The Pathophysiology of Airway Dysfunction

Dennis E. Doherty, MD

Asthma and chronic obstructive pulmonary disease

(COPD) are distinct inflammatory disorders with
differing pathophysiologic mechanisms, different
clinical courses, and, therefore, distinct treatment
strategies. Whereas in asthma airflow limitation is
typically episodic and reversible, airflow limitation in
COPD is progressive and only partially reversible. In
contrast to asthma, which is characterized by an
elevated number of eosinophils in the blood and the
accumulation of elevated numbers of activated eosinophils, mast cells, and CD4 TH2-lymphocytes in
the lungs, the primary inflammatory cells present in
the lungs of patients with stable COPD are neutrophils, macrophages, and CD8 lymphocytes. Bronchoconstriction in COPD is largely regulated by cholinergically mediated vagal tone, and the pathologic
processes of COPD further reduce airway patency.
Bronchodilators, most notably anticholinergics, are
recommended as first-line pharmacologic therapy
for COPD. Proper use of inhaled anticholinergic
medications has been shown to lead to significant
reversibility of acetylcholine-mediated bronchoconstriction during both stable disease and exacerbations of COPD. For patients with asthma, current
guidelines recommend anti-inflammatory medications, specifically inhaled corticosteroids and leukotriene-modifiers, as first-line therapy, making these
agents the mainstay of asthma therapy. In contrast,
the current guidelines for COPD management recommend that inhaled anti-inflammatory agents be
tried in patients with COPD only as second-line therapy for patients who have severe to very severe airflow obstruction with frequent exacerbations and
who remain symptomatic despite maximized bronchodilation with multiple inhaled bronchodilators.
Hence, it is extremely important to understand the
differences between the underlying pathogenesis
and pathophysiology of COPD and those of asthma,
as these differences dictate the implementation of
distinctly different treatment options for these 2
diseases. Am J Med. 2004;117(12A):11S23S. 2004
by Elsevier Inc.

From the Chandler Medical Center, Division of Pulmonary and Critical

Care Medicine, University of Kentucky, Lexington, Kentucky, USA and the
Lexington Veterans Administration Medical Center, Lexington, Kentucky,
USA.
Requests for reprints should be addressed to Dennis E. Doherty, MD,
Division of Pulmonary and Critical Care Medicine, Chandler Medical
Center, University of Kentucky, Room K528, 740 South Limestone,
Lexington, Kentucky 40536-0284.
2004 by Elsevier Inc.
All rights reserved.

hronic obstructive pulmonary disease (COPD) is

characterized by airflow limitation that is not
fully reversible, is usually progressive, and is associated with an abnormal inflammatory response of the
lungs to noxious particles or gases.1 In the United States,
85% of COPD cases arise after prolonged exposure of
the airways and lungs to tobacco smoke. The airflow limitation associated with the disease worsens over a period
of many years and is only partially reversed to age-appropriate levels with maintenance bronchodilator therapy
and sustained smoking cessation. The key symptoms of
COPD are chronic cough, excess sputum production,
and exertional dyspnea out of proportion to that expected for a patients level of activity and age. Patients
slowly develop exercise intolerance and experience decreased quality of life; some individuals with severe
COPD may even exhibit dyspnea at rest, hypoxemia, hypercapnia, pulmonary hypertension, and cor pulmonale.1 In addition to the considerable morbidity caused
by this condition, COPD is associated with significant
premature mortality. In 2000, COPD was the fourth leading cause of death in the United States, with 120,000 persons dying of the disease.2 Also in 2000, for the first time,
the number of deaths in women with COPD exceeded the
number in men. By 2020, COPD is expected to be the
third leading cause of death, not only in the United States
but also worldwide.2,3
Although guidelines for appropriate diagnosis and
treatment are available, COPD continues to be underdiagnosed. The disease is often misdiagnosed as well. It is
particularly common for patients with COPD to receive
an incorrect diagnosis of asthma.4,5 Although both
COPD and asthma involve chronic airway inflammation,
inhaled corticosteroids, which are the mainstay of asthma
therapy because they effectively reverse that diseases inflammatory component, are not very effective in controlling the chronic inflammation associated with COPD.
Accordingly, the use of inhaled corticosteroids in the
management of COPD remains controversial.4 The most
recent comprehensive guidelines for the identification
and management of COPD, the Global Initiative for
Chronic Obstructive Lung Disease (GOLD) guidelines1
and the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines,6 state that bronchodilators are the most effective therapeutic agents for
COPD and should be used as first-line pharmacologic
therapy. Anti-inflammatory agents, specifically inhaled
corticosteroids, are relegated to second-line therapy only
in those patients with severe COPD who remain symp1548-2766/04/$22.00 11S
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tomatic and have frequent exacerbations despite maximized bronchodilation.1,6 The purpose of this review is to
provide an evidenced-based rationale for the diagnosis
and treatment of COPD, in part by distinguishing it from
asthma on the bases of clinical characteristics, pathogenesis, pathophysiology, and pharmacologic treatment options.

