Epidemiology of COPD [621461]

REVIEW
Epidemiology of COPD
C. Raherison* and P-O. Girodet#
ABSTRACT: Chronic obstructive pulmonary disease (COPD) is responsible for early mortality,
high death rates and significant cost to health systems. The projection for 2020 indicates that
COPD will be the third leading cause of death worldwide (from sixth in 1990) and fifth leading
cause of years lost through early mortality or handicap (disability-adjusted life years) (12th in
1990). Active smoking remains the main risk factor, but other factors are becoming better known,
such as occupational factors, infections and the role of air pollution. Prevalence of COPD varies
according to country, age and sex. This disease is also associated with significant comorbidities.
COPD is a disorder that includes various phenotypes, the continuum of which remains under
debate. The major challenge in the coming years will be to prevent onset of smoking along with
early detection of the disease in the general population.
KEYWORDS: Chronic obstructive pulmonary disease, epidemiology, morbidity, mortality,
(cigarette) smoking
Chronic obstructive pulmonary disease
(COPD) is a chronic respiratory disorder
that progresses slowly and is characterised
by an obstructive ventilatory pattern, which is
rarely reversible, very often related to tobacco
smoking and which can lead to chronic respiratory
failure. This definition covers, in reality, a number
of entities, as follows.
1) Chronic bronchitis, with an obstructive venti-
latory pattern that is defined by the existence of
chronic bronchitis with permanent obstruction of
airways (forced expiratory volume in 1 s (FEV 1)
to forced vital capacity (FVC) ratio ,70%)
2) Chronic respiratory failure, which is defined
by the existence of chronic obstructive bronchitis
with hypoxaemia.
3) Emphysema, which is defined at the anatomical
level by destruction of the walls of the alveolar
sacs/ducts beyond the terminal bronchiole with an
abnormal increase in size of distal airways [1].
Centrolobular emphysema is a result of the dilation
or destruction of respiratory bronchioles. It is a
form of emphysema associated with cigarette
smoking. Panlobular emphysema is more often
associated with a deficit in a1-antitrypsin, and is the
result of dilation or destruction of all the lobules [2].
It should be noted that centrolobular and panlob-
ular emphysema can be mutually associated.
It is, therefore, a diverse group of conditions with
a common functional characteristic, that of anobstructive ventilatory disorder that is rarely
reversible.
In this paper we shall review the tools used in
epidemiological studies to assess the scale of the
problem, given the emergence of COPD over the
past 20 yrs in both developed and developing
countries. Although the main cause is active
smoking, from now on we need to consider the
occurrence of COPD as the clinical consequence of
an interaction between environmental factors on
the one hand and the existence of a not yet properly
understood genetic predisposition on the other. It is
a disorder that is still underdiagnosed, and is
sometimes diagnosed too late. Improvement in
management must be based on early detection and
early cessation of smoking in order to reduce the
decline in respiratory function, for which current
pharmacological treatment is ineffective.
What is the objective of an epidemiological study
in COPD? If it is to screen COPD patients in the
population in order to prevent a pejorative
prognosis, it needs simple and robust tools to
identify subjects with an obstructive ventilatory
condition even if they have few symptoms. If the
objective is research on COPD risk factors, it is
necessary to have specific and sensible adapted
tools ( i.e.questionnaires and/or biological or
environmental measures).
ESTIMATE OF PREVALENCE OF COPD
From the point of view of methodology, the
studies published are based on diverse definitions,AFFILIATIONS
*Dept of Respiratory Diseases, CHU
Bordeaux, Institute of Public Health,
Epidemiology and Development,
University of Bordeaux 2, and
#Dept of Pharmacology, CHU
Bordeaux, University of Bordeaux 2,
Bordeaux, France.
CORRESPONDENCE
C. Raherison
Dept of Respiratory Diseases,
Haut-Le ´ve`que,
CHU Bordeaux, EA 3672, Institute of
Public Health, Epidemiology and
Development
University of Bordeaux 2
146 rue Le ´o Saignat
33076 Bordeaux
France
E-mail: chantal.raherison@chu-
bordeaux.fr
Received:
June 02 2009
Accepted after revision:
Sept 09 2009
PROVENANCE
Submitted article, peer reviewed.
European Respiratory Review
Print ISSN 0905-9180
Online ISSN 1600-0617
EUROPEAN RESPIRATORY REVIEW VOLUME 18 NUMBER 114 213Eur Respir Rev 2009; 18: 114, 213–221
DOI: 10.1183/09059180.00003609
Copyright /C223ERSJ Ltd 2009
c

the bases for which are either symptoms, a diagnosis made by a
doctor or spirometric data.
Questionnaires on respiratory health have been issued by the
International Union against Tuberculosis and Lung Disease [3]
and the European Community Respiratory Health Survey
(ECRHS) [4]. The questions used correspond to the clinical
definition of chronic bronchitis, i.e.morning cough and sputum,
and are based on the British Medical Research Council Question-
naire. Although these questionnaires have been validated for
asthma, the method of reference chosen was the presence of
bronchial hyperreactivity, with the objective of measuring the
prevalence of asthma and related symptoms, and not chronic
bronchitis.
These questionnaires have, for the most part, been used in the
general population, in samples of young adults thought to be
representative of these populations.
