REVIEW
THE PATHOGENESIS AND PATHOLOGY OF COPD: IDENTIFYING RISK
FACTORS AND IMPROVING MORBIDITY AND MORTALITY*
—
Paul D. Scanlon, MD†
ABSTRACT
Chronic obstructive pulmonary disease
(COPD) is a chronic inflammatory condition of
the lower airways that includes both emphysema
and chronic bronchitis. COPD has some charac-
teristics in common with asthma, but the distinc-
tion may be important because of different
options for treatment. Development of COPD
requires both exposure to noxious stimuli such as
tobacco smoke as well as susceptibility to the dis-
ease, which is thought to be determined at least
partly by genetics. The most important noxious
stimulus, by far, is cigarette smoking; so many
cases of COPD are preventable. Long-term stud-
ies of smokers show that COPD can be identified
in its presymptomatic stages and that with smok-
ing cessation, the rates of lung function decline
and mortality can be reduced, even in the later
stages of the disease. This means that progres-
sion to severe disease can be prevented in the
vast majority of cases. For persons with more
advanced disease, adherence to published
guidelines for appropriate therapy can improve
symptoms and quality of life, reduce exacerba-
tions, and improve survival. These treatments
include smoking cessation, and appropriate use
of corticosteroids, long-acting bronchodilators,
oxygen, and surgical interventions. Previous
nihilistic attitudes about the treatment of COPD
are no longer appropriate.
(Adv Stud Med. 2004;4(10A):S744-S749)
*Based on the course curriculum from the Johns Hopkins
Lecture Series.
†Professor of Medicine, Mayo Clinic, Rochester,
Minnesota.
Address correspondence to: Paul D. Scanlon, MD, Mayo
Clinic E-18, 200 1st Street SW, Rochester, MN 55905.
E-mail: pscanlon@mayo.edu.
S744
T
he development of chronic obstructive pul-
monary disease (COPD) requires both expo-
sure to noxious agents and predisposition to
the disease. The primary risk factor for
COPD is tobacco use (predominantly cigarette smok-
ing), however other environmental exposures may con-
tribute, such as those found in certain occupations or
living conditions. Of a group of people with identical
exposure history, whether to smoking or to other expo-
sures, only a minority will develop COPD, and those
who do will vary in the severity and manifestations of the
disease. These discrepancies are thought to be due in part
to genetic predisposition to COPD.
COPD RISK FACTORS
There are 2 types of risk factors for COPD: host
factors (ie, inherent in the patient) and exposure to
noxious stimuli (see Sidebar, page S745). Although
intensity and duration of cigarette smoke exposure is
an important determinant of the development of
COPD, there is significant variability in COPD preva-
lence among smokers, illustrating the role that genetic
predisposition plays.1,2 The most well-studied genetic
disorder causing COPD is alpha-1-antitrypsin defi-
ciency. Alpha-1-antitrypsin is a circulatory serine pro-
tease inhibitor. The body normally maintains a
balance between serine proteases and their inhibitors,
which are important in lung function. Alpha-1-antit-
rypsin deficiency is an autosomal recessive trait that
occurs in roughly 1 of every 1000 persons of Northern
European ancestry. Homozygotes for this trait experi-
ence accelerated decline in lung function and emphy-
sema in both smokers and nonsmokers, although
smoking greatly increases the risk and severity of
COPD. Other host factors that contribute to the risk
of developing COPD include asthma and airway
hyperresponsiveness, although the mechanisms are not
Vol. 4 (10A) n November 2004
 REVIEW

clear. Childhood respiratory illness and reduced lung

growth (during gestation, due to low birth weight or Risk Factors for COPD
childhood exposures) may also be markers for Host Factors
increased risk of COPD.1 • Genetic mutations (eg, alpha-1-antitrypsin deficiency)
Although many host factors cannot be modified, • Airway hyperresponsiveness
exposures to noxious stimuli are controllable and • Reduced lung growth
reversible contributing factors for the development of Exposures
COPD. By far, the most common exposure linked to • Tobacco smoke (especially cigarette smoking)
• Occupational dusts and chemicals
COPD is cigarette smoke, although other types of • Indoor and outdoor air pollution
tobacco use, such as cigars and pipes, also produce • Infections
increased morbidity and mortality from COPD. The • Socioeconomic status
increased risk for COPD with tobacco use is propor- Data from GOLD. Global strategy for the diagnosis, management, and pre-
tional to the magnitude of tobacco smoke exposure vention of chronic obstructive pulmonary disease. Workshop Report, updat-
(eg, age at initiation of smoking, total pack-years ed 2003. Available at: www.goldcopd.com. Accessed June 14, 2004.1