CLINICAL DIFFERENCES BETWEEN

CHRONIC OBSTRUCTIVE PULMONARY
DISEASE AND ASTHMA
The clinical characteristics of COPD differ from those of
asthma in a number of ways (Table 1).1,7 Notwithstanding the differences, however, distinguishing between
these 2 inflammatory diseases in the clinic remains a challenge, largely because of the superficial similarities in
symptomatology and clinical presentation that tend to
override their more subtle differences. Developing an accurate differential diagnosis is further complicated by the
fact that 10% to 15% of patients with obstructive pulmonary disease have both COPD and asthma.7 An additional
complication is that some individuals with asthma often
continue to smoke and later develop COPD in addition to
their asthma. Therefore, in determining whether a patient with obstructive pulmonary disease has COPD,
asthma, or a combination of these 2 diseases, it is essential
to consider the totality of symptoms and risk factors.
The age of presentation for a patients first episode of
dyspnea often provides a potential distinguishing characteristic between asthma and COPD. Asthma typically develops at a young age, often during childhood, and it can
appear and disappear. On the other hand, the dyspnea of
COPD is almost always initially recognized or acknowledged after age 40, predominantly in individuals who
have a 20 pack-year history of smoking tobacco.1,8 The
age differentiator is not foolproof, however, because
asthma occasionally develops in older patients as well.
More likely than not, patients aged 40 years presenting
without a history of asthma in youth and with current
symptoms consistent with a chronic obstructive lung disease, a significant smoking history, and their first breathing difficulties are more likely experiencing COPD than
asthma. Certainly the patient must be evaluated for other
nonobstructive causes of shortness of breath, i.e., congestive heart failure, restrictive lung disease, chronic pulmonary embolisms, and so forth must be ruled out. The
older average age of the typical COPD patient highlights a
second characteristic differentiating it from asthma: it is
mainly the result of long-term and heavy tobacco use.9
The association between COPD and long-standing tobacco use reflects the slow and irreversible changes in
lung structure that underpin the disease (see below,
Pathophysiology of Chronic Obstructive Pulmonary
Disease and Asthma). Although it is true that smoking is
a risk factor for both diseases, some persons with asthma
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develop fixed airways obstruction without ever having

smoked.8 It should be noted that, in addition to certain
environmental factors, patients of any age with a rare hereditary deficiency of 1-antitrypsin also can develop
COPD,1,10 and tobacco smoking often hastens the associated loss of lung function. However, the primary characteristic common to patients with COPD is long-term
tobacco use.
Asthma is characterized by acute increased responsiveness (or hyperresponsiveness) of the tracheobronchial
tree. Although airway hyperresponsiveness can be
present in COPD, its magnitude is often less than that
occurring in asthma. Because asthma can be triggered by
allergic responses, it is often associated with increased
levels of serum immunoglobulin E (IgE), i.e., atopy. Consequently, patients with asthma may also present with
rhinitis or eczema.8 In contrast, the COPD patient does
not typically display atopy.9 Ironically, however, nonatopic asthma (i.e., normal serum levels of IgE) can occur
despite the presence of similar inflammatory cell infiltrates and activated cytokine pathways in pulmonary mucosa of both clinical phenotypes of asthma.11,12
Individuals with asthma can often identify triggers or
events that bring on their episodic symptoms, whereas
patients with COPD often fail to acknowledge the symptoms associated with disease. Frequently, patients with
COPD slowly modify their lifestyles over time to engage
in fewer dyspnea-inducing events. Consequently, bouts
of dyspnea often are not reported to the physician during
an office visit. This delays the diagnosis of COPD unless
the clinician specifically questions the patient regarding
changes he or she has made in lifestyle or day-to-day activities over time.
Another important consideration is that whereas the
airflow limitation in patients with asthma tends to occur
episodically, COPD symptoms tend to progress slowly,
with little day-to-day variation. It must be recognized,
however, that patients with COPD can experience exacerbations that are often misinterpreted as asthma episodes. These are triggered by upper respiratory infections
and environmental factors such as air pollution, temperature changes, or exposure to tobacco smoke.13,14 On the
other hand, some patients with asthma fail to display either an initial treatment response or the strong episodic
course characteristic of the disease. This reflects the fact
that chronic mucus plug formation occurs in some individuals with asthma, and, as a result, airflow limitation
can take weeks or longer to resolve after anti-inflammatory therapy.8 Long-standing and severe asthma also can
be associated with structural remodeling of the airways
such that airflow limitation has a fixed component and is
not fully reversible.8
As a result of all of these characteristics, differentiating
between an asthmatic episode and a COPD exacerbation
can be a challenge for the clinician. In the simplest of
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Table 1. Clinical Differences Between Chronic Obstructive Pulmonary Disease (COPD) and Asthma
Characteristic
Age at onset
Symptoms
Allergic etiology
Treatment response
Bronchodilators
Corticosteroids
Smoking status
Airflow limitation (FEV1)

Asthma

COPD

Younger (often during childhood)

Variable dyspnea
Cough and/or wheeze
Allergies present in 50% of patients

Older (age 40 yr)

Progressive dyspnea
Cough and sputum
None

Reversible
Good
Nonsmokers affected
Can normalize after resolution of
episode

Partial reversibility
Poor
Usually history of heavy smoking
Cannot normalize; always reduced; deteriorates
with advancing disease

FEV1 forced expiratory volume in 1 second.

Adapted from Global Initiative for Chronic Obstructive Lung Disease.1,8

cases, the differential diagnosis can be made on the basis

of airflow quantitation, after the episode of acute shortness of breath has resolved. Such measurements are made
using spirometry, a test that can help differentiate COPD
from asthma. The key measurements necessary for the
early detection and monitoring of obstructive lung diseases are the forced expiratory volume in 1 second
(FEV1), forced vital capacity (FVC), and in asthma but
not in COPD, the peak expiratory flow (PEF). Normal
airflow, as assessed by spirometry, typically resumes in
the patient with asthma after therapy (the provisos in the
preceding paragraph notwithstanding) or during exacerbation-free periods. In the COPD patient, however, airflow never returns to an age-appropriate level; therapy
only partially reverses the airflow obstruction. In these
latter patients, postbronchodilator values of FEV1/FVC
70% indicate COPD. These values are used as the diagnostic cut-offs for normal versus obstructive lung disease
(Table 2).
Finally, a consideration of risk factors should play a
role in differentially diagnosing asthma and COPD. In
addition to atopy, risk factors for asthma include exposure to allergens, occupational sensitizers, active and passive smoking, air pollution, and respiratory infections.8
Asthma also has a strong familial component, whereas
COPD, in general, does not.15 As mentioned previously,
the primary risk factor for COPD is cigarette smoking,
and it is a fact that individuals are more likely to smoke if
their parents or a sibling smoke. Cigarette smoking is a
learned behavior. The only well-established genetic risk
factor for COPD is 1-antitrypsin deficiency.1 Other risk
factors for COPD include chronic exposure to occupational dust and other irritants such as noxious vapors and
fumes, as well as air pollution (chronic exposure to biomass fuels). Thus, distinguishing between asthma and
COPD is rarely simple because symptoms and risk factors
can overlap. Therefore, it is essential to consider the entire clinical picture when making a diagnosis.