It can, therefore, be considered that, contrary to asthma, the
questionnaires used in epidemiological studies of COPD are
derived from clinical experience, but have never been
validated.
In clinical practice, accurate history taking is undertaken first,
then clinical examination and, lastly, functional testing. In
primary care, an important issue is how to define airflow
obstruction, i.e.how to conclude that the given test is normal or
abnormal. Without exception, guidelines recommend using a
post-bronchodilator FEV 1/FVC ratio ,0.70 to define irrever-
sible airflow obstruction, whatever the age and the sex of the
patients [5]. This approach is recognised to be easy to perform;
however, it must be appreciated that this advantage should be
balanced against the disadvantage of possible false diagnoses.
It is already known that using pre-bronchodilator spirometry
can overestimate COPD prevalence by as much as 30% [6]. In
primary care, S CHERMER et al. [7] showed in a large population
of patients (n 514,056) that this ratio overestimates airflow
obstruction in middle-aged and elderly patients. The propor-
tion of false-positive diagnoses using the fixed ratio ,0.70 was:
8.9% in 31–40 yr age stratum; 15.5% for those aged 41–50 yrs;
23.9% for those aged 51–60 yrs; 33.2% for those aged 61–70 yrs;
38.7% for those aged 71–80 yrs; and, finally, 42.7% for those
aged over 81 yrs [7]. Other papers have reported an over-
diagnosis; H ANSEN et al. [8] reported overdiagnosis of 20% and
SWANNEY et al. [9] reported false-positive rates of up to 60%.
In epidemiological studies, the challenge is to estimate
accurately the prevalence of COPD and using the correct
definition is very important in order to avoid misclassification
biases. The Burden of Obstructive Lung Disease (BOLD) study
is an international effort to collect population-based estimates
of the prevalence of COPD using standardised methods,
including 14 sites with 10,000 adults aged o40 yrs old [10].
Recently, they published the impact on prevalence estimates of
using the fixed ratio versus various other spirometry-based
definitions of COPD [11].
Prevalence based on fixed ratio c riteria is significantly higher
than for all other estimators, whatever the geographic site.
Adjusting the FEV 1/FVC ratio for normative ageing effects
appears to reduce the false-positive rate reported in ageing
patients. Finally, they showed that the use of the FEV 1/FEV 6ratioin place of FEV 1/FVC when using the lower limit of normal
(LLN) and FEV 1,80% predicted had little impact. The authors
r e c o m m e n dad e f i n i t i o nb a s e do na nF E V 1/FVC ratio less than
the LNN, and an FEV 1either,80% pred or below the LLN.
Recently, the American Thoracic Society (ATS)/European
Respiratory Society (ERS) statement recommends using the
LLN of the FEV 1/FVC in place of using the fixed ratio FEV 1/
FVC,70%, which is defined as 1.645 standard deviations
below the predicted value [12].
As the LLN appeared to be able to more precisely estimate
abnormal values, equations used to calculate FEV 1/FVC and
FEV 1values need to be periodically revised [13].
A meta-analysis of studies of the general population published
between 1990 and 2004 revealed geographical disparities and
differing methodologies [14].
The prevalence of COPD was estimated to be 7.6% (95% CI 6–
9.2%) independent of the defined diagnostic criteria (table 1).
On the basis of 38 studies, the prevalence of chronic bronchitis
was estimated to be 6.4% (95% CI 5.3–7.7%). The prevalence of
emphysema ( viachest radiograph) was estimated to be 1.8%
(95% CI 1.3–2.6%) on the basis of eight studies.
The majority of the studies (62%) concerned patients over
40 yrs of age, in particular those aged between 40 and 64 yrs.
The prevalence of COPD increases with age, with a five-fold
increased risk for those aged over 65 yrs compared with
patients aged less than 40 yrs [15].
The prevalence of COPD increases with smoking status (by a
factor of five), but it needs to be emphasised that prevalence of
COPD in nonsmokers was 4%, suggesting the existence of other
risk factors, such as passive smoking, or factors of occupational
exposure (table 2).
C O P Da f f e c t st w i c ea sm a n ym a l e sa sf e m a l e sb u tt h i sd i f f e r e n c e
will diminish, given the fact that more and more females
TABLE 1 Estimate of prevalence according to diagnostic
criteria
Criteria Surveys n Pooled prevalence
% (95% CI)
COPD 37 7.6 (6–9.5)
Spirometry 26 9.2 (7.7–11)
Reported by patient 7 4.9 (2.8–8.3)
Diagnosed by a doctor 4 5.2 (3.3–7.9)
Clinical/radiological examination 1 13.7 (12.9–14.5)
Chronic bronchitis 38 6.4 (5.3–7.7)
Productive moist cough 29 6.7 (5.4–8.2)
Reported by patient 15 5.3 (3.9–7.1)
Emphysema 8 1.8 (1.3–2.6)
Clinical/radiological examination 1 3.2 (2.8–3.6)
Reported by patient 7 1.7 (1.2–2.5)
COPD: chronic obstructive pulmonary disease. Modified and reproduced from
[14] with permission from the publisher.REVIEW: EPIDEMIOLOGY OF COPD C. RAHERISON AND P-O. GIRODET
214 VOLUME 18 NUMBER 114 EUROPEAN RESPIRATORY REVIEW

throughout the world have taken up smoking in the past few
years in developed countries, and that nonsmoking females are
exposed to biomass combustion products in developing coun-
tries. However, the studies based on spirometric measurements
are somewhat skewed. For instance, the prevalence of COPD also
varied according to successive classifications ( i.e.G l o b a lI n i t i a t i v e
for Chronic Obstructive Lung Disease (GOLD), ERS and ATS). In
addition, the diagnostic criterion used in 25% of cases was the
GOLD II criteria, and approximately one third of studies were
based on the post-bronchodilator FEV 1. Lastly, the criteria of
quality concerning spirometric measures were not available in
these studies, but in the future more rigorously defined and
standardised criteria should enable a better estimate of pre-
valence. In general, the studies using objective criteria report a
higher prevalence of COPD than those based on the answers of
patients to questionnaires. Likewise, the surveys based on the
diagnosis made by a doctor reported a higher prevalence than
those based on the symptoms reported by patients.