smoked, and current smoking status). Not all smokers

develop COPD, illustrating the role that predisposi-
tion (presumably mostly due to genetics) plays in the
development of COPD.1 Exposure to occupational
dusts and chemicals are not as common, and are pre-
sent in more specific populations, based on type of
employment (eg, grain handlers, coal miners).
Exposure to irritants or sensitizing agents may create
airway hyperresponsiveness that is additive with dam-
age due to smoking or asthma.1 Similarly, exposure to Table. Characteristics of Inflammation in COPD and
Asthma
indoor and outdoor pollution is confined to specific
regions. Outdoor pollution has decreased appreciably
in most cities in developed countries, and the exact COPD Asthma
components of outdoor pollution that trigger COPD
Cells Neutrophils Eosinophils
are not known. Poor indoor air quality is produced not
Large increase in Small increase in
only by environmental tobacco smoke, or “second-
macrophages macrophages
hand smoke,” but also by use of “biomass” fuels and Increase in CD8+ Increase in CD4+ Th2 cells
cooking oils without proper ventilation. Lastly, child- T cells
hood viral infections may be more common in those Activation of mast cells
who develop airway hyperresponsiveness, and thus an Mediators LTB4 LTD4
association is established between childhood infections IL-8 IL-4, IL-5
and later development of COPD.1 TNF-alpha Many others
Consequences Squamous metaplasia Fragile epithelium
COPD PATHOGENESIS of epithelium
Parenchymal Thickening of basement
The lower airways begin at the terminal bronchiole destruction membranes
and extend through the respiratory bronchioles and Mucus metaplasia Mucus metaplasia
alveolar ducts to the alveoli. Lungs are perfused with Glandular enlargement Glandular enlargement
blood via the pulmonary and bronchial arteries, Response to Glucocorticosteroids Glucocorticosteroids inhibit
through the pulmonary capillaries in the alveolar walls, treatment have little or no effect inflammation effectively
leaving the lungs via the pulmonary veins. In COPD, COPD = chronic obstructive pulmonary disease; LTB = leukotriene B; LTD =
inflammation causes direct destruction of lung tis- leukotriene D; IL = interleukin; TNF = tumor necrosis factor.
sues and also impairs defense mechanisms used to Reproduced with permission from GOLD. Global strategy for the diagnosis,
management, and prevention of chronic obstructive pulmonary disease.
repair damaged tissues. This results in not only Workshop Report, updated 2003. Available at: www.goldcopd.com. Accessed
destruction of the lung parenchyma (ie, emphysema), June 14, 2004.1

Advanced Studies in Medicine n S745

 REVIEW

but also mucus hypersecretion, and airway narrowing Figure 1. Protease-Antiprotease Imbalance in
and fibrosis. COPD
A wide range of inflammatory cells and mediators
are involved in the pathogenesis of COPD, namely neu-
trophils, macrophages, and CD8+ T cells in different
Neutrophil elastase
areas of the lung.1 Although asthma and COPD share Proteinase 3
Cathepsins
some inflammatory components, important differences Matrix metalloproteinases
Others
distinguish the 2 diseases; however, they often coexist in Decrease
the same patient.1 The characteristics of inflammation
in COPD and asthma are compared and summarized in Increase
the Table. It is important to distinguish the 2 diseases Alpha-1- antitrypsin
Secretory leukoprotease inhibitor
during diagnosis because COPD appears to be poorly Elafin
Tissue inhibitors of matrix metalloproteinases
responsive to glucocorticosteroids as monotherapy,
which are the mainstay of asthma treatment.
COPD results from an imbalance between the body’s proteases and
Overall, COPD pathogenesis can be summarized as antiproteases. In COPD, the imbalance appears to be tipped in favor of
resulting from a combination of genetic susceptibility increased proteolysis, because of either an increase in proteases, such as
combined with exposure to one or more risk factors, neutrophil elastase (which targets the elastin in alveolar walls), or a defi-
ciency in antiproteases, which may include alpha-1-antitrypsin and others.
which leads to inflammatory processes that disrupt the COPD = chronic obstructive pulmonary disease.
balance of proteases and antiproteases (Figure 1).3 These Reproduced with permission from Barnes. Chronic obstructive pulmonary
disease. N Engl J Med. 2000;343(4):269-280.3
abnormal inflammatory mechanisms result in tissue
destruction, airway inflammation and remodeling, and
ultimately airflow limitation (Figure 2).3 Of note, these
imbalances and the presence of inflammation may result
in a “positive feedback loop,” in which inflammation
induces these imbalances, and the imbalances promote
more inflammation.
Once the inflammatory responses are set in
motion, 3 types of damage to the lung occur: disrup- Figure 2. COPD Pathogenesis
tion of the alveolar walls (or attachments), mucus
hypersecretion contributing to airway obstruction,
and fibrosis of the bronchioles (Figure 3).3 The pul- Environmental and
Smoking
Childhood
respiratory
monary vasculature is also affected by inflammatory occupational
exposure infections
processes in COPD, which result in loss of capillary Genetic
susceptibility
bed, lumenal narrowing, and ultimately increased pul-
CD8+ Lymphocyte Alveolar Macrophage
monary vascular pressure that appears first with exer- (IL-8)

