CHRONIC OBSTRUCTIVE PULMONARY DISEASE

A. DEFINITION
Chronic obstructive pulmonary disease (COPD) is characterized by chronic
airflow limitation and a range of pathological changes in the lung, some
significant extra-pulmonary effects, and important comorbidities which may
contribute to the severity of the disease in individual patients.1

Although COPD affects the lungs, it also produces significant systemic

consequences.

Chronic bronchitis is defined clinically as chronic productive cough for 3

months in each of 2 successive years in a patient in whom other causes of
productive chronic cough have been excluded.2

Emphysema is defined pathologically as the presence of permanent

enlargement of the airspaces distal to the terminal bronchioles, accompanied
by destruction of their walls and without obvious fibrosis.3

In patients with COPD either of those conditions may be present. However,

the relative contribution of each to the disease process is often difficult to
discern.

B. RISK FACTOR
1. Genes
COPD is a polygenic disease and a classic example of gene-environment
interaction. The genetic risk factor that is best documented is a severe
hereditary deficiency of alpha-1 antitrypsin, a major circulating inhibitor
 of serine proteases. Premature and accelerated development of panlobular
emphysema and decline in lung function occur in both smokers and
nonsmokers with the severe deficiency, although smoking increases the
risk appreciably. There is considerable variation between individuals in
the extent and severity of the emphysema and the rate oflung function
decline. Although alpha-1 antitrypsin deficiency is relevant to only a
small part of the world’s population, it illustrates the interaction between
genes and environmental exposures leading to COPD. In this way, it
provides a model for how other genetic risk factors are thought to
contribute to COPD.

A significant familial risk of airflow obstruction has been observed in

smoking siblings of patients with severe COPD, suggesting that genetic
factors could influence this susceptibility. Through genetic linkage
analysis, several regions of the genome have been identified that likely
contain COPD susceptibility genes, including chromosome 2q. Genetic
association studies have implicated a variety of genes in COPD
pathogenesis, including transforming growth factor beta 1 (TGF-β1)
microsomal epoxide hydrolase 1 (mEPHX1), and tumor necrosis factor
alpha (TNFα). However, the results of these genetic association studies
have been largely inconsistent, and functional genetic variants
influencing the development of COPD (other than alpha-1 antitrypsin
deficiency) have not been definitively identified.

2. Inhalational Exposures
Because individuals may be exposed to a variety of different types of
inhaled particles over their lifetime, it is helpful to think in terms of the
total burden of inhaled particles. Each type of particle, depending on its
size and composition, may contribute a different weight to the risk, and
the total risk will depend on the integral of the inhaled exposures. Of the
many inhalational exposures that may be encountered over a lifetime,
only tobacco smoke and occupational dusts and chemicals (vapors,
irritants, and fumes) are known to cause COPD on their own. Tobacco
smoke and occupational exposures also appear to act additively to
increase the risk of developing COPD. However this may reflect an
inadequate data base from populations who are exposed to other risk
factors, such as heavy exposures to indoor air pollution from poorly
vented biomass cooking and heating.

Tobacco Smoke: Cigarette smoking is by far the most commonly

encountered risk factor for COPD. Cigarette smokers have a higher
prevalence of respiratory symptoms and lung function abnormalities, a
greater annual rate of decline in FEV1, and a greater COPD mortality
rate than nonsmokers. Pipe and cigar smokers have greater COPD
morbidity and mortality rates than nonsmokers, although their rates are
lower than those for cigarette smokers. Other types of tobacco smoking
popular in various countries are also risk factors for COPD, although
their risk relative to cigarette smoking has not been reported. The risk for
COPD in smokers is dose-related. Age at starting to smoke, total pack-
years smoked, and current smoking status are predictive of COPD
mortality. Not all smokers develop clinically significant COPD, which
suggests that genetic factors must modify each individual’s risk. Passive
exposure to cigarette smoke (also known as environmental tobacco
smoke or ETS) may also contribute to respiratory symptoms and COPD
by increasing the lungs’ total burden of inhaled particles and gases.
Smoking during pregnancy may also pose a risk for the fetus, by
affecting lung growth and development in utero and possibly the priming
of the immune system.

Occupational Dusts and Chemicals: Occupational exposures are an

underappreciated risk factor for COPD. These exposures include organic
and inorganic dusts and chemical agents and fumes. An analysis of the
large US population-based NHANES III survey of almost 10,000 adults
aged 30-75 years, which included lung function tests, estimated the
fraction of COPD attributable to work was 19.2% overall, and 31.1%
among never smokers. These estimates are consistent with a statement
published by the American Thoracic Society that concluded that
occupational exposures account for 10-20% of either symptoms or
functional impairment consistent with COPD.

