Alasan Kerentanan Wanita Yang Lebih Besar Terhadap Pengembangan PPOK Dengan Dominasi Penyakit Saluran Napas Kecil Sebagian Besar Tidak Diketahui

Alasan kerentanan wanita yang lebih besar terhadap pengembangan PPOK dengan dominasi penyakit
saluran napas kecil sebagian besar tidak diketahui. Saluran napas wanita relatif lebih kecil dibandingkan
pria untuk volume paru yang sama, sehingga mungkin terdapat konsentrasi asap tembakau yang lebih
besar per satuan luas permukaan saluran napas kecil (9). Metabolisme asap rokok mungkin berbeda
pada wanita karena perbedaan jenis kelamin dalam ekspresi dan aktivitas enzim sitokrom P450. Pola
merokok antara pria dan wanita mungkin berbeda, dengan pria yang menghirup asap rokok lebih dalam,
meskipun jumlah rokok yang dihisap dan usia mulai merokok serupa di antara jenis kelamin. Ada
kemungkinan bahwa respon inflamasi terhadap asap rokok berbeda pada wanita karena efek hormonal,
meskipun hal ini belum pernah dibuktikan. Gagasan bahwa hormon seks wanita mungkin bertanggung
jawab atas kerentanan PPOK yang lebih besar pada wanita dieksplorasi dalam jurnal edisi ini oleh Tam
dan rekan (hlm. 825-834), pada model tikus yang terpapar asap rokok kronis (10).
Chronic Obstructive Pulmonary Disease (COPD)

ROBERT M. SENIOR , and NICHOLAS R. ANTHONISEN
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https://doi.org/10.1164/ajrccm.157.4.nhlbi-12 PubMed: 9563773
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Recognition of chronic obstructive pulmonary disease (COPD) as a major health

problem is approximately 50 years old, coincident with the 50th anniversary of the
National Heart, Lung, and Blood Institute (NHLBI). Research in COPD was greatly
stimulated by formation of the Division of Lung Diseases (DLD) nearly 30 years ago. In
this presentation we cover some clinical aspects of COPD and aspects of the
pathogenesis of emphysema, with emphasis on findings attributed to support from the
DLD.
CLINICAL ASPECTS OF COPD

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COPD is generally defined as slowly progressive airflow obstruction, which is only

partially reversible (1). It typically occurs in individuals with substantial smoking histories
(at least 20 pack-yr). It is associated with three general types of lesions: emphysema,
small airways inflammation and fibrosis, and mucus gland hyperplasia, most obvious in
larger airways. All of the lesions are uncommon in nonsmokers, and all may be present
in patients with COPD, but this is not always the case. Smokers without dyspnea
frequently have one or more of these lesions.
At present, there are major difficulties with the quantification of emphysema and small
airways disease during life, so clinical investigators study COPD by measuring the
degree of lung function abnormality, notably the impairment in FEV 1. This is justified on
the basis that both emphysema and small airways obstruction reduce maximum
expiratory flow, so that the FEV1 represents some kind of sum of the two influences.
Further, the work of the Burrows group (2-6) showed that in patients with COPD, the
FEV1 is, besides age, the single best predictor of mortality. This finding has been
independently verified by numerous other groups. The tendency to regard COPD as
best assessed by measurement of FEV1 was powerfully supported by the work of
Fletcher and colleagues (7), who studied a group of working men in London over 8
years. Fletcher and colleagues found that the average rate of decline of FEV 1 was 0.03
L/yr in nonsmokers, and that decline was twice as fast in smokers. However, given a
rate of decline of FEV1 of 0.06 L/yr, it was unlikely that the average smoker would live
long enough to develop symptomatic airways obstruction as signified by an FEV 1 < 1.5
L. It followed that people who developed COPD were a subset of smokers whose
decline in FEV1 was considerably larger than the average.
The Fletcher study produced other findings of great interest. Smokers who
spontaneously quit the habit had a normal rate of fall of FEV 1 thereafter, although their
FEV1 values did not increase to levels that would have existed had they never smoked.
These observations have been supported and amplified recently by the DLD-sponsored
Lung Health Study (8), in which smokers were randomly assigned to control or smoking
cessation groups. Smoking cessation had a beneficial effect (Figure 1) that was, if
anything, larger than that described by Fletcher and colleagues (7).
Fig. 1.Rates of decline of lung function in participants in the Lung Health Study (see Reference 8).
The ordinates are postbronchodilator FEV1; the abscissas are years. The top panel shows decline in
the three treatment groups, with the dashed line with squares representing the usual care group, and
the other symbols, the groups that received an anti-smoking interventions. The bottom panel shows
results from participants in one of the treatment groups and compares individuals who stopped
smoking at the onset of the study with those who continued to smoke.
Download figure | Download Powerpoint
Fletcher and colleagues also found that chronic cough and sputum (chronic bronchitis,
chronic mucus hypersecretion) predicted the number of acute exacerbations of cough
and sputum thought to represent airways infection, but did not predict rate of decline of
FEV1. Moreover, there was no discernible effect of exacerbations on long-term fall in
FEV1. These findings essentially refuted the “British hypothesis” concerning the
pathogenesis of COPD, which was that COPD resulted from repetitive airways
infections. This conclusion, in turn, tended to incriminate tobacco smoke as the direct
cause of the lung damage of COPD.
Fletcher did not try to test the alternative “Dutch hypothesis” of the pathogenesis of
COPD (9). This hypothesis was based on the observation that asthma and COPD had
many common features, including airways hyperreactivity and other evidence of allergy.
To oversimplify, patients with COPD were potential asthmatics who smoked. This
approach involved lumping people with asthma and COPD and did not become popular
in the United Kingdom or North America, where most investigators believed that asthma
and COPD were different diseases that could be readily distinguished in the vast
majority of cases. It is only within the last 5–10 years that some rapprochement
between these views has become evident.
Risk Factors
Almost by definition, tobacco use is by far the most important risk factor for COPD, best
summarized as cumulative dose or pack-years. However, as noted above, not all heavy
smokers develop COPD; in fact, most do not, and there has been considerable interest
in other risks. COPD is familial to a greater extent than can be accounted for by the
relatively few cases of α1-antitrypsin (α1-AT) deficiency (10). It is not known whether this
familial tendency reflects genetic or environmental influences, or both. Dusty
occupational environments are well established risks (11), though probably not major
factors in North America. Childhood respiratory illnesses may render some people
susceptible to tobacco-induced lung damage (12). All of these influences are minor
compared to that of smoking, and none satisfactorily explains the differences between
smokers who develop COPD and those who do not.
There was hope that susceptibility to tobacco smoke could be identified early, before
permanent or major damage to the lungs occurs. This was based on the finding that
young smokers had inflammatory and fibrotic lesions of the small airways (13) and the
probability that the conventional lung function tests using forced expiration were
relatively little influenced by such lesions. A variety of tests for small airways diseases,
most notably closing volume, were developed and studied in detail with DLD support
(14). However, the tests were not nearly as reproducible as the FEV 1 and were probably
too sensitive, since abnormalities were often detected in the majority of otherwise
healthy tobacco users. These efforts re- emphasized the value of careful repetitive
spirometry in the assessment of COPD.
As noted previously, for more than 30 years Dutch clinical investigators had argued that
asthma and COPD were different points in a spectrum of obstructive disease with some
risk factors in common, most notably allergy and airways reactivity. Atopy (15) and
eosinophilia (16) have been identified as relatively minor risk factors for COPD, but the
influence of airways reactivity on the course of COPD, as differentiated from asthma,
was unresolved until recently because there was ample evidence that the degree of
airways reactivity was directly related to the degree of airways obstruction of whatever
cause. This meant that individuals with the same level of obstruction, but differing
values of airways reactivity, had to be followed for long enough to discern differences in
disease progress after allowing for variation of potential confounders such as smoking.
The Lung Health Study (8) successfully accomplished this, measuring methacholine
reactivity in a large number of smokers with subclinical airways obstruction at the
beginning of a careful 5-yr follow-up. The initial level of airways (methacholine) reactivity
was, after smoking, the most important single determinant of decline in FEV 1, and this
effect was not explained by variation in the initial level of obstruction (17). Thus, it is
reasonable to conclude that airways reactivity is an important risk factor for COPD. On
the other hand, it is not clear what this represents in terms of biology. In particular, it is
not known whether the reactivity observed in the smokers of the Lung Health Study has
mechanisms similar to those in patients with asthma.
The Lung Health Study also found that airways reactivity was greater in women than
men smokers, and FEV1 may decline more rapidly in women when allowances are
made for lung size and degree of smoking (18). Thus, the female gender may be a risk
for COPD, an influence previously obscured by the preponderance of tobacco use by
men.
Therapy
General. The DLD has been very active in supporting studies of the treatment of COPD.
Indeed, most of the long-term therapy trials have been done with DLD sponsorship, and
DLD-sponsored trials have established the gold standard for this kind of research.
Generally speaking, COPD therapy has two aims: ameliorating the course of the
disease and/or improving the quality of life. Neither of these aims or end points is easy
to assess, and in both cases statistically significant differences may be of little clinical
significance, or achieved at inordinate cost. At present, changing the course of COPD
implies changing the rate of decline of FEV 1 or prolonging life. Study of the first requires
large patient samples with at least 3–5 yr follow-up, and study of mortality requires
either a much longer follow-up or selection of end-stage patients. Both approaches are
laborious and expensive. We need alterative end points that are more easily evaluable,
but comparably robust, and justifiable in terms of cost.
Measures of quality of life include assessment of symptoms, exercise performance, and
health care utilization. None is easy to measure in reproducible fashion, and all have
subjective aspects that make things like standardization between different centers
difficult. Further, quality of life measured in the short term may or may not apply in the
longer term, and long-term studies are expensive and difficult. Some COPD therapies
have been justified on the basis of short-term changes in lung function. Improvements in
FEV1 have been related to improvements in quality of life in the short term, so that
FEV1 can function as a surrogate for quality of life. On the other hand, the use of short-
term studies as the rationale for long-term therapy carries a number of assumptions that
are seldom justified. As indicated above, smoking cessation is the best way to change
the course of the disease (7, 8). Nicotine substitution improves cessation success rates,
but as illustrated by the Lung Health Study, most “good” cessation programs are
expensive and produce long-term quit rates on the order of 25% (8).
Bronchodilators. As is perhaps best illustrated by data from the DLD-sponsored IPPB

