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Eur Respir J. Author manuscript; available in PMC 2016 December 01.
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Published in final edited form as:

Eur Respir J. 2015 December ; 46(6): 1589–1597. doi:10.1183/13993003.02377-2014.

Risk for COPD with Obstruction of Active Smokers with Normal

Spirometry and Reduced Diffusion Capacity
Ben-Gary Harvey#1,2, Yael Strulovici-Barel#1, Robert J. Kaner1,2, Abraham Sanders2,
Thomas L. Vincent1, Jason G. Mezey1,3, and Ronald G. Crystal1,2
1Department of Genetic Medicine, Weill Cornell Medical College, New York, New York
2Divisionof Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medical
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College, New York, New York

3Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New
York
# These authors contributed equally to this work.

Abstract
Background—Smokers are assessed for COPD using spirometry, with COPD defined by the
Global Initiative for Chronic Obstructive Lung Disease (GOLD) as airflow limitation not fully
reversible with bronchodilators. There is a subset of smokers with normal spirometry (by GOLD
criteria), who have a low diffusion capacity (DLCO), a parameter linked to emphysema and small
airway disease. The natural history of these “normal spirometry/low DLCO” smokers is unknown.
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Methods—From a cohort of 1570 smokers in the New York City metropolitian area, all of whom
had normal spirometry, two groups were randomly selected for lung function follow-up: smokers
with normal spirometry/normal DLCO (n=59) and smokers with normal spirometry/low DLCO
(n=46). All had normal history, physical examination, CBC, urinalysis, HIV status, α1-antitrypsin
level, chest X-ray, FEV1, FVC, FEV1/FVC ratio and total lung capacity (TLC). Throughout the
study, all continued to be active smokers.

Findings—In the normal spirometry/normal DLCO group assessed over 45 ± 20 months, 3%

developed GOLD-defined COPD. In contrast, in the normal spirometry/low DLCO group,
followed over 41 ± 31 months, 22% developed GOLD-defined COPD.

Interpretation—Despite appearing “normal” by GOLD, smokers with normal spirometry but

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low DLCO are at significant risk for developing COPD with obstruction to airflow.

Introduction
Chronic obstructive pulmonary disease (COPD), the 3rd leading cause of mortality in the US
and Europe, is caused primarily by cigarette smoking [1-3]. The Global Initiative for
Chronic Obstructive Lung Disease (GOLD) defines COPD as a chronic disease state

Correspondence: Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 164, New York, New
York 10065, Phone: (646) 962-4363, Fax: (646) 962-0220, [email protected].
Confilct of Interest: The authors declare there is no conflict of interest.
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characterized by airflow limitation not fully reversible with bronchodilators [1,2]. The
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GOLD criteria classify COPD into 4 stages based on post-bronchodilator forced expiratory
volume in 1 sec (FEV1) and forced vital capacity (FVC) [2]. With these criteria, if smokers
have normal post-bronchodilator spirometry, they are considered to have normal lung
function. While the evaluating physician will counsel the patient to stop smoking, the
normal post-bronchodilator spirometry reassures both the patient and the physician that the
patient does not have COPD and is at no higher risk for COPD than other smokers with
normal post-bronchodilator spirometry.

Although the GOLD criteria are widely used [1,4-6], it has been recognized that some
smokers with normal spirometry have low diffusion capacity (DLCO), a parameter
associated with alveolar destruction and possibly small airways disease both components of
COPD [7-10]. The DLCO measurement is not part of the GOLD criteria and is not used as a
routine screening tool because of the lack of portability, cost of the equipment, the expertise
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to carry out of the measurement, and the time involved [1,11].

In the context that COPD is associated with both airway and alveolar disease [8], we asked:
are smokers with normal post-bronchodilator spirometry but low DLCO at greater risk for
developing COPD compared to smokers with normal post-bronchodilator spirometry and
normal DLCO? To answer this question, we evaluated a group of cigarette smokers who
answered advertisements in the New York Metropolitan region for assessment of lung
health. After clinical assessment, we characterized 2 groups: “normal spirometry/low
DLCO” – smokers with normal post-bronchodilator spirometry and total lung capacity
(TLC) but low DLCO; and control “normal spirometry/normal DLCO” – smokers with
normal post-bronchodilator spirometry, normal TLC and normal DLCO. A randomly chosen
subset of these groups were asked to return for repeated lung function over time. Strikingly,
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with an average follow-up of <4 yr, compared to smokers with normal spirometry/normal
DLCO, a significant number of smokers in the normal spirometry/low DLCO group
developed GOLD criteria-defined COPD, i.e., smokers who have normal post-
bronchodilator spirometry but low DLCO are at a higher risk for developing COPD with
obstruction to airflow compared to smokers with normal post-bronchodilator and normal
DLCO.