There are geographical disparities, with a higher prevalence of
COPD in South-east Asia (12.5%), but it should be noted that
there is an absence of data available concerning a large part
of the world (the African continent and countries around the
Mediterranean), for the majority of studies are concerned
with Europe.
The studies carried out in Africa and in Asia have enabled an
estimate of the prevalence of chronic bronchitis to be made, butnot on the basis of spirometric data because of a lack of
spirometers in general practice [16]. The definition of cases of
COPD is problematic in these countries where the prevalence
of respiratory infections, such as tuberculosis, is high and
patients often have both risk factors: they have a tubercular
disease and are cigarette smokers. The prevalence of moderate
to severe COPD was modelled in 12 South-east Asian countries
and estimated to be 6.3%, with maximum prevalence in China
(6.5%) and in Vietnam (6.7%) [16]. The data concerning Africa
is only partial, involving pockets of population exposed in
mining regions, agricultural areas or in hospital environments.
The prevalence of chronic bronchitis in nonexposed workers
varied from 3.5% to 17%, and was higher in exposed workers
(4.1% to 38.5%). One South African study in 1998 involved
14,000 adults over 15 yrs old. Prevalence of chronic bronchitis
was estimated to be 2.3% for males and 2.8% for females.
In South America, the PLATINO study enabled the prevalence
of COPD in those aged over 40 yrs to be estimated at between
7.8% and 20% [17]. The spirometric criteria were those of GOLD
(post-bronchodilator FEV 1/FVC,70%). Nonresponders were
principally males, thus constituting a predominantly female
population included in the study.
In France, one of the first studies undertaken estimated the
prevalence of chronic bronchitis in 2002 to be 4% in a sample
representative of the French population of subjects aged over
25 yrs (n 514,076) [18]. Underdiagnosis was also revealed
because only 24% of subjects with symptoms had had chronic
bronchitis diagnosed by a doctor. In the ECRHS, from a sample
of 9,839 adults, the prevalence of COPD according to the
GOLD classification (2001) was estimated to be: 9.2% (stage 0);
1% (stage I); and 0.5% (stage II–III). Mean age was 33 yrs, with
28.5% of smokers consuming ,15 pack-yrs and 30% consum-
ingo15 pack-yrs. This study identified a group of young
subjects at risk of developing COPD, who had already had
recourse to treatment relating to respiratory problems. Within
the framework of longitudinal follow-up in this international
survey, 5,000 adults with no clinical elements to indicate
asthma, aged 20–44 yrs in 1992 were seen again in 2000. The
incidence of COPD was 2.8 cases per 1,000 population per
annum. Chronic cough and sputum were risk factors for COPD
independent of smoking (OR 1.85, 95% CI 1.17–2.93). The
subjects who had presented a moist cough and/or sputum
during the first follow-up had a risk multiplied by three (RR
2.88, 95% CI 1.44–5.79) of presenting COPD 8 yrs later [19].
The worldwide study (BOLD project) provided a unique
opportunity to estimate the prevalence of COPD in population
based-samples in adults aged more than 40 yrs old, in both
developed countries and developing countries, using a
standardised protocol for questionnaires and lung function
testing. Each geographic site agreed to recruit 600 adults (300
males and 300 females). At the 12 sites, 9,425 participants
completed the questionnaire and performed post-bronchodi-
lator spirometry. The prevalence (with standard error) of
patients at stage II or more can be estimated at 10.1 ¡4.8%;
11.8¡7.9% for males and 8.5 ¡5.8% for females, with hetero-
geneity across centres and sex [10]; however, the fairly high
prevalence of COPD in females and in subjects who had never
smoked suggest that other exposures could be implicated, and
suggest the a greater genetic predisposition in females.TABLE 2 Prevalence of chronic obstructive pulmonary
disease according to demographic criteria
Studies n Cumulative prevalence
% (95% CI)p-value
All 37 7.6 (6–9.5)
Age ,0.0001
,40 yrs 9 3.1 (1.8–5)
o40 yrs 34 9.9 (8.2–11.8)
40–64 yrs 23 8.2 (6.5–10.3)
o65 yrs 11 14.2 (11–18)
Status ,0.0001
Active smoker 17 15.4 (11.2–20.7)
Ex-smoker 16 10.7 (8.1–14)
Nonsmoker 16 4.3 (3.2–5.7)
Sex 0.0002
Male 27 9.8 (8–12.1)
Female 27 5.6 (4.4–7)
Geographic zone 0.77
Africa 0
America 3 4.6 (2.8–7.6)
Europe 28 7.4 (5.9–9.3)
South-east Asia 2 11.4 (4.4–26.4)
Pacific 4 9 (3–24.1)
Sample 0.04
Urban 12 10.2 (7.4–13.9)
Rural 4 8 (3.9–15.8)
Mixed 21 6.1 (4.9–7.7)
Modified and reproduced from [14] with permission from the publisher.C. RAHERISON AND P-O. GIRODET REVIEW: EPIDEMIOLOGY OF COPD
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EUROPEAN RESPIRATORY REVIEW VOLUME 18 NUMBER 114 215

Points to remember
COPD is a frequent disorder, which remains difficult to
estimate because of the variability of methods used in the
various studies.
