ABC_of_COPD.pdf
ABC_of_COPD.pdf
ABC of chronic obstructive pulmonary disease
Definition, epidemiology, and risk factors
Graham Devereux
Definition
In 2004, the UK National Institute for Clinical Excellence
defined chronic obstructive pulmonary disease (COPD) as
“characterised by airflow obstruction. The airflow obstruction is
usually progressive, not fully reversible and does not change
markedly over several months. The disease is predominantly
caused by smoking.” COPD is the preferred umbrella term for
the airflow obstruction associated with the diseases of chronic
bronchitis and emphysema. These are closely related to, but not
synonymous with, COPD.
Although asthma is associated with airflow obstruction, it is
usually considered as a separate clinical entity. Some patients
with chronic asthma also develop airflow obstruction that is
relatively fixed (a consequence of airway remodelling) and often
indistinguishable from COPD. Because of the high prevalence
of asthma and COPD, these conditions coexist in many patients,
creating diagnostic uncertainty. Other conditions also associated
with poorly reversible airflow obstruction include cystic fibrosis,
bronchiectasis, and obliterative bronchiolitis. Although these
conditions need to be considered in the differential diagnosis of
obstructive airways disease, they are not conventionally covered
by the definition of COPD.
Epidemiology
Prevalence
Estimating and comparing the prevalence of COPD in different
countries is complicated by differences in its precise definition
and in the level of underdiagnosis. For example, in the United
Kingdom mild COPD is defined as the ratio of forced
expiratory volume in 1 second (FEV1) to the forced vital
capacity (FVC) being < 0.7 and the FEV1 being 50-80% of the
expected value. Other guidelines suggest slightly different
spirometric values (see third article in this series).
A national UK study reported an abnormally low FEV1 in
10% of men and 11% of women aged 16-65 years. Similarly, a
study in Manchester found non-reversible airflow obstruction in
11% of adults aged > 45, of whom 65% had not had COPD
diagnosed. In the United States the reported prevalence of
airflow obstruction with an FEV1 < 80% of the expected value is
6.8%, with 1.5% of the population having an FEV1 < 50% of
expected and 0.5% having more severe obstruction (FEV1 < 35%
of expected). As in the UK, about 60% of those with airflow
obstruction had not had COPD diagnosed. As much as 40-50%
of the actual prevalence of COPD, based on measurements of
ventilatory function, may be undiagnosed; many people present
relatively late with moderate or severe airflow obstruction.
In England and Wales some 900 000 people have COPD
diagnosed—so, after allowing for underdiagnosis, the true
number with COPD is likely to be about 1.5 million. The mean
age at diagnosis in the UK is roughly 67 years, and prevalence
increases with age. COPD is more common in men than
women and is associated with socioeconomic deprivation. The
prevalence of diagnosed COPD in women is increasing (from
0.8% in 1990 to 1.4% in 1997), whereas in men it seems to have
reached a plateau since the middle 1990s. Similar trends have
been reported in the US. These trends in prevalence probably
reflect sex differences in cigarette smoking since the 1970s.
Definitions of conditions associated with airflow obstruction
Chronic obstructive pulmonary disease (COPD)—Airflow obstruction that
is usually progressive, not reversible, and does not change markedly
over several months. It is predominantly caused by smoking
Chronic bronchitis—Presence of chronic productive cough on most days
for 3 months, in each of 2 consecutive years, and other causes of
productive cough have been excluded
Emphysema—Abnormal, permanent enlargement of the distal
airspaces, distal to the terminal bronchioles, accompanied by
destruction of their walls and without obvious fibrosis
Asthma—Widespread narrowing of the bronchial airways which
changes its severity over short periods either spontaneously or after
treatment
Year
Pr
ev
al
en
ce
(%
)
0
1990
0.6
0.9
1.2
1.5
1.8
0.3
Women Men
1991 1992 1993 1994 1995 1996 1997
Prevalence of diagnosed COPD in UK men and women during 1990-7
Year
Pr
ev
al
en
ce
/1
00
0
(lo
g
sc
al
e)
1990 1991 1992 1993 1994 1995 1996 1997
1
10
100
Age (years)
Women
Men
45-65 >6520-44
Prevalence of diagnosed COPD in UK men and women by age, during 1990-7
This is the first in a series of 12 articles
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Mortality
COPD is the fourth leading cause of death in the US and
Europe. With the increase in cigarette smoking in developing
countries, especially China, COPD is expected to become the
third leading cause of death worldwide by 2020. During 2003,
about 26 000 people died from COPD in the UK, accounting
for 4.9% of all deaths, with 14 000 of these deaths occurring in
men and 12 000 in women. These represent 5.4% of all male
deaths and 4.2% of all female deaths.