trial (19, 20), most patients with COPD have a measurable increase in FEV 1 with the
inhalation of beta-agonists, and in some the change is substantial (Figure 2).
Responses to anticholinergic agents are at least comparable, and these agents have
been shown to improve quality of life over the short term. The method of delivery of
inhaled bronchodilators has not been shown to influence their effect in a clinically
significant way. Though there were suggestions that regular, inhaled bronchodilator
therapy might alter the long-term course of COPD, this issue was studied in the Lung
Health Study and no long-term effect was found (8).
Fig. 2.Frequency distribution of bronchodilator response in patients with COPD enrolled in the
Intermittent Positive Pressure Breathing Trial (see References 19 and 20). The ordinate is percent of
patients, and the abscissa is postbronchodilator FEV1 as a percentage of the prebronchodilator
value. There were 985 patients included, with a mean prebronchodilator FEV 1 of 36.1% of predicted
normal.
Systemically administered bronchodilators, particularly aminophylline, have been

extensively studied, with differing results. In general, they add relatively little to inhaled
bronchodilator therapy in the short term. On average, there is a 10% improvement in
FEV1, with some reduction by dyspnea. The size of the effect varies from patient to
patient and includes some who benefit more than others. Though systemic
administration is likely to affect airways not reached by inhaled agents, this is apparently
of little clinical significance. The use of intravenous aminophylline in COPD
exacerbations is probably not justifiable (21). Use of aminophylline for purposes other
than bronchodilation in COPD has not been studied in large numbers of patients in the
long term.
Corticosteroids. Numerous studies show that some patients with stable COPD have
improvements in lung function when given anti-inflammatory corticosteroids. Responses
are substantial in a minority of patients and are most common when steroids are given
systemically in large doses (22). The long-term therapeutic implications of these
findings have not been explored adequately. It is not clear how reproducible steroid
responses are in a given patient with COPD nor whether steroids change the course of
COPD in steroid responders or unselected patients. The advent of high-dose inhaled
steroids has made steroid therapy safe and practical, and at present there are at least
three major clinical trials of these agents in COPD, one of them sponsored by DLD. The
results of these trials will be of great practical and theoretical interest.
Steroid responsiveness in COPD raises the issue of overlap between COPD and
asthma. Some investigators have found that patients with COPD who respond to
steroids have other features reminiscent of asthma, while other investigators have not. It
has been argued that people who respond to steroids should be designated asthmatic,
and the diagnosis of COPD reserved for those who do not. This argument assumes that
steroid responsiveness is an immutable patient characteristic, which has not been
demonstrated. Indeed, there is inferential evidence that this is not the case. Albert and
coworkers (23) showed that systemic steroids improved lung function in unselected
patients with COPD in acute exacerbations; others have confirmed these results (24).
These findings suggest that all or most COPD patients are “steroid responders” during
acute exacerbations, which is not the case in stable COPD. It is possible, therefore, that
patients who do not respond to steroids when stable do so when in exacerbation. This
hypothesis warrants further investigation.
Antibiotics for exacerbations. Acute exacerbations of symptoms of COPD are often

accompanied by increased sputum volume and purulence that suggest infection of the
airways. Treatment of exacerbations with broad spectrum antibiotics is common, and
the balance of the evidence indicates that such treatment improves the quality of life by
speeding symptomatic recovery (25). However, the effect is by no means dramatic and
it is difficult to use these data to argue a purely bacterial origin of exacerbations. Most of
the acceptable studies of this issue were completed more than 10 years ago and used
relatively unsophisticated agents. It is not known whether the organisms involved in
exacerbations have changed or whether newer antibiotics offer advantages.
It is worth noting that neither the causes nor the consequences of COPD exacerbations
are known. The effects of antibiotics and of immunostimulatory agents (26) suggest that
exacerbations are in part infectious, a hypothesis supported by the benefits of flu
vaccine. However, steroid responses in exacerbations may imply other mechanisms. As
to consequences, the studies of Fletcher and colleagues (7), mentioned previously,
showed that exacerbations did not alter the long-term course of COPD in a relatively
normal population. They did not study individuals with severe airways obstruction,
among whom it is axiomatic that some will develop respiratory failure and die during
exacerbations.
Oxygen. The first DLD-sponsored multicenter clinical trial in COPD concerned home

oxygen therapy (27), comparing nocturnal treatment (about 12 h/d) with continuous
treatment (about 19 h/d). This trial, known as NOTT (Nocturnal Oxygen Therapy Trial),
concluded at about the same time as a British Medical Research Council (MRC)-
sponsored trial (28) that compared 15 h/d of oxygen therapy with none at all. Entry
criteria for the two trials were similar, involving COPD patients with chronic, stable
hypoxemia, and the results were strikingly congruent. Oxygen therapy prolonged life,
and the more continuous the therapy the larger the effect (Figure 3).
Fig. 3.Results of North American and British trials of home oxygen therapy in hypoxemic chronic
obstructive pulmonary disease. In both cases, survival is plotted against time of follow-up. The
British trial (top panel ) (see Reference 28) compared no oxygen with 15 h of oxygen per day. The
North American trial (bottom panel ) (see Reference 27) compared 12 h of nocturnal oxygen
(squares) with an average of 19 h per day (circles).
These trials had a major impact upon the treatment of patients with COPD. They
established oxygen therapy for advanced COPD as state of the art, and the DLD entry
criteria were widely adopted as requirements by third-party payers for oxygen therapy.
The success of NOTT gave both the pulmonary community and DLD confidence to
initiate other multicenter trials in COPD. Finally, it is remarkable how well the results of
the MRC and National Institutes of Health (NIH) trials have stood up. Indeed, although
they were accomplished nearly 20 years ago, little of importance in regard to oxygen
therapy has been learned since. The role of oxygen therapy has not been well worked
out in episodic hypoxemia, such as that occurring during sleep and exercise. A recent
Polish trial re-examined oxygen therapy in COPD patients with less severe hypoxemia
than those of the original trials, and found no survival benefit (29).
Nonpharmacologic therapy. Pulmonary rehabilitation for patients with COPD has a long

and controversial history. Broadly speaking, the term refers to patient education and
exercise training, and its supporters believe that it improves exercise tolerance and
quality of life (30). There is little doubt that these benefits can occur, and that they can
outlast the program (31). There are problems, however, in assessing the cost-
effectiveness of such programs, since the benefits are modest on average and the
therapeutic effort may be large (32). Further, it is not entirely clear which component(s)
of a particular program are responsible for the improvement, although most believe it is
the exercise training. If an inexpensive variety of pulmonary rehabilitation could be
shown to be effective, it would be widely adopted.
The ground-breaking work of Macklem drew attention to the fact that COPD
compromises the function of the muscles of inspiration and that the state of these
muscles may determine quality of life and survival. Two therapeutic avenues were
suggested: training the inspiratory muscles so that they performed better, and resting
them on the assumption that they were fatigued. Many investigations of inspiratory
muscle training using a wide variety of techniques showed that task-specific
improvements in inspiratory muscle function were attainable, but that these did not
translate well into improvements in the quality of life (33), rather as if the disease itself
trained the muscles for breathing. Resting the inspiratory muscles was the subject of a
DLD-sponsored clinical trial. Stable patients with COPD were given daily periods of
negative pressure (tank) ventilation. Results showed that it is extremely difficult to
accomplish this in the home and that it had no discernible benefit (34). Thus, it
appeared that inspiratory muscle fatigue was not an important feature of stable COPD,
though in other situations such fatigue might be crucial.
Two surgical procedures have been recommended for COPD: lung transplantion and
volume reduction. The former is impractical in the vast majority of patients with COPD,
who are elderly and infirm. Volume reduction surgery offers promise in that it appears
capable of effecting improvements in ventilatory function that are not achieved by
medical management (35). Patient selection and surgical technique have not been
standardized, however, and results are not predictable. Much important data will
doubtless emerge from the current multicenter study, National Emphysema Treatment
Trial (NETT), sponsored jointly by NHLBI and Health Care Finance Administration.
PATHOGENESIS OF EMPHYSEMA
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Definition of Emphysema
A workshop of the DLD provided the generally accepted definition of emphysema as “a

condition of the lung characterized by abnormal, permanent enlargement of airspaces
distal to the terminal bronchiole, accompanied by destruction of their walls, and without
obvious fibrosis” (36). This definition is useful, but several aspects merit comment. First,
emphysema appears to begin as an increased number and size of holes in alveolar
walls so that destruction of entire alveolar septa must be a process that occurs in stages
(37). Second, disruption of alveolar attachments to small airways is an important
additional site of tissue destruction occurring during the loss of alveolar septal tissue,
and likely important in the mechanism of reduced maximal airflow associated with
emphysema (38). Third, the relationship between enlarged airspaces and lung function
is not clear-cut. Increased lung compliance and decreased diffusing capacity correlate
more closely with microscopic abnormalities of alveolar walls than with the presence of
enlarged airspaces (39). Fourth, increased collagen in both human emphysema (40, 41)
and smoke-induced experimental emphysema (42) suggests that the evolution of
emphysema involves both destruction and synthesis of extracellular matrix.
Historic Note
Emphysema has been known for two centuries at least, but plausible ideas about its
pathogenesis did not appear until the early 1960s, when researchers in Sweden and the
United States made discoveries that have become the cornerstone of current thinking.
One was discovering α1-AT deficiency and its association with emphysema. The other
was finding that lesions resembling human emphysema could be induced with
proteolytic enzymes in experimental animals.
α1-Antitrypsin deficiency. While surveying serum protein electrophoresis patterns of

about 1,500 clinical specimens in Malmo, Laurell and Ericksson (43) noticed five without
the usual distinctive band in the α1 zone. Because α1-AT accounts for the sharply
staining band in the α1 zone, although it is not the only protein there, they reasoned and
demonstrated that these five samples were deficient in α 1-AT. Three of the subjects had
emphysema, leading them to comment, “The clinical material is too small to warrant any
definite conclusions concerning possible connections between the α 1-AT deficiency and
the patient's clinical pictures. It is, however, striking that three of the patients had
widespread pulmonary lesions and that the sister of one had the same lung disease and
obviously the same plasma protein deficiency.”
Shortly after the initial report, Eriksson (44) demonstrated three groups of values of α1-
AT: values corresponding to normal; values about 60% of normal; and values less than
10% of normal in a single family. These findings pointed definitively to genetic
inheritance of the deficiency and to heterozygous and homozygous states. In two of the
individuals with marked deficiency, aged 38 and 48, there was COPD with
hyperinflation. In a large series of deficient subjects and their families, reported in 1965,
Eriksson (45) confirmed the trimodal distribution of α1-AT and conclusively linked the
deficiency with early-onset COPD.
The first five deficient subjects revealed the pulmonary spectrum of α 1-AT deficiency.
Symptomatic emphysema was present in three, who were 35, 38, and 44 yr of age.
Early- onset emphysema has become one of the leading clues to the presence of the
deficiency. On the other hand, two subjects did not have clinical lung disease, including
a woman in her seventies. Similar variability in the occurrence of COPD has been
observed ever since (46). Marked α1-AT deficiency is not necessarily associated with
emphysema and a shortened life span. Because smoking is now known to accelerate
COPD in α1-AT deficiency, it seems likely that the first elderly, asymptomatic individual
never smoked. The Registry for Patients with Severe Deficiency of Alpha-1-Antitrypsin,
sponsored by the NHLBI, has completed its data collection and will be reporting on the
clinical and laboratory course of this group of 1,129 individuals, the largest cohort with
the deficiency (47).
Besides discovering α1-AT deficiency and recognizing the clinical features, Laurell and
Ericksson (43) also concluded that the deficiency is not rare, that it is probably an
inherited defect, and that the α1-AT protein in deficient subjects has a structural
abnormality because it migrated slower than the normal protein upon electrophoresis.
They have been proven correct in each of these conclusions.
Papain-induced emphysema. In 1964, Gross and colleagues (48) in Pittsburgh reported

