Year II Respiratory System

Chronic Obstructive Pulmonary Disease

Dr. Ahmet Baydur
Friday, October 18, 2013 9:00 10:20 AM

Chronic Obstructive Pulmonary Disease (COPD)
Objectives:
By the end of the presentation the student should be able to:
1. Describe the up-to-date definition of chronic obstructive pulmonary disease as
an inflammatory disease state.
2. List at least four factors which place a person at risk for developing COPD
3. Describe the important clinical features of COPD. Be familiar with the
overlapping pathophysiologic and clinical characteristics of individuals with
features of emphysema and chronic bronchitis.
4. List the key abnormalities of pulmonary function seen in a patient with
COPD. Identify differences in flow-volume curve patterns in people with
obstructive, restrictive, and extrathoracic obstructive respiratory disorders.
5. Describe the complications that affect quality of life and longevity in COPD.
Understand the pathogenesis of cor pulmonale and how it relates to chronic
hypoxemia and structural changes in COPD.
6. Be familiar with key therapeutic modalities in the management of COPD,
including pulmonary rehabilitation.
Strongly recommended references (**on reserve at the reference desk in the Norris
medical library):
1. **Weinberger SE, Cockrill BA, Mandel J . Principles of Pulmonary Medicine, 5th
Edition (2008), Saunders, Philadelphia, PA, ch. 6, Chronic Obstructive
Pulmonary Disease, pp. 90-109. Also available on-line:
http://www.usc.edu/e_resources/hsl/gateways/23750.php.
2. **West J B, Pulmonary Pathophysiology: The Essentials (2013), ch. 4, Chronic
Obstructive Pulmonary Disease, pp. 47-73. This reference has excellent study
questions at the end of the chapter, and should be reviewed. Questions on the
quizzes and final exam may come from this source.
3. **Kueppers F. Chronic Obstructive Pulmonary Disease, in Criner GJ , DAlonzo
GE, Pulmonary Pathophysiology, Fence Creek Publishing, Madison Conn., 1999,
Ch. 10, pp. 233-241.
4. Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis,
management, and prevention of chronic obstructive pulmonary disease. GOLD
Executive Summary. Am J Respir Crit Care Med 2007: 176:532-555. Updated
2010.
5. Global Strategy for the Diagnosis, Management, and Prevention of Chronic
Obstructive Pulmonary Disease. Available from:
http//www.goldcopd.org/guidelines-global-strategy-for-diagnosis
management.html (revision of ref. 4, 2011).

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Case presentation 1:

A 65-yr-old man with an 80-pack-year history of smoking complains of shortness of
breath on exertion of several months duration. On inspection, there is increased
anteroposterior diameter of the chest, pursed lips, and dyspnea during conversation. He is
unable to complete more than 4 or 5 words at a time. On physical examination, the
patient is noted to be tachycardic, have hyperresonant lungs with decreased breath
sounds, no crepitations (rales), and no hepatomegaly or liver nodules on palpation. Which
of the following is the most likely diagnosis?

A. Alpha-1-antitrypsin deficiency
B. Asthma
C. Bronchiectasis
D. Centriacinar emphysema
E. Chronic bronchitis
F. Panacinar emphysema



Chronic Obstructive Pulmonary Disease (COPD)

I Synonymous Terms:
Chronic Obstructive Lung Disease (COLD), Chronic Airway Obstruction (CAO)

II Definitions

Chronic obstructive pulmonary disease (COPD) is a preventable and treatable
disease with some significant extrapulmonary (systemic) effects that may contribute to
the severity in individual patients. Its pulmonary component is characterized by airflow
limitation that is not fully reversible. The airflow limitation is usually progressive and
associated with an abnormal inflammatory response of the lung to noxious particles or
gases (GOLD definition, revised, ref. 5, above).

Most clinicians still use the following classifications to distinguish different forms of
COPD based on symptoms and pathologic findings:
A. Chronic Bronchitis chronic production of cough for 3 months in each of
at least two successive years in a patient in whom all other causes of
cough have been excluded.
B. Emphysema abnormal permanent destructive enlargement of airspaces
distal to the terminal bronchioles, accompanied by loss of alveolar
attachments. The normal acinus loses its orderly appearance and may
even become totally lost.
C. Small Airway Disease Inflammation and narrowing of the peripheral
airways, sometimes associated with cough and/or exertional shortness of
breath. It is detected by subtle changes in pulmonary function testing.

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These descriptions should be considered as models for the specific condition. In fact,
most patients with COPD have overlapping features of the above descriptions. For this
reason, the GOLD definitions (refs. 4 and 5, above) do not subdivide COPD into types.
III Epidemiology
A. Prevalence --
1. About 12-14 million adults suffer from COPD in the U.S.
2. Women comprise about 52 % of that number (last 13 years).
3. Prevalence seems to be highest in the Midwest and Southeast states.

