD

(n=27 937)

COPD

(n=3699)

Undiagnosed asymptomatic COPD

(n=851)

Undiagnosed symptomatic COPD

(n=2052)

Diagnosed asymptomatic COPD

(n=47)

Diagnosed symptomatic COPD

(n=749)

Allergy – no. (%) 5550/27 937 (20) 94/851 (11)* 363/2052 (18)† 8/47 (17) 134/749 (18)

Symptoms

Chronic mucus hypersecretion – no. (%) 3063/27 937 (11) 0/851 (0)* 667/2052 (33)* 0/47 (0)† 327/749 (44)*

Dyspnoea – no. (%) 9820/27 937 (35) 0/851 (0)* 1611/2052 (79)* 0/47 (0)* 681/749 (91)*

mMRC ≥2 – no. (%) 2418/27 937 (9) 0/851 (0)* 542/2052 (26)* 0/47 (0)† 424/749 (57)*

Night-time dyspnoea – no. (%) 864/27 937 (3) 0/851 (0)* 120/2052 (6)* 0/47 (0) 87/749 (12)*

Wheezing – no. (%) 5165/27 937 (18) 0/851 (0)* 1080/2052 (53)* 0/47 (0)* 458/749 (61)*

Cough – no. (%) 3461/27 937 (12) 0/851 (0)* 679/2052 (33)* 0/47 (0)† 347/749 (46)*

Any symptom – no. (%) 13 384/27 937 (48) 0/851 (0)* 2052/2052 (100)* 0/47 (0)* 749/749 (100)*

Degree of airflow limitation

FEV1 % predicted ≥80 – no. (%) 24 239/27 937 (87) 0/851 (0)* 0/2052 (0)* 0/47 (0)* 0/749 (0)*

FEV1 % predicted 50-79 – no. (%) 3651/27 937 (13) 809/851 (95)* 1787/2052 (87)* 42/47 (89)* 486/749 (65)*

FEV1 % predicted 30-49 – no. (%) 45/27 937 (<1) 41/851 (5)* 255/2052 (12)* 5/47 (11)* 224/749 (30)*

FEV1 % predicted <30 – no. (%) 2/27 937 (<1) 1/851 (<1) 10/2052 (1)* 0/47 (0) 39/749 (5)*

Levels of inflammatory biomarkers

C-reactive protein (mg/L) 1·5 (1·1-2·6) 1·6 (1·1-2·9)† 2·0 (1·3-3·9)* 1·7 (1·1-3·0) 2·2 (1·4-4·5)*

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Fibrinogen (µmol/L) 11·0 (9·6-12·7) 11·4 (10·1-13·2)* 11·9 (10·4-13·9)* 11·3 (9·3-13·5) 12·2 (10·6-14·4)*

Leucocytes (x 109/L) 7·4 (6·3-8·6) 7·5 (6·5-8·8)† 7·9 (6·7-9·3)* 7·4 (6·1-8·0) 7·8 (6·8-9·3)*

Neutrophils (x 109/L) 4·3 (3·5-5·2) 4·5 (3·7-5·3)* 4·6 (3·8-5·7)* 4·4 (3·8-5·1) 4·8 (4·0-5·9)*

Eosinophils (x 109/L) 0·18 (0·12-0·26) 0·17 (0·11-0·26) 0·19 (0·12-0·28)* 0·17 (0·11-0·26) 0·20 (0·13-0·28)*Number of acute bronchitis or pneumonia episodes in the last 10 years None – no. (%) 21 626/27 937 (77) 664/851 (78) 1278/2052 (62)* 27/47 (58)† 273/749 (36)*

1-5 – no. (%) 5964/27 937 (21) 184/851 (22) 699/2052 (34)* 19/47 (40)† 342/749 (46)*

≥6 – no. (%) 347/27 937 (1) 3/851 (<1)† 75/2052 (4)* 1/47 (2) 134/749 (18)*Number of visits to the GPs office in the last 12 months None – no. (%) 5808/27 937 (21) 225/851 (26)* 339/2052 (17)* 7/47 (15) 58/749 (8)*

Once – no. (%) 5964/27 937 (21) 152/851 (18)† 374/2052 (18)† 9/47 (19) 75/749 (10)*

Twice or more – no. (%) 16 165/27 937 (58) 474/851 (56) 1339/2052 (65)* 31/47 (66) 616/749 (82)*

Data presented as median (25th and 75th percentiles) or number (%). COPD = chronic obstructive pulmonary disease. FEV1 = forced expiratory volume in 1 second. GP = general practitioner. mMRC = modified Medical Research Council dyspnoea scale.*P<0·001 or †P<0·05 for comparison with individuals without COPD, calculated using Wilcoxon rank-sum test, Pearson χ2 test, or Fisher’s exact test.

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Figure legends

Figure 1. Flowchart.

COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity.

Figure 2. Risk of exacerbations, pneumonias, respiratory mortality, and all-cause mortality in individuals with undiagnosed COPD.

CI = confidence interval; COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; HR = hazard ratio.

Figure 3. Kaplan-Meier curves of risk of exacerbations, pneumonias, respiratory mortality, and all-cause mortality in individuals with undiagnosed COPD.

COPD = chronic obstructive pulmonary disease.

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Figure 1

28

Figure 2

29

Figure 3

30

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