enzymatically produced emphysema. This result was uncovered in a project designed to
test the effects of proteolytic enzymes on developing silicotic pulmonary nodules.
Papain, a plant-derived proteinase, or chymotrypsin was injected intratracheally into rats
exposed to quartz dust in inhalation chambers. Animals that received papain developed
centriacinar emphysema; the other animals did not. Emphysema developed quickly
after papain and without apparent inflammation, suggesting a direct proteolytic effect on
lung tissue. Within a few years, other researchers reported marked changes in the
appearance of lung elastic fibers in enzyme-induced emphysema (49).
These initial studies linking emphysema to α1-AT deficiency and intrapulmonary

proteolytic enzymes triggered a burst of research activity, and an international
symposium convened on the topic of pulmonary emphysema and proteolysis in 1971.
The participants accepted a connection between proteases and emphysema and
agreed that α1-AT deficiency presented an important model to dissect the pathogenesis
of emphysema, even though most individuals with emphysema do not have the
deficiency. Eugene Robin, the conference summarizer, noted “the growing maturity of
the discipline of chest disease as one capable of assimilating and using all the basic
disciplines of biology” (50). Indeed, studies into the pathogenesis of emphysema have
helped with the entry of modern cell and molecular biology into lung research generally.
The DLD has played a major role in these developments in many ways, including
support of the first international meeting on elastin and its successor, the Gordon
Research Conference on Elastin and Elastic Tissue, that has been held every 2 years
over the past two decades.
Proteinase–Antiproteinase Hypothesis
The idea that emphysema results from proteolytic injury to alveolar septa has been the
prevailing hypothesis about the pathogenesis of emphysema for the past three
decades. According to the proteinase–antiproteinase hypothesis, there is a steady or
episodic release of proteinases into the lung tissue capable of digesting structural
proteins of the lung. Normally, lung tissue is protected by a shield of proteinase
inhibitors, principally from the blood, but also synthesized locally. Emphysema results
when the proteinase-antiproteinase balance favors proteolytic activity. The importance
of elastin destruction followed recognition that elastolytic activity was required for
proteolytic induction of emphysema and by the finding that the capacity of different
papain preparations to cause emphysema correlated with their elastase activity (51).
The fact that neutrophil elastase was shown to be the principal target of α 1-AT (52)
further strengthened the connection between elastin and emphysema. Janoff (53)
prepared a comprehensive review of this topic in 1985.
Lung elastin and elastic fibers. Emphysematous lung tissue has aberrant-looking elastic
fibers (54) and contains less elastin than normal lung tissue (40). Elastin is the principal
component of elastic fibers. Encoded by a gene on human chromosome 7, elastin is
secreted from several cell types as a soluble monomer precursor of approximately 70
kilodalton (kD) called tropoelastin. In the extracellular space tropoelastin molecules
align on a “scaffold” of microfibrils, which consist of a number of constituents including
fibrillins and microfibril-associated proteins. Under the action of lysyl oxidase, most of
the lysine residues in tropoelastin become modified, causing the tropoelastin monomers
to crosslink and form elastin, a highly insoluble, rubber-like polymer. The lysine-derived
crosslinks are known as desmosines.
Under normal circumstances, the synthesis of lung elastin begins late in fetal life, peaks
in the early neonatal period, continues to a much lesser degree during adolescence,
and stops in adult life, although the tropoelastin gene may remain transcriptionally
active (55). Elastic fibers in the lung normally last a human life span (56). Elastic fibers
are not distributed uniformly in the lung parenchyma. They loop around alveolar ducts,
form rings at the mouths of alveoli, and penetrate as wisps into alveolar septa, where
they are concentrated at bends and junctions (57). Therefore, destruction of entire
alveolar septa must affect matrix components besides elastin. Important in thinking
about the role of elastases in producing emphysema is that all elastases degrade
multiple components of the extracellular matrix in addition to elastin.
Because they are unique to elastin, desmosines have been used to quantify elastin in
tissues and as markers of elastin degradation in biologic fluids. Recently, in smokers
with marked variability in annual deterioration of FEV 1, urinary excretion of desmosine
was found to correlate with the rate of decline in FEV 1 (58). There was, however, no
correlation between emphysema as determined by computed tomography (CT) and
desmosine excretion. Although the sensitivity of CT to microscopic indices of
emphysema may be a limiting factor, these data suggest that desmosines can originate
from breakdown of elastin in small airways as well as lung parenchyma. Other studies,
however, using plasma peptides of elastin as the marker and indices of elastic recoil, do
show a relationship between increased elastin breakdown and emphysema (59).
What little is known about repair of lung elastic fibers in vivo is primarily from studies in
animals given intratracheal elastases. After intratracheal instillation of elastase, much of
the lung elastin is depleted within hours to a few days (60). This phase is followed by a
burst of elastin synthesis so that over the next few weeks the elastin content of the
lungs is restored. Yet, the lung is emphysematous and the alveolar elastic fibers look
abnormal (61), resembling the aberrant alveolar elastic fibers in human emphysema
(54). Accordingly, restoring the elastin content of the lung does not restore normal lung
architecture in this experimental model. This result is not surprising considering that
production of an elastic fiber is complex, involving temporal and physical coordination of
expression of tropoelastin, microfibrillar proteins, and lysyl oxidase.
An intriguing recent finding was restoration of normal alveoli in elastase-induced

emphysema by treatment with retinoic acid (62). This result was achieved in adult male
rats, an animal that has continued lung growth throughout life, unlike people.
Verification in other species and elucidation of the mechanisms involved in producing
alveolar repair in adult lungs could prove extremely valuable.
Elastases, elastin destruction, and the absence of fibrosis dominate thinking about the
pathogenesis of emphysema, but experimental studies and data from human tissue
point to alveolar septal collagen destruction and aberrant collagen repair as part of the
emphysematous process (63). A diet including β-amino-proprionitrile (BAPN) to prevent
crosslinking of newly synthesized collagen, when given to hamsters along with
intratracheal elastase, resulted in worse emphysema with giant bullae than the same
dose of elastase without concomitant BAPN (64). Rats given intratracheal cadmium
chloride and dietary BAPN developed emphysema, but without BAPN the pulmonary
lesions resembled pulmonary fibrosis (65). In guinea pigs exposed to cigarette smoke,
emphysema was associated with a progressive increase in septal collagen after 6 and
12 mo. These experimental studies fit with findings of increased alveolar collagen and
focally thickened alveolar walls in human emphysema (41).
Elastases and anti-elastases in the lung. Recognition that elastic fiber destruction is

probably a central feature in the pathogenesis of smoking-induced emphysema has
focused attention on elastolytic enzymes that might be involved. There are numerous
elastolytic enzymes in lung (Table 1). Establishing their relative importance in the
pathogenesis of emphysema is still not resolved. Knowing which enzyme(s) is involved
is essential to develop proteinase inhibitors that may be useful clinically, because
elastases of different enzyme classes require different inhibitors.
Table 1. ELASTASES IN THE LUNG
Matrix Substrates Other Relative Elasto

Enzyme Cellular Source
Than Elastin Activity (pH 7.5
Neutrophil Neutrophil
Basement membrane †
100
elastase (monocyte) *
Proteinase 3 Neutrophil (monocyte) Basement membrane †

40
Neutrophil (monocyte) 20

Cathepsin G Basement membrane †
(mast cell)
Macrophage, Denatured collagens, types 30

Gelatinase B
neutrophil, eosinophil IV, V, and VII collagens
Macrophage 35
Macrophage Basement membrane †
elastase
Cathepsin L Macrophage (Inactive at pH 7.5) 0
Cathepsin S Macrophage (Unknown) 80

*
Parenthesis denotes minor cellular source.
†
Susceptible basement membrane components include laminins, entactin, and type IV collagens.
Although neutrophil elastase is almost surely pivotal in emphysema associated with α 1-