cise and then at rest as the disease progresses.

Protease Neutrophil
Bronchiole fibrosis results from repeated cycles of Inhibitors Airway
x Proteases
injury and repair to the bronchioles during exposure to inflammation
and remodeling
noxious stimuli. Disrupted repair systems can lead to Tissue
destruction
Airflow
limitation
tissue remodeling affecting structure and function as
well as scar tissue formation. The bronchioles, as part
of the peripheral airways system, are the major site of Cigarette smoke and other irritants activate macrophages, which release
neutrophil chemoattractants, and CD8+ lymphocytes. Neutrophils and
airway obstruction in COPD. macrophages release proteases that break down the connective tissue in
lung parenchyma, resulting in emphysema, as well as stimulate mucus
secretion. These proteases are normally counterbalanced by antiproteases,
COPD PRESENTATION but in COPD the balance between proteases and antiproteases is disrupt-
ed, resulting in airflow limitation, inflammation, and tissue damage and
remodeling.
During normal respiration, when air is taken into COPD = chronic obstructive pulmonary disease; IL = interleukin.
the lungs, the elastic alveolar walls and lung Adapted with permission from Barnes. Chronic obstructive pulmonary dis-
ease. N Engl J Med. 2000;343(4):269-280.3
parenchyma are stretched and thus produce the pres-

S746 Vol. 4 (10A) n November 2004

 REVIEW

sure necessary to expel the air during expiration. Figure 3. COPD Pathology
When the alveolar walls are damaged, recoil pressure
is reduced. This not only reduces driving pressure
for expiration, but also allows collapse of airways; Normal Chronic Obstructive Pulmonary Disease

thus, air in the lungs cannot be expelled fully, leav- Disrupted alveolar
attachments
Mucus hypersecretion
ing an extra reservoir of air remaining in the lungs. (luminal obstruction)
(emphysema)

Reduced elastic recoil can be demonstrated by the

difference between blowing air into a balloon (nor-
mal alveoli) and blowing air into a plastic grocery
bag (COPD). Persons with such lung damage and
increased residual volume often present as the stereo- Airway held Mucosal and peribronchial
typical COPD patient known as the “pink puffer.” open by alveolar
attachments
inflammation and fibrosis
(obliterative bronchiolitis)
They often have a barrel-shaped chest due to perma-
nently overexpanded lungs. These patients often In the peripheral airways of patients with COPD, there is airflow limitation due
to loss of alveolar attachments, as well as inflammation, fibrosis, and mucus
exhibit purse-lipped breathing and are not cyanotic secretion, which result in obstruction of the airway. The contributions to air-
or hypercapnic. flow limitation from these processes vary from individual to individual.
COPD = chronic obstructive pulmonary disease.
Airway lumenal obstruction occurs both because Reproduced with permission from Barnes. Chronic obstructive pulmonary dis-
of the loss of elastic recoil, which holds the airways ease. N Engl J Med. 2000;343(4):269-280.3
open, plus blockage of the airway lumen by mucus
hypersecretions, mucosal thickening, and airway
distortion. This increased airway resistance increas-
es the work of breathing and contributes to labored
breathing in virtually all patients with COPD.
Lumenal obstruction can be illustrated by the dif-
ference between blowing air through a drinking
straw compared with a cardboard tube from a roll of
paper towels.
Persons with COPD can be hypoxemic for a num- Figure 4. Normal Lung Function Decline and the
ber of reasons. In response to the increased work of Impact of Smoking
breathing, some patients simply hypoventilate,
become hypercapnic, and have a lower arterial oxyen
COPD Risk and Smoking Cessation
content as a result. Others have normal, or even
100
increased minute ventilation, but they have increased Never smoked
or not susceptible
physiological dead-space, which reduces the efficiency to smoke
FEV1 (% of value of age 25)