Methods
Recruitment, Screening and Pulmonary Function Tests
Smokers were recruited from the New York metropolitan area via advertisements in
newspapers and websites under a protocol approved by the Weill Cornell Medical College
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and New York/Presbyterian Hospital Institutional Review Board. Healthy nonsmokers were
also recruited to calculate the 95% normal range for PFTs [12]. All subjects gave their
informed written consent prior to any clinical evaluations or procedures. The study
population was randomly chosen, using screening assessment and inclusion and exclusion
criteria as detailed in Supplemental Data. Pulmonary function tests (PFTs) were performed
according to ATS/ERS standards [11,13], and PFT machine calibrations were performed at
the recommended intervals as described in the ATS/ERS guidelines [11] (see Supplemental
Data).

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Study Groups and Assessment

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A total of 2302 active smokers were assessed. Based on the inclusion/exclusion criteria, a
subset of 1570 active smokers were determined to be eligible. Of these, 1173 were
phenotyped as “normal spirometry/normal DLCO” and 397 as “normal spirometry/low
DLCO” based on their DLCO predication values (see Supplemental Data). A subset of these
subjects were randomly contacted and asked to return for additional PFT assessments. The
groups assessed over time included 59 smokers with normal spirometry/normal DLCO and
46 smokers with normal spirometry/low DLCO (Supplemental Data, Table I).

Statistical Analysis
Statistical analysis was performed as detailed in Supplemental Data.

Role of the Funding Source

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The funding sources of the study had no role in study design, data collection, data analysis,
data interpretation, or writing of the report or the decision to submit this report for
publication.

Results
Study Population
Both the normal spirometry/normal DLCO and the normal spirometry/low DLCO groups
had a preponderance of males and individuals of African-American descent, but had a
similar distribution of gender, age and ethnicity (Table I). The 2 groups were assessed over a
similar time period (Supplemental Figure 1) and the age at the last assessment was similar
(49±8 vs 50±9, respectively, p>0.9); there were no differences in the smoking history, cough
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or sputum scores, MMRC scale, or urine nicotine and cotinine levels between the two
groups (p>0.05, all comparisons). Percent emphysema as assessesd by quantitative HRCT
was not significantly different between the groups (p>0.8, Supplemental Figure 2). Except
for slightly higher C-reactive protein (CrP) levels in the normal spirometry/low DLCO
group, other serology (erythrocyte sedimentation rate, immunoglobulin E level and hepatitis
C positive/negative) were not significantly different between the groups (p>0.1, all
comparisons). The BMI was lower in the normal spirometry/low DLCO group (p<0.002).
Comparison of the lung function assessment between the 2 groups revealed, by definition, a
difference in DLCO and DLCO/VA (p<10−4, both comparisons). Of the other PFT
parameters evaluated, all were within normal range, with the normal spirometry/low DLCO
group having a normal but lower VC, FEV1, FEV1/FVC and TLC (p<0.03, all
comparisons). When the groups were divided into African-American, European and
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Hispanic descendants, there there was no significant difference attributed to etnicicty in any
of the above parameters within the groups or between the groups (p>0.05, all comparisons).

Lung Function Over Time

In the normal spirometry/normal DLCO group, the FEV1 % predicted remained normal in
58 of 59 subjects and the FVC % predicted remained normal in all 59 subjects throughout
the follow-up period (Figure 1A, B). The DLCO in this group remained normal in 44 of 59

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(75%), but interestingly, decreased to the normal spirometry/low DLCO category

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(DLCO<80% predicted) in 15 of 59 subjects (25%), suggesting that a significant number of

active smokers with normal spirometry/normal DLCO will progress to have low DLCO over
an average of <4 yr (Figure 1C). Only 2 of the 59 (3%) active smokers in the normal
spirometry/normal DCLO group developed COPD GOLD I as defined by the GOLD criteria
[3] (FEV1/FVC<0.7, FEV1>80% predicted, post-bronchodilators), one subject at month 34
and the second at month 72 from baseline (Figure 1D).

In the normal spirometry/low DLCO group, the FEV1 % predicted remained normal in 44 of
46 subjects and the FVC % predicted remained normal in all 46 subjects (Figure 2A, B). The
DLCO in this group remained low (<80% predicted) in 45 of 46 subjects (Figure 2C). In
contrast to the normal spirometry/normal DLCO, 10 out of 46 (22%) active smokers in the
normal spirometry/low DLCO group developed airflow limitation consistent with the GOLD
criteria for COPD [3] [FEV1/FVC<0.7, 9 with GOLD I (FEV1 ≥80% prediced, post-
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bronchodilators) and 1 with GOLD II (80% predicted<FEV1>50% predicted); Figure 2D,

Table II, p<0.009].

