Chronic Obstructive Pulmonary Disease

Transcription

Section 7
AIRWAY DISEASES
Chapter 41 Chronic Obstructive Pulmonary Disease:
Epidemiology, Pathophysiology, and
Clinical Evaluation
William MacNee
Chronic obstructive pulmonary disease (COPD) is a preventable and treatable chronic lung condition characterized by
airflow limitation that is not fully reversible. COPD is increasingly recognized as a major global problem that places a burden
on both patients who suffer from this disabling condition and
health care resources. Despite significant advances in our
understanding of the pathogenesis, physiology, clinical features,
and management of COPD in recent years, much remains to
be discovered about this condition.
Although hidden by the generic term “chronic obstructive
pulmonary disease,” COPD is a heterogeneous collection of
syndromes with overlapping manifestations, which has led to
major difficulties in obtaining an acceptable definition of the
condition. In addition, as with many chronic inflammatory
conditions, COPD is associated with extrapulmonary effects
and comorbidities that affect both morbidity and mortality.
The acceptance that symptoms of breathlessness, cough, and
sputum production are part of aging or an inevitable consequence of cigarette smoking, and not related to a disease, results
in underdiagnosis despite the diagnosis of COPD being easily
made. This underdiagnosis is exacerbated by the belief, reinforced by many definitions, that COPD is an “irreversible”
condition and that there is nothing “to reverse” with treatment. This leads not only to underdiagnosis but also to
undermanagement.
It is now well recognized that significant responses to treatment do occur, which has led to a much more positive approach
to the diagnosis and treatment of COPD. Whereas previous
treatments largely focused on patients at the severe end of the
disease spectrum, recent guidelines recognize that diagnosis
and treatment at an earlier stage can offer significant benefits
for patients. Although unable to cure COPD, current treatments can reduce symptoms, improve function, and reduce
exacerbations in patients as well as decrease the enormous
health care costs associated with COPD.
DEFINITIONS AND DIAGNOSTIC CONSIDERATIONS
In defining COPD, several problems must be considered. First,
COPD is not just one disease but a group of diseases. Second,
it is difficult to differentiate COPD from asthma; the persistent
airways obstruction in older patients with chronic asthma is
often difficult or even impossible to distinguish from that of
COPD patients, who may demonstrate partial reversibility of
their airflow limitation. Indeed, some patients with asthma may
develop COPD, or these two common conditions may coexist
in the same individual. Therefore the problem often is not
whether the patient has asthma or COPD, but rather whether
either asthma or COPD is present.
Chronic bronchitis is defined clinically by the American Thoracic Society (ATS) and the United Kingdom (UK) Medical
Research Council as “the production of sputum on most days
for at least three months in at least two consecutive years when
a patient with another cause of chronic cough has been
excluded.” This definition does not require the presence of
airflow limitation. Chronic bronchitis results from inflammation in the larger airways, with bronchial gland hypertrophy
and mucus cell hyperplasia.
Emphysema is defined pathologically as “abnormal, permanent enlargement of the distal air spaces, distal to the terminal
bronchioles, accompanied by destruction of their walls and
without obvious fibrosis.” As with chronic bronchitis the definition of emphysema does not require the presence of airflow
limitation. As emphysema progresses, the consequent loss
of lung elastic recoil contributes to the airflow limitation
in COPD.
Bronchiolitis or small airways disease also occurs in COPD,
where chronic inflammation in the smaller bronchi and bronchioles less than 2 mm in diameter leads to airway remodeling,
resulting in airflow limitation. Although relatively little is
known of the natural history, bronchiolitis may contribute
increasingly, as it progresses, to the airflow limitation in COPD.
The relative contributions made by large or small airways
abnormalities or emphysema to the airflow limitation, in individual patients with COPD, is difficult to determine. Thus the
term “chronic obstructive pulmonary disease” was introduced
in the 1960s to describe patients with incompletely reversible
airflow limitation caused by a combination of airways disease
and emphysema, without defining the contribution of these
conditions to the airflow limitation.
In the statement on the standards for diagnosis and care of
patients with COPD by ATS and European Respiratory Society
(ERS), COPD is defined as “a preventable and treatable disease
state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response in the lungs to
noxious particles or gases, primarily caused by cigarette smoking.
Although COPD affects the lungs, it also produces significant
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Section 7 Airway Diseases
systemic consequences.” This is similar to the definition produced by the World Health Organization (WHO) Global
Initiative on Obstructive Lung Disease (GOLD), which first
introduced the concept of COPD as an inflammatory disease
into its definition.
The diagnosis of COPD should be considered in any person
with the following:
• A history of chronic progressive symptoms: cough, wheeze,
and/or breathlessness, with little variation in these
symptoms
• A history of exposure to risk factors: cigarette smoke, occupational and environmental dust, and gaseous exposure
The diagnosis requires objective evidence of airflow limitation assessed by spirometry. A postbronchodilator forced expiratory volume in the first second (FEV1)/forced vital capacity
(FVC) ratio of less than 0.7 confirms the presence of airflow
limitation that is not fully reversible.
A number of specific causes of airflow limitation, such as
cystic fibrosis, bronchiectasis, and bronchiolitis obliterans, are
not included in the definition of COPD, but these should be
considered in its differential diagnosis. COPD is considered
primarily as a lung disease. However, the extrapulmonary
effects and comorbidities should also be considered in patients
with COPD.
PATHOLOGY
The pathologic changes in COPD are complex and occur in
the central conducting airways, the peripheral airways, the lung
parenchyma, and the pulmonary vasculature.
Inflammation initiated by exposure to particles or gases
underlies most of the pathologic lesions associated with COPD
and represents the innate and adaptive immune responses to a
lifetime exposure to noxious particles, fumes, and gases, particularly cigarette smoke. Enhanced inflammation also contributes to disease exacerbations, in which acute inflammation is
superimposed on the chronic disease. There is good evidence
that all smokers have inflammation in their lungs. However,
there is individual susceptibility in the inflammatory response
to tobacco smoking, and those who develop COPD show an
enhanced or abnormal inflammatory response to inhaled toxic
agents.
Although the clinical and physiologic presentation of chronic
asthma may be indistinguishable from COPD, the pathologic
changes are distinct from those in most cases of COPD, largely
because of cigarette smoking. The histologic features of COPD
in the 15% to 20% of COPD patients who are nonsmokers have
not yet been studied in detail. Although complex, the pathology of COPD can be simplified by considering separate disease
sites in which pathologic changes occur in smokers to produce
a clinical pattern of largely fixed airflow limitation (Box 41-1).
The clinicopathologic picture is complicated because chronic
bronchitis, bronchiolitis, and emphysema may exist in an individual patient, resulting in the clinical and pathophysiologic
heterogeneity seen in patients with COPD.
CHRONIC BRONCHITIS
Mucus is produced by mucous glands present in the larger
airways and by goblet cells in the airway epithelium. Chronic
bronchitis is characterized by hypertrophy of the mucous
glands (Figure 41-1). Goblet cells that occur predominantly in
the surface epithelium of the larger airways increase in number
Box 41-1 Chronic Obstructive Pulmonary Disease (COPD):
Pathologic Changes
Proximal Airways (cartilaginous airways >2 mm in diameter)
Macrophages and CD8 T lymphocytes
Few neutrophils and eosinophils (neutrophils increase with
progressive disease)
Submucosal bronchial gland enlargement and goblet cell
metaplasia (results in excessive mucus production or chronic
bronchitis)
Cellular infiltrates (neutrophils and lymphocytes) of bronchial
glands
Airway epithelial squamous metaplasia, ciliary dysfunction,
increased smooth muscle and connective tissue
Peripheral Airways (noncartilaginous airways <2 mm in
diameter)
Bronchiolitis at early stage
Macrophages and T lymphocytes (CD8+ > CD4+)
Few neutrophils or eosinophils
Pathologic extension of goblet cells and squamous metaplasia into
peripheral airways
Luminal and inflammatory exudates
B lymphocytes, lymphoid follicles, and fibroblasts
Peribronchial fibrosis and airway narrowing with progressive
disease
Lung Parenchyma (respiratory bronchioles and alveoli)
Macrophages and CD8+ T lymphocytes
Alveolar wall destruction caused by loss of epithelial and
endothelial cells
Development of emphysema (abnormal enlargement of air spaces
distal to terminal bronchioles)
Microscopic emphysematous changes
Centrilobular (dilation and destruction of respiratory
bronchioles, often found in smokers and predominantly in
upper zones)
Panacinar (destruction of whole acinus, typically found in
α1-antitrypsin deficiency and more common in lower zones)
Macroscopic emphysematous changes
Microscopic changes progress to bullae formation, defined as
an emphysematous air space >1 cm in diameter.
Pulmonary Vasculature
Macrophages and T lymphocytes
Early Changes
Intimal thickening
Endothelial dysfunction
Late Changes
Vascular smooth muscle
Collagen deposition
Destruction of capillary bed
Development of pulmonary hypertension and cor pulmonale
and change in distribution, extending more peripherally. Bronchial biopsy studies confirm findings in resected lungs and show
bronchial wall inflammation in chronic bronchitis. Activated T
lymphocytes are prominent in the proximal airway walls, with
a predominance of the CD8 suppressor T lymphocyte subset,
rather than the CD4 subset, as seen in asthma. Macrophages
are also prominent. Sputum volume correlates with the degree
of inflammation in the airway wall. Neutrophils are present,
particularly in the bronchial mucus-secreting glands (Figure
41-1), and become more prominent as the disease progresses.
In stable chronic bronchitis, the high percentage of intraluminal
41 Chronic Obstructive Pulmonary Disease: Epidemiology, Pathophysiology, and Clinical Evaluation
533
Muscle
Glands
Muscle
Gland
duct
B
Gland
A
Cartilage
C
Figure 41-1 A, Central bronchus from lung of cigarette smoker with normal lung function. Only small amounts of muscle are present, and epithelial
glands are small. This contrasts sharply with B, bronchus from patient with chronic bronchitis, where the muscle appears as a thick bundle and the
glands are enlarged. C, Enlarged glands at higher magnification, showing evidence of chronic inflammation in glands involving polymorphonuclear
leukocytes (arrowhead) and mononuclear cells, including plasma cells (arrow). (Courtesy Dr. J. C. Hogg.)
neutrophils is associated with the presence of neutrophil chemotactic factors, including interleukin-8 (IL-8) and leukotriene
B4 (LTB4). Elastase released from these cells is a potent stimulant for the secretion of mucus. Macrophages and CD8+ T cells
also accumulate in the mucous glands.
Evidence indicates that the airway inflammation in patients
with chronic bronchitis persists after smoking cessation, particularly if the production of sputum persists, although cough
and sputum improve in most smokers who quit. Airway wall
changes include squamous metaplasia of the airway epithelium,
loss of cilia and ciliary function, and increased smooth muscle
and connective tissue.
SMALL AIRWAYS DISEASE AND BRONCHIOLITIS
The smaller bronchioles (<2 mm in internal diameter) normally contribute relatively little to the total airway resistance,
because there are so many airways of this size in parallel. Considerable narrowing of these airways can occur before pulmonary function becomes impaired and symptoms develop. Small
airways inflammation is one of the earliest changes in asymptomatic cigarette smokers. The inflammatory cell profiles in the
small airways are similar to those in larger airways, including
the predominance of CD8+ lymphocytes, increase in CD8/CD4
ratio, and increased macrophages. Mucosal ulceration, goblet
cell hyperplasia, and squamous cell metaplasia may be present,
as well as mesenchymal cell accumulation and fibrosis. With
progression of the condition, structural remodeling may occur,
characterized by increased collagen content and scar tissue
formation that narrows the airways and produces fixed airway
obstruction (Figure 41-2).
EMPHYSEMA
Pulmonary emphysema is defined as abnormal permanent enlargement of air spaces distal to the terminal bronchioles, accom
panied by destruction of bronchiolar walls. The major types
of emphysema are recognized according to the distribution of
enlarged air spaces within the acinar unit, the part of lung parenchyma supplied by a single terminal bronchiole, as follows:
• Centrilobular (or centriacinar) emphysema, in which large
air spaces are initially clustered around the terminal bronchiole (Figure 41-3, A).
• Panlobular (or panacinar) emphysema, where the large
air spaces are distributed throughout the acinar unit
(Figure 41-3, B).
Air space enlargement can be identified macroscopically
when the enlarged space reaches 1 mm. A bulla is a localized
area of emphysema, conventionally defined as greater than
1 cm in size.
Centrilobular and panlobular emphysema can occur alone
or in combination. The association with cigarette smoking is
clearer for centrilobular than panlobular emphysema, although
smokers can develop both types. Those with centrilobular
emphysema appear to have more abnormalities in the small
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A
B
C
Figure 41-2 Histologic sections of peripheral airways. A, Section from cigarette smoker with normal lung function, showing near-normal airway.