PATHOPHYSIOLOGY OF CHRONIC
OBSTRUCTIVE PULMONARY DISEASE
AND ASTHMA
The pathophysiology of asthma has been studied extensively, and within the last decade our understanding of
the inflammatory mechanisms underlying COPD has advanced considerably. Several studies have established that
the respective anatomic sites of pathology, the pathologic
features, and the immunologic mechanisms (pathogenesis) underlying COPD and asthma differ in a number of
aspects that have important functional consequences and
implications for therapy.16
Anatomy and Pathology
Both asthma and COPD are inflammatory diseases, but
they differ in their respective inflammatory cell infiltrates. Asthma is primarily characterized by an accumulation of activated eosinophils, mast cells, and TH2 CD4
lymphocytes in the alveolar capillaries, interstitium, and
alveoli. In contrast, COPD, in the absence of an acute
exacerbation, is characterized primarily by an accumulation of macrophages, neutrophils, and CD8 lymphocytes in the same distribution. The mediators released by
these cells are also distinctly different, with interleukin
(IL)-4, IL-5, and IL-13 predominating in asthma, and
tumor necrosis factor (TNF-), leukotriene B4
(LTB4), and IL-8 predominating in COPD. These different cell types and inflammatory mediators lead to different
pathophysiologic consequences in these diseases (Table 3).
Hence, in asthma, inflammation results in epithelial shedding, enlargement of bronchial smooth muscle in large airways, hyaline thickening of the basement membrane, and
mucus secretion. In COPD, protease activity (i.e., macrophage tryptase, elastases, and other metalloproteinases), free
radicals, cytokines and chemokines, and other factors in the
inflammatory infiltrate result in irreversible remodeling of
lung tissue, consequent narrowing of airways, and a loss of
alveolar tethering. Remodeling includes squamous meta-

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Table 2. Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) Severity-Stage Treatment Guidelines for Patients
With Chronic Obstructive Pulmonary Disease
GOLD Guidelines*
Severity Stage

Stage Description

At risk

Mild

Characteristics

Chronic symptoms
Exposure to risk factors
Normal spirometry
FEV /FVC 70%
FEV 80%
With or without symptoms
FEV /FVC 70%
50% FEV 80%
With or without symptoms
1
1

II

Moderate

IIA (2001)
IIB (2001)

Moderate
Moderate

III (2004)
III (2001)

Severe
Severe

IV (2004)

Very severe

Same as stage II
FEV1/FVC 70%
30% FEV150%
With or without symptoms

Same as 2001 stage IIB

FEV1/FVC 70%
FEV130% or FEV150%
predicted chronic
respiratory failure

Same as 2001 stage III

Treatment

Avoidance of risk factors; influenza

vaccination

Avoidance of risk factors; influenza

vaccination
Add
short-acting bronchodilator when needed
Avoidance of risk factors; influenza
vaccination
Add short-acting bronchodilator when needed
Add regular treatment with 1 long-acting
bronchodilator
Add rehabilitation
Same as stage II
Avoidance of risk factors; influenza
vaccination
Add short-acting bronchodilator when needed
Add regular treatment with 1 long-acting
bronchodilator
Add rehabilitation
Add inhaled corticosteroids if repeated
exacerbations
Same as 2001 stage IIB
Avoidance of risk factors; influenza
vaccination
Add short-acting bronchodilator when needed
Add regular treatment with 1 long-acting
bronchodilator
Add rehabilitation
Add inhaled corticosteroids if repeated
exacerbations
Add long-term oxygen therapy if chronic
respiratory failure
Consider surgical treatments
Same as 2001 stage III

FEV1 forced expiratory volume in 1 second; FVC forced vital capacity.

* Recommendations and staging descriptions are the same for GOLD 2001 and 2004 guidelines unless otherwise indicated.
Adapted with permission from Global Initiative for Chronic Obstructive Pulmonary Disease.1

plasia, fibrosis, goblet cell hyperplasia, and some smooth

muscle hypertrophy.17,18
In contrast to the disease course of asthma, the lung
parenchyma is destroyed in COPD.17 The resulting emphysema may manifest itself as focal damage to the central areas of the acinus (centriacinar or centrilobular emphysema) or as uniform destruction of the walls of
airspaces distal to the terminal bronchiolus (panacinar or
panlobular emphysema).17 Functional elastic tissue in
the parenchyma (and airways) is replaced by inelastic fibrotic tissue, such that elastic recoil of the lung is lost, and
patients experience hyperinflation, a premature collapse
of airways mid exhalation that results in air trapping, a
decrease in inspiratory capacity, and in some cases impaired gas exchange.19 In the advanced stages of COPD,
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impaired gas exchange may result in alveolar hypoxia,

which can lead to pathologic changes in the pulmonary
circulation and respiratory muscles. Ultimately, this can
lead to right ventricular hypertrophy, pulmonary hypertension, and cor pulmonale.17
Inflammatory Mechanisms in Asthma
The inflammatory infiltrate in the pulmonary tissue of
individuals with asthma consists primarily of TH2 CD4
lymphocytes (T-helper cells) and activated eosinophils;
macrophages, mast cells, and other cell types also appear
to play a role in the disease.18,20 22 Elevated levels of
CD4 lymphocytes have been observed in the bronchial
mucosa of biopsy samples, bronchoalveolar lavage, and
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Table 3. Pathologic Changes and Inflammatory Mediators in Asthma and Chronic Obstructive Pulmonary Disease (COPD)
Asthma
Pathology
Airways

