Global Initiative for Chronic Obstructive Lung Disease - GOLD

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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 8 .
The association of starvation and anabolic/catabolic
status with the development of emphysema has been
shown in experimental studies in animals 9 .
HOST FACTORS
Genes
It is believed that many genetic factors increase (or
decrease) a person's risk of developing COPD. Studies
have demonstrated an increased risk of COPD within
families with COPD probands. Some of this risk may be
due to shared environmental factors, but several studies
in diverse populations also suggest a shared genetic risk 10,11 .
The genetic risk factor that is best documented is a
severe hereditary deficiency of alpha-1 antitrypsin 12-14 , a
major circulating inhibitor of serine proteases. This rare
hereditary deficiency is a recessive trait most commonly
seen in individuals of Northern European origin.
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 of
lung function decline. Although alpha-1 antitrypsin
deficiency is relevant to only a small part of the world's
population, it illustrates the interaction between host
factors 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.
Exploratory studies have revealed a number of candidate
genes that may influence a person's risk of COPD,
including ABO secretor status 15,16 , microsomal epoxide
hydrolase 17 , glutathione S-transferase 18 , alpha-1 antichymotrypsin
19 , the complement component GcG 20 , cytokine
TNF- 21 , and microsatellite instability 22 . However, when
several studies of a given trait are available, the results
are often inconsistent. Several of these genes are
thought to be involved in inflammation, and therefore are
related to potential pathogenic mechanisms of COPD.
Airway Hyperresponsiveness
Asthma and airway hyperresponsiveness, identified as
risk factors that contribute to the development of COPD,
are complex disorders related to a number of genetic and
environmental factors. The relationship between asthma/
airway hyperresponsiveness and increased risk of
developing COPD was originally described by Orie and
colleagues 23 and termed the "Dutch hypothesis."
Asthmatics, as a group, experience a slightly accelerated
loss of lung function 24,25 compared to non-asthmatics, as
do smokers with airway hyperresponsiveness compared
to normal smokers 26 . How these trends are related to the
development of COPD is unknown, however. Airway
hyperresponsiveness may also develop after exposure to
tobacco smoke or other environmental insults and thus
may be a result of smoking-related airway disease.
Lung Growth
Lung growth is related to processes occurring during
gestation, birth weight, and exposures during childhood 27-31 .
Reduced maximal attained lung function (as measured by
spirometry) may identify individuals who are at increased
risk for the development of COPD 32 .
EXPOSURES
It may be helpful conceptually to think of a person's
exposures in terms of his or her total burden of inhaled
particles (Figure 3-2). 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 people may encounter over a lifetime, only
tobacco smoke 2,33-39 and occupational dusts and chemicals
(vapors, irritants, and fumes) 40,41 are known to cause
COPD on their own. Tobacco smoke and occupational
exposures also appear to act additively to increase a
person's risk of developing COPD.
Tobacco Smoke
Cigarette smoking is by far the most important risk factor
for COPD and the most important way that tobacco
contributes to the risk of COPD. Cigarette smokers have
a higher prevalence of respiratory symptoms and lung
function abnormalities, a greater annual rate of decline in
FEV 1 , and a greater COPD mortality rate than nonsmokers.
These differences between cigarette smokers and nonsmokers
increase in direct proportion to the quantity of
smoking. Pipe and cigar smokers have greater COPD
morbidity and mortality rates than nonsmokers, although
their rates are lower than those for cigarette smokers 33 .
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.
Age at starting to smoke, total pack-years smoked, and
current smoking status are predictive of COPD mortality.
RISK FACTORS 21