AT deficiency, it is much less certain whether neutrophil elastase has a central role in
emphysema that develops in smokers with normal levels of α 1-AT. Some facts support a
role for it. Increased neutrophil elastase is detectable in bronchoalveolar lavage
immediately after smoking (66), and neutrophil elastase has been detected in
emphysematous tissue (67). The possibility that the smoker's lungs have a local
deficiency of functional α1-AT because smoke oxidizes α1-AT in vitro was an attractive
early hypothesis, but data about this subsequently have been inconclusive.
Recently, alveolar macrophages have come under increasing attention to help explain
emphysema in the typical smoker who has a normal circulating level of α 1-AT. Alveolar
macrophages are strong candidates because smoker's lungs contain a greatly
expanded number of macrophages and because they produce several proteolytic
enzymes with elastase activity, including macrophage elastase, gelatinase B, and
cathepsins L and S. Correlations of alveolar wall destruction in smokers demonstrate a
relationship with the number of alveolar macrophages and T lymphocytes, but not with
neutrophils (68). Young adult smokers have macrophage aggregations in respiratory
bronchioles, the site where emphysema typically begins (13).
One means of pinpointing the enzymes responsible for emphysema is targeting the
genes that code for proteinases in experimental models (69). Using this approach,
recent results show an important role for macrophage elastase, a matrix
metalloproteinase, in smoke-induced emphysema in mice. Mice lacking a functional
macrophage elastase gene as a result of targeted mutagenesis did not develop
emphysema from cigarette smoke exposure under conditions that produced
emphysema in mice and a functional macrophage elastase gene (Figure 4) (70).
Macrophage elastase is not inhibited by α1-AT.
Fig. 4.Mice with the normal expression of macrophage elastase (MME +/+), but not mice deficient in
macrophage elastase (MME –/–), develop emphysema in response to cigarette smoke (two
cigarettes/day, 6 d/wk for 6 mo). The lungs were inflated by intratracheal administration of 10%
formalin under constant pressure, 25 cm H2O. The MM +/+ lung from a smoke-exposed mouse has
centriacinar dilitation of alveolar ducts compared with the MME +/+ non-smoker mouse. In contrast,
the lung of the smoke-exposed MME –/– mouse resembles the lung of the MME −/− non-smoker
mouse. (Courtesy of Steven D. Shapiro, M.D.) (Data adapted from Reference 70.)
As noted, the history of human deficiency of α1-AT began in 1963. Since then, the
progress in understanding α1-AT over the past three decades has been remarkable, and
stands as a shining example of medical science's capacity to unravel basic aspects of
human disease (71). Several rare α1-AT phenotypes are now known to be associated
with low plasma concentrations and a high risk for emphysema, but the Pi Z phenotype
originally identified by Laurell and Erikkson accounts for nearly all the patients with
marked deficiency. Individuals with the Pi Z phenotype have about 15% of the normal
plasma α1-AT concentration. The Pi Z α1-AT protein has a slower association rate with
neutrophil elastase than does normal α1-AT (72), so that the Pi Z phenotype has a
protein that is less effective than normal in addition to the deficiency. The threshold for
the circulating level of α1-AT above which there is little increased risk for emphysema
without the aggravating effective smoking appears to be about 37% of normal (∼ 88
mg/dl). This value comes from finding that Pi SZ heterozygotes who typically have
about this level of α1-AT usually have FEV1 values above 80% of predicted normal if
they have never smoked (73).
With the exception of α2-macroglobulin, each proteinase inhibitor in the lung has activity
that is restricted to one class of proteolytic enzymes (Table 2). Like α1-AT, α2-
macroglobulin is produced primarily in the liver. The other inhibitors are produced
mainly locally in the respiratory tissues. Their relative contributions to protection against
alveolar septal destruction associated with smoking is not known, but the recent data
incriminating macrophage elastase in mice with smoke-induced emphysema, mentioned
previously, suggests that inhibitors of matrix metalloproteinases may prove to be
important.
Table 2. PROTEINASE INHIBITORS IN THE LUNG
Inhibitor Cellular Source Proteinases Inhibited
α -AT
1 Hepatocyte (macrophage) *
Serine †
Large airway epithelium, type II

SLPI Serine ‡
pneumocytes
Elafin Large airway epithelium Serine
α- Matrix metalloproteinase, serin

Hepatocyte, fibroblast (macrophage)
2
Macroglobulin cysteine
TIMPs Macrophage, lung parenchymal cells Matrix metalloproteinase
Cystatin C Airway epithelium (macrophage) Cysteine

Definition of abbreviations: α1-AT = alpha-1-antitrypsin; SLPI = secreted leukocyte protease inhibitor;
TIMPs = tissue inhibitors of metalloproteinases.
*
Parenthesis denotes minor cellular sources.
†
α1-AT has greater affinity for NE than proteinase 3 and cathepsin G.
‡
SLPI does not inhibit neutrophil elastase.
In brief, over the past 30 years a picture of the pathogenesis of emphysema in smokers
has emerged that stresses proteolytic activity against extracellular matrix proteins.
Damage to elastic fibers in the lung parenchyma appears to be a critical event, but the
destruction of alveolar walls clearly affects other extracellular matrix components in the
lung parenchyma as well. Repair, reflected in collagen deposition, also seems to occur
coincident with alveolar septal destruction and may help check alveolar overdistention.
CONCLUDING COMMENTS
Section:
Choose
Much of the progress in understanding and treating COPD during the past 30 years is
ascribable to the NHLBI and DLD. It must be noted that even “negative” efforts, such as
the investigation of small airways disease and the trials of artificial ventilation and
intermittent positive pressure breathing, yielded large amounts of data of value to both
clinicians and investigators. However, COPD is now the fourth leading cause of death in
the United States and exacts an enormous toll in terms of morbidity and health care
resources in industrialized countries worldwide. Accordingly, the problem is by no
means solved; we still need better understanding of pathogenesis and more effective
therapy.
It is important to recognize that the problem is eminently soluble simply by changing the
population's smoking habits. This is, of course, easier said than done, but smoking is
decreasing in North America and western Europe. Though overall mortality has not
declined, the age of death from emphysema has increased steadily, as has the age of
onset of clinically severe disease. People are living long enough to develop COPD who
did not do so previously, and the cohorts of men who began smoking 50–75 yr ago, and
who had very heavy exposure to tobacco, are working their way through the population.
Thus, in North America and western Europe we may expect that COPD will be a less
important problem in the future than it is at present. In contrast, in developing countries
where both life expectancy and cigarette smoking are increasing, COPD will become an
important problem.
A revolution in concepts about the pathogenesis of emphysema has occurred during the
past 30 years. The discovery of α1-AT deficiency led to the idea that emphysema
resulted from enzymatic digestion of lung extracellular matrix. Details became available
about the inhibitor profile of α1-AT that made neutrophil elastase the principal candidate
enzyme. More recent studies have revealed a higher level of complexity, with several
enzymes and inhibitors present in lung tissue that might be involved in the development
of emphysema. Although clinical emphysema is found almost exclusively among
smokers, many smokers do not develop emphysema, and the reasons remain to be
determined. Genetic factors are certain to be important, both in the development of
emphysema from smoking in some individuals and the apparent resistance to this effect
of smoking in others (74). The tools of cell and molecular biology will surely be used
increasingly to identify factors involved in the pathogenesis of emphysema.
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https://www.atsjournals.org/doi/full/10.1164/ajrccm.157.4.nhlbi-12
Disease progression in young