COPD

All

Parenchyma
Airway hyperresponsiveness
Bronchial smooth muscle
Epithelium
Basement membrane
Mucous cell metaplasia/hyperplasia
Mucus secretion
Inflammatory cells

Not involved
Present
Enlarged mass in large airways
Shedding
Thickened with hyaline deposition
Metaplasia debated
Present
Eosinophils (degranulated) CD4,
CD3, CD25, CD45
Mast cells
Macrophages

Cytokines and other factors

Histamine
IL-4, IL-5, IL-13
LTB4
Eotaxin
RANTES
Positive

Response to corticosteroids

Central (bronchitis)
Peripheral (emphysema)
Destruction
May or may not be present
Enlarged mass in small airways
Metaplasia
May or may not be affected
Present
Present, heavy
Neutrophils
Eosinophils (mild elevation, not degranulated)
CD8, CD3, CD68, CD45
VLA-1, HLA-DR
Macrophages
IL-8, IL-4
TNF-
LTB4
GRO-
GM-CSF
Mildly positive/negative

GM-CSF granulocyte/macrophage colony-stimulating factor; GRO- growth-related oncogene; HLA-DR human leukocyte antigenDR;
IL interleukin; LTB4 leukotriene B4; RANTES regulated on activation, normal T-cell expressed; TNF- tumor necrosis factor; VLA-1
very late activation antigen1.
Adapted from Chest7,18 and Thorax.17

ophils also have been found in significantly greater numbers in the bronchial mucosa of patients with asthma
than in those with stable COPD.24 In addition, levels of
activated eosinophils correlate with the extent of airway
hyperresponsiveness and symptoms in patients with
asthma.25,26
TH2 CD4 cells secrete a number of cytokines, of
which IL-4, IL-5, and IL-13 are of particular importance
in asthma (Table 3).7,13,27,28 Allergen challenge has been
associated with cellular activation and upregulation of
mRNA for IL-4 and IL-5 by CD4 in cells obtained by
bronchoalveolar lavage from patients with asthma.29 IL-4
promotes B-cell isotype switching to IgE production, the
stimulation of T-cell differentiation to the TH2 subtype,
and the activation of eosinophils.15,21,30 IL-5 is a chemoattractant and inducer of differentiation for eosinophils.15,21,30 IL-13 also induces B-cell isotype switching
with resultant IgE production; it promotes mast cell
development, increases eosinophil number, stimulates
mucus hypersecretion, induces production of metalloproteinases by macrophages, and promotes airway hyperresponsiveness.15,21,30 The pathophysiologic consequences attributed to these cells and mediators of asthma
have been shown to be responsive and inhibited by the
use of inhaled corticosteroids.

Inflammatory Mechanisms in COPD

In contrast to the inflammation of asthma, a significant
accumulation of activated eosinophils, often responsive
to glucocorticoids, in the lungs of patients with COPD
has generally been observed only in those patients experiencing an acute exacerbation or in those with concomitant asthma.31,32 This in part explains why patients with
stable COPD receive minimal if any benefit from maintenance glucocorticoids, whereas patients with COPD experiencing an exacerbation often show improvement
with a short course of systemic corticosteroids: systemic
corticosteroids inhibit the asthma-like cells transiently
located in the lungs of COPD patients. Moreover, no eosinophils have been observed in the degranulated state in
pulmonary tissue from patients with stable COPD, suggesting that activation of eosinophils does not occur in
the disease in the absence of an exacerbation.33 In further
contrast to asthma, the glucocorticoid-sensitive TH2
pathway does not play a major role in COPD.18 Hence,
the distinctly different underlying inflammatory infiltrate
in stable COPD compared with that in asthma in part
explains the rationale for current treatment guidelines
recommending the use of inhaled corticosteroids only as
second-line therapy in the maintenance treatment
of COPD.

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The predominant cytokines that contribute to COPD

are TNF- and the potent neutrophil chemoattractants
IL-8 and LTB4 (Table 3).7,13 TNF- is produced primarily by macrophages; it induces release of neutrophils from
the bone marrow, stimulates production of other cytokines such as IL-8, and promotes fibroblast growth.34
IL-8 is produced by a variety of cell types, including
monocytes and macrophages, epithelial cells, and smooth
muscle cells in the airway. IL-8 is not only a neutrophil
chemoattractant but also an activator of neutrophils.35
LTB4, also produced by macrophages, is a chemoattractant for neutrophils.7,13
The results of several well-designed and controlled
studies provide the evidence-based data supporting the
concepts and mechanisms stated above and illustrate the
underlying cellular mechanisms of both COPD and
asthma. In a study by Fabbri and colleagues,36 patients
with COPD were shown to have more neutrophils and
macrophages in bronchoalveolar lavage and sputum
samples; fewer eosinophils in airway mucosa, bronchoalveolar lavage, and sputum; and a lower ratio of CD4 to
CD8 lymphocytes in the airway mucosa. Significantly
greater neutrophil counts and IL-8 levels were found in
sputum from patients with COPD compared with those
measured in sputum from patients with asthma or from
healthy control subjects, including smokers and nonsmokers. Patients with COPD also had significantly
greater levels of TNF- compared with smokers and
healthy nonsmoking subjects.37 Neutrophil counts were
elevated in bronchoalveolar fluid samples from patients
with COPD compared with patients with asthma and
healthy control subjects. Finally, although eosinophils
were increased in bronchial biopsy specimens and bronchoalveolar lavage of patients with asthma and patients
with COPD compared with healthy control subjects, the
eosinophils seen in samples from patients with COPD
were not degranulated, unlike those seen in samples from
patients with asthma.33
The preceding studies, as well as others not summarized here, demonstrate that the key inflammatory lung
cells involved in the pathogenesis of COPD are CD8 T
lymphocytes, neutrophils, and macrophages.13,17,20,31,38
In asthma, the numbers of CD8 lymphocytes in lung
tissue are low and CD4 lymphocytes predominate39; the
involvement of CD8 lymphocytes in the pathogenesis of
asthma is thought to be minor at most.21 Moreover,
changes in neutrophil number in the bronchial mucosa of
patients with asthma are minimal in comparison with the
increase seen in lung tissue eosinophils in these
patients.39,40
To further support the model that COPD is caused
primarily by macrophage, CD8 lymphocyte, and neutrophilic inflammation as well as the mediators released
by these cells, a number of studies have attempted to correlate the presence of these specific inflammatory cells
16S December 20, 2004 THE AMERICAN JOURNAL OF MEDICINE

