COPD: Epidemiology,

Pathogenesis, & Pathophysiology

Wyatt E. Rousseau, MD
May 11, 2006
 COPD Definition
Chronic obstructive pulmonary disease
(COPD) is a preventable and treatable disease
state characterized by airflow limitation that is
not fully reversible. The airflow limitation is
usually progressive and is associated with an
abnormal inflammatory response of the lungs
to noxious particles or gases, primarily caused
by cigarette smoking. Although COPD affects
the lungs, it also produces significant systemic
consequences.
 COPD Definitions/Terms
• Simple chronic bronchitis
• Asthmatic bronchitis/Chronic asthmatic
bronchitis
• Chronic obstructive bronchitis – “small airways
disease
• Pulmonary emphysema
 Simple chronic bronchitis

Exposure to irritants without

hyperreactive airways. Characterized
by mucoid sputum production,
decreased ciliary activity, and
impaired resistance to infection.
Chronic asthmatic bronchitis or
COPD with asthma
Exposure to irritants in individuals
with reactive or twitchy airways.
Bronchospasm is frequently
accompanied by excessive mucous
production and edema of bronchial
walls. Episodic worsening of airway
obstruction often called asthma, but
there is persisting obstruction, and
often productive cough, with the
episodic bronchospasm.
Obstructive Chronic Bronchitis

Irreversible narrowing of airways,

usually bronchioles or bronchi
smaller than 2 mm., associated with
increased resistance to airflow,
hypoxemia, hypercapnea.
 Pulmonary Emphysema

Permanent, abnormal distension of

the air spaces distal to the terminal
bronchiole with destruction of
alveolar septae, with or without
fibrosis. Reduces lung elastic recoil
causing airway collapse and
irreversible airway obstruction.
Histology
 Pathology – Chronic Bronchitis
• Hypertrophy of mucous glands in submucosa of
airways. Reid index (submucosa to bronchial
wall).
• Small airways obstruction esp. with goblet cell
hyperplasia, mucosal and submucosal
inflammatory cells, edema, peribronchial fibrosis,
mucous plugs, and increased smooth muscles.
• Alveolar epithelium is the target and the initiator
of inflammation in CB, with neutrophils,
macrophages, and CD8 lymphocytes causing
epithelial cell release of IL-8 and other
chemotactic and proinflammatory cytokines, and
colony stimulating factors released in response to
toxic, infectious, or inflammatory stimuli.
 More CB Pathology