In the UK over the past 30 years, mortality from COPD has
fallen in men and risen in women, and the sex difference in
COPD deaths will probably disappear in the near future. In the
US, mortality from COPD in women has also risen substantially,
from 20.1 to 56.7 per 100 000 between 1980 and 2000, while in
men the increase has been more modest, from 73.0 to 82.6 per
100 000. In 2000, for the first time, more women than men died
from COPD (59 936 v 59 118). Mortality increases with age,
disease severity, and socioeconomic disadvantage. On average,
COPD reduces life expectancy by 1.8 years in the UK (76.5 v
78.3 years for controls)—mild disease reducing it by 1.1 years,
moderate disease by 1.7 years, and severe disease by 4.1 years.
Morbidity and economic impact
The morbidity and economic costs associated with COPD are
high, largely unrecognised, and more than twice those from
asthma. The impact on quality of life is particularly high in
patients with frequent exacerbations, and even patients with
mild COPD have an impaired quality of life.
Since the mid-1990s, emergency admissions for COPD have
increased by at least 50%, so that in 2002-3 there were 110 000
hospital admissions for an exacerbation of COPD in England,
accounting for 1.1 million bed days. At least 10% of emergency
admissions to hospital are as a consequence of COPD, and this
proportion is even greater during the winter. Most admissions
are of people older than 65 years with advanced disease, who
are often admitted repeatedly and use a disproportionate
amount of resources. About 25% of patients with COPD
diagnosed need admission to hospital, with some 15% of
patients being admitted each year.
The impact in primary care is even greater, with 86% of care
being provided exclusively by primary care. An average general
practitioner’s list will contain some 200 patients with COPD
(even more in areas of social deprivation), although not all will
have it diagnosed. On average, patients with COPD make six or
seven visits annually to their general practitioner. Each patient
costs the UK economy an estimated £1639 annually, equating
to a national burden of £982m (€1450, $1741m). For each
patient, annual direct costs to the NHS are £819, with 54% of
this being due to hospital admissions and 19% due to drug
treatment. COPD results in further costs to society in that
roughly 40% of UK patients are below retirement age, and the
disease prevents about 25% from working and reduces the
capacity to work in a further 10%. Annual indirect costs of
COPD have been estimated at £820 per patient and consist of
the cost of disability, absence from work, premature mortality,
and the time caregivers miss work.
Risk factors
Smoking
Cigarette smoking is clearly the single most important risk
factor in the development of COPD. Current smoking is also
associated with an increased risk of death. Pipe and cigar
smoking also significantly increase morbidity and mortality
from COPD, though the risk is less than for cigarettes. Around
half of cigarette smokers develop some airflow obstruction, and
Year
St
an
da
rd
is
ed
m
or
ta
lit
y/
m
ill
io
n
1971 1975 1979 1983 1987 1991 1995 1999 2003
0
200
400
600
800
1000
Men
Women
UK mortality from COPD since 1971
Social class
St
an
da
rd
is
ed
m
or
ta
lit
y/
m
ill
io
n
0
I
100
150
200
250
300
50
II IIIN IIIM IV V
UK mortality from COPD by socioeconomic status
Age (years)
M
or
ta
lit
y/
10
00
p
er
so
n
ye
ar
s
>65
0
200
300
400
100
No COPD
Mild COPD
Moderate COPD
Severe COPD
45-65<45
UK mortality from COPD by age and disease severity
Laboratory
testsUnscheduled GP and
emergency department care
Scheduled GP and
specialist care
Treatment
Inpatient
hospitalisation
Direct costs of COPD to the NHS
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10-20% develop clinically significant COPD. Although smoking
is the most important risk factor, it is not a prerequisite: COPD
can occur in non-smokers with longstanding asthma or with
1 antitrypsin deficiency. Moreover, about 20% of COPD cases
in men are not attributable to smoking.
A more contentious issue is the possible relation between
environmental tobacco smoke and development of COPD:
several case-control studies have shown a trend towards an
increased risk of COPD with passive smoking. However, the
adverse effect of maternal smoking on childhood ventilatory
function is clearer: smoking during and after pregnancy is
associated with reduced infant, childhood, and adult ventilatory
function. Most studies have shown that the effects of antenatal
smoking are greater in magnitude than, and independent of,
the effects of postnatal exposure.