and mediators directly with the incidence and clinical

course of patients with COPD. The results show that the
density of CD8 T lymphocytes in the basement membrane of tissue from patients with COPD (along with
CD3 T lymphocytes, CD68 cells [monocytes/macrophages], and HLA-DR cells) was measurably higher
than that seen in healthy subjects. Moreover, the density
of CD8 cells in lung tissue from patients with chronic
bronchitis with normal airflow was not significantly different from that observed in lung samples from healthy
subjects. However, there was a negative correlation between the CD8 lymphocyte density in lung tissue of
COPD patients with their lung functionthat is, the
lower the FEV1, the higher the CD8 content.32 These
data suggest an association between CD8 lymphocytes
and airflow limitation. In another study, CD8 lymphocyte counts in the parenchyma and arterial tissue of
smokers with COPD was higher than in smokers without
COPD and healthy controls, and the CD8 cell density
correlated with airflow limitation.41 Finally, a negative
correlation between numbers of neutrophils in the bronchial mucosa and the extent of airway limitation in patients with COPD has been reported.39,42 Together, these
findings support a role for neutrophils and CD8 lymphocytes in the pathogenesis and severity of COPD.43
Other studies have gone a step further, attempting to
define specific mechanisms regulating the structural and
functional changes to the airway and lung parenchyma in
COPD. Specifically, in COPD, neutrophils and macrophages are likely to synthesize and secrete proteins such as
proteinases (neutrophil elastase, macrophage-derived
tryptases) and other matrix metalloproteinases that potentially digest lung tissue, promote fibrosis and airway
remodeling, and stimulate excessive secretion of mucus.13,44,45 Alveolar macrophages also appear to act as reservoirs for proteases, such as neutrophil elastase, that are
secreted by other cell types.45 It is hypothesized that
CD8 cells mediate apoptosis of epithelial cells on the
walls of alveoli by means of perforins and TNF-,13,46
which in turn leads to a noninflammatory loss of alveolar
walls and the subsequent development of emphysematous lesions.

PHARMACOLOGIC STRATEGIES FOR

ASTHMA AND CHRONIC OBSTRUCTIVE
PULMONARY DISEASE
In general, physicians are more aware of appropriate diagnostic and treatment strategies for asthma than for
COPD. At the time of initial evaluation, these 2 syndromes present to the clinician with a similar constellation of symptoms (cough, dyspnea, excess mucus production, and wheeze). Many of the treatments and
therapeutic goals are similar for COPD and asthma
(Table 4). Together, these facts can lead the healthcare
provider to assume that the pharmacologic options for
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Table 4. Goals of Treatment for Asthma and Chronic Obstructive Pulmonary Disease (COPD)
Asthma

COPD
Reduce exposure
Relief
Prevent progression of pulmonary
dysfunction

Activity and exercise

Reduce exposure
Control
Maintain normal or close-to-normal pulmonary
function; prevent development of irreversible
airflow limitation
Maintain normal levels of activity and exercise

Exacerbations
Drug-related adverse event
Disease-related mortality

Prevent and treat

Avoid
Prevent

Risk factors
Symptoms
Pulmonary function/airflow
limitation

Improve exercise tolerance

(strength, endurance)
Prevent and treat
Avoid
Reduce

Adapted from Global Initiative for Chronic Obstructive Lung Disease.1,8

asthma are appropriate for COPD. Unfortunately, this

assumption is incorrect, as might be expected after reviewing the data above and appreciating the significant
differences in the pathogenesis of these 2 obstructive lung
diseases. If one approaches these diseases from the perspective of their unique cellular mechanisms and pathologic processes rather than from the perspective of their
similar symptoms, it is easier to understand why some of
the first-line therapies that provide relief for asthma are
not as efficacious for the first-line maintenance treatment
of COPD.
Perhaps the best example of this is the use of inhaled
corticosteroids, alone or in combination with other antiinflammatory agents (leukotriene modifiers) or with 2agonists in the treatment of asthma. Inhaled corticosteroids are the mainstay of first-line asthma treatment.8 It is
beyond the scope of this review to provide a detailed molecular explanation for the efficacy of these agents, but
they are effective in asthma because they directly block
the transcriptional induction of a number of proinflammatory cellular mediators and gene products in cells that
have been shown to cause the bronchospasm and airway
remodeling of asthma, most notably, activated eosinophils, TH2 lymphocytes, and the mediators IL-4, IL-5,
and IL-13. In contrast, the macrophage and neutrophilic
inflammation and elaboration of mediators (TNF-,
IL-8, and LTB4) underlying COPD are not as effectively
controlled with inhaled corticosteroids.47,48 Furthermore, the airflow narrowing that occurs in COPD is a
result of fibrotic changes in the airway wall, or a loss of
alveolar units and elastic recoil. These processes are not
altered by inhaled corticosteroid therapy.
Efficacy of Inhaled Corticosteroids in COPD:
FEV1 Decline and Disease Progression
Because the use of inhaled corticosteroids in the treatment of patients with COPD is somewhat controversial, it
is worthwhile to review a number of translational clinical
trials that directly examine this issue and provide evidenced-based clinical data that bring the above-described