patients with COPD: rethinking the
Fletcher and Peto model
Pablo Sanchez-Salcedo, Miguel Divo, Ciro Casanova, Victor Pinto-Plata, Juan P. de-
Torres, Claudia Cote, Carlos Cabrera, Jorge Zagaceta, Roberto Rodriguez-Roisin, Javier
J. Zulueta, Jose Maria Marin, Bartolome Celli
European Respiratory Journal 2014 44: 324-331; DOI: 10.1183/09031936.00208613
 Article
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Abstract
Chronic obstructive pulmonary disease (COPD), although frequent in older individuals, can also occur at
younger age; this latter population has not been well described.
We reviewed the functional progression of 1708 patients with COPD attending pulmonary clinics. Those with
three or more annual spirometries were divided into those who, at enrolment, were ≤55 (n=103) or ≥65
(n=463) years of age (younger and older COPD, respectively). Baseline and annual changes in lung function
(forced expiratory volume in 1 s (FEV1)) and BODE (body mass index, airflow obstruction, dyspnoea, exercise
capacity) score were recorded and compared between both groups.
Severity distribution by Global Initiative for Chronic Obstructive Lung Disease and BODE scores were similar
in both groups, except for mild obstruction, which was higher in the younger group. Mean FEV 1 decline was
38.8 and 40.6 mL·year−1, while BODE scores increased 0.19 and 0.23 units per year, for younger and older
COPD, respectively. Both groups had similar proportion of FEV1 rapid decliners (42% and 46%, respectively).
The severity distribution and progression of disease in younger patients with COPD is similar to that of
patients of older age. This observation suggests that younger individuals presenting with COPD develop the
disease from an already compromised pulmonary and systemic status, complementing the model of steeper
decline of lung function proposed by Fletcher and Peto.
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Introduction
Chronic obstructive pulmonary disease (COPD) is a major public health problem [1, 2] that is projected to
become the third cause of mortality worldwide by 2020 [3]. It is characterised by persistent airflow limitation
that is thought to be progressive and to be diagnosed late in life, usually in individuals >65 years of age [4].
However, COPD can also be diagnosed at much younger age, and the clinical characterisation of this subgroup
has not been well established [4–7].
The traditional model of COPD progression was proposed by FLETCHER and PETO [8] more than 30 years ago
and describes disease progression as resulting from an accelerated decline in lung function in susceptible
subjects, resulting clinical COPD over a period of years. Recent publications have argued against this model,
showing that lung function change is heterogeneous, with the minority of patients actually having a rapid
decline while many patients manifest nonrapid decline and some even sustain improved lung function over
time [5, 9–13]. Most of these studies were based on sample populations with a mean age of 65 years [9–13].
We hypothesised that younger individuals presenting with clinical COPD could provide important information
regarding disease progression. To investigate this and as part of the BODE (body mass index, airflow
obstruction, dyspnoea, exercise capacity) cohort study of patients attending pulmonary clinics, we have
followed over time a large group of younger patients attending clinics because of COPD and compared their
progression with that of older patients with COPD followed during the same time, at the same location and by
the same personnel.
Methods
Subjects
Subjects were selected from the prospective, multicentre BODE cohort. The details of the inclusion and
exclusion criteria have been previously published [9, 14, 15]. In brief, the cohort included sequential patients
with COPD who attend pulmonary clinics in Tampa, FL, and Boston, MA, in the USA, and Pamplona,
Tenerife and Zaragoza in Spain between November 1997 and October 2011. COPD was diagnosed on the basis
of 20 pack-years of smoking history and a post-bronchodilator spirometry showing a forced expiratory volume
in 1 s (FEV1)/forced vital capacity ratio <0.7 following the American Thoracic Society/European Respiratory
Society standards [16]. Values from HANKINSON et al. [17] were used as reference for spirometric
measurements for the USA and those from ROCA et al. [18] for Spain. Patients were excluded if they had
asthma as defined by any of the following: history of asthma, wheeze, or >200 mL or >12% increase in
FEV1 after inhalation of 400 μg albuterol. The Global Initiative for Chronic Obstructive Lung Disease (GOLD)
2007 criteria were used for grading the disease severity [19]. The ethics committee at each centre approved the
study and all patients gave their informed consent [14].
Variables and follow-up
Age, and anthropometric and functional parameters were measured at baseline and at each yearly visit,
including spirometry, body mass index, distance walked in 6 min and dyspnoea score on the Modified Medical
Research Council scale. The BODE index was also recorded at each visit as previously described [14].
Medications were reviewed and tabulated. Comorbidities were also considered using the Charlson index.
For the current study, we selected those patients aged ≤55 and ≥65 years at enrolment (younger COPD and
older COPD, respectively). In each group, only those individuals who had baseline measurements and at least
two visits were considered for analysis (at least three measurements in total). This implied a minimum follow-
up of 24 and a maximum of 167 months.
Data analysis
Disease progression in each age group was assessed by calculating the annual change in their functional
parameters. Time series trend analysis was performed to estimate the individual slope of variables using at
least three measurements (mean number of spirometries was five). A linear model was used to estimate the
slope of the FEV1 decline and BODE index progression. Annual changes in FEV1 were expressed in absolute
values (millilitres per year) and as proportions (% predicted), whereas the BODE index change was expressed
as simple variations in units. The annual changes were also compared between the two study groups.
For the assessment of lung function decline, we defined “rapid decliners” as those subjects who had a loss of
≥40 mL FEV1 per year, according to ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive
Surrogate End-points) data [8]. Lastly, we stratified the two study groups by GOLD grades and BODE
quartiles (quartile 1: 0–2; quartile 2: 3–4; quartile 3: 5–6; quartile 4: 7–10) and compared their baseline
characteristics and disease progression. In order to increase the number of individuals with severe disease, we
unified GOLD grades 3 and 4 into a single group.
We used the two-sample t-test when comparing continuous, normally distributed variables between groups.
For non-normal variables, we used the Wilcoxon rank test or Chi-square test where appropriate. A p-value of
<0.05 was considered significant and 95% confidence intervals are reported when appropriate. All statistical
analyses were performed using JMP Pro 10.0 for Windows (SAS Institute Inc., Cary, NC, USA).
Results
Study population
From a total of 1708 subjects participating in the BODE cohort during the study period, there were 288 (17%)
patients ≤55 years and 911 (53%) individuals ≥65 years of age. From these groups, those with at least three
measurements were 103 and 463 patients, respectively (fig. 1). We compared the characteristics of those
patients with three or more clinical assessments with that of patients with only two measurements and the
results are shown in table E1 of the online supplementary material. The patients were similar in all
characteristics, except for the expected shorter follow-up time and fewer clinical assessments in the patients
evaluated only twice.
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Figure 1–
Consort diagram showing patient selection from the BODE (body mass index, airflow obstruction, dyspnoea,
exercise capacity) cohort. COPD: chronic obstructive pulmonary disease.
Baseline comparisons
The baseline characteristics of younger and older COPD are shown in table 1. Although there was a difference
in age of >20 years between the two groups, there was no difference in lung function at baseline (FEV 1 %
predicted) or in distribution of COPD severity between groups, except for GOLD grade 1, which was observed
in a larger proportion of patients in the younger population (p=0.002). The proportion of patients on
bronchodilators (short- and long-acting) or inhaled long-acting β-agonists and inhaled corticosteroids was
similar in both groups. The older patients showed worse BODE scores and more comorbidities. More patients
in the older age group were receiving statins and angiotensin-converting enzyme inhibitors (data not shown).
When divided into quartiles, the BODE index was equally distributed in both groups.
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Table 1–Baseline characteristics and disease progression in both study groups
Disease progression
The progression of COPD, whether determined by lung function or BODE index scores, was similar in the two
groups (table 1).
Lung function progression
The distribution of lung function and the mean annual lung function change in millilitres per year showed a
similar rate of decline in young and older patients (fig. 2a and b). The mean±SD rate of decline was 38.8±93
mL·year−1 and 40.6±96 mL·year−1, respectively (p=0.86). Similar behaviour was observed if the data were
expressed as FEV1 % predicted (p=0.80).
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Figure 2–
Distribution of the mean annual changes in lung function for each study group: a) younger and b) older chronic
obstructive pulmonary disease. c) Lung function progression expressed as forced expiratory volume in 1 s
(FEV1) % predicted, stratified by Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades (1, 2
and 3+4) and by age group, compared with the curve from FLETCHER and PETO [8] for smokers (FP).
The proportion of rapid decliners (≥40 mL·year−1) was similar in both groups (p=0.41). Interestingly, table
2 shows that the pattern of disease progression was similar in younger and older COPD when stratified by
baseline GOLD grade. Indeed, figure 2b shows that the mean rate of FEV1 decline stratified by baseline
GOLD grade was similar in the younger and older COPD subgroups when superimposed on the F LETCHER and
PETO [8] graph. The average annual rate of decline between rapid decliners was similar in younger and older
COPD (114±77 and 117±66 mL·year−1, respectively; p=0.85) (tables 3 and 4).
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Table 2–Baseline functional characteristics and annual changes in younger and older patients classified
by baseline Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade
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Table 3–Baseline characteristics in younger and older patients according to rapid or nonrapid lung
function decline
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Table 4–Annual change in characteristics in rapid and nonrapid decliners according to age
BODE progression
BODE scores increased (worsened) over time similarly in each age set (0.19±0.5 and 0.23±0.6 units per year,
p=0.42) and there was a wide distribution of changes (fig. E1). Mean annual BODE score progression was
maintained after stratification by disease severity (table 2). In the younger COPD group, the increase per year
was slightly higher in milder COPD grades, in contrast to the older COPD group, where no particular pattern
was noticed along the GOLD grades. After stratifying by BODE quartiles, the functional change over time had
no particular pattern (table E2).
When each BODE quartile was compared between the two study groups, no significant differences were found
in lung function decline rates or in BODE score progression, except in quartile 3, where younger patients had a
significantly lower rate of lung function decline (11±59 versus 43±79 mL·year−1, p=0.03) and less pronounced
progression in BODE score (−0.1±0.5 versus 0.28±0.7, p=0.01).
Discussion
This study expands the limited available information regarding young individuals presenting with clinical
COPD, not only in their baseline characteristics, but also their progression over time. In this study, 17% of
patients attending clinics were <55 years of age and, surprisingly, the clinical expression of the disease,
whether evaluated with lung function or multidimensionally with the BODE index, was similar to that of older
COPD patients. Furthermore, the progression over time, when stratified by baseline disease severity, was very
similar. The similar progression of disease independent of age of diagnosis suggests that the process has
developed in individuals with already compromised lung function, and that the idealised baseline take-off point
and subsequent pattern originally described by FLETCHER and PETO [8] may not apply to most patients with
COPD attending pulmonary clinics.
Few studies have described the clinical characteristics and progression of individuals diagnosed with COPD at
a younger age [4–7, 20]. HERSH et al. [6] studied 137 patients with an FEV1 <40% predicted who were
candidates for lung transplant. However, no description was made of the progression of lung function and there
was no comparison with older subjects with the disease. A subsequent cross-sectional study of 2500 subjects
[4] compared 70 patients with early-onset COPD (FEV1 <50% predicted and age <55 years) with 306 patients
with the same degree of airways obstruction but who were >64 years of age, but there was no longitudinal
follow-up. A recent report by DRUMMOND et al. [5] of 5885 subjects in the Lung Health Study did evaluate
sequential lung function and outcomes in younger patients (49 years). However, the inclusion criteria only
considered individuals with mild COPD (FEV1 55–90% predicted) and 21% of the subjects did not have
COPD. Furthermore, no analysis by individual rate of FEV1 decline was performed. The most important
conclusion was that subjects with lower lung function at baseline lost lung function at a steeper rate. Finally,
MORICE et al. [7] noted that 356 patients of the >5800 enrolled in the UPLIFT (Understanding Potential Long-
term Impacts on Function with Tiotropium) study were <50 years of age. Although that work did not explore
differences in rate of decline between young and older patients, it did show that in patients with COPD, the
distribution of airflow obstruction severity by GOLD category was similar irrespective of age. To our
knowledge, ours is the first report to compare the progression of disease in younger and older patients
encompassing the whole spectrum of mild to very severe COPD.
The fact that the proportion of patients with similar degree of impairment measured by lung function or BODE
index is similar in younger or older patients is difficult to reconcile with the FLETCHER and PETO [8]
theoretical framework of COPD progression because we would expect that if the individuals started from the
same baseline, younger patients would have better lung function than older patients, but this does not occur.
An alternative explanation could be selection bias, where the younger patients are seen early and, thereby,
decrease their contribution to the older cohort, because they would die prematurely. However, the findings
from the longitudinal follow-up, where younger patients had a lower mortality rate, as shown in table 1, argue
against this possibility.
The second and most important contribution of this study is derived from the long-term follow-up (a median of
50 and 62 months for the two groups). As can be seen in table 2, and figure 2a and b, the rate of FEV1 decline
was almost equal and parallel for both groups at all baseline GOLD grades (fig. 2c). This suggests that the
severity of COPD is already established at a young age and that patients maintain their trajectory over time so
that the relative position at younger age determines their final position at an older age. Our findings are
consistent with the concept that some individuals just do not reach the optimal peak value of FEV 1 and may
actually have defective lung function to begin with, as was postulated by BURROWS [21] over three decades
ago. Some of the factors that have been thought to define altered early lung function include female sex,
maternal factors, race and, more importantly, poor airway function in early infancy, which is a known risk
factor for lower lung function in young adults [4, 22], which in turn is associated with airway obstruction 20
years later [23]. Our findings are in agreement with this hypothesis and support the need to move upstream for
early case detection if we are to prevent ulterior deterioration of lung function.
The third finding is that stratification by GOLD grade revealed that those with a faster rate of decline had
milder disease in both age groups. This trend is similar to that of other publications in elderly patients
[9, 11, 24] and different from the “horse-racing effect” described in other studies, whereby those with the most
severe FEV1 impairment have faster FEV1 decline [5, 8]. Our results could be explained by the selection of
patients, where the BODE cohort is constituted by patients attending clinics and not evaluated in
epidemiological or clinical trials.
Data on the progression of BODE indexes or other functional parameters besides lung function in COPD
patients are limited [9, 25, 26]. When stratifying by BODE quartiles, the BODE progression maintained a slow
and steady increase. This suggests that the use of multiple dimensions helps smooth the acute variations of
individual variables and may provide a better comprehensive evaluation of COPD progression [27].
This study has strengths and limitations. We believe the most important aspect of this work is the first broad
and longitudinal description of patients of younger age. Not only does it provide information regarding their
baseline characteristics, but also their progression over time in a multidimensional approach. One potential
limitation would be the relatively small sample size. However, the total cohort size is four times larger than the
study by FOREMAN et al. [4] and HERSH et al. [6]. Furthermore, a power analysis assuming similar
FEV1 decline and variance showed that a sample size of 10 000 patients would still fail to reach statistical
significance. A second limitation is the fact that the BODE cohort is an observational study of patients
attending pulmonary clinics and, therefore, the results may not be necessarily applicable to all COPD
populations. Indeed, this is not a study to determine the incidence or prevalence of COPD but rather the
clinical behaviour of patients with the diagnosis. Thirdly, the spirometric confirmation of obstruction was
based on the fixed ratio criterion and, thus, may overestimate disease prevalence in the elderly. However, this
should not affect the rate of decline or the distribution of severity, which was based on normative values for
the population. In addition, we calculated individual slopes of FEV 1 and the precise description of spirometric
changes over time can be influenced by many different factors. However, the mean number of spirometries
was five and this should provide a reliable value for its interpretation [27, 28]. Finally, the significant baseline
differences found between our study groups (sex, follow-up in months, smoking status, GOLD 1 distribution,
Charlson comorbidity index and number of clinical assessments) are inherent to the stratification by age.
Comparison of patients with a 20-year age difference is likely to show that younger individuals will have a
longer follow-up time and that older subjects will have a greater number of comorbidities [15]. It is also
expected that at a younger age there will be more active smokers and, with time, the proportion of individuals
who continue doing so would decay, with physicians emphasising smoking cessation. Regarding the
significant greater proportion of females in the younger COPD group, this is consistent with published data
that suggest an increased proportion of smoking in younger females [6].
In conclusion, our data suggest that the severity and activity of COPD seem to have the same distribution in
older and young individuals. We also show that younger patients with COPD do not suffer from a more
aggressive disease. The similar progression of disease independent of age of diagnosis suggests that the
process has developed in individuals with already compromised lung function and that the idealised baseline
take-off point and subsequent pattern originally described by FLETCHER and PETO [8] may not apply to the
majority of patients with COPD. More longitudinal studies of even younger individuals at risk are needed to
confirm these observations.
Footnotes
 For editorial comments see page 280.