B. Mortality
1. In 2009, there were approximately 134,000 deaths due to COPD in
the U.S. - third leading cause of death, behind cancer and heart
disease.
2. Nearly 80% of COPD deaths are in non-Hispanic whites; Hispanics
exhibit the least number of deaths with 3,714 (in 2009).
(Data from American Lung Association, Epidemiology and Statistics Unit,
Research and Health Education Division, March 2013)
IV Risk Factors for COPD
1. Tobacco smokeespecially cigarettesis by far the most important cause
of COPD.
a. Age of starting, total pack-years and current smoking status are all
predictive of mortality.
b. It accounts for over 90% of all COPD risk factors in developed
countries.
2. Passive smoking (second hand smoke)children of parents who smoke
have more respiratory symptoms and respiratory disease than those from
nonsmoking parents.
3. Ambient air pollution causes harm to persons with heart and lung disease.
Recently, in addition to pollution from gasoline engines, diesel exhaust
(especially from trucks and buses) has been shown to increase respiratory
symptoms and disease.
4. In developing countries, inhalation of smoke from biomass fuels is also an
important cause of COPD, particularly among women who cook in poorly
ventilated homes.
5. Hyperresponsive airways
a. Asthma may progress to COPD through remodelling of airways
b. Hyperreactive airways in smokers is a double edged sword
6. Sex, race, socioeconomic status
a. Higher prevalence in men
b. Higher mortality in whites
c. Higher prevalence among lower socioeconomic classes.
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7. Occupation Exposure to inhaled environmental toxins is especially lethal
for smoking workers.
8. Bacterial Infection and Pathogenesis of COPD.
a. Childhood infection and adult lung function
b. Vicious circle hypothesis (Fig.1)
c. Bacterial infection and chronic mucus hypersecretion
d. Bacterial infection and mucociliary clearance
e. Bacterial infection and airway epithelial injury ( Fig. 2 )
f. Bacterial infection and airway inflammation ( Fig. 2 )
g. Chronic bacterial infection of respiratory tissues ( Fig. 2 )
h. Intracellular Hemophilus influenza infection of respiratory tissues
i. Chronic Chlamydia Pneumoniae infection in COPD
9. Genetic / Molecular factors
COPD develops in only a minority of heavy smokers (10% to 20%),
indicating that there are differences in individual susceptibility to the
effects of tobacco smoking:
A. Alpha 1 antitrypsin (anti-protease) deficiency
a. The only definitely proven genetic abnormality leading to COPD.
Associated with lower lobe and panlobular emphysema.
b. Over 95% of persons with A
1
AT deficiency are homozygous for
the Z allele, i.e., PiZZ, but it is rare.
c. Those with heterozygous deficiency (Pi MZ) may also become
affected with increased airway hyperreactivity, but not all
necessarily progress to COPD.
B. Neutrophil chemokines and cytokines (tumor necrosis factor- and
interleukin-8) and matrix metalloproteinases (MMPs) produced by
macrophages and neutrophils play a role in the development of COPD.
These substances recruit and activate more neutrophils to the lung,
causing further elastolytic destruction of alveoli.
V. Clinical characteristics
A. History:
1. Smoking at least one pack of cigarettes daily for 20 years.
2. Cough with mucoid to mucopurulent sputum, seen especially with
acute exacerbations. Most patients do not experience fever, chills or
sweats if they, do, worry about pneumonia on top of the COPD.
3. Dyspnea (breathlessness) first with exertion then ultimately at rest.
Exercise intolerance is due to many contributing factors:
a. Ventilatory limitation due to hyperinflation, dead-space
ventilation, impaired gas exchange, deconditioning, peripheral
muscle dysfunction.
b. Gas exchange limitations Hypoxemia, hypercarbia increase
ventilatory demands lactic acid production from fatiguing
respiratory muscles.
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c. Cardiac dysfunction right ventricular hypertrophy cor
pulmonale left ventricular dysfunction.
d. Skeletal muscle dysfunction due to deconditioning, oxidative
stress, systemic inflammation, hypoxemia, chronic steroid use,
weight loss.
e. Respiratory muscle dysfunction from chronic overload and
hyperinflation.
Important concept -- COPD is a systemic disease!
4. Increased frequency of respiratory illnesses, i.e., chest colds, upper
respiratory infections (URIs), flu episodes. These lead to
exacerbations.
5. May experience wheezing.
6. Late symptoms and signs are: hypoxemia, heart failure, weight loss,
poor appetite, early satiety, secondary erythrocytosis (in chronic
bronchitis)
7. Patients with predominantly emphysematous features exhibit dyspnea,
hyperinflated lungs, severe reduction in airflows, relatively normal
blood gases). Those with predominantly bronchitic characteristics
exhibit productive cough, hypoxemia/hypercarbia, cor pulmonale
and secondary erythrocytosis. Most patients have overlapping
features.