basic science mechanisms to the bedside of patients being

treated for COPD. The following clinical studies examined the safety, efficacy, and long-term effects of inhaled
corticosteroid therapy in patients with mild to very severe
COPD (GOLD stages I through IV). In these studies, inhaled corticosteroids were administered in doses known
to be anti-inflammatory in patients with asthma.
The European Respiratory Society Study on Chronic
Obstructive Pulmonary Disease (EUROSCOP) was a
long-term (3-year), double-blind, randomized, placebocontrolled, multicenter study comparing the effects of
budesonide 400 g b.i.d. with those of placebo. This trial
included 1,277 patients (912 of whom completed the
study) with mild COPD and a history of smoking, and
included patients who continued smoking. Patients with
a history of asthma, allergic eczema, or allergic rhinitis
were excluded. The rate of smoking cessation during the
trial was similar for the 2 groups. Patients receiving placebo exhibited a decline in FEV1 of 65 mL/year, which
was similar to that observed in other long-term follow-up
COPD trials. Patients receiving budesonide demonstrated improvement in FEV1 at the rate of 17 mL/year,
but this only occurred during the first 6 months of therapy. Changes in the rate of FEV1 from month 9 to the end
of the study were not significantly different between the
budesonide and placebo groups (57 mL/year and
69 mL/year, respectively; P 0.39). The proportion of
patients with a rapid decline in FEV1 (60 mL/year) was
similar in both groups (55% for the budesonide group,
49% for the placebo group; P 0.06).49
The Copenhagen City Lung Study was a randomized,
double-blind, placebo-controlled, single-center trial that
included patients without asthma who had mild to moderate COPD. Patients received inhaled budesonide 400 g
b.i.d. or placebo for 3 years. The minimum clinically relevant difference in rate of decline of FEV1 was defined as
20 mL/year. The crude annual rate of FEV1 decline for the
placebo group was 41.8 mL/year. The mean rates of FEV1
decline from the regression model for the budesonide

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and placebo groups were not significantly different (46.0

mL vs. 49.1 mL, respectively; P 0.7). No changes in
symptoms, if present initially, were noted in this study
between the control and inhaled corticosteroid groups.50
The Lung Health Study II was a long-term (4-year,
with mean follow-up at 40 months), randomized, placebo-controlled, multicenter study that compared the effects on FEV1 of triamcinolone acetonide 600 g b.i.d.
with those of placebo in 1,116 patients with mild to moderate COPD. Mean declines in FEV1 for the triamcinolone and placebo groups were not significantly different
(48.6 mL vs. 49.9 mL, respectively; P 0.78).51 In those
patients with more severe COPD, there was a modest improvement in dyspnea and the onset of severe symptoms.
However, bone mass density measurements obtained
from some of these patients revealed that those on the
inhaled corticosteroids were at an increased risk for the
development of osteoporosis.51
The Inhaled Steroids in Obstructive Lung Disease in
Europe (ISOLDE) study was a double-blind, placebocontrolled, multicenter trial of 990 patients without
asthma who had severe COPD (387 of whom completed
the study) randomized to inhaled fluticasone propionate
500 g b.i.d. or placebo; follow-up was at 36 months.
Mean annual declines in FEV1 were not significantly different (50 mL/year for patients receiving fluticasone and
59 mL/year for patients receiving placebo; 95% confidence interval [CI], 3 to 20; P 0.161). However, on
average, there was a 100-mL increase in FEV1 after 3 to 6
months of therapy that was maintained over the 3-year
period and a decrease in exacerbations of 25% compared
with placebo; the differences in exacerbation rates, however, were restricted to patients with severe COPD (FEV1
50% of predicted).52
In summary, investigators for the Copenhagen City
Lung Study, ISOLDE, the Lung Health Study II, and
EUROSCOP all concluded in their respective studies that
inhaled corticosteroid therapy did not affect FEV1 decline
over the long term. The Lung Health and ISOLDE studies
also showed that inhaled corticosteroids slowed the onset
of severe symptoms and decreased exacerbations, but
these effects were only apparent in those patients with
severe COPD and were not associated with clinical benefits.49,5153 In addition, a recent meta-analysis of 6 randomized, double-blind, placebo-controlled trials that assessed the long-term effects of inhaled corticosteroid
treatment on patients with COPD found that inhaled
corticosteroids had no significant effect on FEV1.54
Inhaled and Systemic Corticosteroids in
COPD: Exacerbations
Exacerbations of COPD are a common cause of visits to
the emergency department.55,56 Although it has no effect
on the overall decline in lung function, maintenance
therapy with inhaled corticosteroids in patients with se18S December 20, 2004 THE AMERICAN JOURNAL OF MEDICINE