Air pollution
Urban air pollution may affect lung function development and
consequently be a risk factor for COPD. Cross sectional studies
have shown that higher concentrations of atmospheric air
pollution are associated with increased cough, sputum
production, and breathlessness and reduced ventilatory
function. Exposure to particulate and nitrogen dioxide air
pollution has been associated with impaired ventilatory
function in adults and reduced lung growth in children. In
developing countries indoor air pollution from biomass fuel
(used for cooking and heating) has been implicated as a risk
factor for COPD, particularly in women.
Occupation
Intense prolonged exposure to dusts and chemicals can cause
COPD independently of cigarette smoking, though smoking
seems to enhance the effects of such occupational exposure to
increase the risk of developing COPD. About 20% of diagnosed
cases of COPD are thought to be attributable to occupation; in
lifelong non-smokers this proportion increases to 30%.
Exposure to noxious gases and particles—such as grain,
isocyanates, cadmium, coal, other mineral dusts, and welding
fumes—have been implicated in the development of chronic
airflow obstruction. Thus, a full chronological occupational
history should be taken, as relevant occupational exposures are
often missed by clinicians.
1 antitrypsin deficiency
The best documented genetic risk factor for COPD is
1 antitrypsin deficiency. However, this is rare and is present in
only 1-2% of patients with COPD. 1 antitrypsin is a
glycoprotein responsible for most of the antiprotease activity in
serum. Its gene is highly polymorphic, but some genotypes
(usually ZZ) are associated with low serum concentrations
(typically 10-20% of normal). Severe deficiency of 1 antitrypsin
is associated with premature and accelerated development of
COPD in smokers and non-smokers, though the rate of decline
in lung function is greatly accelerated in those who smoke.
The 1 antitrypsin status of patients with severe COPD who
are less than 40 years old should be determined since over half
of such patients have this deficiency. Detection of such cases
identifies family members who will require genetic counselling
and patients who might be suitable for future potential
treatment with 1 antitrypsin replacement.
Graham Devereux is senior lecturer and honorary consultant,
Department of Environmental and Occupational Medicine, University
of Aberdeen, Aberdeen.
The ABC of chronic obstructive pulmonary disease is edited by
Graeme P Currie, specialist registrar, Respiratory Unit, Aberdeen
Royal Infirmary, Aberdeen. The series will be published as a book by
Blackwell Publishing in autumn 2006.
Current cigarette smoking is the most important risk factor for the
development of COPD
Pr
ev
al
en
ce
o
f a
irf
lo
w
o
bs
tru
ct
io
n
(%
)
Never smoked
0
4
6
8
10
12
14
2
Former smokers Current smokers
Prevalence of airflow obstruction in US adults aged >17 years by smoking
status
Further reading
x Anto JM, Vermiere P, Vestbo J, Sunyer J. Epidemiology of chronic
obstructive pulmonary disease. Eur Respir J 2001;17:982-94
x Britton M. The burden of COPD in the UK: results from the
confronting COPD survey. Respir Med 2003;97(suppl C):S71-9
x Pride NB, Soriano JB. Chronic obstructive pulmonary disease in
the United Kingdom: trends in mortality, morbidity and smoking.
Curr Opin Pulm Med 2002;8:95-101
x National Collaborating Centre for Chronic Conditions. National
clinical guideline on management of chronic obstructive
pulmonary disease in adults in primary and secondary care. Thorax
2004;59(suppl 1):1-3, 192-4
x Chapman RS, He X, Blair AE, Lan Q. Improvement in household
stoves and risk of chronic obstructive pulmonary disease in
Xuanwei, China: retrospective cohort study. BMJ 2005;331:1050-2.
The figure of a COPD patient wearing an oxygen facemask was supplied
by Mediscan. The figures of prevalence of COPD in UK men and women
and of deaths from COPD by age and disease severity are adapted from
Soriano JB, et al, Thorax 2000; 55:789-94. The data for the figures of UK
mortality from COPD and of mortality from COPD by socioeconomic
status are from Mortality statistics: cause. Review by the registrar general on
deaths by cause, sex and age, in England and Wales, 2003. London: Office for
National Statistics, 2004. The data for the diagram of management costs of
COPD are from Britton M, Resp Med 2003;97(suppl C): S71-9. The data
for the figure of prevalence of airflow obstruction by smoking status are
from Mannino DM, et al, Arch Intern Med 2000;1601683-9.