75
of ventilation. Many have impaired gas exchange, Stopped smoking
at 45 (mild COPD)
which results in reduced oxygen uptake despite ade-
50
quate ventilation and CO2 elimination. Smoked regularly
and susceptible Stopped
smoking at 65
In some persons with advanced COPD with Disability
to effects of smoke
(severe COPD)
25
hypoxemia, the combination of hypoxic vasocon-
striction plus loss of pulmonary capillary bed due to Death
0
emphysema gradually leads to permanently 25 30 35 40 45 50 55 60 65 70 75
increased pulmonary vascular resistance. Pulmonary Age (years)

hypertension is associated with the development of
cor pulmonale (hypertrophy and dilation of the
right ventricle) and is associated with a poor prog-
nosis. Some COPD patients with severe hypoxia and
pulmonary hypertension present another stereotypi-
cal picture, the “blue bloater.” These patients are
typically hypoxic, hypercapnic, overweight, edema-
Fletcher and Peto showed that stopping smoking at any point during a
patient’s life, even in the later years, can have important benefit in pro-
longing the onset of disability (in those who stop early enough in life) and
death.
COPD = chronic obstructive pulmonary disease; FEV1 = forced expirato-
ry volume in 1 second.
Reproduced with permission. Fletcher et al. The natural history of chronic
airflow obstruction. BMJ. 1977;1(6077):1645-1648.4

Advanced Studies in Medicine n S747

 REVIEW

tous, and cyanotic, with a productive cough. The Figure 5. Impact of Smoking Cessation on Lung
“pink puffer” and the “blue bloater” are stereotypes. Function After 11 Years of Follow-Up: Results from
Some patients present as one type or the other, but the Lung Health Study
many COPD patients exhibit signs of both stereo-
types. A Continuous Smokers Intermittent Quitters Sustained Q uitters

Most patients with COPD develop chronic 2.9

2.8
cough and sputum production even before they 2.7
develop airway obstruction. However, dyspnea dur-

FEV1 (L)
2.6
2.5
ing exertion is the first symptom to herald the devel- 2.4
opment of airway obstruction in COPD. The 2.3
2.2
mechanisms leading to development of dyspnea are 2.1
numerous and include combinations of the follow- 2

ing: increased work of breathing, dynamic hyperin- 0 1 2 3 4 5 6 7 8 9 10 11

Y ear
flation, decreased maximal ventilation, abnormal gas
exchange, pulmonary hypertension and ventricular B Contin uous Smokers Intermittent Quitters Su stained Quitters
dysfunction, and peripheral muscle deconditioning
85
(due to decreased use and oxygenation). The sys-

FEV1 (% of predicted)
80
temic effects of these mechanisms include nutrition-
al deficiency and weight loss, and peripheral muscle 75

weakness and loss of muscle mass. Along with the 70

pulmonary and cardiovascular processes previously 65

described, these lead to a progressive downward spi-
60
ral of disease, dyspnea, deconditioning, disability, 0 1 2 3 4 5 6 7 8 9 10 11
and ultimately death. Y ear
Loss of lung function over the years of study among sustained quitters, continu-
COPD IS TREATABLE ing smokers, and intermittent smokers. Average values of postbronchodilator
FEV1 are shown, expressed in absolute measures (A), and as a percentage of the
predicted normal value (B).
In the past, many healthcare practitioners have COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory vol-
ume in 1 second.
approached COPD with a nihilistic attitude, consider- Reproduced with permission from Anthonisen et al. Smoking and lung function
ing it incurable, untreatable, and self-inflicted. This atti- of Lung Health Study participants after 11 years. Am J Respir Crit Care Med.
2002;166(5):675-679.5
tude overlooks the fact that the vast majority of persons
with COPD have mild disease, and that smoking cessa- Figure 6. Impact of Smoking on Clinical Presentation
tion is benefitted by aggressive coordinated support from of Lung Function Loss
medical caregivers. With early detection and interven-
tion, these persons can prevent the development of COPD Risk and Smoking Cessation
Detectable
severe disease. Furthermore, for the patients with 100

advanced stages of disease, many interventions devel- Asymptomatic withdrawal from activity

oped in recent years reduce the rate of decline in disease Symptomatic

75

or reduce exacerbation frequency, improve lung func-

FEV1 (% of value at age 25)