B, Section from patient with small airways disease, showing inflammation in wall and inflammatory exudate in airway lumen. C, More advanced case of
small airways disease, with reduced lumen, structural reorganization of airway wall, increased smooth muscle, and deposition of peribronchiolar
connective tissue. (Courtesy Dr. J. C. Hogg.)
airways than those with panlobular emphysema. Panacinar
emphysema appears more severe in the lower lobes, in contrast
to centriacinar emphysema, which usually concentrates in the
upper lobes. Panlobular emphysema is associated with α1antitrypsin deficiency, but can also be found in patients with
no identified genetic abnormality.
Other types include paraseptal (periacinar or distal acinar)
emphysema, in which enlarged air spaces occur along the edge
of the acinar unit, but only where it abuts against a fixed structure such as the pleura or a vessel. Mixed types of emphysema
occur in COPD patients.
The bronchioles and small bronchi are supported by attachment to the outer aspect of adjacent alveolar walls. This
arrangement maintains the tubular integrity of the airways.
Loss of these attachments and consequent loss of lung elastic
recoil may lead to distortion or irregularities of the airways,
which contributes to the airflow limitation. The inflammatory
cell profile in the alveolar walls is similar to that described in
the airways and persists throughout the disease.
PULMONARY VASCULATURE
Changes in the pulmonary vasculature occur early in the course
of COPD; thickening of the intima is followed by increase
in smooth muscle and infiltration of the vessel wall
with inflammatory cells, including macrophages and CD8+ T
lymphocytes. As the disease progresses, greater amounts of
smooth muscle, proteoglycans, and collagen accumulate, thickening the arterial wall. The development of chronic alveolar
hypoxia in patients with COPD results in hypoxic vasoconstriction and subsequently leads to structural changes in the
pulmonary vasculature, pulmonary hypertension, and right
ventricular hypertrophy and dilation (cor pulmonale).
ETIOLOGY
RISK FACTORS
Cigarette Smoking
Cigarette smoking is the single most important identifiable
etiologic factor in COPD. The cause-and-effect relationship
between cigarette smoking and COPD derives from several
well-controlled population studies over the last four decades.
Maternal smoking is associated with low birth weight and
decreased lung function at birth, which may lead to decreased
level of function in early adulthood, increasing the risk of
developing COPD depending on lifestyle, particularly smoking
history. Further, smoking by either parent is associated with an
increase in respiratory illness in the first 3 years of life, which
may contribute to airflow limitation in later life.
Normal respiratory
bronchioles and alveoli
A
Centrilobular
emphysema
Upper lobe predominance
Common type in smokers
Normal respiratory
bronchioles and alveoli
B
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Panacinar emphysema
Lower lobe predominance
Common type in alpha1-antitrypsin deficiency
Figure 41-3 Diagrammatic representation and CT scans of distribution of abnormal air spaces within acinar unit in two major types of emphysema.
A, Acinar unit in normal lung (left top) and in centrilobular emphysema, showing focal enlargement of air spaces around respiratory bronchiole. CT scans
show patchy centrilobular emphysema. B, Panlobular (panacinar) emphysema, showing confluent, even involvement of acinar unit. CT scans show
diffuse, low-attenuation areas of panlobular emphysema.
Mild airflow limitation and a reduced increase in lung function occur in smoking adolescents. In addition, the plateau
FEV1 in the third decade of life is also shortened considerably
by cigarette smoking, which results in the initiation of FEV1
decline years earlier than in those who do not smoke.
In adulthood the effect of smoking on FEV1 decline is well
known. In general there is a significant dose-response effect,
with smokers having lower lung function the more and the
longer they smoke. There is, however, considerable variation.
Most longitudinal studies indicate that the decline in FEV1
in smokers ranges from 45 to 90 mL per year, in contrast
to the normal 30 mL/yr (Figure 41-4). However, values vary
considerably among individuals, and some experience significantly greater decline, at least temporarily, which may explain
why COPD may seem to surface over a short period in the
fifth and sixth decades of life. Some nonsmokers have impaired
lung function, and 15% to 20% of COPD patients are lifelong
nonsmokers. Conversely, some heavy smokers are able to maintain normal lung function, although the frequently quoted
“15% to 20%” of smokers who are thought to develop clinically
significant COPD is probably an underestimate. About 35% of
smokers with normal lung function initially developed COPD
during a 25-year follow-up in the Copenhagen City Heart
Study.
FEV1 (% of value at age 25)
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100
Never smoked or not
susceptible to smoke
Susceptible
smoker
75
50
Disability
25
Death
0
25
50
75
Age (years)
Predicted decline if patient stops smoking
Figure 41-4 Decline in forced expiratory volume in 1 second (FEV1) in
smokers and nonsmokers. Horizontal dashed lines represent level of FEV1
consistent with disability or death; curved dashed lines represent change
in FEV1 decline with smoking cessation.
Pipe and cigar smokers have significantly greater morbidity
and mortality from COPD than nonsmokers, although the risk
is less than that from cigarettes. There is a trend to an increased
relative risk of chronic airflow limitation from passive smoking,
but the effect is not powerful enough to demonstrate clinical
significance. Epidemiologic studies have associated cessation of
smoking with a decrease in the prevalence of respiratory symptoms and improvement in the subsequent decline in FEV1
(Figure 41-4). The first effect on lung function after smoking
cessation is a small increase of 50 to 100 mL in FEV1. There is
some debate on whether decline in FEV1 after smoking cessation completely normalizes, although in general those who quit
smoking continue to have an FEV1 decline slightly larger than
in those who never smoked.
Air Pollution
Air pollution has been recognized as a risk factor in chronic
respiratory disease in association with various air pollution
episodes in the past. The introduction of air quality standards
in the 1950s and 1960s led to a decrease in smoke and sulfur
dioxide levels, which produced less discernible peaks of pollution related to morbidity and mortality. However, more recent
studies show an association between respiratory symptoms,
general practitioner consultations and hospital admissions in
patients with airways disease, including COPD, at levels of
particulate air pollution below 100 µg/m3, levels currently
experienced in many urban areas in Western countries.
The role of long-term exposure to outdoor air pollution as a
risk factor for the development of COPD is still debated. Air
pollution does appear to be a risk factor for mucus hypersecretion, although the association with airflow limitation and accelerated decline in FEV1 is less clear. Air pollution may affect the
development of lung function in childhood, which may influence the risk of COPD in adulthood. It is also recognized that
indoor air pollution, derived from the combustion of biomass
fuel in fires and stoves, is an important etiologic factor in
COPD and is a particular problem among women in developing countries. Exposure to biomass smoke is thought to increase
the risk of COPD two-fold to three-fold.
Occupational Exposure to Dusts
There is a causal link between occupational dust exposure and
the development of mucus hypersecretion. In addition,
longitudinal studies in workforces exposed to dust show an
association between dust exposure and a more rapid decline in
FEV1. Selection bias must be considered in these associations,
resulting from the “healthy worker effect,” with those having
respiratory symptoms or lower lung function excluded before
entering the occupation. An estimated 15% to 20% of COPD
cases are caused by occupational dusts, which increases to 30%
in never-smokers. A study of male workers in the Paris
area exposed to occupational dusts showed a 5 to 15 mL/yr
successive decline in FEV1 from dust exposure. Exposure
to welding fumes is also associated with a small but significant
risk of developing COPD, from a study in shipyard workers.
Workers exposed to cadmium have an increased risk of
emphysema.
Chronic Mucus Hypersecretion
Population studies of respiratory symptoms indicate a higher
prevalence of cough and sputum among smokers than nonsmokers. Cessation of smoking is associated with cessation of
sputum production in most cases. Earlier studies of working
men in London showed that smoking accelerated the decline
in FEV1, but failed to show a correlation between the degree
of mucus hypersecretion and an accelerated decline in FEV1 or
mortality. By contrast, mortality was strongly related to the
development of a low FEV1. Data from a more general population study in Copenhagen between 1976 and 1994 suggested
that mucus hypersecretion was associated with increased risk
of hospital admission and excessive decline in FEV1 of 10 to
15 mL. Moreover, as FEV1 decreases, the association between
mucus hypersecretion and mortality becomes stronger.
Chronic Bronchopulmonary Infection
The “British hypothesis” suggested that chronic sputum production (chronic bronchitis) predisposed patients to recurrent
bronchopulmonary infections, which subsequently resulted in
biologic changes in the airways and alveoli, causing the progression of chronic airflow limitation. In the 1960s and 1970s,
Fletcher and Peto refuted this hypothesis, showing no relationship between recurrent infective exacerbations of bronchitis
and the decline in lung function in men with chronic bronchitis.
This has been challenged more recently in the Lung Health
Study, which showed an association in continued smokers
between lower respiratory tract infection and a faster rate of
decline in lung function. This is supported by more recent
studies of patients with COPD.
Cough and sputum production in adulthood is more often
reported in those with a history of chest illness in childhood.
The association between childhood respiratory illness and ventilatory impairment in adulthood is probably multifactorial.
Low economic status, greater exposure to passive smoking,
poor diet and housing, and residence in areas of high pollution
may all contribute to this finding.
HOST FACTORS
Lung Growth
Several studies indicate that mortality from chronic respiratory
diseases and adult ventilatory function correlate inversely with
birth weight and weight at 1 year of age. Thus, impaired growth
in utero may be a risk factor for the development of chronic
respiratory diseases, including COPD. Any factor that affects
lung growth during gestation or in childhood, and thus subsequent attainment of maximum lung function, has the potential
to increase the risk of developing COPD.
Diet
Diet may influence the development of COPD. Because oxidative stress is thought to have a role in the pathogenesis of
COPD, dietary antioxidants such as vitamins A, C, and E should
have a protective effect in smokers. The Seven Countries Study
found an inverse relationship between baseline intake of fruit
and fish and subsequent COPD mortality. In the U.S. Third
National Health and Nutrition Examination Survey (NHANESIII), dietary factors, particularly a low intake of vitamin C and
low plasma levels of ascorbic acid, were related to a diagnosis
of bronchitis. Two British studies also showed that dietary
intake of vitamins C and E influences lung function in adults.
Studies further suggest a decreased risk of COPD in subjects
with a high intake of omega-3 fatty acids.
Atopy and Airway Hyperresponsiveness
The “Dutch hypothesis” proposed that smokers with chronic,
largely irreversible airflow limitation and subjects with asthma
shared a common constitutional predisposition to allergy,
airway hyperresponsiveness, and eosinophilia. Smokers tend to
have higher levels of immunoglobulin E (IgE) and higher eosinophil counts than nonsmokers, but not as high a level as in
asthmatic patients. Studies in middle-aged smokers with a
degree of airflow limitation found a positive correlation between
accelerated decline in FEV1 and increased airway responsiveness to either methacholine or histamine. Over a range of
studies, the presence of airway hyperresponsiveness adds
approximately 10 mL/yr to decline in FEV1.
Bronchodilator reversibility has been suggested as a proxy
for airway hyperresponsiveness, and some studies suggest
reversibility as a predictor of FEV1 decline. However, these
studies have not been adjusted for the actual value of the postbronchodilator FEV1; when this is done, minimal association
appears to exist between reversibility and FEV1 decline.
Whether airway hyperresponsiveness is a cause or consequence of COPD remains a subject of debate. Although asthma
has been considered confusingly as a risk factor for COPD,
good evidence supports that asthmatic patients have a more
rapid decline in FEV1 than nonasthmatic patients, as well as an
increased mortality, primarily from COPD. Poorly controlled
asthma will likely lead to airway remodeling and fixed airflow
obstruction, fulfilling the definition of COPD.
Genetic Factors
Chronic obstructive pulmonary disease is a prime example of
a condition of gene-environment interaction. The observation
of a familial association for an increased risk of airflow limitation in smoking siblings of subjects with severe COPD suggests
a genetic component to this disease. Genetic linkage analysis
has identified several sites in the genome that may contain
susceptibility genes, such as chromosome 2q. Genetic association studies show that a number of candidate genes are associated with the development of COPD or with rapid decline in
FEV1. However, the associations are not consistent in different
populations (Box 41-2).
Because COPD is a complex and heterogeneous condition,
COPD-related phenotypes may differ between different
genetic subtypes of COPD. Several studies suggest polymorphisms in various genes related to emphysema severity or
distribution of emphysema. A genetic predisposition to
the development of COPD exacerbations has also been
suggested.