Competing interests: GPC has received funding for attending
international conferences and honoraria for giving talks from
pharmaceutical companies GlaxoSmithKline, Pfizer, and AstraZeneca.
BMJ 2006;332:1142–4
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ABC of chronic obstructive pulmonary disease
Pathology, pathogenesis, and pathophysiology
William MacNee
Pathology
Chronic obstructive pulmonary disease (COPD) is characterised
by poorly reversible airflow obstruction and an abnormal
inflammatory response in the lungs. The latter represents the
innate and adaptive immune responses to long term exposure
to noxious particles and gases, particularly cigarette smoke. All
cigarette smokers have some inflammation in their lungs, but
those who develop COPD have an enhanced or abnormal
response to inhaling toxic agents. This amplified response may
result in mucous hypersecretion (chronic bronchitis), tissue
destruction (emphysema), and disruption of normal repair and
defence mechanisms causing small airway inflammation and
fibrosis (bronchiolitis).
These pathological changes result in increased resistance to
airflow in the small conducting airways, increased compliance of
the lungs, air trapping, and progressive airflow obstruction—all
characteristic features of COPD. We have good understanding
of the cellular and molecular mechanisms underlying the
pathological changes found in COPD.
Pathogenesis
Inflammation is present in the lungs, particularly the small
airways, of all people who smoke. This normal protective
response to the inhaled toxins is amplified in COPD, leading to
tissue destruction, impairment of the defence mechanisms that
limit such destruction, and disruption of the repair mechanisms.
In general, the inflammatory and structural changes in the
airways increase with disease severity and persist even after
smoking cessation. Besides inflammation, two other processes
are involved in the pathogenesis of COPD—an imbalance
between proteases and antiproteases and an imbalance between
oxidants and antioxidants (oxidative stress) in the lungs.
Inflammatory cells
COPD is characterised by increased numbers of neutrophils,
macrophages, and T lymphocytes (CD8 more than CD4) in the
Sagital slice of lung removed from
a patient who received a lung
transplant for COPD. Centrilobular
lesions have coalesced to produce
severe lung destruction in the
upper lobe
Pathological changes found in COPD
Proximal cartilaginous airways (>2 mm in diameter)
x Increased numbers of macrophages and CD8 T lymphocytes
x Few neutrophils and eosinophils (neutrophils increase with
progressive disease)
x Submucosal bronchial gland enlargement and goblet cell metaplasia
(results in excessive mucous production or chronic bronchitis)
x Cellular infiltrates (neutrophils and lymphocytes) of bronchial
glands
x Airway epithelial squamous metaplasia, ciliary dysfunction,
hypertrophy of smooth muscle and connective tissue
Peripheral airways (non-cartilaginous airways <2 mm diameter)
x Increased numbers of macrophages and T lymphocytes (CD8 > CD4)
x Increased numbers of B lymphocytes, lymphoid follicles, and
fibroblasts
x Few neutrophils or eosinophils
x Bronchiolitis at an early stage
x Luminal and inflammatory exudates
x Pathological extension of goblet cells and squamous metaplasia into
peripheral airways
x Peribronchial fibrosis and airway narrowing with progressive disease
Lung parenchyma (respiratory bronchioles and alveoli)
x Increased numbers of macrophages and CD8 T lymphocytes
x Alveolar wall destruction from loss of epithelial and endothelial
cells
x Development of emphysema (abnormal enlargement of airspaces
distal to terminal bronchioles)
x Microscopic emphysematous changes:
Centrilobular—dilatation and destruction of respiratory bronchioles
(commonly found in smokers and predominantly in upper zones)
Panacinar—destruction of the whole acinus (commonly found in
1 antitrypsin deficiency and more common in lower zones)
x Macroscopic emphysematous changes:
Microscopic changes progress to bulla formation (defined as an
emphysematous airspace > 1 cm in diameter)
Pulmonary vasculature
x Increased numbers of macrophages and T lymphocytes
x Early changes—Intimal thickening, endothelial dysfunction
x Late changes—Hypertrophy of vascular smooth muscle, collagen
deposition, destruction of capillary bed, development of
pulmonary hypertension and cor pulmonale
Lung inflammation
Oxidative
stress
Oxidative
stress
Pathological changes of COPD
Host factor amplifying mechanisms
Antiproteases
Stimulatory
Inhibitory
Effects:
Antioxidants
Cigarette smoke and
environmental particles
Impaired repair
mechanisms
The pathogenesis of COPD; dashed bars represent inhibitory effects
This is the second in a series of 12 articles
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