Detectable
tion, quality of life, and improve survival. The magni- 50

tude of the effect of these interventions is the same or Disability

25
greater than much better publicized interventions for
cardiovascular disease. The nihilistic attitudes of the past Death
0
are thus obsolete. 25 30 35 40 45 50 55 60 65 70 75

The importance of early detection and interven- Age (years)

tion is worth stressing. Millions of persons have mild
disease, and need not progress to severe disease. The
impact of smoking on lung function has long been
known, in part due to the seminal study by Fletcher
People with COPD often lose 50% of their baseline function before they com-
plain of symptoms (ie, dyspnea, wheezing).
COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory vol-
ume in 1 second.
Adapted with permission from Fletcher et al. The natural history of chronic air-
flow obstruction. BMJ. 1977;1(6077):1645-1648.4

S748 Vol. 4 (10A) n November 2004

 REVIEW
and Peto comparing the rate of decline in lung func-
tion among smokers versus nonsmokers. As shown in
Figure 4, stopping smoking at any point in life, even
in the later years, can have important benefit in pre-
venting or delaying the onset of impairment and
death.4 The results of the studies by Fletcher and Peto
were confirmed by the Lung Health Study, a random-
ized clinical trial of smoking cessation in nearly 6000
middle-aged smokers with mild-to-moderate COPD.
Analysis of lung function after 11 years confirmed that
smoking cessation improves lung function and reduces
mortality (Figure 5).5,6
It is also important for healthcare practitioners to rec-
ognize that people who have supranormal initial lung
function may lose as much as 40% of their initial lung
function before they fall below “normal” values. People
with COPD often lose 50% of their baseline function
before they complain of symptoms (eg, prolonged respi-
ratory infections, dyspnea, wheezing), as demonstrated
in Figure 6.4 So, screening people who are at risk for
COPD is critical to detect and stop the disease before
severe damage develops.
For persons with more advanced disease needing
symptomatic therapy, there is still cause for optimism,
based on better-targeted and more effective therapy.
Fibrosis and narrowing of the airways as well as dis-
ruption of alveolar walls and loss of elastic recoil are
irreversible processes; however, other manifestations of
COPD are reversible and respond to treatment. These
include the accumulation of inflammatory cells in the
peripheral airways, mucus hypersecretion, and smooth
muscle contraction in the airways. Treatment of these
reversible processes (see “Managing COPD:
Incorporating Guidelines into Primary Care Practice”
by Dr Barry J. Make) offers improved longevity and
quality of life for the COPD patient. In addition,
recognition of the intermittent nature of COPD, with
Advanced Studies in Medicine n S749
periods of relative stability punctuated by exacerbations,
has led to a new style of therapy directed at preventing
and treating exacerbations aggressively and proactively.
CONCLUSION
The most common noxious stimulus of COPD, by
far, is cigarette smoking. However, not all smokers
develop COPD, and COPD can develop in nonsmok-
ers. Nonetheless, COPD is both preventable and treat-
able. Important studies of long-term smokers show
that the rate of lung function decline and mortality
can be positively affected by smoking cessation, even
in the later stages of the disease. Our understanding of
COPD pathogenesis shows that numerous aspects of
this disease are not only preventable by cessation of
smoking or other noxious exposure, but also are part-
ly reversible in the later stages of the disease. Thus,
COPD is a preventable and treatable disease. Obsolete
nihilistic attitudes about therapy may result in missed
treatment opportunities and are no longer appropriate
for the majority of patients with COPD.
REFERENCES
1. GOLD. Global strategy for the diagnosis, management,
and prevention of chronic obstructive pulmonary disease.
Workshop Report, updated 2003. Available at: www.gold-
copd.com. Accessed June 14, 2004.
2. Molfino NA. Genetics of COPD. Chest.
2004;125(5):1929-1940.
3. Barnes PJ. Chronic obstructive pulmonary disease. N Engl J
Med. 2000;343(4):269-280.
4. Fletcher C, Peto R. The natural history of chronic airflow
obstruction. BMJ. 1977;1(6077):1645-1648.
5. Anthonisen NR, Connett JE, Murray RP. Smoking and lung
function of Lung Health Study participants after 11 years.
Am J Respir Crit Care Med. 2002;166(5):675-679.
6. Anthonisen NR, et al. Lung Health Study mortality paper,
submitted to Annals of Internal Medicine, June 2004.