Many genes with unknown functions likely contribute to the
pathogenesis of COPD, and until recently, it has not been
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Box 41-2 Candidate Genes in Chronic Obstructive
Pulmonary Disease
Epoxide hydrolase
Glutathione-s-transferase
Heme oxygenase-1
Catalase
Tumor necrosis factor (TNF)
Transforming growth factor beta-1
Serpine-2
Matrix metalloproteinase (MMP-1)
Interleukins (IL-4RA); IL-6; IL-8A-251T; IL-IRN
Nicotine acetylcholine receptor (CHRNA5)
Table 41-1 Alpha1-Antitrypsin Phenotypes: Frequency in UK
Population, Concentration, and Emphysema Risk
Phenotype
Frequency
(%)
MM
86
MS
Average
Concentration*
(g/L)
Risk Factor for
Emphysema
2
No
9
1.6
No
MZ
3
1.2
No
SS
0.25
1.2
No
SZ
0.2
0.8
Yes
ZZ
0.03
0.4
Yes
*Serum α1-protease inhibitor.
practical to interrogate the entire genome. Genome-wide association studies may provide a better alternative to candidate
gene approaches. Recent genome-wide association studies have
identified a single nucleotide polymorphism (SNP) on chromosome 15 that has a significant association with COPD. Multiple
genes of interest are present near the most likely associated
SNP, including subunits of the nicotinic acetylcholine receptor
(CHRNA3 and CHRNA5) and an iron-binding protein
(IREB2). A further genome-wide association study identified
four SNPs on chromosome 4q, which is strongly associated
with FEV1/FVC. Thus, although genome-wide association
studies are at an early stage, chromosome 4 and 15 genetic
associations appear to be most significant in COPD.
The most consistent association with COPD is alpha1antitrypsin (α1-proteinase inhibitor) deficiency. Alpha1antitrypsin is a glycoprotein that is the major inhibitor of serine
proteases, including neutrophil elastase. More than 75 biochemical variants of α1-antitrypsin have been described relating
to their electrophoretic properties, giving rise to the phase
inhibitor (Pi) nomenclature (Table 41-1). The most common
allele in all populations is PiM, and the most common genotype
is PiMM, which occurs in 93% of the alleles in subjects of
Northern European descent. PiMZ and PiMS are the next two
most common genotypes and are associated with α1-proteinase
inhibitor levels of 15% to 75% of the mean levels of PiMM
subjects. Similar levels occur in the much less common PiSS
type. The most important other type is PiSZ, in which basal
levels are 35% to 50% of normal values. The threshold point
for increased risk of emphysema is a level of about 80 mg/dL,
which is about 30% of normal.
The homozygous PiZZ type, in which serum levels are 10%
to 20% of the average normal value, is the strongest genetic risk
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factor for the development of emphysema. This recessive trait
is most frequently seen in individuals of Northern European
descent. Such individuals, particularly if they smoke, are likely
to develop COPD, usually panlobular emphysema, at an early
age. The onset of disease occurs at a median age of 50 in nonsmokers and 40 years in smokers.
The defect resulting in α1-antitrypsin deficiency is related to
a single point mutation at position 342, where the nucleotide
sequence for this codon is changed from GAG to AAG, resulting in an amino acid change from glutamic acid to lysine. In
the PiZZ subject, α1-antitrypsin protein accumulates in the
endoplasmic reticulum of the liver. The structure of the protein
reveals that the defect results in the development of abnormal
protein polymers, which prevents the α1-antitrypsin passing
through the endoplasmic reticulum and thus prevents the
secretion of the protein. These polymers may also be chemotactic for inflammatory cells and may thus contribute to the
increased elastase burden. It is postulated that a deficiency in
α1-proteinase inhibitor results in excess activity of neutrophil
elastase and therefore tissue destruction and emphysema.
Studies of U.S. blood donors identify a 1 : 2700 prevalence
of PiZZ subjects, the majority of whom had normal spirometry.
An estimated 1 : 5000 UK children are born with the homozygous deficiency (PiZZ). However, the number of subjects identified with disease is much lower than predicted from the
known prevalence of the deficiency. It is therefore by no means
inevitable that all individuals with homozygous deficiency will
develop respiratory disease.
OTHER FACTORS
An association between COPD patients’ economic status, education, and lung function and COPD hospitalization has been
shown in a Danish study, despite relatively small differences
among social classes. However, social risk factors are likely
multifactorial and may relate to intrauterine exposure, childhood infections, childhood environment, diet, housing conditions, and occupational factors.
The role of gender as a risk factor for COPD remains unclear.
Previous studies typically showed greater COPD mortality in
men than women, but more recent studies show that COPD
now has almost equal prevalence in men and women, probably
reflecting the change in tobacco smoking. Women may be more
susceptible to the effects of tobacco smoke than men, but this
is still debated.
EPIDEMIOLOGY
Although COPD is a leading cause of morbidity and mortality
worldwide, its prevalence varies across countries. The imprecise, variable definitions of COPD and the lack of spirometry
to confirm the diagnosis make it difficult to quantify morbidity
and mortality. In addition, prevalence data underestimate the
total disease burden because COPD typically is not diagnosed
until it is clinically recognized, usually at a moderately advanced
stage. Mortality from COPD is also likely to be underestimated
because it is often cited as a “contributory factor” rather than
a cause of death.
PREVALENCE
In the past, imprecise definitions of COPD and underdiagnosis
have resulted in underreporting of the condition. Prevalence
studies of COPD vary depending on the survey method
employed, including self-report of physician diagnosis of
COPD, prebronchodilator or postbronchodilator spirometry,
and respiratory symptom questionnaires. The lowest prevalence
figures come from physician self-reporting; most national
surveys indicate that about 6% of the general population has
been diagnosed with COPD. This figure probably reflects the
underrecognition of COPD, particularly in the early stages,
when symptoms are not recognized as representing a disease.
Studies based on standardized spirometry suggest that 25%
of subjects over age 40 have airflow limitation (FEV1/FVC
<0.7). However, prevalence data vary depending on the spirometric criteria used to define COPD. The use of a postbronchodilator, fixed FEV1/FVC (<0.7) leads to potential
underdiagnosis in younger adults and overdiagnosis in older
adults (>50). Other prevalence studies are based on percent
predicted FEV1. In a UK population survey, 10% of men
and 11% of women age 18 to 64 years had an FEV1 greater
than 2 standard deviations (SD) below their predicted values;
the numbers increased with age, particularly in smokers. In
current smokers 40 to 65 years old, 18% of men and 14% of
women had an FEV1 greater than 2 SD below normal, compared with 7% and 6% of male and female nonsmokers,
respectively.
Approximately 14 million people in the United States have
COPD, increasing by 42% since 1982. The best data available
come from the 1988-1994 NHANES-III study. Prevalence of
mild COPD (defined as FEV1/FVC <0.7 and FEV1 >80% predicted) was 6.9% and prevalence of moderate COPD (defined
as FEV1/FVC <0.7 and FEV1 ≤80% predicted) was 6% for those
age 25 to 75. The prevalence of both mild and moderate COPD
was higher in males than females, in whites than in blacks,
and increased steeply with age. Airflow limitation affected an
estimated 14.2% of current white male smokers, 6.9% of
ex-smokers, and 3.3% of never-smokers. Airflow limitation
occurred in 13.6% of white female smokers, 6.8% of ex-smokers,
and 3.1% of never-smokers. Less than 50% of COPD patients,
based on the presence of airflow limitation, had a physician
diagnosis of COPD.
Data from five Latin American cities in five different countries showed the presence of COPD (FEV1/FEC ratio <0.7)
increased sharply with age. The highest prevalence was in the
over-60 age-group and ranged from 18.4% in Mexico City to
31.1% in Montevideo, Uruguay. In 12 Asian-Pacific countries,
prevalence of moderate to severe COPD in those over age 30
was 6.3%. However, prevalence rates ranged from 3.5% to 6.7%
across the Asia-Pacific region.
The UK national study reported abnormally low FEV1 in
10% of males and 11% of females age 60 to 65 years. In England
and Wales, an estimated 900,000 people have a diagnosis of
COPD, although because of underdiagnosis, the true number
is likely closer to 1.5 million. The mean age at diagnosis in the
UK was 67 years, and prevalence increased with age. COPD
was more common in men than in women and was associated
with socioeconomic deprivation. The prevalence of diagnosed
COPD has increased in the UK in women from 0.8% in 1990
to 1.4% in 1997, but did not change over the same period in
men. Similar trends are found in the United States, again probably reflecting differences in smoking habits. National surveys
of consultations in British general practices found a modest
decline in the number of middle-aged men with symptoms of
COPD and a slight increase in middle-aged women. These
trends are confounded by changes over the years in the application of the diagnostic labels for this condition, particularly the
overlap between COPD and asthma.
MORBIDITY AND SOCIOECONOMIC IMPACT
Morbidity data in patients with COPD are less available and
less reliable than mortality data, but the number of physician
visits, emergency department (ED) visits, and hospitalizations
in COPD patients increases with age, is greater in men than
women, and is likely to increase with the aging population.
The ERS White Book provides data on the mean number of
consultations for major respiratory diseases across 19 European
countries. In most, consultations for COPD equal the number
for asthma, pneumonia, lung cancer, and tuberculosis combined. In the United States in 2000, there were 8 million physician office/hospital outpatient visits for COPD, 1.5 million ED
visits, and 673,000 hospitalizations.
The disability-adjusted life years (DALYs) for a condition is
the sum of years lost because of premature mortality and years
of life lived with disability, adjusted for the severity of the disability. In 1990, COPD was the 12th leading cause of DALYs
in the world, about 2.1% of the total. COPD is projected to
be the fifth leading cause of DALYs worldwide in 2020.
In the UK, emergency admissions for exacerbations of
COPD increased from 0.5% of all hospital admissions in 1991
to 1% in 2000. Morbidity from COPD increases with age and
is greater in men than women. COPD morbidity also may be
affected by comorbidities (e.g., ischemic heart disease, diabetes
mellitus) and may impact health status. Airway diseases
(chronic bronchitis and emphysema, COPD, and asthma)
account for a calculated 24.4 million lost working days per year
in the UK, which represents 9% of all certified sickness absence
among men, and 3.5% of the total in women. Respiratory diseases in the UK rank as the third most common cause of days
of certified incapacity, with COPD accounting for 56% of these
days lost in men and 24% in women. Most admissions are in
the over-65 age-group and patients with advanced disease,
although admissions recur at all stages. About 25% of patients
diagnosed with COPD are admitted to the hospital, and 15%
of all outpatients are admitted each year. In 2002-2003, there
were 110,000 hospital admissions for COPD exacerbations in
England, representing 8% of all emergency admissions. The
burden in primary care is even greater, providing 86% of COPD
care. Patients with COPD average six or seven visits annually
to their general practitioner.
MORTALITY
Chronic obstructive pulmonary disease is the fourth leading
cause of death in the United States and Europe and is projected
to be the third leading cause of death (now fifth) worldwide
by 2020, a result of the increase in smoking in the developing
world and the changing demographics in those countries with
increasing longevity of their populations. Large international
variations in mortality for COPD cannot be entirely explained
by differences in diagnostic patterns, diagnostic labels, or
smoking habits. Death certification figures underestimate mortality because as previously stated, COPD is often cited as a
contributory factor to the cause of death. COPD death rates
are low under age 45 and increase steeply with age. Although
mortality from COPD in men has been falling slightly, mortality in women has increased. U.S. data (2000-2005) indicate that
COPD accounts for 5% of all deaths, with age-standardized
mortality rate stable at approximately 64 deaths per 100,000
population; however, mortality in males fell from 83.8 in 2000
to 77.3 per 100,000 in 2005 and increased in females from
54.4 to 56.0 per 100,000.
539
In the UK in 2003, an estimated 26,000 persons (14,000
men, 12,000 women) died from COPD, 4.9% of all deaths,
5.4% of all male deaths, and 4.2% of all female deaths. Mortality from COPD in the UK has fallen in men but risen in women
over the last 25 years, except in the over-75 age-group. In
American women the decline in mortality which was recorded
until 1975 has reversed and has increased substantially between
1980 and 2000, from 20.1 to 56.7 per 100,000, whereas the
increase in men has been more modest, from 73.0 to 82.6 per
100,000. These trends presumably relate to the later peak
prevalence of cigarette smoking in women compared with men.
In the UK, age-adjusted death rates from chronic respiratory
diseases vary by a factor of 5 to 10 in different geographic locations. Mortality rates tend to be higher in urban areas than in
rural areas.
In the UK, COPD reduces life expectancy by an average of
1.8 years (76.5 vs. 78.3). The reduction in life expectancy
increases with age, from 1.1 year in mild disease to 1.7 years
in moderate disease and 4.1 years in patients with severe
disease.
NATURAL HISTORY AND PROGNOSIS
Chronic obstructive pulmonary disease is generally progressive,
particularly if the patient’s exposure to noxious agents continues. However, the natural history of COPD is variable; not all
individuals follow the same course. Stopping exposure to
noxious agents, such as cigarette smoke, may result in some
improvement in lung function and may slow or halt progression
of the disease.