Comparison of the last lung function assessment to the baseline lung function within the
normal spirometry/normal DLCO group showed no significant difference in the FEV1 or
FVC % predicted (p>0.3, both comparisons), but a significant decrease in the DLCO %
predicted and FEV1/FVC % observed (p<10−4, both comparisons, Figure 3 A-D). We did
not assess whether this was or was not associated with symptoms, such as cough, sputum or
dyspnea at the last time point. Assessment of the last lung function to the baseline lung
function within the normal spirometry/low DLCO group showed no change in FEV1, FVC
or DLCO % predicted (p>0.06, all comparisons), but a significant reduction in FEV1/FVC
% observed (p<10−11, Figure 3 E-H). Comparison of the rate of change of the FEV1/FVC
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over time from baseline to last assessment of the normal spirometry/normal DLCO group to
the normal spirometry/low DLCO group showed a significantly greater decrease over time
for the normal spirometry/low DLCO group (normal spirometry/low DLCO −0.14±0.18 %
change in FEV1/FVC/month compared to the normal spirometry/normal DLCO −0.07±0.11
% change, p<0.02).

Assessment of the 46 smokers with normal spirometry/low DLCO who were followed over
time showed that the distribution of male to female and African-Americans to Eauropeans or
Hispanics was similar in the 10 individuals who developed COPD vs the 36 who did not
(Supplemental Table I). The smoking history, cough and sputum scores, and MMRC scale
and serology were also similar in both groups and the age at the last assessment was similar
(54±7 vs 48±9, respectively, p>0.09). Percent emphysema assessed by HRCT was not
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significantly different between the groups (p>0.05). The 10 individuals who developed
COPD had lower, but within the normal range, FEV1/FVC % observed at baseline
compared to the 36 individuals who did not developed COPD (p<0.003). All other lung
function parameters were similar between the 2 groups (p>0.05, all comparisons). On the
average, there were no differences in the time of follow-up, number of lung function tests or
intervals between lung function tests (p>0.1, all comparisons). There were no significant
differences in any of the parameters or in the prevelnce of COPD development between
African-Americans, Europeans or Hispanics within and between the low DLCO smokers

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who developed COPD and those who did not (p>0.09, all comparisosns). The assessment of
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using DLCO levels at baseline as a predictor for development of COPD yielded an area
under the curve (AUC) score of 0.75; i.e., DLCO levels can be used to predict COPD
development within 41 months with accuracy of 75%.

In addition to using a cutoff of FEV1/FVC<0.7 to define developing COPD and DLCO %

predicted<80% to define low DLCO, a 95% range of normal DLCO % predicted and
FEV1/FVC [12] was calculated based on the lung function of a 405 healthy nonsmoker
dataset (Supplemental Methods) and used to compare the study population prevalence of
developing COPD. Using the normal range for FEV1/FVC and DLCO % predicted
calculated for each gender and ethnicity based on this dataset yielded the same results, with
significantly higher prevalence of developing COPD (defined as FEV1/FVC <95% normal)
in the normal spirometry/low DLCO group vs the normal spirometry/normal DLCO group
(low DLCO = below 95% range).
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Discussion
Cigarette smoking represents the major risk factor for the development of COPD, although
only a fraction of smokers develop the disease [1,2,5,6,14]. Identification of those smokers
at higher risk represents an important step in that the early detection of COPD leads to early
therapeutic intervention [1,2,15]. Spirometry with bronchodilators is the gold standard tool
to screen smokers for COPD [1]. In this study we focused on evaluating the addition of the
DLCO parameter to identify smokers at risk for the development of COPD. We observed
that in a population of 2302 active smokers randomly recruited in the New York
metropolitan area responding to advertisements to assess lung health in active cigarette
smokers, 17% had the phenotype of normal spirometry/low DLCO, i.e., the phenotype of
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low DLCO is quite common among active smokers with normal spirometry. Strikingly, of
105 active smokers randomly chosen for follow-up lung function studies over an average of
<4 yr, 22% with the normal spirometry/low DLCO phenotype developed COPD by the
GOLD criteria, compared to only 3% of the normal spirometry/normal DLCO phenotype.
These observations suggest that the normal spirometry/low DLCO phenotype is at higher
risk for developing COPD than normal spirometry/normal DLCO.