vere COPD appears, in some instances, to reduce the frequency of exacerbations in the COPD patient as outlined
above. For example, a systematic review of 9 randomized,
placebo-controlled trials of corticosteroid therapy of at
least 6 months duration, including 3,976 patients
(budesonide, n 1,730; fluticasone, n 1,032; triamcinolone n 1,116; and beclomethasone, n 98), found
that active therapy was associated with a reduction in
exacerbations of about 30% compared with placebo in
patients with severe COPD (relative risk, 0.70; 95% CI,
0.58 9.84).57
The administration of systemic corticosteroids may
also positively affect COPD exacerbations. In 2 randomized trials, systemic corticosteroids appeared to prevent
treatment failure and shorten the hospital stays for patients experiencing COPD exacerbations.58,59 Another
randomized, double-blind, placebo-controlled trial examined the effect of a 10-day course of oral prednisone
(40 mg) on relapse rates in 147 patients who were discharged from the hospital after experiencing an exacerbation of COPD. The overall rate of relapse at 30 days was
significantly lower in the prednisone group than in the
placebo group (27% vs. 43%, P 0.05), and the time to
relapse was significantly prolonged in those taking prednisone (P 0.04).60 The authors conclude, however, that
the short-term improvements in relapse rates must be
balanced against the long-term cumulative risk and costs
of side effects associated with corticosteroid use, which
include suppression of the hypothalamic-pituitary-adrenal axis, bone demineralization, posterior subcapsular
cataracts, and behavioral effects.61 The efficacy of systemic corticosteroids during an exacerbation of COPD is
likely due to the fact that activated eosinophils, as well as
other inflammatory cells and mediators known to be involved in the pathogenesis of asthma, have been found in
the lungs of COPD patients only during the acute phases
of exacerbations. Therefore, these steroid-sensitive
cells and mediators can be attenuated, thus relieving the
bronchospasm occurring secondary to their presence and
activation.
Corticosteroids in COPD: Summary
Given the data in the 2 preceding sections, questions remain concerning the use of inhaled and systemic corticosteroids in the maintenance therapy of stable COPD. Accordingly, the 2004 revised GOLD guidelines,1 as well as
the recently published ATS/ERS COPD guidelines,6 recommend that a trial of high-dose inhaled corticosteroids
should be considered as add-on therapy in the maintenance treatment of only those patients with severe stage
III (FEV1 50% of predicted) or very severe stage IV
(FEV1 30% of predicted) COPD who remain symptomatic and continue to have frequent exacerbations despite maximal bronchodilation with 1 inhaled bronchodilator. At this time, inhaled corticosteroids should be
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reevaluated after a 6-week to 3-month trial. They should

be discontinued if, after that period of time, there is no
evidence of clinical benefiti.e., if the patients lung
function has not improved according to evaluation by
spirometry and defined as an increase in FEV1 of 200 mL
and/or 12% from baseline, with FEV1 assessment conducted after bronchodilator use, no relief of chronic
symptoms or exacerbations, and no improvements in activities of daily living.1 Acute exacerbations may be managed with a short course of a systemic corticosteroid
(prednisone 30 to 40 mg/day for 10 to 14 days in addition
to a bronchodilator). Long-term use of oral corticosteroids is not recommended because of an absence of data
showing clinical benefit and the increased risk of adverse
events.
The GOLD consensus workshop found that the existing data regarding the predictive value of a short-term
(i.e., 2-week) trial of therapy with an oral corticosteroid
for long-term response to inhaled corticosteroid therapy
were unconvincing.1,52,62 Instead, after stabilization with
bronchodilator therapy (discussed below), a 3-week to
6-month trial of therapy is recommended. If there is no
evidence of clinical benefit (defined as a 200 mL increase
in FEV1 and a 12% increase in FEV1 from baseline, with
FEV1 assessment conducted after bronchodilator use),
inhaled corticosteroid therapy should be discontinued.1
Bronchodilators in COPD
In the past, COPD has been characterized as an irreversible structural alteration that permanently narrows airways; however, a reversible component nonetheless remains in some patients. Even slight improvements in
airflow can have significant clinical benefits for the patient with COPD, and COPD is now defined as a partially reversible disease. Clinicians must start to think
more optimistically about COPD and realize that they
can slow the progression of the disease and improve their
patients quality of life. Accordingly, the GOLD guidelines recommend that after avoidance of risk factors
(smoking cessation), maximizing bronchodilation, with
1 inhaled agent if necessary, is first-line maintenance
therapy in COPD (stages I to IV).1,6
Residual airway patency is controlled primarily by parasympathetic innervation of smooth muscles surrounding
bronchioles as well as by secretion of the bronchoconstricting mediator acetylcholine. Therefore, bronchodilators
typically inhaled anticholinergics or 2-agonists, or the
combination of both agentsare the preferred first-line
treatment to relieve the symptoms of COPD.1,6,16
Until recently, the anticholinergic ipratropium bromide has been the medication of choice for long-term
maintenance therapy for patients with COPD. Short-acting 2-agonists, such as albuterol, which play a more important role in asthma therapy, have been reserved for the
intermittent treatment of exacerbations. A retrospective

combined analysis of 7 studies including 1,445 patients

with COPD compared the effects of ipratropium with
2-agonists (metaproterenol, n 474; albuterol sulfate,
n 1,362). The combined analysis found that use of ipratropium was associated with significant improvements in
FEV1 and FVC from baseline compared with lung function measured before bronchodilator use (28 mL and 131
mL, respectively; both P 0.01). Changes in prebronchodilator FEV1 and FVC with 2-agonist treatment were
not significant (1 mL and 20 mL; both P 0.2).63 The
use of ipratropium is hampered, however, by its relatively
short duration of action (4 to 6 hours), which necessitates
dosing 4 times daily.64 New, longer-acting anticholinergic agents recently have been developed to circumvent
this issue.
The effect of cholinergic tone of the airways of patients
with COPD is magnified compared with normal controls
due to preexisting airway narrowing, leading to a higher
baseline airways resistance during periods of stable disease. Cranial nerve X, the vagus nerve, exits the brain and
enters the lung at the area of the hilum. It courses posteriorly on airways, but this innervation ends at the terminal bronchioles. Therefore, the vagus innervates the
larger airways within the lung. Along this neural pathway,
acetylcholine is released from peribronchial ganglion
cells, which interact with 3 muscarinic cholinergic receptors on the airways and mucus-secreting glands. The acetylcholine causes airway smooth muscle cells to constrict
and mucous glands to secrete both of which narrow the
caliber of the airway. There is a negative feedback loop to
protect the lung from excessive bronchoconstriction. If
too much acetylcholine is secreted, M2 muscarinic receptors are activated, and subsequent acetylcholine release is
inhibited (Figure 1). An ideal agent to prevent acetylcholine-induced bronchoconstriction, therefore, would interrupt this mechanism by blocking M3 but not M2
receptors in the airways of COPD patients.
Tiotropium bromide is a new anticholinergic agent
that provides constant, 24-hour relief of symptoms.
Available in Europe since 2002, Canada and Mexico since
early 2003, and most recently in the United States in 2004,
tiotropiums long-acting effects result from prolonged
M3 receptor antagonism.65 Several large, long-term trials
of tiotropium in the treatment of patients with COPD
have been published.66 69
Casaburi and colleagues66 reported the findings of 2
randomized, double-blind, placebo-controlled 1-year trials in which 921 patients received tiotropium 18 g q.d. or
placebo. Patients receiving tiotropium demonstrated significantly greater FEV1 response at trough (P 0.01), significantly less dyspnea (P 0.001), and significantly
greater health status scores (P 0.05) compared with
those receiving placebo. Trough FEV1 is defined as the
FEV1 obtained immediately before the next scheduled