The airway obstruction in susceptible smokers develops
slowly because of an accelerated rate of decline in FEV1 that
continues for years. As noted previously, impaired lung function
development during childhood and adolescence as a result of
recurrent infections or exposure to tobacco smoke may lead to
lower maximally attained lung function in adulthood. This
failure in lung growth, often combined with a shortened plateau
phase in teenage smokers, increases the risk of COPD (Figure
41-5). In never-smokers the FEV1 declines at a rate of 20 to
30 mL/yr (see Figure 41-4). Smokers as a population have a
faster rate of decline, and reported changes in FEV1 in patients
with COPD exceed 50 mL/yr. However, decline in COPD
patients varies considerably. The initial level of FEV1 is related
to the annual rate of decline in FEV1, and individuals in the
highest or lowest FEV1 percentiles remain in the same percentiles over subsequent years. This suggests that susceptible
cigarette smokers can be identified in early middle age by a
reduction in FEV1.
Longitudinal data from the Lung Health Study in the United
States show that stopping smoking, even after significant airflow
limitation is present, can result in some improvement in function, and that it will slow or even stop the progression of airflow
limitation. Men who quit smoking at the beginning of the study
had an FEV1 decline of 30.2 mL/yr, whereas for those who
continued to smoke throughout the study, the decline was
66.1 mL/yr. Similar findings were seen in women.
The FEV1 is a strong predictor of survival. Less than 50% of
patients whose FEV1 has fallen to 30% of the predicted values
are alive 5 years later. The best association between FEV1 and
survival is the postbronchodilator FEV1, rather than prebronchodilator. Other clinical parameters shown to be important
prognostic indicators independent of FEV1 include weight loss,
a poor prognostic sign. Other unfavorable prognostic factors
include severe hypoxemia, raised pulmonary arterial pressure,
Figure 41-5 Different patterns of obtaining abnormally
low forced expiratory volume in 1 second (FEV1) in middle
age. FEV1 plotted as a percentage of maximal at age 20
against years of age. Line a, normal age-related decline in
FEV1 in healthy subjects; b, abnormal growth rate but
normal age-related decline in FEV1; c, premature or early
decline; d, accelerated decline in lung function. (From
Weiss ST, Ware JH: Am J Respir Crit Care Med 154:s208–
s211, 1996.)
100
c
FEV1 (% normal level at age 20)
540
80
d
a
60
b
40
20
0
0
and low carbon monoxide transfer, which become apparent in
patients with severe disease.
PATHOGENESIS
Central to the pathogenesis of COPD is an enhanced inflammatory response to inhaled particles or gases. The following
pathogenic processes are involved in this inflammatory response
(Figure 41-6):
• Increased air space inflammation
• Increased protease burden and decreased antiprotease
function
• Oxidant/antioxidant imbalance and oxidative stress
• Defective lung repair
AIR SPACE INFLAMMATION
Inflammation is present in the lungs, particularly in the small
airways, of all smokers. This inflammatory response is thought
to be a normal, protective, innate immune response to inhaled
toxins. This response is amplified in patients who develop
COPD, through mechanisms not fully understood. COPD does
develop in some patients who do not smoke, but the inflammatory response in these patients is not well characterized. The
abnormal inflammatory response in COPD leads to tissue
destruction, impairment of defense mechanisms that limit
such destruction, and defective repair mechanisms. In general,
the inflammatory and structural changes in the airways
increase with disease severity and persist even after smoking
cessation.
The innate inflammatory immune system provides primary
protection against the continuing insult from inhalation of
toxic gases and particles. The first line of defense consists of the
mucociliary clearance apparatus and macrophages that clear
foreign material from the lower respiratory tract; both are
impaired in COPD. The second line of defense of the innate
immune system is the exudation of plasma and circulating cells
into both large and small conducting airways and the alveoli.
This process is controlled by an array of proinflammatory chemokines and cytokines (Box 41-3). COPD is characterized by
increased neutrophils, macrophages, T lymphocytes (CD8 >
CD4), and dendritic cells in various parts of the lungs (see Box
41-2). Generally, the extent of inflammation is related to degree
of airflow limitation. These inflammatory cells are capable of
10
20
30
40
50
Age (years)
60
70
80
90
Box 41-3 Inflammatory Mediators in COPD
Leukotriene B4 (LTB4)
Neutrophil and T cell chemoattractant
Produced by macrophages, neutrophils, and epithelial cells
Chemotactic factors
CXC chemokines, interleukin-8 (IL-8), growth-related
oncogene-α
Produced by macrophages and epithelial cells
Attract cells from circulation; amplify proinflammatory
responses
Proinflammatory cytokines
Tumor necrosis factor alpha (TNF-α)
Interleukin-1beta (IL-1β) and IL-6
Growth factors
Transforming growth factor beta (TGF-β)
May cause fibrosis in airways directly or through release of
another cytokine, connective tissue growth factor
COPD, chronic obstructive pulmonary disease.
releasing a variety of cytokines and mediators that participate
in the disease process. This inflammatory cell pattern is greatly
different from that found in asthma.
An adaptive immune response is also present in the lungs of
patients with COPD, as shown by the presence of mature
lymphoid follicles, which increase in number in the airways
according to disease severity. Their presence has been attributed to the large antigen load associated with bacterial colonization or frequent low respiratory tract infections, or possibly
an autoimmune response. Dendritic cells are major antigenpresenting cells, are increased in the small airways, and provide
a link between the innate and adaptive immune responses.
Both central airways and peripheral airways are inflamed in
smokers with COPD. Smokers with chronic bronchitis have
greater inflammation in bronchial glands. Recent studies characterizing the inflammation show increased infiltration of mast
cells, macrophages, and neutrophils in smokers with chronic
bronchitis (see Box 41-1). An increase in T lymphocytes, mainly
in the CD8+ subset, occurs, in contrast to the predominance of
the CD4 T cell subset in asthma. CD8 lymphocytes may have
a role in apoptosis and destruction of alveolar wall epithelial
cells, through the release of perforins and tumor necrosis factor
alpha (TNF-α). Excessive recruitment of CD8 T lymphocytes
may occur in response to repeated viral infections, damaging
the lungs in susceptible smokers.
Cigarette smoke
(and other irritants)
541
Amplifying process
Innate immunity
Acquired immunity
Oxidative stress
Genetics
Epigenetics
Chemotactic
factors
Epithelial cells
Alveolar macrophage
TGF-β
CTG
Fibroblast
CD8+ lymphocyte
Neutrophil
Proteases
Oxidants
Fibrosis
(bronchiolitis)
Monocyte
Cellular processes
Inflammatory cell
recruitment/activation
Mediator release
Transcription factor
activation
Autoimmunity
Impaired tissue repair
Cell senescence
Apoptosis
Alveolar wall destruction
(emphysema)
Mucus
hypersecretion
(chronic bronchitis)
Figure 41-6 Overview of pathogenesis of chronic obstructive pulmonary disease. Cigarette smoke activates macrophages in epithelial cells to produce
chemotactic factors that recruit neutrophils and CD8+ cells from the circulation. These cells release factors that activate fibroblasts, resulting in
abnormal repair processes and bronchiolar fibrosis. Imbalance between proteases released from neutrophils and macrophages and antiproteases leads
to alveolar wall destruction (emphysema). Proteases also cause the release of mucus. Increased oxidant burden resulting from smoke inhalation or
release of oxidants from inflammatory leukocytes causes epithelial and other cells to release chemotactic factors, inactivates antiproteases, directly
injures alveolar walls, and causes mucus secretion. Several processes are involved in amplifying the inflammatory responses in COPD. TGF-β,
Transforming growth factor beta; CTG, connective tissue growth factor. (From MacNee W: Pathology and pathogenesis. In ABC of COPD, ed 2, London,
2011, Blackwell.)
PROTEINASE/ANTIPROTEINASE IMBALANCE
Important for understanding the pathogenesis of COPD, an
association was seen between α1-antitrypsin deficiency and
development of early-onset emphysema. Alpha1-antitrypsin is
a potent inhibitor of serine proteases and has greatest affinity
for the enzyme neutrophil elastase. It is synthesized in the liver
and increases from its usual plasma concentration as part of the
acute-phase response. The activity of this protein is critically
dependent on the methionine-serine sequence at its active site.
Table 41-1 provides the average α1-antitrypsin plasma levels for
the more common phenotypes.
A deficiency in alpha1-antitrypsin levels, particularly the
inability to increase levels in the acute response, results in
unrestrained proteolytic damage to lung tissue, leading to
emphysema, which develops at an earlier age than in the
patient with the more common emphysema in COPD. Cigarette smoking is a cofactor in the development of emphysema
in alpha1-antitrypsin–deficient patients, probably as a result of
oxidation and thus inactivation of the remaining functional
α1-antitrypsin by oxidants in cigarette smoke. Hypothetically,
under normal circumstances, the release of proteolytic enzymes
from inflammatory cells, which migrate to the lungs to fight
infection or after cigarette smoke inhalation, does not cause
damage because of inactivation of these proteolytic enzymes
by an excess of inhibitors. In conditions of excessive enzyme
load or with absolute or functional deficiency of antiproteinases, however, an imbalance develops between proteinases and
antiproteinases that favors proteinases, leading to uncontrolled
enzyme activity and degradation of lung connective tissue in
alveolar walls, resulting in emphysema. Cigarette smoke and
inflammation produce oxidative stress, which primes several
inflammatory cells to release a combination of proteases and to
inactivate several antiproteases by oxidation.
This simplified protease/antiprotease theory is complicated
by the presence of other antiproteases (e.g., antileukoprotease)
and other proteases (e.g., metalloproteases) released from
macrophages (Table 41-2).
ELASTASE SYNTHESIS AND REPAIR
An abnormality of elastin synthesis and repair may be involved
in the pathogenesis of emphysema. Severe starvation has been
reported to cause COPD in both humans and animals;
542
Table 41-2 Proteinases and Antiproteinases in COPD
Proteinases
Antiproteinases
Serine proteinases
α1-Antitrypsin
Neutrophil elastase
α1-Antitrypsin
Cathepsin G
Secretory leukoprotease inhibitor
Proteinase 3
Elafin
Cysteine proteinases
Cystatins
Cathepsins: B, K, L, S
Matrix metalloproteinases
(MMP-8, MMP-9, MMP-12)
Tissue inhibitor of MMPs (TIMP-1
to TIMP-4)
in addition, starvation can exacerbate proteinase-induced
emphysema in animal models. Whether the milder malnutrition that occurs in emphysematous patients has a role in the
pathogenesis is unknown.
Certain disorders of connective tissues, including EhlersDanlos syndrome and cutis laxa (generalized elastolysis), have
been associated with the development of emphysema. Emphysema also develops in some animal models with genetic defects
in tissue metabolism.
OXIDANT/ANTIOXIDANT IMBALANCE
Considerable evidence supports the presence of an imbalance
between oxidants and antioxidants that favors the oxidants
(oxidative stress) in patients with COPD. Cigarette smoke
itself produces a huge oxidant burden in the air spaces, and
oxidants are released in increased amounts from the activated
inflammatory cells that migrate into the air spaces in response
to smoking, as noted earlier. Important antioxidants such as
glutathione may also be affected by inhalation of cigarette
smoke. Smoking initially depletes glutathione, but a subsequent
rebound of levels occurs, presumably as a protective mechanism against the effects of cigarette smoking.
Studies have measured increased markers of oxidative stress,
such as products of lipid peroxidation reactions, in biologic
fluids of patients with COPD as indirect measurements of
reactive oxygen species activity. Evidence shows increased
markers of oxidative stress in bronchoalveolar lavage (BAL)
fluid, sputum, exhaled breath, and breath condensate as well
as systemically in the blood and skeletal muscle in patients
with COPD, supporting a role for oxidative stress in its pathogenesis. Oxidative stress can directly damage cells, increase air
space epithelial permeability, inactivate antiproteases, and
importantly, trigger an enhanced inflammatory response by
activating redox-sensitive transcription factors (e.g., NF-κB,
AP-1). Also, oxidative modification of target molecules occurs
more in the lungs in patients with COPD than in smokers
without COPD.
Histone deacetylase-2 (HDAC2) is modified by oxidative
stress in COPD, resulting in decreased level and activity.
Decrease in HDAC2 results in acetylation of the lysine residues
and DNA, resulting in uncoiling of DNA and increasing the
accessibility of transcription factors and RNA polymerase to
the transcriptional machinery, thus increasing gene transcription. Studies of resected lungs indicate that HDAC2 protein
and activity is reduced in lung tissue in COPD as a result of
oxidative modification of the molecule and is associated with
an increase in histone-4 acetylation at the IL-8 promoter and
increased IL-8 mRNA expression. This mechanism may be
responsible for perpetuating inflammation in COPD.
The transcription factor nuclear erythroid-related factor 2
(Nrf2) controls the expression of several of the most important
antioxidant enzymes. COPD lungs have decreased expression
of Nrf2 transcriptional activity, which may result in reduced
protection against oxidative stress.