Indoor Air Pollution: Wood, animal dung, crop residues, and coal,
typically burned in open fires or poorly functioning stoves, may lead to
very high levels of indoor air pollution. The evidence that indoor
pollution from biomass cooking and heating in poorly ventilated
dwellings is an important risk factor for COPD (especially among
women in developing countries) continues to grow, with case-control
studies and other robustly designed studies now available.

Almost 3 billion people worldwide use biomass and coal as their main
source of energy for cooking, heating, and other household needs, so the
population at risk worldwide is very large. In these communities, indoor
air pollution is responsible for a greater fraction of COPD risk than SO2
or particulates from motor vehicle emissions, even in cities densely
populated with people and cars. Biomass fuels used by women for
cooking account for the high prevalence of COPD among nonsmoking
women in parts of the Middle East, Africa, and Asia34,35. Indoor air
pollution resulting from the burning of wood and other biomass fuels is
estimated to kill two million women and children each year.

Outdoor Air Pollution: High levels of urban air pollution are harmful to
individuals with existing heart or lung disease. The role of outdoor air
pollution in causing COPD is unclear, but appears to be small when
compared with that of cigarette smoking. It has also been difficult to
assess the effects of single pollutants in long-term exposure to
atmospheric pollution. However, air pollution from fossil fuel
combustion, primarily from motor vehicle emissions in cities, is
 associated with decrements of respiratory function. The relative effects of
short-term, high-peak exposures and long-term, low-level exposures is a
question yet to be resolved.

3. Lung Growth and Development

Lung growth is related to processes occurring during gestation, birth, and
exposures during childhood. Reduced maximal attained lung function (as
measured by spirometry) may identify individuals who are at increased
risk for the development of COPD. Any factor that affects lung growth
during gestation and childhood has the potential for increasing an
individual’s risk of developing COPD. For example, a large study and
meta-analysis confirmed a positive association between birth weight and
FEV1 in Adulthood.

4. Oxidative Stress
The lungs are continuously exposed to oxidants generated either
endogenously from phagocytes and other cell types or exogenously from
air pollutants or cigarette smoke. In addition, intracellular oxidants, such
as those derived from mitochondrial electron transport, are involved in
many cellular signaling pathways. Lung cells are protected against this
oxidative challenge by well-developed enzymatic and nonenzymatic
systems. When the balance between oxidants and antioxidants shifts in
favor of the former i.e., an excess of oxidants and/or a depletion of
antioxidants oxidative stress occurs. Oxidative stress not only produces
direct injurious effects in the lungs but also activates molecular
mechanisms that initiate lung inflammation. Thus, an imbalance between
oxidants and antioxidants is considered to play a role in the pathogenesis
of COPD.

5. Gender
The role of gender in determining COPD risk remains unclear. In the
past, most studies showed that COPD prevalence and mortality were
 greater among men than women. Studies from developed countries show
that the prevalence of the disease is now almost equal in men and
women, which probably reflects changing patterns of tobacco smoking.
Some studies have suggested that women are more susceptible to the
effects of tobacco smoke than men. This is an important question given
the increasing rate of smoking among women in both developed and
developing countries.

6. Infections
Infections (viral and bacterial) may contribute to the pathogenesis and
progression of COPD, and the bacterial colonization associated with
airway inflammation, and may also play a significant role in
exacerbations. A history of severe childhood respiratory infection has
been associated with reduced lung function and increased respiratory
symptoms in adulthood. There are several possible explanations for this
association (which are not mutually exclusive). There may be an
increased diagnosis of severe infections in children who have underlying
airway hyperresponsiveness, itself considered a risk factor for COPD.
Susceptibility to viral infections may be related to another factor, such as
birth weight, that is related to COPD. HIV infection has been shown to
accelerate the onset of smoking-related emphysema; HIV-induced
pulmonary inflammation may play a role in this process.

7. Socioeconomic Status
There is evidence that the risk of developing COPD is inversely related
to socioeconomic status. It is not clear, however, whether this pattern
reflects exposures to indoor and outdoor air pollutants, crowding, poor
nutrition, or other factors that are related to low socioeconomic status.
 8. Nutrition
The role of nutrition as an independent risk factor for the development of
COPD is unclear. Malnutrition and weight loss can reduce respiratory
muscle strength and endurance, apparently by reducing both respiratory
muscle mass and the strength of the remaining muscle fibers. The
association of starvation and anabolic/catabolic status with the
development of emphysema has been shown in experimental studies in
animals. Lung CT scans of women chronically malnourished because of
anorexia nervosa showed emphysema-like changes.