The presence of cough and/or sputum production identifies a
group at risk of presenting COPD (in those o40 yrs and
smoking o10 pack-yrs)
Using LLN seems to be more accurate for COPD diagnosis,
than fixed ratio FEV 1/FVC.
SCREENING FOR COPD
Early screening for COPD is based on early detection by a
general practitioner. Some authors have developed the
application of scores to increase detection of COPD by using
spirometers in general practice [20]. The objective of screening
is to detect with accuracy airflow obstruction even in patients
with few symptoms. Thus, validity of screening in COPD
depends directly on the validity of airflow obstruction.
Sensitivity, specificity and positive and negative predictive
values were calculated for the fixed FEV 1/FVC ratio, con-
sidering LLN definition as the gold standard for assessment of
airflow obstruction [7]. Sensitivity was 97.9%, specificity 91.2%,
positive predictive value 72% and negative predictive value
99.5% for both males and females.
The agreement between the two definitions for the subgroup of
current and ex-smokers aged o50 yrs was better for the most
severe patients. Screening for COPD was based on carrying out
a free spirometric test on patients considered to be at risk for
COPD, i.e.those aged at least 40 yrs and having a cigarette
consumption of o10 pack-yrs. In this population (n 5110,355)
the mean age was 53 yrs. Bronchial obstruction was defined in
relation to a FEV 1/FVC,70%. Screening enabled a diagnosis
of chronic obstruction in 20.3% of subjects. In terms of severity,
7.6% had mild obstruction (FEV 1o70% pred), 6.7% moderate
obstruction (FEV 150–69% pred), and 5.9% severe obstruction
(,50% pred). Among patients with severe obstruction, no
diagnosis by a doctor had previously been made. The
prevalence of bronchial obstruction increased with age and
the level of smoking. As far as symptoms were concerned,
52.5% of participants presented a moist cough and sputum,
whereas the respiratory function was normal [21].
Future challenges in screening COPD will be to update prediction
equations so that the most reliable LLN can be obtained.
Detection of COPD may provide opportunities for early
interventions, including smoking cessation, that may improve
quality of life and survival.
Points to remember
COPD is underdiagnosed, including in young people.
Screening criteria for COPD need to fulfil validity criteria in
the general population.
IMPACT OF COPD ON MORBIDITY
In diagnosed patients, COPD is a disabling disorder which is
accompanied by a negative impact on quality of life, including
in patients aged over 40 yrs with mild obstruction [22]. The
factors significantly associated with a poor quality of life are:
severity of respiratory damage, estimated by FEV 1; the use ofoxygen treatment; the frequency of visits to the emergency
room; and the frequency of hospitalisation.
The impact, in terms of cost and consumption of treatment, is
significant and includes: medical prescriptions, consultations,
visits to the emergency room and hospitalisation.
In 2001, according to the white book published by the ERS, the
annual cost of COPD was estimated to be J38.7 billion, with
73% of costs being related to inability to work, 12% to
ambulatory care, 7.5% to hospitalisation, and 7.5% to medica-
tion [23]. In France, the mean direct annual cost per patient was
estimated to be J4,366. 41% of this cost was directly related to
medical care and follow-up of the patient, 25% to medical care
of exacerbations, and 34% to other associated disorders. 33% of
the cost was related to hospitalisation and 31% directly to
prescriptions for medication [24]. In Europe, the annual cost
per patient varies from J151 to J3,912 [25].
In addition, the weight of comorbidities which are frequently
associated with COPD is important to consider. It is estimated
that approximately two-thirds of patients with COPD have one or
two comorbidities. The main comorbidities present are cardio-
vascular disorders, bronchial cancer, lung infections, thromboem-
bolic disorders [26], the existence of associated asthma, high
blood pressure, osteoporosis, joint pain, gastroduodenal ulcer,
depression and anxiety [27]. Table 3 shows the principal
comorbidities frequently associated with COPD by aetiology [28].
TABLE 3 Principal comorbidities associated with chronic
obstructive pulmonary disease
Cardiovascular
Coronary artery disease
High blood pressure
Left heart failure
Tachyarrhythmia
Malignant tumours
Nonsmall cell lung cancer
Respiratory
Pneumonia
Pulmonary embolism
Chronic cor pulmonale
Asthma
Rhinitis
Endocrine
Obesity
Diabetes
Dyslipidaemia
Denutrition
Gastroenterology
Gastric ulcer
Gastro-oesophageal reflux
Osteoarticular
Fractures
Osteoporosis
Psychiatric
Depression
AnxietyREVIEW: EPIDEMIOLOGY OF COPD C. RAHERISON AND P-O. GIRODET
216 VOLUME 18 NUMBER 114 EUROPEAN RESPIRATORY REVIEW

In another study published by B ARR et al. [29], among 1,003
patients with COPD, 61% reported moderate or severe dyspnoea
and 41% reported a prior hospitalisation for COPD. The most
prevalent comorbid diagnoses were hypertension (55%),
hypercholesterolaemia (52%), depression (37%), cataracts (31%)
and osteoporosis (28%).