OTHER MECHANISMS
Autoimmunity, apoptosis, and cell senescence also may be
involved in the pathogenesis of emphysema (Figure 41-6).
Studies show that apoptosis occurs in emphysematous lungs,
predominantly involving endothelial cells in the alveolar walls
and resulting from a decrease in vascular endothelial growth
factor (VEGF) or VEGF signaling, also shown to occur in association with emphysema in human lungs. These data led to the
concept of an “alveolar maintenance program” required for the
structural preservation of the lungs. Cigarette smoke is thought
to cause disruption of this maintenance program, resulting in
emphysema. The lung destruction or tissue destruction of
emphysema is therefore caused by the mutual interaction of
alveolar cell apoptosis, oxidative stress, and protease/antiprotease
imbalance.
Similar features between pulmonary emphysema and lung
aging led to the hypothesis that both conditions share underlying mechanisms, including oxidative stress, inflammation, and
apoptosis. The cellular equivalent of aging is senescence, which
is characterized by a nonproliferative stage in which cells are
metabolically active and apoptosis resistant. Mechanisms associated with cell senescence include accumulation of DNA
damage, impairment of DNA repair, epigenetic modifications
in nuclear DNA, protein damage, oxidative stress, and telomere
attrition. Telomere length is decreased in cells from emphysematous lungs, as are antiaging molecules such as sirtuins, suggesting a role for accelerated aging and cell senescence in the
pathogenesis of emphysema.
Considerable evidence supports the role of the adaptive
immune response in the progression of COPD. The presence
of autoantibodies to lung structural cells and elastase suggests
involvement of autoimmune mechanisms in pathogenesis
of COPD.
Both oxidants and proteases such as elastase are important
secretagogues for mucus and thus may be involved in the
hypersecretion of mucus that occurs in chronic bronchitis.
Airway mucus synthesis is regulated by the epidermal growth
factor receptor (EGFR) system. Cigarette smoke upregulates
EGFR expression and activates EGFR tyrosine phosphorylation, causing mucus synthesis in epithelial cells by a mechanism
that probably involves oxidative stress.
PATHOPHYSIOLOGY
AIRFLOW LIMITATION AND HYPERINFLATION
The characteristic physiologic abnormality in COPD is a
decrease in maximum expiratory flow, which results from (1)
loss of lung elasticity and (2) increase in airway resistance in
small airways.
The main site of airflow limitation in COPD occurs in the
small conducting airways (<2 mm in diameter) and results
from inflammation, narrowing (airway remodeling), and inflammatory exudates in the small airways, features that correlate
Figure 41-7 In health, the body meets the increased oxygen
demand produced by exercise by using some of the inspiratory
reserve volume of the lungs to increase tidal volume. COPD,
chronic obstructive pulmonary disease. EELV, end-expiratory lung
volume; EILV, end-inspiratory lung volume; IC, inspiratory capacity;
IRV, inspiratory reserve volume; TLC, total lung capacity. (Data
from O’Donnell DE et al: Am J Respir Crit Care Med 164:770, 1999.)
Normal
Lung volumes (% predicted TLC)
0
Minimal inspiratory reserve volume
10
543
Inspiratory reserve volume (IRV)
20
IC
30
Tidal volume (V1)
40
50
60
70
10
Normal
Vital capacity
20
30
40
50
60
70
80
70
80
Ventilation (L/min)
COPD
Lung volumes (% predicted TLC)
0
Minimal IRV
10
IRV
20
(V1)
EILV
IC
EELV
30
40
Vital capacity
50
60
70
10
COPD
20
30
40
50
60
Ventilation (L/min)
with the reduction in FEV1. Other factors contributing to the
airflow limitation include loss of the lung elastic recoil (caused
by destruction of alveolar walls) and destruction of alveolar
support (from alveolar attachments). The resultant airway
obstruction causes progressive trapping of the air during expiration, resulting in hyperinflation at rest and dynamic hyperinflation during exercise. Lung hyperinflation reduces the inspiratory
capacity, and thus functional residual capacity (FRC) increases,
particularly during exercise (Figure 41-7). These features are
thought to occur early in the course of the disease and result
in the breathlessness and limited exercise capacity typical of
COPD. Bronchodilators reduce air trapping and thus decrease
lung volumes, improving symptoms and exercise capacity. Tests
of overall lung mechanics (e.g., FEV1, airway resistance) are
usually abnormal in patients with COPD when breathlessness
develops.
Residual volume, FRC, and (in some cases) total lung
capacity (TLC) increase. Maximum expiratory flow-volume
curves show a characteristic convexity toward the volume axis,
with preservation of peak expiratory flow initially. The uneven
distribution of ventilation in advanced COPD causes a reduction in “ventilated” lung volume, and thus the carbon monoxide
transfer factor (TLCO) is almost always reduced, although
the lung diffusing capacity for carbon monoxide (DLCO),
normalized to ventilated alveolar volume (DLCO/VA/KCO),
may remain relatively well preserved in patients without
emphysema.
The ability to draw air through the conducting airways
during inspiration depends on the strength of the respiratory
muscles, which in turn depends on their resting length; the
compliance of the respiratory system (lung and chest wall); and
the resistance of the airways. Exhalation is normally passive and
results from the elastic recoil of the lungs. The characteristic
changes in the static pressure-volume curve of the lungs in
COPD are an increase in static compliance and a reduction in
static transpulmonary pressure at any given lung volume. These
changes are generally thought to indicate emphysema.
The resistance to airflow depends on the length and diameter of the airways and the physical properties of the respirable gas. At a constant airway diameter, airflow on inhalation is
proportional to the difference between atmospheric gas pressure and alveolar pressure. During exhalation, airflow depends
on the difference between alveolar and atmospheric pressures.
Throughout inhalation and during the initial portion of exhalation, this relationship is constant. However, at a certain
point during exhalation, flow cannot increase despite further
544
Flow
Maximum
expiratory effort
RESPIRATORY MUSCLES
Normal
COPD
Three fourths
maximum effort
Half maximum
effort
Tidal breathing
Figure 41-8 Flow-volume loop over normal individual and patient with
chronic obstructive pulmonary disease (COPD). Patients who have COPD
may reach airflow limitation even during tidal breathing. (From Celli B.
In Albert R, Spiro SG, Jett JR, editors: Comprehensive respiratory medicine,
St Louis, 1999, Mosby.)
increases in alveolar pressure. This is a result of dynamic compression of the airways, which limits flow, as illustrated by the
flow-volume loop (Figure 41-8). During exhalation from TLC,
flow increases to a point beyond which additional expiratory
effort has no effect. During tidal breathing, expiratory flow is
well below that attainable during maximum expiration. In
COPD, however, the flow-volume loop is different. The major
site of the fixed airway narrowing in COPD is in peripheral
airways of diameter less than 2 mm. Loss of lung elastic recoil
pressure is also an important mechanism of airway obstruction, resulting from a reduction in the distending force applied
to the intrathoracic airways. Dynamic expiratory compression
of the airways is enhanced by loss of lung recoil and by atrophic changes in the airways and loss of support from the surrounding alveolar walls, allowing flow limitation at lower
driving pressure and flow.
In addition to a decrease in peak expiratory flow, the later
expiratory portion of the flow-volume curve is concave relative
to the volume axis in patients with COPD. In severe disease
the flow generated during tidal breathing may actually reach
the maximum possible flow (Figure 41-8). Such patients, in
response to the increased metabolic demands of exercise, for
example, are unable to increase ventilation. Increased respiratory rate results in gas trapping from incomplete alveolar emptying, so-called dynamic overinflation. This increased lung
volume increases the elastic recoil and is associated with an
increase in the end-expiratory alveolar pressure. The result is
an increase in the work of breathing because pleural pressure
must drop below alveolar pressure before inspiration of air can
occur.
PULMONARY GAS EXCHANGE
Ventilation-perfusion (V/Q) mismatching (as a result of
decreased alveolar ventilation without a corresponding reduction in perfusion) is the most important cause of impaired
pulmonary gas exchange in COPD. Other causes, such as
impaired alveolar-capillary diffusion of oxygen and increased
shunt, are much less important. In general, gas exchange
worsens as the disease progresses. The distribution of ventilation is uneven in patients with COPD. Mechanisms that reduce
blood flow include local destruction of vessels in alveolar walls
as a result of emphysema, hypoxic vasoconstriction in areas of
severe alveolar hypoxemia, and passive vascular obstruction
from increased alveolar pressure and distention.
In patients with severe COPD, a combination of lung overinflation and malnutrition results in muscle weakness, reducing the
capacity of the respiratory muscles to generate pressure over
the range of tidal breathing. In addition, the load against which
the respiratory muscles need to act is increased because of the
increase in airway resistance. Overinflation of the lungs leads
to shortening and flattening of the diaphragm, impairing its
ability to generate force to lower pleural pressure. During quiet
tidal breathing in normal subjects, expiration is largely passive
and depends on the elastic recoil of lungs and chest wall.
Patients with COPD increasingly need to use their rib cage
muscles and inspiratory accessory (e.g., sternocleidomastoid)
muscles, even during quiet breathing. During exercise, this
pattern may be even more distorted and may result in paradoxical motion of the rib cage.
Patients with COPD have impaired values of global function
of the respiratory muscles, such as maximum inspiratory mouth
pressure (PEmax), although these measurements are effortdependent. Diaphragmatic function can be assessed during
inspiration by measurement of transdiaphragmatic pressure
(Pdi), using balloon-tipped catheters with small transducers in
the esophagus and stomach. Pdi values are reduced in patients
with COPD.
PULMONARY HYPERTENSION
Pulmonary hypertension complicating COPD is generally
defined by a mean pulmonary artery pressure (Ppa) greater
than 20 mm Hg. This is different from the definition of
idiopathic hypertension (Ppa >25 mm Hg). In the natural
history of COPD, pulmonary hypertension is often preceded
by an abnormally large increase in Ppa (>30 mm Hg) during
exercise.
The term cor pulmonale is often used synonymously with
pulmonary hypertension in COPD. However, cor pulmonale is
defined as right ventricular (RV) hypertrophy (enlargement)
resulting from disease that affects the structure or function of
the lungs. This is a pathologic definition and thus of limited
value in clinical practice, because the diagnosis of RV hypertrophy is difficult to make. Pulmonary hypertension is the cause
of cor pulmonale, so it is best to use the term pulmonary hypertension in COPD rather than cor pulmonale.
There are few data on the prevalence of pulmonary hypertension resulting from COPD, because large studies of rightsided heart catheterization or Doppler echocardiography have
not been undertaken. An estimate of the prevalence of pulmonary hypertension in COPD can be obtained from calculating
the number of subjects with significant hypoxemia who require
long-term oxygen therapy. Significant hypoxemia (PaO2
<55 mm Hg, FEV1 <50% of predicted) occurs in 0.3% of the
UK population 45 or older. Extrapolation from this figure suggests that in England and Wales, 60,000 patients may be at risk
of pulmonary hypertension and eligible for long-term oxygen
therapy. Extrapolating these figures to the United States,
300,000 COPD patients are at risk of pulmonary hypertension.
Box 41-4 lists the factors leading to pulmonary hypertension in
patients with COPD.
Pulmonary artery hypertension occurs late in the course
of COPD, concurrent with the development of hypoxemia.
Alveolar hypoxia is the most important functional factor
in the development of pulmonary hypertension in COPD.
Acute hypoxia causes pulmonary vasoconstriction, and chronic
Box 41-4 Factors Leading to Increased Pulmonary Vascular
Resistance in COPD
Functional Factors
Alveolar hypoxia
Acute hypoxia (vasoconstriction)
Chronic hypoxia (remodeling of pulmonary vascular bed)
Hypercapnia, acidosis
Hyperviscosity (polycythemia)
Structural Factors
Destruction of pulmonary vascular bed
Thromboembolic lesions
Fibrosis
Emphysema
Compression of alveolar vessels
hypoxia induces structural changes or remodeling of the
pulmonary vasculature, leading to sustained pulmonary
hypertension.
The pulmonary hypertension in COPD is precapillary,
because of an increased pressure difference between Ppa and
pulmonary capillary wedge pressure, reflecting the increased
pulmonary vascular resistance. Pulmonary hypertension in
COPD is mild to moderate, with a resting Ppa in the stable
stage of the disease ranging between 20 and 35 mm Hg. Ppa
of 40 mm Hg or greater is unusual in COPD patients, except
when measured during an acute exacerbation or during
exercise; approximately 1% of patients exhibit severe pulmonary hypertension (Ppa >40 mm Hg). These patients are characterized by less severe airflow limitation but profound
hypoxemia and hypocapnia. These patients may have an
increased reactivity of the pulmonary arteries to hypoxia or
coexisting idiopathic pulmonary hypertension. COPD patients
with severe pulmonary hypertension in COPD have a poorer
prognosis.