9. Asthma
Asthma may be risk factor for the development of COPD, although the
evidence is not conclusive. In a report from a longitudinal cohort of the
Tucson Epidemiological Study of Airway Obstructive Disease adults
with asthma were found to have a twelvefold higher risk of acquiring
COPD over time than those without asthma, after adjusting for smoking.
Another longitudinal study of people with asthma found that around 20%
of subjects developed functional signs of COPD, irreversible airflow
limitation, and reduced transfer coefficient.

C. STAGES OF COPD
Stage I: Mild COPD - Characterized by mild airflow limitation (FEV1/FVC
< 0.70; FEV1 ≥ 80% predicted). Symptoms of chronic cough and sputum
production may be present, but not always. At this stage, the individual is
usually unaware that his or her lung function is abnormal.

Stage II: Moderate COPD - Characterized by worsening airflow limitation

(FEV1/FVC < 0.70; 50% ≤ FEV1 < 80% predicted), with shortness of breath
typically developing on exertion and cough and sputum production
sometimes also present. This is the stage at which patients typically seek
medical attention because of chronic respiratory symptoms or an exacerbation
of their disease.
 Stage III: Severe COPD - Characterized by further worsening of airflow
limitation (FEV1/FVC < 0.70; 30% ≤ FEV1 < 50% predicted), greater
shortness of breath, reduced exercise capacity, fatigue, and repeated
exacerbations that almost always have an impact on patients’ quality of life.

Stage IV: Very Severe COPD - Characterized by severe airflow limitation

(FEV1/FVC < 0.70; FEV1 < 30% predicted or FEV1 < 50% predicted plus
the presence of chronic respiratory failure). Respiratory failure is defined as
an arterial partial pressure of O2 (PaO2) less than 8.0 kPa (60 mm Hg), with
or without arterial partial pressure of CO2 (PaCO2) greater than 6.7 kPa (50
mm Hg) while breathing air at sea level. Respiratory failure may also lead to
effects on the heart such as cor pulmonale (right heart failure). Clinical signs
of cor pulmonale include elevation of the jugular venous pressure and pitting
ankle edema. Patients may have Stage IV: Very Severe COPD even if the
FEV1 is > 30% predicted, whenever these complications are present. At this
stage, quality of life is very appreciably impaired and exacerba-tions may be
life threatening.

D. PATHOLOGY, PATHOGENESIS AND PATHOFISIOLOGY

1. Pathology
Pathological changes characteristic of COPD are found in the proximal
airways, peripheral airways, lung parenchyma, and pulmonary
vasculature. The pathological changes include chronic inflammation,
with increased numbers of specific inflammatory cell types in different
parts of the lung, and structural changes resulting from repeated injury
and repair. In general, the inflammatory and structural changes in the
airways increase with disease severity and persist on smoking cessation.

Proximal airways (trachea, bronchi > 2 mm internal diameter)

Inflammatory cells: ↑ Macrophages, ↑ CD8+ (cytotoxic) T lymphocytes,
few neutrophils or eosinophils
 Structural changes: ↑ Goblet cells, enlarged submucosal glands (both
leading to mucus hypersecretion), squamous metaplasia of epithelium.

Peripheral airways (bronchioles < 2mm i.d.)

Inflammatory cells: ↑ Macrophages, ↑ T lymphocytes (CD8+ > CD4+), ↑
B lymphocytes, lymphoid follicles, ↑ fibroblasts, few neutrophils or
eosinophils
Structural changes: Airway wall thickening, peribronchial fibrosis,
luminal inflammatory exudate, airway narrowing (obstructive
bronchiolitis) Increased inflammatory response and exudate correlated
with disease severity.

Lung parenchyma (respiratory bronchioles and alveoli)

Inflammatory cells: ↑ Macrophages, ↑ CD8+ T lymphocytes
Structural changes: Alveolar wall destruction, apoptosis of epithelial and
endothelial cells
 Centrilobular emphysema: dilatation and destruction of respiratory
bronchioles; most commonly seen in smokers
 Panacinar emphysema: destruction of alveolar sacs as well as
respiratory bronchioles; most commonly seen in alpha-1 antitrypsin
deficiency

Pulmonary vasculature
Inflammatory cells: ↑ Macrophages, ↑ T lymphocytes
Structural changes: Thickening of intima, endothelial cell dysfunction, ↑
smooth muscle → pulmonary hypertension.