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Figure 1. Muscarinic receptor subtypes in airways. ACh acetylcholine; CNS central nervous system; cranial nerve X vagus
cranial nerve. (Drawing by Dennis E. Doherty, MD.)

dose of a bronchodilator; in the case of tiotropium this is

approximately 23.5 hours after its last administration.
Donohue and co-workers68 reported the results of a
6-month, randomized, double-blind, placebo- and active-controlled trial in which 623 patients received tiotropium 18 g q.d., salmeterol 50 g b.i.d., or placebo.
Tiotropium was associated with significantly greater increases in trough FEV1 versus placebo than salmeterol
(140 mL vs. 90 mL; P 0.01). Significantly greater improvements in dyspnea and health-related quality-of-life
(HRQOL) measures versus placebo were also seen with
tiotropium treatment compared with salmeterol therapy.
However, in a combined analysis of 2 salmeterol- and
placebo-controlled clinical trials, which included the
aforementioned trial, transitional dyspnea index focal
scores improved in both the tiotropium (1.1 0.3 U) and
salmeterol (0.7 0.3 U) groups compared with placebo
(P 0.001 and P 0.05, respectively), without a significant difference between the tiotropium and salmeterol
groups (P 0.17).69
Vincken and associates67 reported the results of 2 randomized, double-blind, active-controlled studies in
which 535 patients received tiotropium 18 g q.d. or
ipratropium 40 g q.i.d. for a period of 1 year. Patients
receiving tiotropium had a significantly greater mean
change in trough FEV1 compared with patients receiving
ipratropium (P 0.001) and significantly greater improvements in dyspnea and HRQOL compared with
20S December 20, 2004 THE AMERICAN JOURNAL OF MEDICINE

those receiving ipratropium (P 0.004 and P 0.05,

respectively).
Tiotropium also was associated with decreases in the
frequency of exacerbations and hospitalizations in some
of these trials. Casaburi and colleagues66 reported significantly fewer exacerbations and hospitalizations with
tiotropium compared with placebo (P 0.05). Vincken
and associates67 observed significantly fewer exacerbations (P 0.01) as well as greater time to the first exacerbation (P 0.01) and first hospitalization owing to an
exacerbation (P 0.05) with tiotropium than with
ipratropium.
The studies with the 2 long-acting 2-agonists, twicedaily formoterol and salmeterol, also have reported improved pulmonary function in patients with COPD. Dahl
and co-workers70 reported clinically relevant improvements in FEV1 (120 mL) after formoterol treatment
and significantly greater increases in the area under the
curve (AUC) for FEV1 measured over a 12-hour postdose
period in the patients receiving formoterol compared
with those taking placebo (P 0.001) or ipratropium (P
0.025). Similar improvements in lung function have
been reported after treatment with salmeterol compared
with placebo, but the comparisons with ipratropium have
been variable. Mahler and colleagues71 reported statistically significant improvements in the AUC FEV1 after
treatment with salmeterol compared with placebo (P
0.001) at weeks 0, 4, 8, and 12, but the results were
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superior to ipratropium only at weeks 4 and 8 (P

0.005). In the trial by Rennard and associates,72 however, although the duration of action of salmeterol was
significantly longer than ipratropium, 1 dose of salmeterol and 2 doses of ipratropium (repeated after 6 hours)
produced similar average improvements in FEV1 and
FVC over the 12-hour dosing period.

CONCLUSION
Asthma and COPD are distinct obstructive pulmonary
diseases with differing clinical courses, pathophysiologic
profiles, and treatment strategies. The symptomatology
of the 2 diseases can overlap, making differential diagnosis challenging. In patients with COPD, bronchodilators
are the foundation of first-line pharmacologic therapy. In
patients with asthma, inhaled corticosteroids (with or
without a leukotriene modifier) are first-line therapy,
with bronchodilators being used for relief of symptoms
that persist despite adequate anti-inflammatory treatment. In patients with COPD, however, the use of inhaled
corticosteroids is recommended only in limited and specific circumstances as a second-line therapythat is, only
for the COPD patient who has been bronchodilated with
multiple agents in combination but who continues to experience symptoms (including frequent exacerbations).
For patients with asthma, the underlying pathophysiology supports the use of inhaled corticosteroids, and the
clinical evidence for the benefit of these agents is unequivocal. The pathophysiologic basis of bronchoconstriction (cholinergic-mediated vagal tone acting in already narrowed airways) in COPD supports the use of
anticholinergics as first-line agents, with the addition of a
2-agonist if additional bronchodilation is needed. The
theoretical benefits of anticholinergics are borne out by
evidenced-based clinical studies.

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December 20, 2004

THE AMERICAN JOURNAL OF MEDICINE

Volume 117 (12A)

23S