The progression of pulmonary hypertension is slow in
COPD patients, and Ppa may remain stable for several years.
The mean change in Ppa in a cohort of COPD patients is
small (0.5 mm Hg/yr). Also, symptoms and physical signs are
of little help in the diagnosis of pulmonary hypertension
in COPD patients. The sensitivity of electrocardiography in
diagnosing pulmonary hypertension is poor as well. Doppler
echocardiography is the best method for the noninvasive
diagnosis of pulmonary hypertension. However, right-sided
heart catheterization remains the “gold standard” for diagnosing
pulmonary hypertension.
The Ppa value is a good indicator of prognosis in patients
with COPD. Five-year survival in a group of patients with
initial Ppa less than 25 mm Hg was 66%, whereas in those with
initial Ppa greater than 25 mm Hg, survival was only 36%.
The development of structural changes in the pulmonary
arteries results in persistent pulmonary hypertension and RV
hypertrophy/enlargement and dysfunction. Cor pulmonale is
the major cardiovascular complication of COPD and is associated with a poor prognosis. Peripheral edema results from a
combination of increased venous pressure and renal hormonal
changes, leading to increased salt and water retention.
SYSTEMIC EFFECTS AND COMORBIDITIES
Although primarily a disease of the lungs, it is increasingly
recognized that, as in many chronic diseases, COPD results in
545
important systemic features that may affect morbidity and
mortality. Comorbid conditions are frequently observed in
patients with COPD at all stages, and many patients have
multiple comorbidities.
The prevalence of COPD morbidity varies among studies.
In a cohort of 1522 patients with COPD, 50% had one or two
comorbidities, 15.8% had three or four comorbidities, and 6%
had five or more. Comorbidities not only are highly prevalent
but also have important prognostic implications. In the Lung
Health Study of patients with mild to moderate COPD, deaths
from respiratory disease were relatively uncommon (7%); lung
cancer was the most common cause of death (33%). Coronary
artery disease (CAD) accounted for 10.5%, and cardiovascular
disease (including CAD) accounted for 22% of deaths. In a
large, pharmacologic intervention study, with cause of death
assessed by independent review panel, 27% of deaths were
related to COPD, 26% to cardiovascular disease, and 21% to
lung cancer.
In a large cohort of COPD patients, the presence of diabetes,
hypertension, or cardiovascular disease significantly increased
the risk of hospitalization or mortality. Furthermore, combinations of multiple comorbid diseases in an individual resulted in
an even higher risk of death. Systemic inflammation in patients
with COPD is thought to contribute to these systemic effects
and comorbidities.
SKELETAL MUSCLE DYSFUNCTION/WASTING
AND WEIGHT LOSS
Peripheral muscle dysfunction is a prominent contributor to
exercise limitation, increases health care utilization, and is an
independent indicator of morbidity and mortality in COPD.
Weight loss is common in patients with COPD. A decreased
body weight is reported in 49% of patients referred to a UK
center for pulmonary rehabilitation. The prevalence of muscle
wasting in COPD is probably underestimated, as extrapolated
from body weight measurements, because fat-free mass (FFM)
may be reduced despite preservation of body weight. Independent of body mass index (BMI) and disease severity, FFM index
can predict mortality in COPD patients. The prevalence of
FFM depletion was about 30% in patients with an FEV1 of 30%
to 70% of predicted and is associated with impaired peripheral
muscle strength. Weight loss and loss of muscle mass result
from the effects of systemic inflammation, an imbalance
between muscle protein synthesis and breakdown, muscle
apoptosis, and muscle disuse. Increased systemic inflammatory
mediators (e.g., TNF-α, IL-6, O2 free radicals) may mediate
some systemic effects.
Osteoporosis is recognized as one of the systemic effects of
COPD. In the TORCH study (Towards a Revolution in COPD
Health), 18% of men and 30% of women had osteoporosis, and
42% of men and 41% of women had osteopenia, based on bone
mineral density (BMD) assessments. The etiology of osteoporosis in COPD is complex. Several risk factors for osteoporosis
are common features in COPD patients, including aging,
limited physical activity, vitamin D deficiency, cigarette
smoking, hypogonadism, and systemic corticosteroid use. A
consequence of osteoporosis is that prevalence of vertebral
fractures in COPD patients is 20% to 30%. This can result in
increased kyphosis, compromising pulmonary function.
Osteoporosis is related to emphysema and to arterial wall
stiffness. Moreover, the osteoprotegerin (OPG)/receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL)
system has been identified as a possible mediator of arterial
546
calcification, suggesting common links between osteoporosis
and vascular diseases.
CARDIOVASCULAR DISEASE
Cardiovascular disease is one of the most important comorbidities related to COPD. A study that included 11,943 COPD
patients reported a two-fold to four-fold increase in mortality
risk from cardiovascular disease over a 3-year follow-up compared with an age-matched and gender-matched control group
without COPD. In a cohort of patients with mild COPD in the
Lung Health Study, cardiovascular complications accounted for
22% of all deaths during follow-up and for 42% of first hospitalizations. In this study, for every 10% increase in FEV1,
cardiovascular mortality increased by 28%, and nonfatal cardiovascular events increased by almost 20%, after adjustments for
relevant confounders such as age, gender, smoking status, and
treatment. There is strong epidemiologic evidence that reduced
FEV1 is a marker of cardiovascular mortality. A systematic
review and meta-analysis included more than 80,000 patients
identified and almost a twofold risk of cardiovascular mortality
in patients with the lowest versus the highest lung function
quintiles. COPD is an important risk factor for atherosclerosis,
ischemic heart disease, cerebrovascular accident (stroke), and
sudden cardiac death. Underlying mechanisms that contribute
to the increased risk of atherosclerosis in COPD patients are
not well understood and probably multifactorial, including
low-grade systemic inflammation, endothelial dysfunction, and
arterial stiffness.
ANEMIA
Although hypoxemia in COPD can be associated with secondary polycythemia, as a compensatory mechanism to improve
oxygen transport to the tissues, polycythemia is present in only
6% of COPD patients, whereas anemia is present in 13% to
33%. The anemia in COPD is normochromic, normocytic, and
is likely mediated by shortened red blood cell survival, decreased
erythropoietin, and dysregulation of iron homeostasis. Anemia
contributes to impaired oxygen transport to the tissues and
exercise intolerance and has been associated with increased
mortality in COPD patients.
DEPRESSION
Depression has been reported in 10% to 80% of patients with
COPD, 2% to 5% higher than in the normal age-matched
population. Depression is part of a vicious cycle involving poor
health status, isolation, sedentary lifestyle, and worsening health
status, resulting in the development of a reactive depression.
Depression may also precede the development of COPD. Systemic inflammation may also contribute to development of
depression.
LUNG CANCER
Lung cancer is three to four times more common in COPD
patients than in the general population and constitutes an
important mortality risk in COPD patients. Patients with
COPD have a higher incidence of lung cancer independent of
the history of cigarette smoking. COPD is associated with the
risk of developing small cell and squamous cell carcinoma,
although no relationship seems to exist between COPD and
the risk of developing adenocarcinoma.
DIABETES
The prevalence of diabetes in COPD patients has ranged from
1% to 16% of patients in different studies. Smoking is also a
risk factor, and quitting smoking reduces the risk of diabetes. A
reduction in lung function has also been associated with diabetes. Inflammatory markers such as TNF-α, IL-6, and C-reactive
protein (CRP) have been associated with diabetes, and these
inflammatory markers are elevated in COPD and may mediate
insulin resistance by blocking signaling through the insulin
receptor. The metabolic syndrome also appears to be more
common in COPD patients, reflecting concomitant diabetes
and cardiovascular disease with airway obstruction.
GASTROESOPHAGEAL REFLUX
An increase in gastroesophageal reflux disease (GERD) has
been identified in COPD patients, being more common in
those patients with an FEV1 less than 50% predicted. GERD
also appears to be a precipitant of exacerbations of COPD.
CLINICAL FEATURES
SYMPTOMS
Patients with COPD characteristically complain of the symptoms of breathlessness on exertion, chest tightness, wheeze,
chronic cough, and lower respiratory tract infections. The
cough is often, but not invariably, productive. Breathlessness is
the symptom that usually causes the patient to seek medical
attention and is the most disabling symptom.
Patients often date the onset of their illness to an acute
exacerbation of cough with sputum production, which leaves
them with a degree of chronic breathlessness. Close questioning, however, usually reveals a cough with small amounts of
mucoid sputum (usually <60 mL/day), often in the morning
for many years. A productive cough occurs in up to 50% of
cigarette smokers and may precede the onset of breathlessness.
Many patients may dismiss this as simply “smoker’s cough.” The
frequency of nocturnal cough does not appear to be increased
in stable COPD. Paroxysms of coughing in the presence of
severe airflow limitation generate high intrathoracic pressures,
which can produce syncope and “cough fractures” of the ribs.
Breathlessness is usually first noticed on climbing hills or
stairs, or hurrying on level ground, which later becomes progressive and persistent. It usually heralds at least moderate
impairment of expiratory flow. Patients may adapt their breathing pattern and their behavior to minimize the sensation of
breathlessness. The perception of breathlessness varies greatly
among patients with the same impairment of ventilatory capacity. However, when the FEV1 has fallen to 35% or less of the
predicted value, breathlessness is usually present on minimal
exertion. Severe breathlessness is often affected by changes in
environmental temperature or occupational exposure to dust
and fumes. Some patients have severe orthopnea, relieved by
leaning forward, whereas others find greatest ease when lying
flat. The impact of breathlessness can be assessed on the UK
Medical Research Council (MRC) Dyspnea Scale (Table 41-3).
Wheeze (wheezing) is common but not specific to COPD
because it results from turbulent airflow in large airways from
any cause.
Chest tightness is also common in patients with COPD,
resulting from the disease itself, underlying ischemic heart
disease, or GERD. Chest tightness is a frequent complaint
Table 41-3 Modified MRC Dyspnea Scale for Assessing
Breathlessness
Grade
Degree of Breathlessness Related to Activities
1
Not troubled by breathlessness, except on strenuous
exercise.
2
Short of breath when hurrying or walking up a slight hill.
3
Walks slower than contemporaries on level ground
because of breathlessness, or has to stop for “breather”
when walking at own pace.
4
Stops for breath after walking about 100 m or after a
few minutes on level ground.
5
Too breathless to leave the house, or breathless when
dressing or undressing.
547
Table 41-4 Modified Borg Scale for Assessing Breathlessness
Scale
Severity Experienced by Patient
0
Nothing at all
0.5
Very, very slight (just noticeable)
1
Very slight
2
Slight (light)
3
Moderate
4
Somewhat severe
5
Severe (heavy)
6
Very severe
Very, very severe (almost maximal)
Maximal
Data from UK Medical Research Council.
during periods of worsening breathlessness, particularly during
exercise and exacerbations, and this is sometimes difficult
to distinguish from ischemic cardiac pain. Pleuritic chest pain
may suggest concurrent pneumothorax, pneumonia, or pulmonary infarction. Hemoptysis can be associated with purulent
sputum and may be caused by inflammation or infection.
However, blood-tinged sputum should also suggest bronchial
carcinoma.
OTHER ASPECTS OF THE HISTORY
As part of the assessment of patients with COPD, the following
factors need to be determined from the history:
•
•
•
•
•
•
•
•
•
•
•
•
•
Current medications
History of other medical conditions
Symptoms of anxiety and depression
Sleep quality
Frequency of exacerbations; number of courses of corticosteroids and antibiotics in preceding year
Hospital admissions
Occupational and environmental exposure to dust, chemicals, gases, and fumes
Exposure to biomass fuel
Previous respiratory problems (chronic asthma or
tuberculosis)
Number of days missed from work
Social and family support
Anorexia and weight loss
Current smoking status and number of pack-years (1 packyear is defined as 20 cigarettes [1 pack] smoked per day for
1 year)
Several conditions should be considered in the differential
diagnosis in patients with COPD. Asthma can be particularly
difficult; scales (e.g., the modified Borg scale) can be used to
assess the degree of breathlessness (Table 41-4).
CLINICAL SIGNS
Patients with COPD typically present in the fifth decade of life.
The physical examination may be completely negative early in
the disease course. The physical signs are not specific and
depend on the degree of airflow limitation and pulmonary
overinflation. Because of the heterogeneity of COPD, patients
may show a range of phenotypic clinical presentations. The
sensitivity of physical examination to detect or exclude moderately severe COPD is rather poor.
PATIENT ASSESSMENT
GENERAL EXAMINATION
The respiratory rate may be increased. A breathing pattern with
a prolonged expiratory phase, with or without pursing of the
lips, is characteristic of patients with COPD. A forced expiratory time greater than 5 seconds strongly suggests the presence
of airflow limitation. Use of accessory muscles of respiration,
particularly the sternocleidomastoids, is often seen in advanced
disease, and these patients often adopt a posture in which they
lean forward, supporting themselves with their arms to fix the
shoulder girdle. This allows use of the pectoral muscles and the
latissimus dorsi muscle to increase chest wall movement.