 Earn CME accreditation by answering questions about this article. You will find these
at erj.ersjournals.com/misc/cmeinfo.xhtml
 This article has supplementary material available from erj.ersjournals.com
 Conflict of interest: None declared.
 Received November 29, 2013.

 Accepted March 15, 2014.
 ©ERS 2014
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https://erj.ersjournals.com/content/44/2/324
Several studies have assessed whether typical COPDsymptoms differ by sex. A number of
studies haveshown similar COPD symptoms between men andwomen. 56,57However, other
studies have reported morefrequent and/or more severe exacerbations and higherlevels of
dyspnea in women compared withmen.28,49,52,55,58-60Although further studies are required,a
higher prevalence of airway hyperresponsiveness inwomen than men may, at least partially,
account forsome of the variability between sexes in symptoms suchas dyspnea. 45,46
Gender Bias in the Diagnosis of COPD

Author links open overlay panelChapmanKenneth R.MD, FCCPa
TashkinDonald P.MD, FCCPbPyeDavid J.PhDc
https://doi.org/10.1378/chest.119.6.1691Get rights and content
Background
COPD is thought to be more prevalent among men than women, a finding usually attributed to
higher smoking rates and more frequent occupational exposures of significance for men.
However, smoking prevalence has increased among women and there is evidence that women
may be more susceptible to the adverse pulmonary function effects of smoking than men. There
may also be underdiagnosis and misdiagnosis of COPD in both sexes because objective
measures of lung function are underused.
Objectives
We undertook the present study to determine if there is gender bias in the diagnosis of COPD,
such that women are less likely than men to receive a diagnosis of COPD. We also attempted to
determine if underuse of lung function measurements was a factor in any bias detected.
Methods
We surveyed a random sample of 192 primary-care physicians (96 American and 96 Canadian;
154 men and 38 women) using a hypothetical case presentation and a structured interview. The
case of cough and dyspnea in a smoker was presented in six versions differing only in the age
and sex of the patient. After presentation of the history and physical findings, physicians were
asked to state the most probable diagnosis and to choose the diagnostic studies needed.
Physicians were then presented with spirometric findings of moderate or severe obstruction
without significant bronchodilator response, and the questions repeated. Finally, the negative
outcome of an oral steroid trial was described.
Results
Initially, COPD was given as the most probable diagnosis significantly more often for men than
women (58% vs 42%; p < 0.05). The likelihood of a COPD diagnosis increased significantly and
initial differences between sexes decreased as objective information was provided. After
spirometry, COPD diagnosis rates for men and women were 74% vs 66% (p = not significant);
after the steroid trial 85% vs 79% (p = not significant). Only 22% of physicians would have
requested spirometry after the initial presentation.
Conclusions
In North America, primary-care physicians underdiagnose COPD, particularly in women.

Spirometry reduces the risk of underdiagnosis and gender bias but is underused.
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Key words
asthma
misdiagnosis
physician decision making
spirometry
underdiagnosis
The authors received a research grant-in-aid from Boehringer Ingelheim Canada Ltd and
Boehringer Ingelheim Pharmaceuticals Inc.
View full text
Lung India. 2009 Jul-Sep; 26(3): 63–69.

doi: 10.4103/0970-2113.53226
PMCID: PMC2862508
PMID: 20442838
Validation of a structured questionnaire for

COPD and prevalence of COPD in rural area
of Mysore: A pilot study
P. A. Mahesh, B. S. Jayaraj, S. T. Prahlad, S. K. Chaya, A. K. Prabhakar, A. N. Agarwal,1 and S.
K. Jindal1
Author information Copyright and License information Disclaimer
This article has been cited by other articles in PMC.
Go to:
Abstract
Background:
The prevalence of chronic obstructive pulmonary disease (COPD) is increasing in India and
there is a need to study the prevalence of COPD, particularly in the rural areas, which may be
most affected due to their lifestyle.
Materials and Methods:
First stage: Validation of the questionnaire–105 consecutive patients underwent administration of

the structured questionnaire and spirometry was used as a gold standard for the diagnosis of
COPD. Second stage: Adults above 40 years (n = 900) in two villages of Mysore district were
administered with the validated questionnaire, Knowledge and Attitude questionnaire and
Fagerstorm questionnaire, to assess nicotine dependency.
Results:
The questionnaire was found to have a sensitivity of 62.5% and specificity of 87.6% to diagnose
COPD. Of the total 900 adults surveyed (Males: 453, Females: 447), the total prevalence of
COPD was 7.1%. Males had a higher prevalence (11.1%) compared to females (4.5%). The
prevalence of smoking was very high among men at 71.9% and all the women were nonsmokers.
The prevalence of COPD was 14.7% in smokers, 19.3% had mild to moderate nicotine
dependency and 12.8% were highly dependent. Of the women exposed to regular biomass fuels,
the prevalence of COPD was 3.9%, which increased to 4.8% on addition of regular passive
smoking. In smoking, male gender and age were significantly associated with COPD (P < 0.05).
Conclusion:
The structured questionnaire is a useful tool for the screening of COPD in field studies. Smoking
and biomass fuel exposure are important risk factors for COPD.
Keywords: Biomass fuels, chronic obstructive pulmonary disease, nicotine dependence,

prevalence, screening questionnaire
Go to:
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is an important cause of morbidity and
mortality. It is listed as the fourth leading cause of death worldwide.[1] The estimates for 2020,
predict an even further increase in the number of people suffering from the disease.[2] India is
one of the countries identified to have a significant increase in the burden of tobacco related
mortality.[2]
There is a paucity of data regarding the prevalence and socioeconomic burden of COPD
available in India. Only few population-based surveys have been carried out in India so far. India
is a heterogenous country and it is important that different regions are represented in prevalence
studies. In one of the pioneering studies in India, a large multicentric general population based
survey[3] was undertaken using a structured questionnaire in adults (aged more than 35 years)
and discovered that the prevalence of COPD was 4.1%. A total of 35,295 subjects in Bangalore,
Chandigarh, Delhi, and Kanpur, were studied using uniform methodology and a standardized
questionnaire. A prevalence of 5% in males and 3.2% in females was observed.
Prior to this study, there were only few single center studies,[4–13] most of which were
conducted in North India. Only two studies[7,13] were conducted in Tamilnadu, South India.
Prevalence rates varied from 2-22% in males and 1.2-19% in females. In 1964, Wig et al.,[4]
compared the prevalence of rural and urban chronic bronchitis, smoking, and related factors. The
prevalence rates in urban and rural areas were similar, approximately 10%. The prevalence rates
for people above 55 years were 17% (for males) and 12% (for females), with a male
preponderance. Bhattacharya[6] studied chronic bronchitis in rural population (aged above 30
years) and found the prevalence of chronic bronchitis to be 57/1000, with male preponderance.
Overall prevalence is greater in males due to higher prevalence of smoking. Malik[11] found that
bidi smokers had decreased lung functions and 13.55% of them had chronic bronchitis. In a
community-based study, Jindal[12] found prevalence of COPD to be 5% in males and 2.8% in
females. It was similar in both sexes, depending upon who were nonsmokers. Ray et al.,[13]
found age specific prevalence of 33.0/1000 (40.8/1000 in males and 22.5% in females) in people
above 30 years; all female were nonsmokers. Behera et al.,[14] studied effects of various fuels in
rural homes of Chandigarh and observed the prevalence of COPD as 11.9%.
The present study was conducted as a pilot study for the validation of a structured questionnaire
for the diagnosis of COPD in our population to estimate the prevalence of COPD in adults in
rural Mysore and to identify the importance of risk factors associated with COPD and assess the
knowledge and attitudes regarding smoking and nicotine dependence among smokers.
Go to:
MATERIALS AND METHODS

