Chronic Obstructive Pulmonary Disease (COPD)_Dea

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DEFINITION
a disease state characterized by airflow limitation that is not fully reversible
includes emphysema (an anatomically defined condition characterized by destruction and
enlargement of the lung alveoli); chronic bronchitis (a clinically defined condition with chronic cough
and phlegm); and small airways disease (a condition in which small bronchioles are narrowed)
RISK FACTORS
1. Cigarette Smoking
accelerated decline in the volume of air exhaled within the first second of the forced expiratory
maneuver (FEV1) in a dose-response relationship to the intensity of cigarette smoking, which is
typically expressed as pack-years (average number of packs of cigarettes smoked per day
multiplied by the total number of years of smoking)
2. Airway Hyperresponsiveness
increased bronchoconstriction in response to a variety of exogenous stimuli, including
methacholine and histamine, is one of the defining features of asthma; considerable overlap
between persons with asthma and those with COPD in airway responsiveness, airflow obstruction,
and pulmonary symptoms led to the formulation of the Dutch hypothesis: asthma, chronic
bronchitis, and emphysema are variations of the same basic disease, which is modulated by
environmental and genetic factors to produce these pathologically distinct entities
alternative British hypothesis contends that asthma and COPD are fundamentally different
diseases: asthma is viewed as largely an allergic phenomenon, while COPD results from smokingrelated inflammation and damage
3. Respiratory Infections
childhood respiratory infections have also been assessed as potential predisposing factors for the
eventual development of COPD; however, although respiratory infections are important causes of
exacerbations of COPD, the association of both adult and childhood respiratory infections to the
development and progression of COPD remains to be proven
4. Occupational Exposures
several specific occupational exposures, including coal mining, gold mining, and cotton textile
dust, have been suggested as risk factors for chronic airflow obstruction
5. Ambient Air Pollution
some investigators have reported increased respiratory symptoms in those living in urban
compared to rural areas, which may relate to in- creased pollution in the urban settings
prolonged exposure to smoke produced by biomass combustiona common mode of cooking in
some countriesalso appears to be a significant risk factor for COPD
6. Passive-or Secondhand, Smoking Exposure
exposure of children to maternal smoking results in significantly reduced lung growth
in utero tobacco smoke exposure also contributes to significant reductions in postnatal pulmonary
function
7. Genetic Considerations
1 antitrypsin deficiency
o 1 antitrypsin protects tissues from enzymes of inflammatory cells, especially neutrophil
elastase; in its absence, neutrophil elastase is free to break down elastin, which contributes to
the elasticity of the lungs
o 1 antitrypsin deficiency causes defective production of alpha 1-antitrypsin (A1AT), leading to
decreased A1AT activity in the blood and lungs, and deposition of excessive abnormal A1AT
protein in liver cells
other genetic risk factor
o familial aggregation of airflow obstruction within families
NATURAL HISTORY
effects of cigarette smoking on pulmonary function appear to depend on the intensity of smoking
exposure, the timing of smoking exposure during growth, and the baseline lung function of the
individual
most individuals follow a steady trajectory of increasing pulmonary function with growth during
childhood and adolescence, followed by a gradual decline with aging
risk of eventual mortality from COPD is closely associated with reduced levels of FEV1
rate of decline in pulmonary function can be modified by changing environmental exposures (i.e.,
quitting smoking), with smoking cessation at an earlier age providing a more beneficial effect than
smoking cessation after marked reductions in pulmonary function have already developed; genetic