Tar-stained fingers indicate the smoking habit in many
patients. In advanced disease, cyanosis may be present, indicating hypoxemia, but it may be masked by anemia or accentuated
by polycythemia, and is a fairly subjective sign. The “flapping
tremor” associated with hypercapnia is neither sensitive nor
specific, and papilledema associated with severe hypercapnia
is rare.
As described earlier, weight loss may also be apparent in
advanced disease, as well as a reduction in muscle mass. The
body mass index (BMI; weight/height2) should be calculated.
Finger clubbing is not a feature of COPD and should suggest
the possibility of complicating bronchial neoplasm, pulmonary
fibrosis, or bronchiectasis.
CHEST EXAMINATION
In the later stages of COPD, the chest is often barrel-shaped
with a kyphosis, resulting in an increased anterior/posterior
chest diameter, horizontal ribs, prominence of the sternal angle,
and a wide subcostal angle. The distance between the suprasternal notch and the cricoid cartilage (normally 3 fingerbreadths) may be reduced because of the elevation of the
sternum. These are all signs of overinflation. An inspiratory
tracheal tug may be detected, attributed to contraction of the
low, flat diaphragm. The horizontal position of the diaphragm
also acts to pull the lower ribs in during inspiration (Hoover
sign). The xiphisternal angle widens, and abdominal protuberance results from forward displacement of the abdominal
548
contents, giving the appearance of weight gain. Increased intrathoracic pressure swings may result in indrawing of the suprasternal and supraclavicular fossae and intercostal muscles.
Decreased hepatic and cardiac dullness on percussion indicates overinflation. A useful sign of gross overinflation is the
absence of a dull percussion note, normally caused by the
underlying heart, over the lower end of the sternum. Breath
sounds may have a prolonged expiratory phase or may be uniformly diminished, particularly in the advanced stages of
COPD. Wheezing may be present both on inspiration and
expiration but is not an invariable sign. Crackles may be heard,
particularly at the lung bases, but are usually scant and vary
with coughing.
CARDIOVASCULAR EXAMINATION
Air trapping decreases venous return and compresses the heart.
Accordingly, tachycardia is common in COPD patients. The
presence of positive alveolar pressure at the end of exhalation
(i.e., intrinsic positive end-expiratory pressure, or auto-PEEP)
results in the need to create a more negative pleural pressure
than usual, manifested by paradoxical pulse. Overinflation
makes it difficult to localize the apex beat and reduces the
cardiac dullness. The characteristic signs that indicate the
presence or consequences of pulmonary hypertension may be
detected in advanced cases. The heave of RV hypertrophy may
be palpable at the lower left sternal edge or in the subxiphoid
regions. Heart sounds are usually soft, although the pulmonary
component of the second heart sound may be exaggerated in
the second left intercostal space, indicating pulmonary hypertension. An RV gallop rhythm may be detected in the fourth
intercostal space to the left of the sternum. The jugular venous
pressure can be difficult to estimate in patients with COPD
because it swings widely with respiration and is difficult to
discern if there is prominent accessory muscle activity. There
may be evidence of functional tricuspid incompetence, producing a pansystolic murmur at the left sternal edge. The liver may
be tender and pulsatile, and a prominent v wave may be visible
in the jugular venous pulse. The liver may also be palpable
below the right costal margin as a result of overinflation of the
lungs.
Peripheral vasodilation accompanies hypercapnia, producing
warm peripheries with a high-volume pulse. Pitting peripheral
edema may also be present as a result of fluid retention.
the FEV1 can be used to assess susceptibility in cigarette
smokers and progression of disease.
It is important that a volume plateau is reached when performing the FEV1 maneuver, which can take 15 seconds or
more in patients with severe airway obstruction. If this maneuver is not carried out, the vital capacity (VC) can be underestimated. FEV1 within ±20% of predicted value is considered in
the normal range. Thus, an FEV1 of 80% or more of the predicted value is normal. Under usual circumstances, 70% to 80%
of the total volume of the air in the lungs (FVC) should be
exhaled in the first second. When the FEV1/FVC ratio falls
below 0.7, airflow limitation is present. The reproducibility of
the FEV1 varies by less than 200 mL between maneuvers.
Spirometric measurements are evaluated by comparison of
the results with appropriate reference values based on age,
gender, height, and race. The presence of a postbronchodilator
FEV1/FVC ratio <0.7 confirms the presence of airflow limitation that is not fully reversible. However, in older adults, values
of FEV1/FVC between 0.65 and 0.7 may be normal. Thus, use
of a fixed ratio of FEV1/FVC <0.7 postbronchodilator leads to
overdiagnosis of COPD in elderly patients. FEV6 measures the
volume of air that can be forcibly exhaled in 6 seconds. It
approximates the FVC, although in healthy individuals the
FEV6 and FVC are identical. Use of FEV6 instead of FVC may
be helpful in patients with more severe airflow limitation. To
avoid the effect of airway collapse in patients with COPD
during forced expiration, the clinician should use a slow
or relaxed VC measurement, which allows patients to exhale
at their own pace. The slow VC is often 0.5 L greater than
the FVC.
The FEV1 as a percentage of the predicted value can be used
to assess the severity of disease (Table 41-5). FEV1 does not
fully capture the impact of COPD on the patient’s functional
capabilities, however, and thus other measurements in addition
to spirometry are required to assess the effect of COPD on
functional ability. Breathlessness can be gauged by the MRC
scale (see Table 41-3). Exercise capacity can be objectively
measured by a reduction in self-paced walking distance (e.g.,
6-minute walking distance [6MWD]), which is a strong predictor of health status impairment and prognosis. A combination
of these variables to give a more detailed indication of disease
severity has been proposed as the BODE index, a composite
score of body mass index, airways obstruction, dyspnea, and
exercise that appears to be a better predictor of subsequent
survival than any of the individual components (Table 41-6).
PHYSIOLOGIC ASSESSMENT
Expiratory Flow
The degree of airflow limitation cannot be predicted from the
symptoms and signs noted on clinical evaluation. Accordingly,
the degree of airflow limitation should be assessed in every
patient. At an early stage of the disease, conventional spirometry may reveal no abnormality. Results of tests of small airways
function, such as the frequency dependency of compliance and
closing volume, may be abnormal. However, these tests are
difficult to perform, have high coefficient of variation (CV),
and are valid only when lung elastic recoil is normal and there
is no increase in airway resistance. These tests therefore are not
recommended in normal clinical practice.
Expiratory flows measured at 75% or 50% of VC have also been
used to identify patients with COPD. These measurements
Spirometry
Spirometry is the best test of airflow limitation in patients with
COPD. Spirometric measurements have a well-defined range
of normal values. A postbronchodilator FEV1/VC ratio less than
0.7 is a diagnostic criterion for COPD. The rate of decline of
Table 41-5 Spirometric Classification of COPD Severity
Stage
Characteristics
I: Mild
FEV1/FVC <0.7
FEV1 ≥80% predicted
II: Moderate
FEV1/FVC <0.7
50% ≤ FEV1 <80% predicted
III: Severe
FEV1/FVC <0.7
30% ≤ FEV1 <50% predicted
IV: Very severe
FEV1/FVC <0.7
FEV1 <30% predicted or FEV1 <50% predicted
plus chronic respiratory failure
Table 41-6 Variables and Point Values in Computation of
BODE* Index
Points on BODE Index
Variable
0
1
2
3
FEV1 (% of predicted)
≥65
50-64
36-49
≤35
Distance walked in
6 minutes (m)
≥350
250-349
150-249
≤149
MMRC dyspnea scale†
0-1
2
3
4
Body mass index
>21
≤21
—
—
*Body mass index, degree of airflow obstruction and dyspnea, and exercise
capacity.
†
See Table 41-3.
are less reproducible than the FEV1, such that an abnormal
value must fall below 50% of predicted value. Flows at lung
volume less than 50% of VC were previously considered to
be an indicator of small airways function, but probably provide
no more clinically useful information than measurements of
the FEV1.
Peak expiratory flow can either be read directly from the
flow-volume loop or measured with a handheld peak flow
meter. Flowmeters are relatively easy to use and are particularly
useful in subjects with asthma, who have variations in serial
measurements. In patients with COPD, however, many of the
variations are often within the error of the measurement. The
peak expiratory flow may underestimate the degree of airflow
limitation in COPD and is thus not used as a routine
assessment.
Reversibility Testing
Assessment of reversibility to bronchodilators was performed
in COPD patients (1) to help distinguish patients with marked
reversibility who have underlying asthma and (2) to establish
the postbronchodilator FEV1, which is the best predictor of
long-term prognosis.
There is no agreement on a standardized method of assessing
reversibility, but this is usually quantified on the basis of a
change in the FEV1 or peak expiratory flow. However, there
may be changes in other lung volumes after bronchodilators
(e.g., inspiratory capacity, residual volume) which may explain
why some symptoms improve in some patients after a bronchodilator without a change in spirometry. An improvement in
FEV1 in response to a bronchodilator is not a good predictor
of a symptomatic response.
Bronchodilator reversibility can vary from day to day,
depending on the degree of bronchomotor tone. A change in
FEV1 that exceeds 200 mL is considered greater than random
variation. Therefore, changes should be reported as significant
only if they exceed 200 mL. In addition to this absolute change
of 200 mL in FEV1, a percentage change of 12% over baseline
has been suggested as significant by the ERS/ATS and GOLD
guidelines.
Approximately 30% of patients with COPD show significant reversibility of their airflow limitation in response to a
bronchodilator. It is usually recommended that reversibility be
assessed using a large bronchodilator dose, either with repeated
doses from a metered dose inhaler or by nebulization, because
this results in more patients with a significant response. In some
cases, addition of a second drug, such as an anticholinergic
agent to a β2-agonist, further increases FEV1. Reversibility
549
testing with a bronchodilator is usually indicated only at diagnosis. Although not a requirement for the diagnosis of COPD,
postbronchodilator spirometry is recommended to assess for
chronic airflow limitation (see earlier discussion). A formal
assessment of steroid reversibility is not included in the most
recent guidelines for assessment and management of COPD.
The most common method is to measure FEV1 before and after
treatment with 30 mg of prednisolone for 2 weeks. Although
patients with previous response to nebulized bronchodilators
are more likely to respond to steroids, individual patient
responses cannot be predicted.
Lung Volumes
Static lung volumes such as TLC, residual volume (RV) and
FRC, and the ratio RV/TLC are measured in patients with
COPD, to assess the degree of overinflation and gas trapping,
and are usually increased. These measurements are not necessary in every patient. The standard method of measuring static
lung volumes, using the helium dilution technique during
rebreathing, may underestimate lung volumes in COPD, particularly in patients with bullous disease, because the inspired
helium may not have sufficient time to equilibrate properly in
the enlarged air spaces. Body plethysmography uses Boyle’s law
to calculate lung volumes from changes in mouth and plethysmographic pressures. This technique measures trapped air in
the thorax, including poorly ventilated areas, and therefore
gives higher readings than the helium dilution technique.
Gas Transfer for Carbon Monoxide
A low DLCO is present in many patients with COPD. Although
there is a relationship between the DLCO and the extent of
microscopic emphysema, the severity of the emphysema in an
individual patient cannot be predicted from the DLCO, and a
low DLCO is not specific for emphysema. The usual method is
the single-breath technique, which uses alveolar volume calculated from the helium dilution during a single-breath test. This
method underestimates alveolar volume in patients with severe
COPD, however, producing a lower value for the DLCO. This
test can be useful to distinguish patients with COPD from
those with asthma because a low DLCO excludes asthma.
Arterial Blood Gases
Arterial blood gases (ABGs) are needed to confirm the degree
of hypoxemia and hypercapnia that develops in patients with
COPD. Hypoxemia and hypercapnia are not usually observed
until the FEV1 falls below 50% of predicted. It is essential to
record the fraction of inspired oxygen concentration (FIO2)
when reporting ABGs. It may take at least 30 minutes for a
change in FIO2 to have its full effect on the arterial oxygen
partial pressure (PaO2), because of long time constants for alveolar gas equilibration in COPD, particularly during exacerbations. Pulse oximetry is increasingly used to measure the level
of oxygenation, but it should not replace ABG assessment in
patients with FEV1 below 50% predicted, because measurements of PaCO2 are often required. ABG abnormalities may
worsen during exercise and sleep and during exacerbations.
Exercise Tests
Although exercise testing is rarely needed to diagnose COPD,
useful functional information may be obtained from doing any
of three types of tests.