The study was carried out in two stages. In the first stage, a structured questionnaire that would
be used in the field was validated and its diagnostic utility was determined. In the second stage,
all the adults in two villages of Mysore district were administered the questionnaire as a pilot
study to estimate the prevalence of COPD. A knowledge, attitude questionnaire and Fagerstorm
questionnaire were also administered in the same population.
The structured questionnaire developed by Dr. Jindal for field studies which was validated in
earlier studies, was utilized. The questionnaire elicited information on the demographic data and
various respiratory symptoms; and a detailed analysis of the most important risk factors for
COPD, tobacco smoking, passive smoking and exposure to biomass fuels, relevant to the rural
population.
The validation in the present study was carried out on 105 consecutive adult patients, able to
perform spirometry according to the American thoracic society (ATS),[15] criteria and were
administered this questionnaire. The questionnaire was translated into the local language
according to standard procedures for translation and back-translation. The respiratory nurse was
trained to administer the questionnaire. The questionnaire was read out to the patient in exactly
the same order as listed and sufficient time was given to the patient to respond to the questions.
If the patient did not understand the questions, it was repeated; and if he was still doubtful, it was
recorded as “No”. The respiratory nurse was unaware of the spirometry results while
administering the questionnaire. The patients who underwent spirometry included patients with
COPD, asthma, interstitial lung disease, bronchiectasis, and posttubercular sequelae, allergic
rhinitis, evaluation of cough, dyspnea, preoperative evaluation or were normal. Spirometry was
performed according to the ATS criteria.[15] After spirometry, the COPD patients were graded
according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD)[16] criteria.
The diagnostic utility of the questionnaire was assessed by calculating sensitivity, specificity,
positive predictive value, negative predictive value, and accuracy. The COPD diagnosed
according to the GOLD[16] criteria was taken as the gold standard for the above calculations.
The validated questionnaire was used for screening the COPD cases in the second stage
prevalence study. In addition, a questionnaire for assessing the knowledge regarding the adverse
health effects of tobacco smoking and attitude about smoking, and Fagerstorm questionnaire to
assess nicotine dependence, were administered to all the smokers. The study was conducted in
two villages, Hadinaru and Suttur, near Mysore city. All the adults above 40 years were included
in the study. The survey was conducted in the morning and evening to ensure compliance. The
household list was obtained from the gramsabha register. The houses were visited at least on
three occasions before declaring them as nonresponders. The questionnaire was administered by
the coauthor, in the same manner as described in the first stage.
Data analysis
The definition of COPD according to the structured questionnaire in the first stage was based on
presence of all the following factors–(i) age above 40 years, (ii) smoking status of above 10 pack
years or exposure to biomass fuels, (iii) presence of whistling in the chest or breathlessness, or
early morning cough for at least three months in an year, for at least two consecutive years.
The definition of COPD according to the GOLD guidelines[17] was based on spirometry. Stage
I-FEV1 >80% with FEV1/FVC <70%; stage II-FEV1 50–80% predicted, FEV1/FVC <70% with
or without symptoms; stage III-FEV1 30–49%, FEV1/FVC <70% with or without symptoms;
and stage IV-FEV1 <30% predicted, FEV1/FVC <70% or FEV1 <50% with chronic respiratory
failure.
Other diseases were diagnosed with appropriate investigations. Asthma was diagnosed according
to GINA[18] criteria; ILD and bronchiectasis were confirmed with high resolution CT scan; and
posttubercular sequelae were confirmed with past history of tuberculosis, negative sputum smear
for AFB and radiological evidence.
True positives were those “COPD cases” identified by both, the spirometry as well as the
questionnaire. True negatives were those classified as “not a COPD case” by both, the
spirometry as well as the questionnaire. False positives were those identified by only the
questionnaire, but not by spirometry; and false negatives were those identified by spirometry, but
not by the questionnaire. Sensitivity, specificity, positive predictive value (PPV), negative
predictive value (NPV), and accuracy were calculated according to the standard methods.
In the second stage, prevalence of COPD was calculated as the number of subjects categorized as
having COPD divided by the total number of subjects surveyed. Potential risk factors for COPD
such as smoking, exposure to biomass fuels, and passive smoking were categorized based on the
information available from the questionnaire. The percentage of subjects correctly answering the
knowledge questions and their attitudes towards smoking were noted. A Fagerstorm
questionnaire[19] score of 6 or less indicated mild to moderate nicotine dependence and above 6
indicated severe nicotine dependence.
Go to:
RESULTS
In the first stage, 105 consecutive patients underwent spirometry and were administered the
structured questionnaire by a trained respiratory nurse. Sixteen of these subjects were suffering
from COPD. The remaining subjects were normal,[11] suffering from allergic rhinitis and
postnasal drip[20] and underwent spirometry for evaluation of cough, had asthma, restrictive
lung diseases[5] including interstitial lung disease (pulmonary) or ascites (extra pulmonary),
bronchiectasis and posttubercular sequelae,[2] underwent spirometry as a preoperative
evaluation[13] or had spirometry as an evaluation of sensation of breathlessness due to anxiety.
[3] Spirometry was used for the confirmation of COPD according to the GOLD criteria. Out of
16 patients, 10 belonged to GOLD stage II, 4 to stage III and 2 to stage IV. The mean age of the
subjects studied was 43.09 years (SD 17.47). There were 62 males and 43 females.
The structured questionnaire could identify 10 out of 16 cases of COPD identified by spirometry
giving a sensitivity of 62.5%. The specificity was 87.6%, PPV was 47.6%, NPV was 92.85%,
and overall accuracy was 83.8% [Figure 1]. The 10 cases which were correctly diagnosed as
COPD, were all males above 55 years and smokers. Of the 6 cases of COPD missed, 4 were
males (one smoker) and 2 were females. A total of 11 cases (males, smokers, and above 48
years), were wrongly categorized as COPD. These involved, 7 asthma, 1 posttubercular sequelae,
and 3 ILD cases. Seventy-eight cases were correctly classified as not having COPD. The
sensitivity of the questionnaire increased with increasing severity of COPD as assessed by the
GOLD criteria. It could correctly identify 5 of 10 COPD cases (50%) in stage II; 3 of 4 COPD
cases (75%) in stage III; and both the cases (100%) in stage IV.
Figure 1
Diagnostic utility of the COPD screening questionnaire
In the second stage, all the adults above 40 years in two villages, were administered the
questionnaire by one of the coauthors, a total of 900 adults were interviewed with 453 (50.3%)
males and 447 (49.7%) females. The response rate was 99.5%. The demographic characteristics
including age, occupation and smoking status of male [Table 1] and female [Table 2] subjects in
the study are presented. The proportion of subjects who ever smoked was 71.9%. Most of the
men had smoked more than 20 pack years (61.5%). The mean pack years in subjects smoking
more than 20 pack years were 48.02 (SD 25.73), and in those smoking less than 20 pack years
were 11.14 (SD 5.36). Beedis (96.9%) were the most co3mmon tobacco used. It was observed in
males that prevalence rate of COPD increase with increasing age and smoking (P < 0.05). The
prevalence of COPD in males aged 40-49 years was 5.68% and increased to 28.57% in those
aged more than 70 years. The prevalence of COPD in smokers who had smoked less than 20
pack years was 9.6%, which increased to 18% in subjects who smoked more than 20 pack years.
The predominant occupation in males was agriculture followed by manual labor. Very few
COPD cases were noted in nonsmokers. Most of the women in the study group were housewives
(81.4%), and a small number of women worked as unskilled laborers (8.7%) and in agriculture
(6.48%). Firewood was the most common domestic fuel used (91.95%) and most women had an
exposure of more than 20 years to biomass fuels (80.9%). There were no female smokers in the
study population. The proportion of females exposed to passive smoking at home was 55%. The
common respiratory symptoms in males (smokers and nonsmokers) and females elicited by the
questionnaire are given in [Table 3]. Cough and Sputum were the most common symptoms noted
in both males and females followed by breathlessness and wheezing. The overall prevalence of
COPD in the population interviewed was 7.1% of 900 subjects. It was 11.1% among men [Figure
2], 4.5% among women [Figure 3]. The prevalence was found to increase with advancing age. In
males, highest prevalence was seen in subjects aged 70 and above (28.7%). The highest number
of COPD cases in males was noted in the unemployed/retired group, which was due to the fact
that many subjects in this group were elderly. The prevalence among male smokers was 14.7%.
In females a similar trend was observed. Highest prevalence in females (above 70 years) was
noted at 7.35%. Among females, 91.95% were exposed to biomass fuels. Prevalence of COPD
among those who used biomass fuels without exposure to passive smoking was 3.9% and in
those exposed to both biomass fuels and passive smoking was 4.8%. People using other fuels
including kerosene were less in number and therefore no conclusions could be drawn. On
assessing the knowledge and attitudes of smokers in the rural population regarding the health
effects of smoking [Figure 4] it was observed that most of the people were unaware of the ill
effects associated with smoking. Approximately 24% smokers were aware that smoking caused
respiratory diseases and 12.3% were aware that smoking is associated with cancers. The attitudes
of the subjects towards smoking are summarized [Figure 5]. Most of the smokers smoked to
relieve stress (92.3%) and to keep company (76.3%). On educating about the adverse effects of
smoking, the number of patients willing to quit was 67.3%. On applying Fagerstorm
questionnaire for nicotine dependence, it was noted that 177 smokers (54.5%) had mild to
moderate nicotine dependence and 148 (45.5%) had severe nicotine dependence [Figure 6]. The
number of COPD cases in mild to moderate nicotine dependent subjects was 18 (10.16%) and in
severe nicotine dependent subjects it was 30 (20.3%). The mean Fagerstorm score among
patients with COPD was 6.29 (SD 2.76) and in patients without COPD it was 5.20 (SD 2.73).
Presence of COPD was significantly related to severity of nicotine dependence (P < 0.005).
Figure 2
Prevalence of COPD in males, smokers and nonsmokers

Figure 3
Prevalence of COPD in females, exposed to biomass fuels and passive smoking and biomass
fuels alone without exposure to passive smoking. (BMF–biomass fuels, PS–passive smoking)
Figure 4
Knowledge among smokers regarding adverse effects of tobacco smoking

Figure 5
Attitudes regarding smoking among smokers in rural population

Figure 6
Severity of nicotine dependence according to Fagerstorm questionnaire
Table 1
Prevalence of COPD according to age, occupation, passive smoking (both at home and working
place), smoking habits (males)
Variable Classification Prevalence

P value
Number No. of cases %
Age 40-49 176 10 5.68 >0.05
50-59 119 15 12.6
60-69 102 15 14.7
70+ 56 16 28.57
Occupation Unemployed/retired 11 4 36.36 >0.05
Housewife (Females) 0 0 0
Unskilled worker 79 12 15.19
P value
Skilled worker 44 8 18.18
Bussiness 28 3 10.71
Farmer 267 27 10.11
Government/private worker 23 2 6.25
Government/private supervisor 1 0 0
Government/private officer 0 0 0
Smoking Yes 325 53 16.31 <0.05
No 128 3 2.34
Passive smoking Yes 107 14 13.08 <0.05
(At home) No 346 42 12.14
Passive smoking Yes 287 43 14.18 <0.05
(At work) No 166 13 7.83
Types of smoking Beedi 315 50 15.87 <0.05
cigarette 9 2 22.22
Others 2 1 50
None 127 3 2.36
Open in a separate window
Table 3
Prevalence and gender distribution of symptoms in smokers and nonsmokers
Male Female
Smokers (325) % Non smokers (128) % Non smokers (447) %

Cough
Presence 48 14.76 2 1.56 20 4.47
>3 months/yr 48 14.76 2 1.56 20 4.47
Sputum
Presence 48 14.76 2 1.56 20 4.47
>3 months/yr 47 14.46 1 0.78 20 4.47
Breathlessness
Presence 40 12.3 2 1.56 18 4.02
Severity
Ground 10 3.07 1 0.78 2 0.44
Stair 30 9.23 0 0 16 3.58
At rest 6 1.84 1 0.78 0 0
None 7 2.15 1 0.78 2 0.44
Wheezing 40 12.3 2 1.56 18 4.02
Table 2
Prevalence of COPD according to age, occupation, passive smoking (both at home and working
place), cooking habits (females)