Chronic Obstructive Pulmonary Disease (COPD)_Dea

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factors likely contribute to the level of pulmonary function achieved during growth and to the rate of
decline in response to smoking and potentially to other environmental factors as well
PATHOGENESIS
1. Elastase:Antielastase Hypothesis
elastin, the principal component of elastic
fibers, is a highly stable component of the
extracellular matrix that is critical to the
integrity of both the small airways and the lung
parenchyma; elastase:antielastase hypothesis
proposed in the mid-1960s states that the
balance of elastin-degrading enzymes and their
inhibitors determines the susceptibility of the
lung to destruction resulting in airspace
enlargement
2. Inflammation and Extracellular Matrix Proteolysis
macrophages patrol the lower airspace under
normal conditions; upon exposure to oxidants
from cigarette smoke, histone deacetylase-2 is
inactivated, shifting the balance toward
acetylated or loose chromatin, exposing
nuclear factor B sites and resulting in
transcription of matrix metal- loproteinase-9,
proinflammatory cytokines interleukin 8 (IL-8),
and 1639 tumor necrosis factor (TNF-); this
leads to neutrophil recruitment. CD8+ T-cells
are also recruited in response to cigarette
smoke
and release interferon inducible protein-10 (IP10, CXCL-7) that in turn leads to macrophage
production of macrophage elastase [matrix
metalloproteinase-12 (MMP-12)]
concomitant cigarette smoke-induced loss of cilia in the airway epithelium predisposes to
bacterial infection with neutrophilia
collagen turnover in COPD is complex; three collagenases (MMP-1, MMP-8, and MMP-13) that
initiate the cleavage of interstitial collagens are also induced in both inflammatory cells and
structural cells in COPD. While collagen is disrupted as alveolar units are obliterated, overall there
is a net increase in collagen content in the COPD lung, with prominent accumulation in the airway
submucosa
3. Cell Death
airspace enlargement with loss of alveolar units obviously requires disappearance of both
extracellular matrix and cells
inflammatory cell proteinases degrade lung extracellular matrix as the primary event, with
subsequent loss of cell anchoring leading to apoptosis
4. Ineffective Repair
ability of the adult lung to repair damaged alveoli appears limited; whether the process of
septation that is responsible for alveogenesis during lung development can be reinitiated is not
clear; in animal models, treatment with all-trans retinoic acid has resulted in some repair
lung resection results in compensatory lung growth in the remaining lung in animal models
PATHOPHYSIOLOGY
persistent reduction in forced expiratory flow rates is the most typical finding in COPD. Increases in the
residual volume and the residual volume/total lung capacity ratio, nonuniform distribution of
ventilation, and ventilation-perfusion mismatching also occur
1. Airflow Obstruction
patients with airflow obstruction related to COPD have a chronically reduced ratio of FEV1/FVC.
airflow during forced exhalation is the result of the balance between the elastic recoil of the lungs
promoting flow and the resistance of the airways limiting flow; in normal lungs, as well as in lungs
affected by COPD, maximal expiratory flow diminishes as the lungs empty because the lung
parenchyma provides progressively less elastic recoil and because the cross-sectional area of the

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airways falls, raising the resistance to airflow; decrease in flow coincident with decreased lung
volume is readily apparent on the expiratory limb of a flow-volume curve
in early stages of COPD, the abnormality in airflow is only evident at lung volumes at or below the
functional residual capacity (closer to residual volume), appearing as a scooped-out lower part of
the descending limb of the flow-volume curve; in more advanced disease the entire curve has
decreased expiratory flow compared to normal
2. Hyperinflation
in COPD there is often air trapping (increased residual volume and increased ratio of residual
volume to total lung capacity) and progressive hyperinflation (increased total lung capacity) late
in the disease
hyperinflation of the thorax during tidal breathing preserves maximum expiratory airflow, because
as lung volume increases, elastic recoil pressure increases and airways enlarge so that airway
resistance decreases; helps to compensate for airway obstruction
however, hyperinflation can push the diaphragm into a flattened position with a number of
adverse effects:
1. by decreasing the zone of apposition between the diaphragm and the abdominal wall, positive
abdominal pressure during inspiration is not applied as effectively to the chest wall, hindering
rib cage movement and impairing inspiration
2. because the muscle fibers of the flattened diaphragm are shorter than those of a more
normally curved diaphragm, they are less capable of generating inspiratory pressures than
normal
3. the flattened diaphragm (with increased radius of curvature, r) must gen- erate greater tension
(t) to develop the transpulmonary pressure (p) required to produce tidal breathing. This follows
from Laplaces law, p = 2t/r
4. because the thoracic cage is distended beyond its normal resting volume, during tidal
breathing the inspiratory muscles must do work to overcome the resistance of the thoracic
cage to further inflation instead of gaining the normal assistance from the chest wall recoiling
outward toward its resting volume
3. Gas Exchange
PaO2 usually remains near normal until the FEV1 is decreased to 50% of predicted, and even
much lower FEV1s can be associated with a normal PaO2, at least at rest; elevation of PaCO2 is
not expected until the FEV1 is <25% of predicted; pulmonary hypertension severe enough to
cause cor pulmonale and right ventricular failure due to COPD occurs only in those individuals
who have marked decreases in FEV1 (<25% of predicted) together with chronic hypoxemia (PaO2
<55 mmHg)
nonuniform ventilation and ventilation-perfusion mismatching are characteristic of COPD,
reflecting the heterogeneous nature of the disease process within the airways and lung
parenchyma
nitrogen wash-out while breathing 100% oxygen is delayed due to regions that are poorly
ventilated, and the profile of the nitrogen wash-out curve is consistent with multiple parenchymal
compartments having different wash-out rates due to regional differences in compliance and
airway resistance
ventilation/perfusion mismatching accounts for essentially all of the reduction in PaO2 that occurs
in COPD; shunting minimal
PATHOLOGY
1. Large Airway
cigarette smoking often results in mucous gland enlargement and goblet cell hyperplasia; these
changes are proportional to cough and mucus production that define chronic bronchitis, but these
abnormalities are not related to airflow limitation
goblet cells not only increase in number but in extent through the bronchial tree
bronchi undergo squamous metaplasia, which not only predisposes to carcinogenesis but also
disrupts mucociliary clearance
patients may have smooth-muscle hypertrophy and bronchial hyperreactivity leading to airflow
limitation
neutrophil influx is associated with purulent sputum of URTIs that hamper patients with COPD
2. Small Airway
major site of increased resistance in most individuals with COPD is in airways 2 mm diameter;
characteristic cellular changes include goblet cell metaplasia and replacement of surfactant-