Low DLCO in Otherwise Healthy Smokers

The DLCO assesses the potential of the lung for gas exchange [16]. A pathologic correlate
of decreased DLCO in smokers is the destruction of the pulmonary capillary bed, and a low
DLCO in the context of a normal TLC suggests alveolar destruction, i.e., emphysema [8,16].
A good correlation between low DLCO and emphysema on chest computed tomography has
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been reported [17,18]. Consistent with these observations, active smokers with normal
spirometry but low DLCO have high circulating levels of endothelial microparticles derived
from apoptotic pulmonary capillary endothelium [19]. Decreased DLCO has also been
correlated with small airway disease in the presence of severe expiratory airflow limitation
and hyperinflation [20].

Our observation that 17% of active smokers responding to advertisements to assess lung
health had a normal spirometry/low DLCO phenotype suggests that, despite a normal

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spirometry, a significant number of active smokers have a low DLCO, an observation

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consistent with a number of other studies. Interestingly, while the phenotype of smokers
with normal spirometry but low DLCO is recognized, there are no data regarding what
happens to lung function over time in these individuals.

Risk Markers for COPD in Smokers

Identification of markers that trigger early intervention in smokers is important in that even
mild COPD is associated with increased mortality [21]. Parameters that help identify the
“most vulnerable” smokers, include age, gender, cough, sputum production, dyspnea,
continuation of smoking and pack-yr [1,2,5,6,14,22-28].

In smokers, the prevalence of COPD increases with age [6]. A 25 yr follow-up study found
that the incidence of COPD for active smokers was 35.5%, with age being a significant
predictor for the development of COPD [5]. Advanced age was found significantly related to
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the incidence of COPD in 7 and 10 yr follow-up studies [26,27]. In the present study, there
was no difference in age between the normal spirometry/normal DLCO and normal
spirometry/low DLCO groups or within the normal spirometry/low DLCO group, when
comparing the individuals who developed COPD and those who did not.

In addition to age, cough and sputum production have been found by prospective studies to
identify individuals with higher risk of developing COPD [24,26]. A study of Japanese male
smokers and nonsmokers demonstrated that productive cough was an independent risk factor
for the development of COPD [28]. These data contrast with the studies by Fletcher et al
[25] and Vestbo et al [14] that mucus hypersecretion in smokers is a benign condition. In our
study there were no differences in cough and sputum scores between the active smokers
with normal spirometry/low DLCO and normal spirometry/normal DLCO. Further, the
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individuals followed over time with normal spirometry/low DLCO who developed COPD
did not differ in terms of symptoms compared to those who did not develop COPD.

The data pertaining to gender in the development of COPD are conflicting. Studies of
smokers, ex-smokers and nonsmokers over 7 and 10 yr did not identify gender as a risk
factor [26,27]. However, a study using the GOLD criteria found that despite similar smoking
history, men are more susceptible to development of COPD [23], and male smokers have
more emphysema than female smokers [22]. In the present study, the development of COPD
was gender independent.

All individuals in our study continued to be active smokers. Continuation of smoking has
been found to be an important risk factor to the development of COPD. In the Lung Health
Study, smoking cessation significantly slowed the progression to COPD [1,2,5,15].
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Implications
The central observation in this study is that, among active smokers with normal spirometry
and normal lung volumes, a decreased DLCO is a risk factor for progression to COPD.
These observations need to be verified by larger, randomized trials. Further, the
identification of the “low DLCO” phenotype is complicated by ethnic variations in “normal”
DLCO, and significant attention must be focused on quality control. However, with these

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caveats, the concept that active smokers with normal spirometry/low DLCO are at
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significantly higher risk for the development of COPD over an average period of <4 yr than
a comparable group of active smokers with normal spirometry/normal DLCO has important
implications.

First, the data suggest that DLCO measurement could be an additional tool for early
detection of the smoker at risk for COPD, and thus help contribute to early intervention.

Second, while the measurement of DLCO is not presently suitable for routine screening,
engineering technology could be developed to make the DLCO an early, inexpensive,
reproducible measurement, suitable for routine office visits and field use for epidemiologic
studies.

Third, in the past, the DLCO has not been measured in large epidemiologic studies such as
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SPIROMICS and COPDGene [29,30]. While there are many reasons (mostly cost) for this,
the observation that a significant percent of active smokers have a low DLCO and of these, a
significant percent will develop COPD in an average of <4 yr, has significant implications
for the “risk for COPD” parameters assessed in these studies.