MORTALITY ATTRIBUTABLE TO COPD
According to the World Health Organization, COPD is the
fourth leading cause of death in the world, with approximately
2.75 million deaths per annum, or 4.8% of deaths. In Europe,
mortality rates vary from country to country: ,20 per 100,000
population in Greece, Sweden, Iceland and Norway, up to
more than 80 per 100,000 population in Ukraine and in
Romania. In France, the mortality rate is approximately 40
deaths per 100,000 population [30]. In developing countries,
mortality is also on the increase, in relation to the increase in
cigarette smoking. In China, tobacco is responsible for 12% of
deaths, with projections which show that this rate could reach
30% in 2030 [31].
Mortality from COPD is higher in males and increases with age
in those over 45 yrs old. Mortality also increases with severity
of disease. In the USA, within the framework of the National
Health and Nutrition Examination Survey (NHANES I), 1,301
deaths were analysed in a cohort of 5,542 adults. The presence
of COPD at various GOLD stages was associated with the
following risk of death, as defined by hazard ratio (HR). Stage
I: HR 1.4, 95% CI 1.31–1.70; stage II: HR 2.04, 95% CI 1.34–3.11;
severe COPD: HR 2.7, 95% CI 2.1–3.5 [32].
Several factors have been found to be predictive of mortality in
patients with COPD: severity of airflow obstruction, nutritional
status (body mass index), exercise capacity using the 6-min
walk test and severity of dyspnoea (the BODE index). This
index appears to predict mortality better than the FEV 1alone
[33]. The mortality rate during hospitalisation for exacerbation
of COPD is estimated to be 2.5–10%. The mortality rate after
hospitalisation varies between 16% and 19% in the 3 months
following hospitalisation, between 23% and 43% at 1 yr and is
55–60% at 5 yrs. After classifying patients by GOLD stage,mortality rate at 5 yrs was 17% for stage I, 42% for stage II, 49%
for stage III and 73% for stage IV [23].
In France, an analysis of cause of death in subjects aged over
45 yrs revealed that in 2002 COPD represented 3% of deaths. The
diagnosis of COPD was associated in 48% of subjects with other
causes of death. Between 1979 and 1999, the trend in rate of
mortality remained stable in males and increased in females [34].
The only factors having demonstrated a reduction in mortality
in COPD are cessation of smoking [35] and oxygen treatment
[36] for patients with chronic respiratory failure (fig. 1).
RISK FACTORS FOR COPD
Risk factors are directly related to the interaction existing between
genetic predisposition and exposure to environmental factors.
The clinical manifestations resulting from this interaction will
also depend on the existence of associated comorbidities.
Active and passive smoking
Active smoking is the main risk factor for COPD. The risk
attributable to active smoking in COPD is thought to vary from
40% to 70% according to the country. Figure 2 shows that the
prevalence of chronic bronchitis increases with smoking and
with age. It should be noted that, at the time of this study, there
was a small proportion of patients with chronic bronchitis
despite the fact that they were nonsmokers [15].
Active smoking by females during pregnancy will also alter
fetal lung development and be responsible for asthma in
predisposed children [38]. In addition, consequence of passive
smoking is the lateness in lung development of the fetus.
The mechanisms of action of the components of cigarette
smoke on lung tissue and parenchyma are probably multiple.
Many arguments arising from in vitro and ex vivo experiments
are in favour of an inflammation of the airways, where the cell
and molecular agents differ from those present in asthma.
Histological analyses of bronchial biopsies from patients with
mild to moderate COPD show the presence of an infiltrate of
CD8+lymphocytes in proximal airways. Neutrophils are
present in high concentrations in the sputum of patients with
COPD [39]. In addition, cigarette smoke directly stimulates
various types of cells, in particular macrophages [40, 41] and
epithelial cells of the airways [42], thus contributing to
increased production of mediators and cytokines that partici-
pate in maintaining the inflammatory reaction. Through their
interactions with the epithelium and extracellular matrix, the
bronchial smooth muscle cells would also appear to play an
important role in the remodelling of the airways observed in
COPD [43].
Other theories have been established to try and explain the
irreversible histological lesions caused by tobacco components.