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secreting Clara cells with mucus-secreting and infiltrating mononuclear inflammatory cells,
smooth-muscle hypertrophy may also be present
abnormalities may cause luminal narrowing by excess mucus, edema, and cellular infiltration
reduced surfactant may increase surface tension at the air-tissue interface, predispose to airway
narrowing or collapse
fibrosis in the wall may cause airway narrowing directly or, as in asthma, predispose to
hyperreactivity
respiratory bronchiolitis with mononuclear inflammatory cells collecting in distal airway tis- sues
may cause proteolytic destruction of elastic fibers in the respiratory bronchioles and alveolar
ducts where the fibers are concentrated as rings around alveolar entrances
loss of bronchiolar attachments as a result of extracellular matrix destruction cause airway
distortion and narrowing
3. Lung Parenchyma
emphysema is characterized by destruction of gas-exchanging airspaces, i.e., the respiratory
bronchioles, alveolar ducts, and alveoli; their walls become perforated and later obliterated with
coalescence of small distinct airspaces into abnormal and much larger airspaces
macrophages accumulate in respiratory bronchioles of essentially all young smokers; in smokers
lavage fluid, macrophages comprise >95% of the total cell count, and neutrophils, nearly absent
in nonsmokers lavage, account for 12% of the cells; T lymphocytes, particularly CD8+ cells, are
also increased in the alveolar space of smokers
emphysema is classified into distinct pathologic types, the most important being centriacinar and
panacinar; centriacinar emphysema, the type most frequently associated with cigarette smoking,
is characterized by enlarged airspaces found (initially) in association with respiratory bronchioles,
is most prominent in the upper lobes and superior segments of lower lobes and is often quite
focal; panacinar emphysema refers to abnormally large airspaces evenly distributed within and
across acinar units, is usually observed in patients with 1AT deficiency, which has a predilection
for the lower lobes
CLINICAL PRESENTATION
1. History
three most common symptoms in COPD are cough, sputum production, and exertional dyspnea
development of exertional dyspnea, often described as increased effort to breathe, heaviness, air
hunger, or gasping, can be insidious
activities involving significant arm work, particularly at or above shoulder level, are particularly
difficult for patients with COPD
as COPD advances, the principal feature is worsening dyspnea on exertion with increasing intrusion
on the ability to perform vocational or avocational activities; in most advanced stages, patients are
breathless doing simple activities of daily living

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2. Physical Findings
current smokers may have signs of active smoking, including an odor of smoke or nicotine
staining of fingernails
prolonged expiratory phase and expiratory wheezing; signs of hyperinflation include a barrel chest
and enlarged lung volumes with poor diaphragmatic excursion as assessed by percussion
exhibit use of accessory muscles of respiration, sitting in the characteristic tripod position to
facilitate the actions of the sternocleidomastoid, scalene, and intercostal muscles; may develop
cyanosis, visible in the lips and nail beds
systemic wasting, with significant weight loss, bitemporal wasting, and diffuse loss of
subcutaneous adipose tissue
signs of overt right heart failure, termed cor pulmonale, are relatively infrequent since the advent
of supplemental oxygen therapy
3. Laboratory Findings
pulmonary function testing shows airflow obstruction with a reduction in FEV1 and FEV1/FVC
lung volumes may increase, resulting in an increase in total lung capacity, functional residual
capacity, and residual volume
change in pH with PCO2 is 0.08 units/10 mmHg acutely and 0.03 units/10 mmHg in the chronic
state
obvious bullae, paucity of parenchymal markings, or hyperlucency suggest the presence of
emphysema; increased lung volumes and flattening of the diaphragm suggest hyperinflation