Progressive symptom-limited exercise tests require the patient
to maintain exercise on a treadmill or a cycle until symptoms
prevent the person from continuing, while the workload is
550
continuously increased. A maximum test is usually defined as
a heart rate greater than 85% of predicted or ventilation greater
than 90% predicted. The results are particularly useful when
simultaneous electrocardiography and blood pressure monitoring are performed, to assess whether coexisting cardiac or psychological factors contribute to exercise limitation.
Self-paced exercise tests are simple to perform and give information on sustained exercise that may be more relevant to
activities of daily living. The 6MWD has approximately 8% CV.
A learning effect, however, may influence the result of repeated
tests. The 6MWD test is useful only in patients with moderately severe COPD (FEV1, <1.5 L) who would be expected to
have an exercise tolerance of less than 600 m in 6 minutes.
There is a weak relationship between 6MWD and FEV1,
although walking distance is a predictor of survival in COPD
patients. An alternative test is the shuttle walking test, in which
the patient performs a paced walk between two points 10 m
apart (the shuttle). The pace of the walk is increased at regular
intervals, as dictated by bleeps on a tape recording, until the
patient is forced to stop because of breathlessness. The number
of completed shuttles is recorded.
Steady-state exercise tests involve exercise at a sustainable
percentage of maximum capacity for 3 to 6 minutes, during
which ABGs are measured, enabling calculation of dead space/
tidal volume ratio (VD/VT) and shunt. This assessment is
seldom required in patients with COPD.
OTHER TESTS
Lung pressure-volume curves are difficult to measure, requiring assessment of esophageal pressure with an esophageal
balloon, and are not part of the routine assessment of patients
with COPD. These tests may be necessary in special
circumstances.
Measurements of small airways function with nitrogen
washout test, helium flow-volume loops, or frequency dependence of compliance have poor reproducibility in patients with
COPD. Although these tests can differentiate smokers from
nonsmokers, they are not useful for predicting in which smokers
COPD will develop, and thus are not used in routine
practice.
Respiratory Muscle Function Test
The usual tests of respiratory muscle function in COPD are
maximum inspiratory and expiratory mouth pressures. These
tests can be useful in cases where breathlessness or hypercapnia
is not fully explained by other lung function testing or when
peripheral muscle weakness is suspected (see Chapter 42).
Sleep Studies
Selected patients should be assessed for the presence of nocturnal hypoxemia. Finding nocturnal hypoxemia, however, provides no further prognostic or clinically useful information in
the assessment of patients with COPD, unless coexisting sleep
apnea syndrome is suspected.
HEALTH STATUS
Health-related or health status quality of life is a measure of
the impact of the disease on daily life and well-being. Breathlessness in patients with COPD limits exercise, reduces expectation, diminishes daily activity, restricts social activities,
disturbs mood, and impairs well-being. Several questionnaires
are available to assess health status and are used in hospital
rehabilitation programs and research. The Chronic Respiratory
Disease Index Questionnaire is sensitive to change but is timeconsuming and requires training to administer properly. The
Breathing Problems Questionnaire is a self-completed test that
is easy to complete but relatively insensitive to change.
The St. George’s Respiratory Questionnaire is a self-completed
test with three components—symptoms (distress caused by
respiratory symptoms), activity (disturbance in daily activities),
and impact (psychosocial function)—summed to give a total
score of overall health status. This is the most validated health
status tool in COPD. However, a rather poor relationship exists
between the St. George’s Respiratory Questionnaire and the
FEV1. It is clear from various studies that there can be improvement in health status without any improvement in FEV1 in
response to treatment. An example of this is the response to
pulmonary rehabilitation. The threshold of clinical improvement is a change of four units in the St. George’s Respiratory
Questionnaire. Exacerbations of COPD have a clear detrimental effect on health status.
More recently, the COPD Assessment Test (CAT) has been
shown to correlate well with the more detailed St. George’s
Respiratory Questionnaire. The CAT may be useful clinically
in assessing functional status, health status, and response to
treatment.
OTHER MEASUREMENTS
Erythrocythemia or polycythemia is important to identify in
patients with COPD because it predisposes to peripheral vascular, cardiovascular, and cerebrovascular events. Erythrocythemia does not develop until there is clinically important
hypoxemia (PaO2 <55 mm Hg) and is not inevitable even
at this level. Polycythemia should be suspected when the
hematocrit is greater than 47% in women and 52% in men,
and/or the hemoglobin is greater than 16 g/dL in women or
18 g/dL in men, provided other causes of spurious polycythemia from decreased plasma volume (dehydration, diuretics)
can be excluded. A complete blood count may reveal the
anemia of chronic disease that occurs in COPD.
Alpha1-antitrypsin deficiency screening with measurements
of the level and determination of allelic phenotype are indicated for patients (<45 years old) with early onset of emphysema and in those with a family history of premature
emphysema. Because of the potential importance for other
family members, some experts recommend that all patients
with COPD be screened.
Electrocardiography is not routinely required in the assessment of patients with COPD, except when coexisting cardiac
morbidity is suspected. It is an insensitive technique for the
diagnosis of cor pulmonale.
Overinflation of the chest increases the retrosternal air
space, which transmits sound waves poorly, making echocardiography difficult in patients with COPD. Thus, an adequate
examination can be achieved in only 65% to 85% of patients
with COPD. Two-dimensional echocardiography has been
used in the investigation of right ventricular dimensions.
Pulsed-wave Doppler echocardiography is used to assess ejection flow dynamics of the right ventricle in patients with pulmonary hypertension. The tricuspid gradient can be used to
calculate the right ventricular systolic pressure. The technique
estimates the pressure gradient across the tricuspid regurgitant
jet recorded by Doppler ultrasound. The maximum velocity of
the regurgitant jet is measured from the continuous-wave
Doppler recordings, and the simplified Bernoulli equation is
used to calculate the maximum pressure gradient between the
right ventricle and the right atrium, PRV – PRA = 4v 2, where PRV
and PRA are the right ventricular and right atrial pressures
and v is the maximum velocity. The right atrial pressure is
estimated from clinical examination of the jugular venous
pressure.
IMAGING
Plain Chest Radiography
All patients with suspected COPD should have a posteroanterior (PA) chest radiograph performed at diagnosis. COPD does
not produce any specific features on plain chest radiography
unless features of emphysema are present. There may be no
abnormalities, however, even in patients with severe disability.
A chest x-ray film is used to discount other causes of respiratory
symptoms and to identify complications with COPD, such
as bulla formation. The most reliable radiographic signs of
emphysema can be divided into those caused by overinflation,
by vascular changes, and by bullae (see Computed Tomog
raphy). The following radiologic features are indicative of
overinflation:
• Low, flattened diaphragm; the border of the diaphragm in
the midclavicular line on the PA film is at or below the
anterior end of the seventh rib, and it is flattened if the
perpendicular height from a line drawn between the costal
and cardiophrenic angles to the border of the diaphragm is
less than 1.5 cm.
• Increased retrosternal air space, visible on the lateral film at
a point 3 cm below the manubrium; it is present when the
horizontal distance from the posterior surface of the aorta
to the sternum exceeds 4.5 cm.
• Obtuse costophrenic angle on the PA or lateral chest
radiograph.
• Inferior margin of the retrosternal air space 3 cm or less
from the anterior aspect of the diaphragm.
The vascular changes associated with emphysema result
from loss of alveolar walls and are shown on the plain chest
radiograph by the following:
• Reduction in the number and size of pulmonary vessels,
particularly at the lung periphery
• Vessel distortion, producing increased branching angles and
excess straightening or bowing of vessels
• Areas of increased lucency
Critical to the assessment of vascular loss in emphysema
is the quality of the chest radiograph, because increased
transradiancy (translucency) may be only an overexposure.
The accuracy of diagnosing emphysema on plain chest
radiography increases with severity of the disease, reported at
50% to 80% in patients with moderate to severe disease.
However, the sensitivity is as low as 24% in patients with mild
to moderate COPD.
Computed Tomography
Computed tomography (CT) has been used to detect and
quantify emphysema. Techniques can be divided into (1) those
that provide a visual assessment of low-density areas on the CT
scan, which can be semiquantitative or quantitative, and (2)
those that use CT lung density to quantify areas of low x-ray
attenuation. These techniques are used to measure macroscopic
and microscopic emphysema, respectively. A visual assessment
of emphysema on CT scanning shows the following:
551
• Areas of low attenuation without obvious margins or walls
• Attenuation and pruning of the vascular tree
• Abnormal vascular configurations
Areas of low attenuation correlate best with areas of macroscopic emphysema. Visual inspection of the CT scan can be
used to locate macroscopic emphysema, although assessing the
extent is insensitive and subject to high intraobserver and
interobserver variability. The CT scan can be used to assess
different types of emphysema; centrilobular emphysema produces patchy areas of low attenuation prominent in the upper
zones, whereas those of panlobular emphysema are diffuse
throughout the lung zones (see Figure 41-3).
A more quantitative approach to assessing macroscopic
emphysema is by highlighting picture elements (pixels) in the
lung fields in a predetermined low-density range, between −910
and −1000 Hounsfield units, the “density mask” technique.
Although the choice of the density range is arbitrary, there is
good correlation between pathologic emphysema score and the
CT density score. This technique may still miss areas of mild
emphysema.
Microscopic emphysema can be quantified by measuring
CT lung density. CT density is measured on a linear scale in
Hounsfield units (water = 0 H; air = −1000 H). CT lung density
is a direct measure of physical density, and thus, as emphysema
develops, a decrease in alveolar surface area occurs as alveolar
walls are lost, associated with an increase in distal air space size,
which would decrease lung CT density. A standardized protocol on either an inspiratory or an expiratory CT scan of the
chest is required to measure lung density accurately.
A bulla is defined arbitrarily as an emphysematous space
greater than 1 cm in diameter. On the plain chest radiograph,
a bulla appears as a localized avascular area of increased lucency,
usually separated from the rest of the lung by a thin, curvilinear
wall. Marked compression of the surrounding lung may be seen,
and bullae may also depress the diaphragm. CT is much more
sensitive than plain radiography in detecting bullae and can be
used to determine the number, size, and position. CT can
quantify the extent and distribution of emphysema as part of
surgical assessment in bullous disease and for lung volume
reduction.
SUGGESTED READINGS
Agusti A: Systemic effects of chronic obstructive pulmonary disease:
what we know and what we don’t know (but should), Proc Am
Thorac Soc 4:522–525, 2007.
Calverley PMA, MacNee W, Pride NB, Rennard SI, editors: Chronic
obstructive pulmonary disease, ed 2, London, 2003, Chapman &
Hall.
Celli BR, MacNee W: Standards for the diagnosis and treatment of
patients with COPD, Eur Respir J 23:841–845, 2004.
Cosio MG, Saetta M, Agusti A: Immunologic aspects of chronic
obstructive pulmonary disease, N Engl J Med 360:2445–2454,
2009.
Global Initiative for Chronic Obstructive Pulmonary Disease Workshop Report: Medical Communications Resources. www.goldcopd.
com, 2008.
Hogg JC, Senior RM: Chronic obstructive pulmonary disease. II.
Pathology and biochemistry of emphysema, Thorax 57:830–834,
2002.
Hogg JC, Timens W: The pathology of chronic obstructive pulmonary
disease, Ann Rev Pathol 4:435–459, 2009.
Hogg JC, Chu F, Utokaparch S, et al: The nature of small-airway
obstruction in chronic obstructive pulmonary disease, N Engl J Med
350:2645–2653, 2004.
552
MacNee W: Pathogenesis of chronic obstructive pulmonary disease,
Proc Am Thorac Soc 2:258–266, 2005.
MacNee W, Tuder R: New paradigms in the pathogenesis of chronic
obstructive pulmonary disease. 1, Proc Am Thorac Soc 6:527–531,
2009.
MacNee W, Maclay J, McAllister D: Cardiovascular injury and repair
in chronic obstructive pulmonary disease, Proc Am Thorac Soc
5:824–833, 2008.
Management of chronic obstructive pulmonary disease, Eur Respir
Monogr www.ersnet.org, 38:2006.
Mannino DM, Watt G, Hole D, et al: The natural history of chronic
obstructive pulmonary disease, Eur Resp J 27:627–643, 2006.
Peinado VI, Pizarro S, Barbera JA: Pulmonary vascular involvement in
COPD, Chest 134:808–814, 2008.
Rabinovich RA, MacNee W: Chronic obstructive pulmonary disease
and its comorbidities, Br J Hosp Med 72:137–145, 2011.
Vestbo J, Hogg JC: Convergence of the epidemiology and pathology
of COPD, Thorax 61:86–88, 2006.
Voelkel NF, MacNee W, editors: Chronic obstructive lung disease, ed 2,
Hamilton, Ontario, 2008, BC Decker.
Wouters EF: Local and systemic inflammation in chronic obstructive
pulmonary disease, Proc Am Thorac Soc 2:26–33, 2005.

Chronic Obstructive Pulmonary Disease

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