For example, an imbalance in proteases/antiproteases is
thought to lead to the destruction of compounds in the
extracellular matrix, in particular elastin. This concept remains
controversial and is based on an original study demonstrating
a 40% alteration in the function of an antiprotease, a1-
antitrypsin, in subjects who were smokers, in comparison to
those who were nonsmokers [44]. Finally, there is a permanent
antagonism between the toxicity of oxidants present in
cigarette smoke and the antioxidant immune system. The/MT49/MT48/MT48
/MT48/MT70/MT69/MT86/MT49/MT32/MT37/MT55/MT53
/MT53/MT48
/MT50/MT53
/MT50/MT53 /MT55/MT48 /MT56/MT53 /MT52/MT48 /MT53/MT53
/MT65/MT103/MT101/MT32/MT121/MT114/MT115/MT68/MT101/MT97/MT116/MT104/MT68/MT105/MT115/MT97/MT98/MT105/MT108/MT105/MT116/MT121/MT82/MT101/MT103/MT117/MT108/MT97/MT114/MT32/MT115/MT109/MT111/MT107/MT101/MT114
/MT97/MT110/MT100/MT32/MT115/MT101/MT110/MT115/MT105/MT116/MT105/MT118/MT101/MT32/MT116/MT111
/MT115/MT109/MT111/MT107/MT101/MT78/MT111/MT110/MT115/MT109/MT111/MT107/MT101/MT114/MT32/MT111/MT114/MT32/MT110/MT111/MT116
/MT115/MT101/MT110/MT115/MT105/MT116/MT105/MT118/MT101/MT32/MT116/MT111/MT32/MT115/MT109/MT111/MT107/MT101
/MT67/MT101/MT115/MT115/MT97/MT116/MT105/MT111/MT110/MT32/MT97/MT116/MT32/MT52/MT53
/MT121/MT114/MT115
/MT67/MT101/MT115/MT115/MT97/MT116/MT105/MT111/MT110/MT32/MT97/MT116
/MT54/MT53/MT32/MT121/MT114/MT115
FIGURE 1. Decrease in forced expiratory volume in 1 s (FEV 1) according to
smoking status. Adapted from [37].C. RAHERISON AND P-O. GIRODET REVIEW: EPIDEMIOLOGY OF COPD
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EUROPEAN RESPIRATORY REVIEW VOLUME 18 NUMBER 114 217

upset in this oxidant–antioxidant balance results in oxidative
stress, the presence of which has been shown in subjects who
were smokers and patients with COPD [45].
Genetic factors
Although cigarette smoking represents the most important risk
factor, not all smokers develop COPD in their lifetime, which
implies that genetic factors may be involved [46]. Generally, it
would seem that the respiratory function of a child is
determined by the respiratory function of both of its parents.
Thus, among children whose parents have a low respiratory
function (last quintile), 37% will have a comparatively low
respiratory function. Conversely, among children whose
parents have a normal or high respiratory function, 41% will
have a normal function [47].
At present, only a severe deficit in a1-antitrypsin, responsible
for the PiZZ phenotype, is a proven genetic causal factor. This
deficit concerns 1–3% of patients with COPD [48] and is
expressed as a clinical picture of panlobular emphysema.
Identification of simple nucleotide polymorphisms in the six
haplotypes of the SERPINA 1 gene, which controls synthesis of
a1-antitrypsin, means that this gene is considered to be an
important causal factor in COPD [49].
Numerous other gene candidates have been studied, in
particular genes coding for metalloproteinase of the extracel-
lular matrix (MMP). Thus, MMP-9 is involved in the deteriora-
tion of components of the extracellular matrix such as gelatin,
the collagens (IV, V, XI and XVII) and elastin. It has been shown
that a polymorphism of MMP-9 (C-1562T) is associated with
upper lung dominant emphysema [50, 51]. In addition, a genetic
predisposition for proteolysis of elastin in connection with the
expression of a variant of the terminal exon in human elastin has
been described for patients with severe COPD [52]. The interest
shown in the gene coding for phospholipase A 2, a protein
involved in the metabolism of fatty acids, is related to the fact
that the plasma concentration of this enzyme is high in a certain
number of inflammatory diseases [53]. The weight loss observed
in some patients with COPD is thought to be related to theexpression of variants of the subfamily of phospholipase A 2
belonging to group II [54]. Finally, it is necessary to note the
associations described between COPD and various genetic
polymorphisms: microsomal epoxide hydrolase, glutathione S-
transferase, haemoxygenase-1 and tumour necrosis factor [55].
Systematic collections of blood samples for genetic measures
could be useful in COPD epidemiological studies, and this
needs to be further explored in future.
Occupational exposure
The risk attributable to occupational exposure in COPD has
been estimated at 19%, and for nonsmokers at 31%. For
nonsmokers, the principal areas of exposure are to be found in
the rural environment, where subjects are exposed to a
significant level of organic particles (vegetable dust, and
bacterial or fungal toxins), in the textile industry, where
subjects are exposed to a high level of plant dust ( e.g.cotton
dust) and in the industrial environment (mining, smelter
plants and iron and steel industry, the wood industry and the
building trade) [56]. The contribution of occupational expo-
sures to COPD and, in particular, their potential interaction
with cigarette smoking remains underappreciated. Joint
exposure to both smoking and occupational factors has been
found to markedly increase the risk of COPD [57].
Air pollution
Exposure to pollution inside the home, in particular in
developing countries, is an important risk for COPD (risk
accounting for 35% of cases), due to exposure to smoke when
cooking or to the method of heating in badly ventilated housing,
in particular for females. In China, the prevalence of COPD in
nonsmoking females is thought to be three times higher in rural
environments in comparison with females living in urban
environments who are not thus exposed [58]. The role of air
pollution in terms of risk factors is not well known. Its impact as
an aggravating factor has been shown in patients with the most
severe forms of COPD during peaks in air pollution [59–61].