P value
Age 40-49 174 7 4.02 <0.05
50-59 118 7 5.93
60-69 87 4 3.39
70+ 68 5 7.35
Occupation Unemployed/retired 0 0 0 <0.05
Housewife (Females) 364 13 3.57
Unskilled worker 39 5 12.82
Skilled worker 10 3 30
Bussiness 3 1 33.33
Farmer 29 1 3.45
Government/private worker 2 0 0
Government/private supervisor 0 0 0
Government/private officer 0 0 0
Exposure to smoke Lpg 25 1 4 <0.05
Kerosene 6 1 16.66
charcoal 0 0 0
Firewood 411 21 5.11
cowdung 0 0 0
Biogas 1 0 0
Lpg+firewood 4 0 0
Passive smoking (At home) Yes 246 14 5.69 >0.05
No 201 9 4.47
Passive smoking (At work) Yes 36 7 19.44 <0.05
No 411 16 3.89
Go to:
DISCUSSION
In the hospital, individual patients are usually diagnosed to have COPD based on their clinical
presentation and spirometry. In the field setting, in population-based surveys, spirometry may
not be possible in many studies and data collection and interpretation is based on questionnaires.
It is important to understand the strengths and limitations of the questionnaire used in the local
population, before it is administered in the field. Different investigators have used different
methods in estimating the prevalence of COPD. The most reliable studies have used a validated
questionnaire along with spirometry, as spirometry helps to identify many early cases of COPD
in the individuals who do not have any clinical symptoms and therefore will not be detected by
the questionnaire alone. There are limitations with using spirometry alone as studies have shown
that acute bronchodilator response has limited value in differentiating asthma from COPD.[21]
Earlier studies in India have used questionnaires alone, questionnaires with PEF and only one
study has used a validated questionnaire for the diagnosis of COPD.[22]
Respiratory symptoms are among the commonest clinical symptoms in the general population
and may be due to various diseases. The classical definition of chronic bronchitis, which is a
clinical definition with cough with or without sputum for at least three months in a year for at
least two consecutive years, would be very simple to apply in field studies. However, various
other chronic lower and upper respiratory diseases can give rise to similar symptoms. COPD has
such varied presentations, many of which may not fit into the above simple definition. The
population being studied also affects the diagnostic utility of the questionnaire. For example,
selecting the subjects above 40 years of age for the study, rules out many nonCOPD cases, which
may fit into the definition of chronic bronchitis, described above in younger age groups and thus,
improves the diagnostic utility of a questionnaire to detect COPD. In the present study, the
specificity of the questionnaire was probably enhanced by the definition used for COPD in both
the stages of the study, which included not only the clinical symptoms, but also the presence of
sufficient risk factors associated with COPD. The present study questionnaire showed an
acceptable sensitivity and excellent specificity. A large study in Poland[23] on 1,10,355 subjects
in the general population, showed that airflow limitation is noted in 23% of smokers aged >40
years and having smoked >10 pack years in the general population and 33% of these subjects did
not have any respiratory symptoms. The lung health study[20] screened 73,000 smokers, aged
between 35-60 years, and found that the airflow limitation in 30% subjects. These numbers for
airflow limitation are far more than the prevalence of COPD in the general population. The study
by Buffels,[24] which analyzed the usefulness of spirometry performed by general practitioners
in early diagnosis of COPD, found that the number of newly diagnosed cases of COPD increased
by 42% with spirometry compared to the diagnosis based on a questionnaire on signs and
symptoms of COPD alone. These data clearly show that the addition of spirometry increases the
number of COPD cases identified compared to questionnaire alone. In this light, the sensitivity
of 62.5% for the validated questionnaire used in this study can be considered as excellent.
The information regarding prevalence of COPD in India is patchy at best and large parts of the
country have not been covered. India is a large heterogeneous country with differing cultural and
socioeconomic background and a recent review on COPD[22] prevalence, listed only 10 studies
in the last 30 years. The studies were limited to the states of UP, Delhi, Punjab, Haryana, and
Tamilnadu. Only one of these studies was conducted in the last decade. The lowest figures were
observed by Thiruvengadum et al.,[7] in South India in Madras and reported prevalence rates of
1.9% in males and 1.2% in females. The highest figures reported in males were in Punjab, North
India, by Joshi et al.[5] and reported a figure of 12.5%. In females, Radha et al.,[9] observed a
prevalence of 4.6% in Delhi. A total of 3 out of 10 studies were conducted only in the rural
population. The most recent of these studies by Jindal et al.,[3] was also the largest using proper
epidemiological techniques, appropriate sample size, and sampling strategies and a validated
questionnaire; and observed a prevalence of 5.0% in males and 3.2% in females. Our study
reported a higher prevalence of 11.1% in males and 4.5% in females. This may be influenced by
the fact that 71.9% males in this study were smokers and is higher than the national figures of
13.3 to 59.4% in men. In the recent study by Jindal et al., the average prevalence of smoking in
men was 28.5%. More than 90% females in the study were exposed to biomass fuels for more
than 20 years.
Smoking and biomass fuel exposures were significantly associated with COPD as were passive
smoking and increasing age. These risk factors are similar to those identified in earlier studies. In
India, smoking association is reported in 82.3% of male patients.[22] In our study, it was 96.4%
of male patients and very few cases were observed in nonsmoking males. The population
attributable risk of COPD in the OLIN (Obstructive Lung Disease in Northern Sweden)
study[25] for smoking was 45%, less than the figures of 80–90% commonly quoted. The recent
multicentric study by Jindal et al.,[22] reports a smoker: Nonsmoker ratio of 2.65:1. In our study,
we observed a smoker: Nonsmoker ratio of 6.70:1. A dose response relationship was also
observed in our study as described in earlier studies, where 9.6% smokers who smoked for less
than 20 pack years had COPD (n = 125). The prevalence increased to 18% in those who smoked
for more than 20 pack years (n = 200). In the OLIN study,[25] it was demonstrated that 50%
smokers would develop COPD in their lifetime. This was a cohort study and raised important
concerns about the risks associated with tobacco smoking. In our study, we found that 14.7%
smokers developed COPD, which increased to 28.7% in the 70+ age group. Ours was a cross
sectional study and it is important to perform longitudinal studies in India to understand the full
implications of smoking.
Biomass fuels have been identified as one of the major risk factor for COPD in both developing
and developed countries.[26,27] Up to 20% of COPD cases worldwide can be attributed to
indoor air pollution from exposure to smoke from cooking and heating with biomass fuels in
poorly ventilated dwellings. Smith et al.,[28] were the first to suggest that exposure to wood
smoke could equal up to 20 pack years of active exposure to cigarette smoke. Dennis et al.,[29]
showed that wood smoke exposure is associated with the development of COPD among females
of low socio-economic status in Bogota (Colombia).
In a study in Spain,[27] one of the first studies of wood smoke exposure in a developed country,
wood smoke exposure explained around 50% of all COPD cases. In a review of the health effects
of Environmental Tobacco Smoke (ETS),[30] an increased risk of COPD was found. The excess
risk related to ETS exposure was estimated to be from 60% to 400%. Dose-response relation was
also noted.
In our study, most of the COPD cases in women were associated with exposure to biomass fuels.
The prevalence of COPD in women using biomass fuels alone was 3.9% and increased to 4.8%
when there was combined exposure to biomass fuels and passive smoking thus demonstrating an
additive effect. Since 99.5% of women used biomass fuels, it was not possible to study the
effects of passive smoking alone. The number of women using other fuels was very small and so
no conclusions could be drawn about their association with COPD.
In a study in Morocco,[31] more than 70% of the smokers were aware of the respiratory and
cardiovascular risk of tobacco smoking. In comparison, our population in the rural area had very
little knowledge of the risks of tobacco smoking with only 24% aware that tobacco smoking is
associated with respiratory disease and around 12% for cancer, less than 9% for heart disease,
and less than 5% for other diseases. The proportion of male subjects who smoked in our study
was very high at 71.7% and coupled with poor knowledge about the adverse effects of smoking
are likely to have a significant impact on morbidity and mortality associated with smoking in this
population. Larger studies are needed in the rural areas of the country to assess the knowledge
regarding smoking and ill health and if found to be similar to our study demands an extensive
education drive, if we are to control the epidemic of COPD in India in the coming decades. Most
people who smoked did so for relief of stress and to keep company or for enjoyment. It is
important to train the health staff of the primary health centers in the rural areas for counseling
on the ill effects of smoking. Smoking cessation will have to be taken up on a large scale as a
national control program.
In a study in Spain,[32] Fagerstorm questionnaire was used to assess characteristics in smokers

with and without COPD. It was observed that smokers with COPD had higher mean Fagerstorm
test scores, 4.77 (SD 2.45) compared to smokers without COPD, 3.15 (SD 2.38). The study
concluded that smokers with COPD were more likely to have greater physical nicotine
dependence than smokers who did not develop COPD. In our study, 54.5% smokers had mild to
moderate nicotine dependence and 45.5% had severe nicotine dependence. The mean Fagerstorm
scores in smokers with COPD were 6.29 (SD 2.76) compared to 5.20 (SD 2.73) in smokers
without COPD. The prevalence of COPD among severe nicotine dependent smokers was 20.3%
compared to 10.16% in mild to moderate nicotine dependence. Higher dependency scores were
noted in our population than the subjects in Spain and we observed similar results identifying
greater nicotine dependence as a significant risk factor associated with COPD.
Go to:
Footnotes
Source of Support: Nil
Conflict of Interest: None declared.
Go to:
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Articles from Lung India : Official Organ of Indian Chest Society are provided here courtesy of
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These initial studies linking emphysema to α1-AT deficiency and intrapulmonary

An intriguing recent finding was restoration of normal alveoli in elastase-induced

Elastases and anti-elastases in the lung. Recognition that elastic fiber destruction is

Matrix Substrates Other Relative Elasto

Proteinase 3 Neutrophil (monocyte) Basement membrane †

Neutrophil (monocyte) 20

Macrophage, Denatured collagens, types 30

Cathepsin L Macrophage (Inactive at pH 7.5) 0

Cathepsin S Macrophage (Unknown) 80

Although neutrophil elastase is almost surely pivotal in emphysema associated with α 1-

Inhibitor Cellular Source Proteinases Inhibited

Large airway epithelium, type II

Elafin Large airway epithelium Serine

α- Matrix metalloproteinase, serin

TIMPs Macrophage, lung parenchymal cells Matrix metalloproteinase

Cystatin C Airway epithelium (macrophage) Cysteine

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