• Injured epithelium may release reduced amounts

of regulatory products such as ACE or neutral
peptidase.
• Sputum production is stimulated by increased
exocytosis from secretory cells, lipid mediators,
and inflammatory cell products.
• Mucin gene expression is amplified by TNF-alpha,
and secretory cell hyperplasia by the neutrophil
enzymes elastase and cathepsin G.
 Pathology - Emphysema
• Classified by pattern of involvement of the acini
distal to terminal bronchiole.
• Centriacinar or Centrilobular – limited to
respiratory bronchioles primarily with little
change in acinus. Normal aging is associated
with this.
• Panacinar or Panlobular – involves both central
and peripheral portions of the acinus.
 Epidemiology
• Background - Lung function over time
• Cigarette smoking
• Airway responsiveness and Allergy
• Air Pollution
• Occupational exposure to environmental
dust and organic antigens
• Infection
• Antioxidant deficiency
• Molecular/Genetic risk factors
 Cigarette Smoking
• Responsible for 80% of risk of Chronic
Bronchitis
• Doubles or triples rate of FEV1 decline
• Responsible for 2-20 fold increase in death
from COPD
• Never smokers account for 23% of COPD
• Only 15% of white and 5% Asian smokers
develop COPD
 Cigarette Smoking
• Impairs ciliary movement
• Inhibits alveolar macrophages
• Leads to hypertrophy and hyperplasia of
mucus-secreting glands
• Probably inhibits antiprotease
• Acutely increases vagally mediated
smooth-muscle constriction
 Airway Responsiveness-Dutch
Hypothesis
• Increased airways responsiveness and allergy are
clinical phenotypes that predict increased
susceptibility to cigarette smoke.
• Methacholine and histamine responsiveness
precedes and predicts accelerated decline in lung
function, thus a risk factor for COPD.*
• Increased airways responsiveness noted among 1st
degree relatives of patients with early onset
COPD.@
*Silva, GE et al. Asthma as a risk factor for COPD in a longitudinal study.
Chest 2004; 126:59.
@Celedon JC et al. Bronchodilator responsiveness and serum total IgE levels
in families of probands with severe early-onset COPD. Eur Respir J 1999;
14:1009.
 Air Pollution
• Increased incidence and higher mortality
rates of COPD in industrialized urban
areas.
• Exacerbations of CB clearly related to
periods of heavy sulfur dioxide pollution
and particulates.
• Nitrogen dioxide NOT implicated in
human airways obstruction.
 Occupational Exposures
• Environmental dusts – gold and coal miners
• Organic antigens – COPD is most common
respiratory syndrome in agricultural workers, and
there is a 10% prevalence of COPD among farm
workers
• Accelerated decline in lung function among
plastics workers exposed to toluene diisocyanate
and in carding room workers in cotton mills
 Infection
• Severe viral pneumonia in childhood may lead to
small airways obstruction (SAO).
• Mortality, morbidity, and frequency of ARI are
higher in patients with chronic bronchitis.
• The Rhinovirus is found more often during
COPD exacerbations…pathogenic bacteria, other
viruses, & mycoplasmas found as often between
as during exacerbations. However there is
increased chance of detecting bacteria if sputum
purulent*, and isolating new strain of bacteria
may be associated with exacerbations.@
*Stockley RA et al. Relationship of sputum color to nature and outpatient
management of acute exacerbation of COPD. Chest 2000; 117: 1638.
@Sethi S et al. New strains of bacteria and exacerbations of COPD. N Engl
J Med 2002; 347: 465.
 Antioxidant Deficiency
• Oxidizing radicals derive from cigarette smoke or
may be released by phagocytes in the lung.
Deficiencies of antioxidants vitamins may impair
host defenses against oxidative radicals and
permit tissue destruction leading to COPD.
– Sanguinetti, CM. Oxidant/antioxidant imbalance: role
in the pathogenesis of COPD. Respiration 1992; 59
Suppl 1:20.
 Molecular/Genetic Risk Factors

• Protease/antiprotease
• TNF-a gene polymorphisms
• Microsomal epoxide hydrolase*
• Glutathione S-transferase P1
• Transforming growth factor beta 1*
• Metalloproteinase dysregulation
– Hersh, CP et al. Genetic association analysis of functional
impairment in chronic obstructive pulmonary disease. Am J Respir
Crit Care Med 2006; 173: 977-984.
 Protease/Antiprotease
• Alpha –1- antitrypsin/elastase imbalance.
• Alveolar macrophages from COPD patients
express more matrix metalloproteinase (MMP)-9
than normals. Elevated MMP-9 is associated
with an increase in degradation of elastin.
– Russell RE et al. Release and activity of matrix
metalloproteinase-9 and tissue inhibitor of
metalloproteinase-1 by alveolar macrophages from
patients with chronic obstructive pulmonary disease.
Am J Respir Cell Mol Biol. 2002;283:L867-L873.
 TNF – alpha gene
polymorphisms
• May influence host immune responses,
increase inflammatory tissue damage, and
favor the development of chronic
bronchitis- a specific TNF-a polymorphism
found in 19% CB vs. 5% schoolchildren
vs. 2% of controls
– Huang SL et al. Tumor necrosis factor-alpha
gene polymorphism in chronic bronchitis. Am
J Respir Crit Care Med 1997; 156:1436
 Microsomal epoxide hydrolase
• Microsomal epoxide hydrolase (MEH) reduces
highly reactive epoxide intermediates generated
by smoking. The genotypes associated with
decreased activity of MEH were found in 19 and
22 per cent of COPD patients vs. 6% controls
– Smith CAD, Harrison DJ. Association between
polymorphism in gene for microsomal epoxide
hydrolase and susceptibility to emphysema. Lancet
1997; 350:630.
 Glutathione S-transferase P1
• Glutathione S-transferase P1 aids in the
detoxification of substances in cigarette smoke,
and COPD may occur more frequently among
persons with decreased activity of this enzyme by
virtue of genetic polymorphisms.
– Ishii, T et al. Glutathione S-transferase P1
polymorphism in patients with chronic obstructive
pulmonary disease. Thorax 1999; 54:693.
Transforming growth factor beta
1
• Transforming growth factor beta 1 is a member
of a large family of polypeptides involved in
cellular growth, differentiation, and activation.
Specific, single nucleotide polymorphisms of the
gene encoding transforming growth factor beta 1
have been associated with the development of
COPD in smokers.
– Wu, L et al. Transforming growth factor beta1
genotype and susceptibility to chronic obstructive
pulmonary disease. Thorax 2004; 59:126.
 Systemic Inflammation in
Pathogenesis of COPD
• COPD is a systemic disease.
• Cytokines and other inflammatory markers are a
response to cigarette smoke.
• They circulate and may impact other diseases and
symptoms, e.g. cardiac disease and cachexia.
• Reduced lung function associated with increased
levels of systemic inflammatory markers,
including CRP, fibrinogen, WBC’s, and TNF-
alpha.*
– Gan WQ et al. Association between chronic obstructive
pulmonary disease and systemic inflammation: a systematic
review and meta-analysis. Thorax 2004; 59:574.
 Noxious particles
and gases
Host factors