Recently, a significant effect of long-term exposure to airborne
particles on the risk of death was found in a large multi-city
study of elderly subjects discharged alive following an
admission for COPD [62].
Validity of environmental measurement is crucial and recon-
structing individual exposure with traffic air pollutant disper-
sion models remains an important challenge in epidemiology
studies [63].
Age
The prevalence of COPD increases with age [15]. In the course
of life, there is a physiological decline in respiratory function
which begins around the age of 30–40 yrs.
Because of the increase in life expectancy in developed countries,
the proportion of older subjects with COPD also increases.
Sex
From an epidemiological point of view, males were classically
more at risk of developing COPD in comparison with females
because of their smoking habits. Progressively, however, and
depending on the country, females who smoke as much as
males seem to have an equivalent risk of developing COPD./MT55/MT48
/MT48/MT80/MT114/MT101/MT118/MT97/MT108/MT101/MT110/MT99/MT101/MT32/MT37/MT54/MT48
/MT53/MT48
/MT52/MT48
/MT51/MT48
/MT50/MT48
/MT49/MT48
/MT50/MT48/MT150/MT50/MT57 /MT51/MT48/MT150/MT51/MT57 /MT52/MT48/MT150/MT52/MT57 /MT53/MT48/MT150/MT53/MT57 /MT54/MT48/MT150/MT55/MT48
/MT65/MT103/MT101/MT32/MT121/MT114/MT115
FIGURE 2. Prevalence of chronic bronchitis in relation to active smoking,
stratified by age. h: nonsmokers; &: 1–10 cigarettes per day; &: 11–20 cigarettes
per day; &:.20 cigarettes per day. Reproduced from [15] with permission from
the publisher.REVIEW: EPIDEMIOLOGY OF COPD C. RAHERISON AND P-O. GIRODET
218 VOLUME 18 NUMBER 114 EUROPEAN RESPIRATORY REVIEW

Whether females are more at risk of developing COPD when
they undertake similar smoking habits to their male counter-
parts is still under debate [64, 65].
Infections
Infections seem to play an important role in the occurrence of
COPD, depending on age. During childhood, exposure to
infections could alter the respiratory function of a child [66]. As
an adult, the repeated occurrence of exacerbations which are
viral or bacterial in origin could also contribute to lung
function decline [67].
People with early life disadvantage had permanently lower
lung function, no catch-up with age but slightly larger lung
function decline, and substantially increased COPD risk. The
impact of childhood disadvantage was as large as that of heavy
smoking [68].
As is the case for the gastroduodenal ulcer and colonisation by
Helicobacter pylori , some authors have suggested that the onset
of COPD might be facilitated by a latent adenoviral infection.
Through its interaction with DNA, the adenoviral protein E1Aassists recruitment of numerous transcription factors that
cause activation of pro-inflammatory genes [69]. In addition,
concentration of the protein E1A in lung tissue is greater for
patients who are smokers affected by COPD, in comparison
with patients who are smokers but who have not developed
the disease [70]. These studies are corroborated by experi-
mental work using the transfection of human epithelial calls by
the protein E1A, which induces activation of the pro-
inflammatory transcription factor nuclear factor- kB and the
production of cytokines such as interleukin-8 and transforming
growth factor (TGF)- b[71, 72].
Bronchial hyperreactivity
Asthmatic smokers have an increased risk of decline in
respiratory function, in comparison with subjects who are
not asthmatic. Whether bronchial hyperreactivity is a factor in
the development of COPD is still under debate [73].
Social and economic factors
Populations living in disadvantaged social and economic
conditions are more at risk of developing COPD after smoking/MT70/MT69/MT86/MT49/MT32/MT37/MT32/MT112/MT114/MT101/MT100
/MT66/MT105/MT114/MT116/MT104/MT82/MT105/MT115/MT107/MT32/MT102/MT97/MT99/MT116/MT111/MT114/MT115
/MT84/MT111/MT98/MT97/MT99/MT99/MT111/MT32/MT101/MT120/MT112/MT111/MT115/MT117/MT114/MT101/MT32 /MT105/MT110/MT32/MT117/MT116/MT101/MT114/MT111
/MT71/MT101/MT110/MT101/MT116/MT105/MT99/MT32/MT102/MT97/MT99/MT116/MT111/MT114/MT115
/MT78/MT117/MT116/MT114/MT105/MT116/MT105/MT111/MT110
/MT83/MT101/MT120