B. Physical Exam

1. Prolonged expiration with or without wheezes
2. Decreased breath sounds
3. Hyperresonance to percussion (indicates hyperinflated lungs)
4. Use of accessory muscles of respiration
5. Cyanosis (usually seen with with PaO
2
<40 mmHg)

C. Laboratory Findings

1. Chest x-ray
Hyperinflation, flat, depressed diaphragms, long narrow heart
shadow, increased space behind the sternum (seen on lateral
upright view), loss of vascularity -- most commonly present with
emphysema. Thickened bronchial markings seen in chronic
bronchitis.
2. Pulmonary Function Tests
a. Spirometry consistent with airflow obstruction -- FVC,
FEV
1
and FEV
1
/ FVC all decreased. Severity of COPD is
currently classified as mild, moderate and severe according
to the reduction in predicted FEV
1
.
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b. Little or no response to bronchodilators (<12% increase in
FEV
1
(as opposed to asthma, characterized by
improvement in the FEV
1
by at least 12%).
c. Flow-volume curves (Fig. 3, first and second curves)
show a characteristic downward expiratory convexity,
indicative of expiratory flow limitation. Compare this curve
to the restrictive pattern (no concavity) and to those with
variable extrathoracic or intrathoracic, or fixed airway
obstruction (upper airway narrowing), where the curves are
flattened at the top or bottom, or both.
d. Lung Volumes TLC, RV, and RV/TLC all increased.
These findings indicate lung hyperinflation, an
important factor contributing to breathlessness and
disability.
e. Diffusing Capacity (DL
CO
) Decreased in emphysema
because of reduced alveolar surface area available for gas
exchange and loss of pulmonary vascular bed. By
contrast, DL
CO
is normal or slightly increased in
asthma (due to air trapping without alveolar destruction)
and normal, slightly decreased (because of mucus
plugging the airways), or increased (because of increased
hematocrit) in chronic bronchitics.

3. Arterial Blood Gases
a. Hypoxemia [clinically significant when PaO
2
falls below
55 mmHg because of the risk for developing pulmonary
hypertension and cor pulmonale (see below)].
b. Hypercapnia later in the disease when FEV
1
falls below
1.0 L.

4. Sputum-
1. Only good to evaluate possible cause for
intercurrent infections; Grams stain more valuable
than culture
2. Major infecting agents-
Viral agents, Streptococcus pneumoniae,
Haemophilus influenzae, Moraxella catarrhalis
5. Erythrocytosis in persons whose PaO
2
is chronically below 55
mmHg on room air.



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Sample case studies with PFTs:

Patient FVC FEV
1
FEV
1
/FVC FEF
25-75
TLC DL
CO

1 3.0 L (73%) 0.7 L (23%) 23% 0.2 LPS (6%) 9.6 L (150%) 0.9 (19%)
2 2.9 L (82%) 1.8 L (59%) 61% 0.9 LPS (23%) 4.9 L (100%)
6.8
(122%)

1. 63-year- old man with a 60 pack/year smoking history and dyspnea on exertion. An
arterial blood gas demonstrates a PO
2
=56 and a PCO
2
=44.
2. 24-year-old woman with dyspnea on exertion. She also notes dyspnea when exposed to
cats. On physical exam, she is wheezing.
Answers:
1. This patient has emphysema. His FEV
1
/FVC ratio is <70% which indicates
obstruction. His FEV
1
is <34% of predicted which indicates very severe obstruction.
His TLC is elevated and his diffusing capacity is very low. Emphysema can be defined
from a radiographic standpoint, a pathologic standpoint, or a physiologic standpoint.
For the purpose of the latter, we consider PFTs consistent with emphysema if there is
(1) non-reversible obstruction, (2) elevated lung volumes, (3) low diffusing capacity,
and (4) an adequate smoking history.
2. This case is typical for asthma. The FEV
1
/FVC ratio is <70% so she is obstructed. The
FEV
1
puts her in the moderate obstruction category. She is not restricted and the
diffusing capacity is increased, likely because of increased pulmonary blood flow,
allowing increased carbon monoxide extraction from the carbon monoxide
inhalation. Confirmation of asthma is by demonstrating an increase in FEV
1
by at least
12% (and by at least 200 mL) following bronchodilator inhalation (bronchodilator
response does not occur to the same extent with emphysema or chronic bronchitis,
hence these conditions are referred to as nonreversible forms of airflow limitation or
COPD).
Of the flow-volume curves depicted in Fig. 3, case 1 would exhibit a F-V curve
consistent with the second tracing in the upper group, and case 2 a less severely
obstructed version as depicted by the first curve in the upper group. The other curves
are consistent with obstruction located somewhere in the large upper airways (bottom
row), or with restrictive disorders (interstitial or neuromuscular-chest wall disorders,
third tracing, top row).