2. Pathogenesis
The inflammation in the respiratory tract of COPD patients appears to be
an amplification of the normal inflammatory response of the respiratory
tract to chronic irritants such as cigarette smoke. The mechanisms for this
amplification are not yet understood but may be genetically determined.
Some patients develop COPD without smoking, but the nature of the
inflammatory response in these patients is unknown. Lung inflammation
is further amplified by oxidative stress and an excess of proteinases in the
lung. Together, these mechanisms lead to the characteristic pathological
changes in COPD.

Inflammatory Cells
COPD is characterized by a specific pattern of inflammation involving
neutrophils, macrophages, and lymphocytes. These cells release
inflammatory mediators and interact with structural cells in the airways
and lung parenchyma.
Neutrophils: ↑ in sputum of normal smokers. Further ↑ in COPD and
related to disease severity. Few neutrophils are seen in tissue. They may
be important in mucus hypersecretion and through release of proteases.
Macrophages: Greatly ↑ numbers are seen in airway lumen, lung
parenchyma, and bronchoalveolar lavage fluid. Derived from blood
monocytes that differentiate within lung tissue. Produce increased
inflammatory mediators and proteases in COPD patients in response to
cigarette smoke and may show defective phagocytosis.
T lymphocytes: Both CD4+ and CD8+ cells are increased in the airway
wall and lung parenchyma, with ↑ CD8+:CD4+ ratio. ↑ CD8+ T cells
(Tc1) and Th1 cells which secrete interferon-γ and express the
chemokine receptor CXCR3. CD8+ cells may be cytotoxic to alveolar
cells, contributing to their destruction.
B lymphocytes: ↑ in peripheral airways and within lymphoid follicles,
possibly as a response to chronic colonization and infection of the
airways.
Eosinophils: ↑ eosinophil proteins in sputum and ↑ eosinophils in airway
wall during exacerbations.
Epithelial cells: May be activated by cigarette smoke to produce
inflammatory mediators.

Inflammatory Mediators
The wide variety of inflammatory mediators that have been shown to be
increased in COPD patients attract inflammatory cells from the
circulation (chemotactic factors), amplify the inflammatory process
(proinflammatory cytokines), and induce structural changes (growth
factors).
Chemotactic factors:
 Lipid mediators: e.g., leukotriene B4 (LTB4) attracts neutrophils
and T lymphocytes
 Chemokines: e.g., interleukin-8 (IL-8) attracts neutrophils and
monocytes.
Proinflammatory cytokines: e.g., tumor necrosis factor-α (TNF-α), IL-
1β, and IL-6 amplify the inflammatory process and may contribute to
some of the systemic effects of COPD.
Growth factors: e.g., transforming growth factor-ß (TGF-ß) may induce
fibrosis in small airways.
Oxidative Stress
Oxidative stress may be an important amplifying mechanism in
COPD11. Biomarkers of oxidative stress (e.g., hydrogen peroxide, 8-
isoprostane) are increased in the exhaled breath condensate, sputum, and
systemic circulation of COPD patients. Oxidative stress is further
increased in exacerbations. Oxidants are generated by cigarette smoke
and other inhaled particulates, and released from activated inflammatory
cells such as macrophages and neutrophils. There may also be a
reduction in endogenous antioxidants in COPD patients. Oxidative stress
has several adverse consequences in the lungs, including activation of
inflammatory genes, inactivation of antiproteases, stimulation of mucus
secretion, and stimulation of increased plasma exudation. Many of these
adverse effects are mediated by peroxynitrite, which is formed via an
interaction between superoxide anions and nitric oxide. In turn, the nitric
oxide is generated by inducible nitric oxide synthase, which is expressed
in the peripheral airways and lung parenchyma of COPD patients.
Oxidative stress may also account for a reduction in histone deacetylase
activity in lung tissue from COPD patients, which may lead to enhanced
expression of inflammatory genes and also a reduction in the
antiinflammatory action of glucocorticosteroids.

Protease-Antiprotease Imbalance
There is compelling evidence for an imbalance in the lungs of COPD
patients between proteases that break down connective tissue
components and antiproteases that protect against this. Several proteases,
derived from inflammatory cells and epithelial cells, are increased in
COPD patients. There is increasing evidence that they may interact with
each other. Protease-mediated destruction of elastin, a major connective
tissue component in lung parenchyma, is an important feature of
emphysema and is likely to be irreversible.
 Differences in Inflammation Between COPD and Asthma
Although both COPD and asthma are associated with chronic
inflammation of the respiratory tract, there are marked differences in the
inflammatory cells and mediators involved in the two diseases, which in
turn account for differences in physiological effects, symptoms, and
response to therapy. However, there are greater similarities between the
lung inflammation in severe asthma and COPD. Some patients with
COPD have features of asthma and may have a mixed inflammatory
pattern with increased eosinophils. Finally, people with asthma who
smoke develop pathological features similar to COPD.