/MT83/MT111/MT99/MT105/MT111/MT45/MT101/MT99/MT111/MT110/MT111/MT109/MT105/MT99/MT32/MT115/MT116/MT97/MT116/MT117/MT115
/MT70/MT69/MT86/MT49/MT32/MT37/MT32/MT112/MT114/MT101/MT100 /MT70/MT69/MT86/MT49/MT32/MT37/MT32/MT112/MT114/MT101/MT100 /MT70/MT69/MT86/MT49/MT32/MT37/MT32/MT112/MT114/MT101/MT100
/MT82/MT105/MT115/MT107/MT32/MT102/MT97/MT99/MT116/MT111/MT114/MT115
/MT84/MT111/MT98/MT97/MT99/MT99/MT111/MT32/MT101/MT120/MT112/MT111/MT115/MT117/MT114/MT101/MT32 /MT105/MT110/MT32/MT117/MT116/MT101/MT114/MT111
/MT65/MT99/MT116/MT105/MT118/MT101/MT32/MT115/MT109/MT111/MT107/MT105/MT110/MT103
/MT71/MT101/MT110/MT101/MT116/MT105/MT99/MT32/MT102/MT97/MT99/MT116/MT111/MT114/MT115
/MT78/MT117/MT116/MT114/MT105/MT116/MT105/MT111/MT110
/MT83/MT111/MT99/MT105/MT111/MT45/MT101/MT99/MT111/MT110/MT111/MT109/MT105/MT99/MT32/MT115/MT116/MT97/MT116/MT117/MT115
/MT66/MT114/MT111/MT110/MT99/MT104/MT105/MT97/MT108/MT32/MT104/MT121/MT112/MT101/MT114/MT114/MT101/MT97/MT99/MT116/MT105/MT118/MT105/MT116/MT121
/MT82/MT105/MT115/MT107/MT32/MT102/MT97/MT99/MT116/MT111/MT114/MT115
/MT84/MT111/MT98/MT97/MT99/MT99/MT111/MT32/MT101/MT120/MT112/MT111/MT115/MT117/MT114/MT101/MT32 /MT105/MT110/MT32/MT117/MT116/MT101/MT114/MT111
/MT65/MT99/MT116/MT105/MT118/MT101/MT32/MT115/MT109/MT111/MT107/MT105/MT110/MT103
/MT71/MT101/MT110/MT101/MT116/MT105/MT99/MT32/MT102/MT97/MT99/MT116/MT111/MT114/MT115
/MT79/MT99/MT99/MT117/MT112/MT97/MT116/MT105/MT111/MT110/MT97/MT108/MT32/MT101/MT120/MT112/MT111/MT115/MT117/MT114/MT101
/MT78/MT117/MT116/MT114/MT105/MT116/MT105/MT111/MT110
/MT83/MT111/MT99/MT105/MT111/MT45/MT101/MT99/MT111/MT110/MT111/MT109/MT105/MT99/MT32/MT115/MT116/MT97/MT116/MT117/MT115
/MT66/MT114/MT111/MT110/MT99/MT104/MT105/MT97/MT108/MT32/MT104/MT121/MT112/MT101/MT114/MT114/MT101/MT97/MT99/MT116/MT105/MT118/MT105/MT116/MT121
/MT82/MT105/MT115/MT107/MT32/MT102/MT97/MT99/MT116/MT111/MT114/MT115
/MT84/MT111/MT98/MT97/MT99/MT99/MT111/MT32/MT101/MT120/MT112/MT111/MT115/MT117/MT114/MT101/MT32 /MT105/MT110/MT32/MT117/MT116/MT101/MT114/MT111
/MT65/MT99/MT116/MT105/MT118/MT101/MT32/MT115/MT109/MT111/MT107/MT105/MT110/MT103
/MT71/MT101/MT110/MT101/MT116/MT105/MT99/MT32/MT102/MT97/MT99/MT116/MT111/MT114/MT115
/MT79/MT99/MT99/MT117/MT112/MT97/MT116/MT105/MT111/MT110/MT97/MT108/MT32/MT101/MT120/MT112/MT111/MT115/MT117/MT114/MT101
/MT78/MT117/MT116/MT114/MT105/MT116/MT105/MT111/MT110
/MT83/MT111/MT99/MT105/MT111/MT45/MT101/MT99/MT111/MT110/MT111/MT109/MT105/MT99/MT32/MT115/MT116/MT97/MT116/MT117/MT115
/MT66/MT114/MT111/MT110/MT99/MT104/MT105/MT97/MT108/MT32/MT104/MT121/MT112/MT101/MT114/MT114/MT101/MT97/MT99/MT116/MT105/MT118/MT105/MT116/MT121/MT73/MT110/MT32/MT117/MT116/MT101/MT114/MT111
/MT48/MT150/MT50/MT48/MT32/MT121/MT114/MT115
/MT50/MT48/MT150/MT52/MT48/MT32/MT121/MT114/MT115
/MT62/MT52/MT48/MT32/MT121/MT114/MT115
FIGURE 3. Impact of risk factors in the occurrence of chronic obstructive pulmonary disease. FEV 1: forced expiratory volume in 1 s; % pred: % predicted. Proposal for a
theoretical model adapted from R IJCKEN and B RITTON [15].C. RAHERISON AND P-O. GIRODET REVIEW: EPIDEMIOLOGY OF COPD
c
EUROPEAN RESPIRATORY REVIEW VOLUME 18 NUMBER 114 219

is taken into account [74]. However, these criteria probably
cover various risk factors, such as diet [75], the risk of infection
and occupational exposure. Since these factors exist from
childhood, they could have an impact on adult respiratory
function [76].
Conclusion
To conclude, the various risk factors mentioned above could
have a different impact on respiratory function, depending on
the age of the subject. Respiratory function evolves in several
main stages, a development stage which takes place in utero ,a
pulmonary growth stage which continues to young adulthood
(20 yrs), a maturity stage between the ages of 20 and 30 yrs
and a stage of physiological decline, which is thought to begin
after the age of 40 yrs. The possibility of cumulated risks
should also be taken into account, because of the simultaneous
presence or absence of these various risk factors in the same
individual, showing a possible variability of natural history of
COPD (fig. 3).
STATEMENT OF INTEREST
None declared.
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