Lung inflammation
Anti-oxidants Anti-proteinases

Oxidative stress Proteinases

Repair mechanisms

COPD pathology
 Elastic Recoil Pressure of the
Lung
• Provides radial support.
• Major determinant of maximal expiratory
flow.
• Static recoil pressure of the lung is alveolar
pressure minus pleural pressure.
• Maximum expiratory flow rates represent a
complex and dynamic interplay between
airways caliber, elastic recoil pressures, and
collapsibility of the airways.
Lung Volumes and Capacities in
COPD
• RV increased
• FRC is the volume at which inward recoil
of lung = outward recoil of chest
wall…loss of elastic recoil will increase
FRC
• TLC increased due to loss of elastic recoil
• VC may be normal to decreased
 Time Constants
• Prolonged in all obstructive diseases due to
increased airways resistance and/or increased
compliance.
• If sufficiently prolonged, there is insufficient time
for expiration, progressively increasing lung
volume, moving tidal breathing to a higher, less
compliant portion of the P/V curve, increasing
work of breathing.
• The increased elastic recoil pressure associated
with the higher end-tidal volume is termed auto-
PEEP or intrinsic PEEP, and this represents and
additional threshold load that must be overcome.
 Vd/Vt

• Areas of wasted ventilation and wasted blood flow

in COPD
• Some maintain increased minute volume, with
normal to low pCO2, and relatively high pO2
• Others may have less dyspnea, accepting higher
pCO2 and a depressed pO2
• Difference debated – ventilatory drive related to
peripheral or central chemoreceptor sensitivity or
through other afferent pathways
 Pulmonary Circulation
Malfunctions
• Regional maldistribution of blood flow
• Abnormal pressure-flow relationships
• Pulmonary hypertension often present
– Reduced cross-sectional area due to anatomic
changes and destruction of alveolar septae
– Vessel constriction due to alveolar hypoxemia
– Erythrocytosis also due to chronic hypoxemia
 Clinical Correlates
• Dyspnea and work capacity impairment
• Emphysema usually greater impairment with less
airways obstruction than chronic bronchitis
• Usually dyspnea when FEV1<50%
• Dyspnea at rest when FEV1<25%
• CO2 retention and cor pulmonale often when
FEV1<25%
• Survival: 20-30% live >5years with CO2 retention
 TORCH
Towards a Revolution in COPD
Health*

*The TORCH Study Group. Eur Respir J 2004;

24: 2006-210.
 TORCH
• Multicenter, randomised, double-blind,
parallel-group, placebo-controlled
• 6200 patients, mod-severe COPD
• Salmeterol/fluticasone 500/50 vs.
Salmeterol 50 vs. Fluticasone 500 vs.
placebo
 TORCH preliminary results- to
be published late 2006
• 17% relative reduction in mortality over 3
years cf. placebo.
• Reduced exacerbations of COPD by 25%
cf. placebo.
• Improved QOL by St. George’s
Respiratory Questionnaire.
• Despite reduced rate of excerbations
overall, there was increased reporting of
adverse events classified as LRI cf.
placebo.