3. Pathophysiology
Airflow Limitation and Air Trapping
The extent of inflammation, fibrosis, and luminal exudates in small
airways is correlated with the reduction in FEV1 and FEV1/FVC ratio,
and probably with the accelerated decline in FEV1 characteristic of
COPD4. This peripheral airway obstruction progressively traps air during
expiration, resulting in hyperinflation. Although emphysema is more
associated with gas exchange abnormalities than with reduced FEV1, it
does contribute to air trapping during expiration. This is especially so as
alveolar attachments to small airways are destroyed when the disease
becomes more severe. Hyperinflation reduces inspiratory capacity such
that functional residual capacity increases,particularly during exercise
(when this abnormality is known as dynamic hyperinflation), and this
results in dyspnea and limitation of exercise capacity. It is now thought
that hyperinflation develops early in the disease and is the main
mechanism for exertional dyspnea. Bronchodilators acting on peripheral
airways reduce air trapping, thereby reducing lung volumes and
improving symptoms and exercise capacity.
Gas Exchange Abnormalities
Gas exchange abnormalities result in hypoxemia and hypercapnia, and
have several mechanisms in COPD. In general, gas transfer worsens as
the disease progresses. The severity of emphysema correlates with
arterial PO2 and other markers of ventilation-perfusion (VA/Q)
imbalance. Peripheral airway obstruction also results in VA/Q imbalance,
and combines with ventilatory muscle impaired function in severe
disease to reduce ventilation, leading to carbon dioxide retention. The
abnormalities in alveolar ventilation and a reduced pulmonary vascular
bed further worsen the VA/Q abnormalities.

Mucus Hypersecretion
Mucus hypersecretion, resulting in a chronic productive cough, is a
feature of chronic bronchitis and is not necessarily associated with
airflow limitation. Conversely, not all patients with COPD have
symptomatic mucus hypersecretion. When present, it is due to mucous
metaplasia with increased numbers of goblet cells and enlarged
submucosal glands in response to chronic airway irritation by cigarette
smoke and other noxious agents. Several mediators and proteases
stimulate mucus hypersecretion and many of them exert their effects
through the activation of epidermal growth factor receptor (EGFR).

Pulmonary Hypertension
Mild to moderate pulmonary hypertension may develop late in the course
of COPD and is due to hypoxic vasoconstriction of small pulmonary
arteries, eventually resulting in structural changes that include intimal
hyperplasia and later smooth muscle hypertrophy/hyperplasia. There is
an inflammatory response in vessels similar to that seen in the airways
and evidence for endothelial cell dysfunction. The loss of the pulmonary
capillary bed in emphysema may also contribute to increased pressure in
the pulmonary circulation. Progressive pulmonary hypertension may lead
 to right ventricular hypertrophy and eventually to right-side cardiac
failure (cor pulmonale).

Systemic features
It is increasingly recognized that COPD involves several systemic
features, particularly in patients with severe disease, and that these have a
major impact on survival and comorbid diseases. Cachexia is commonly
seen in patients with severe COPD. There may be a loss of skeletal
muscle mass and weakness as a result of increased apoptosis and/or
muscle disuse. Patients with COPD also have increased likeliness of
having osteoporosis, depression and chronic anemia. Increased
concentrations of inflammatory mediators, including TNF-α, IL-6, and
oxygen-derived free radicals, may mediate some of these systemic
effects. There is an increase in the risk of cardiovascular diseases, which
is correlated with an increase in C-reactive protein (CRP).
 Cachexia: loss of fat free mass
 Skeletal muscle wasting: apoptosis, disuse atrophy
 Osteoporosis
 Depression
 Normochromic normocytic anemia
 Increased risk of cardiovascular disease: associated with ↑ CRP

4. Exacerbations
Exacerbations represent a further amplification of the inflammatory
response in the airways of COPD patients, and may be triggered by
infection with bacteria or viruses or by environmental pollutants. There is
a relative lack of information about the inflammatory mechanisms
involved in exacerbations of COPD. In mild and moderate exacerbations
there is an increase in neutrophils and in some studies also eosinophils in
sputum and the airway wall. This is associated with increased
concentrations of certain mediators, including TNF-α, LTB4 and IL-8,
and an increase in biomarkers of oxidative stress. There is even less
information about severe exacerbations, although one study showed a
marked increase in neutrophils in the airway wall and increased
expression of chemokines23. During an exacerbation there is increased
hyperinflation and air trapping, with reduced expiratory flow, thus
accounting for the increased dyspnea. There is also worsening of VA/Q
abnormalities resulting in severe hypoxemia.