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D. Clinical-Physiologic-Pathologic correlations:
1. Epidemiologic studies show that disability and death from COPD
are related to an accelerated decline in lung function over time. The
progressive reduction in FEV
1
and increasing severity of disease
result in increasing exertional dyspnea that slowly advances to
respiratory failure.
2. Exacerbations of COPD cause morbidity, hospital admissions,
mortality, and adversely affect quality of life. Exacerbations are
associated with airway inflammation and physiologic deterioration.
Bacteria, viruses, and changes in air quality (including smoking)
interact to produce increased inflammation.
E. Complications
1. Hypoxic pulmonary hypertension
2. Right heart failure (cor pulmonale)
3. Frequent intercurrent respiratory tract infections (>2/ yr)
4. Weight loss and loss of appetite
5. Respiratory failure with severe hypoxemia, hypercapnia, and
respiratory acidosis
VI Principles of Therapy
A. Smoking cessation
B. Chronic oxygen therapy to maintain PaO
2
at above 55 mm Hg. Long-term
oxygen therapy improves quality of life and prolongs survival.
C. Bronchodilators inhaled anticholinergic agents (e.g., ipratropium) and
beta-agonists (See Fig. 4).
D. Phosphodiesterase inhibitors block the enzymatic breakdown of cAMP,
and exhibit anti-inflammatory and antioxidant activities.
E. Corticosteroids during acute exacerbations of COPD. Inhaled
corticosteroids now used for maintenance; they reduce the number of
acute exacerbations, and may slow the progression in functional decline
(this point is still controversial). These medications are usually prescribed
in progressive fashion depending on the severity of the COPD (see Fig. 4).
F. Antibiotics for intercurrent infection
G. Good nutrition
H. Patient and caregiver education
I. Pulmonary rehabilitation in patients who are physically (and
psychologically, with depression and anxiety) impaired
J . Mechanical ventilators during episodes of respiratory failure (invasive and
non-invasive)
K. Lung volume reduction surgery or transplantation, in selected cases, for
emphysema
Remember again, COPD is a systemic disease!
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The NHLBI/WHO Workshop summary on the Global Initiative for COPD (GOLD) (ref.
4) is a current review of the state of the art on all aspects of COPD, and is highly
recommended for those who wish to read more on this subject contains practical
aspects of definition, classification of severity, epidemiology, risk factors, and the 4
components of COPD management (assess and monitor disease, reduce risk factors,
pharmacologic and nonpharmacologic treatment of stable COPD, and management of
exacerbations).

Case revisited:

A 65-yr-old man with an 80-pack-year history of smoking complains of shortness of
breath on exertion of several months duration. On inspection, there is increased
anteroposterior diameter of the chest, pursed lips, and dyspnea during conversation. He is
unable to complete more than 4 or 5 words at a time. On physical examination, the
patient is noted to be tachycardic, have hyperresonant lungs with decreased breath
sounds, no crepitations (rles), and no hepatomegaly or liver nodules on palpation. Which
of the following is the most likely diagnosis?

G. Alpha-1-antitrypsin deficiency
H. Asthma
I. Bronchiectasis
J . Centriacinar emphysema
K. Chronic bronchitis
L. Panacinar emphysema






















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Fig. 1: Schematic diagram of the vicious circle hypothesis of the role of bacterial
colonization in the progression of COPD (from Sethi Chest 2000;117:286S-291S).





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Fig. 2: Potential pathways by which infection-induced lung damage could contribute to
the pathology of COPD. This diagram summarizes the known and proposed mechanisms
by which bacterial infection of the tracheobronchial tree can produce the symptom
complex, pathologic features, and pathophysiology of COPD. This model parallels in
many respects the mechanisms by which tobacco smoking causes chronic bronchitis and
airway obstruction. The proposed mechanism therefore emphasizes how tobacco
smoking and tracheobronchial infection can synergistically induce this chronic disabling
disease (from Sethi, Chest 2000;117:286S-291S).



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Fig. 3: Flow-volume curve patterns in different
conditions (dashed curve normal). Expiration is
that portion of the curve above the zero flow line,
inspiration is below the line.

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Fig. 4: Step-wise management of COPD based on severity of functional loss (modified
from ref. 4).

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