Finally, the findings suggest that in smokers, a normal spirometry post-bronchodilator test
may give a false sense of “normal”, in that a significant subgroup may have a low DLCO,
and that subgroup is at a significant risk for developing COPD with obstruction.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
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Acknowledgments
We thank A. Tilley, S. Hyde and C. Gordon for help with this study; and N. Mohamed for help in preparing this
manuscript. The studies were supported, in part, by NIH P50 HL084936 and UL1-RR024996. BGH and RJK were
supported, in part, by the JP Smith Clinical Scholar Program.

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Figure 1.
Lung function assessment over time of 59 active smokers with baseline normal history,
physical exam and laboratory tests, and with normal spirometry, lung volumes, and normal
diffusion capacity (normal spirometry/normal DLCO). The abscissa shows time in months.
Each symbol represents an individual, with lines connecting the follow-up data over time for
the same individual. The dashed lines represent the limit of normal. Orange data points
indicate individuals that initially had normal values at baseline but became abnormal over
time. Blue data points indicate individuals that had normal values at baseline and remained
normal over time.A. FEV1 (% predicted); B. FVC (% predicted); C. DLCO (% predicted);
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and D. FEV1/FVC (% observed).

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 Harvey et al. Page 11
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Figure 2.
Lung function assessment over time in 46 active smokers with normal history, physical
exam and laboratory tests, and with normal spirometry, lung volumes, but low diffusion
capacity (normal spirometry/low DLCO). The abscissa shows time in months. Each symbol
represents an individual, with lines connecting the follow-up data over time for the same
individual. The dashed lines represent the limit of normal. Orange data points indicate
individuals that initially had normal values but became abnormal over time. Blue data points
indicate individuals that had normal values at baseline and remained normal over time. A.
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FEV1 (% predicted); B. FVC (% predicted); C. DLCO (% predicted); and D. FEV1/FVC (%

observed).

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 Harvey et al. Page 12
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Figure 3.
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Lung function changes from baseline to the last pulmonary function test in the normal
spirometry/normal DLCO group (A-D) and normal spirometry/low DLCO group (E-H)
comparing individuals who did not develop COPD (white bars) to those who did develop
COPD (grey bars). A, E. FEV1 (% predicted); B, F. FVC (% predicted); C, G. DLCO (%
predicted); and D, H. FEV1/FVC (% observed). Data is presented as mean ± standard
deviation.

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Table I
1
Demographics of Study Groups at Baseline
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Smokers with normal spirometry

Parameter Normal DLCO Low DLCO p value

n 59 46
Gender (male/female) 43/16 31/15 >0.6
Age 45 ± 8 46 ± 8 >0.5
2 41/10/8 37/5/4 >0.6
Ethnicity (AA/E/H)
2 28 ± 5 25 ± 5 <0.002
BMI (kg/m )
3
Smoking history
    Pack-yr 24 ± 13 30 ± 15 >0.05
    Pack per day 1.0 ± 0.5 1.1 ± 0.6 >0.5
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    Age of smoking initiation 17 ± 5 17 ± 4 >0.9

    Urine nicotine (ng/ml) 1102 ± 1290 951 ± 1285 >0.6
    Urine cotinine (ng/ml) 1276 ± 927 1298 ± 894 >0.9
4 1.2 ± 1.3 1.7 ± 1.5 >0.06
Cough score
4 1.1 ± 1.3 1.3 ± 1.3 >0.3
Sputum score
4 0.4 ± 0.6 0.5 ± 0.6 >0.2
MMRC score
5 2.0 ± 0.02 2.2 ± 0.04 >0.8
% emphysema
6
Serology
    αl-antitrypsin (mg/dl) 152 ± 24 145 ± 21 >0.1
    ESR (mm/hr) 13 ± 11 12 ± 10 >0.7
    IgE (IU/mL) 129 ± 208 169 ± 259 >0.4
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    CrP (mg/Dl) 0.2 ± 0.2 0.3 ± 0.2 <0.005

7 46/9 39/6 >0.8
    Hepatitis C (negative/positive)
8
Lung function
    VC 114 ± 14 108 ± 14 <0.05
    FVC (% predicted) 111 ± 14 104 ± 14 >0.1
    FEV1 (% predicted) 111 ± 15 104 ± 14 <0.03
    FEV1/FVC (% observed) 81 ± 4 79 ± 5 <0.03
    TLC (% predicted) 99 ± 13 94 ± 14 <0.03
    RV (% predicted) 90 ± 25 89 ± 37 >0.8
    RV/TLC 28 ± 7 31 ± 11 >0.1
    DLCO (% predicted) 93 ± 10 68 ± 9 <10−4
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    DLCO/VA (mL/mHg/min/L) 4.4 ± 0.6 3.6 ± 0.7 <10−6

Assessment over time
    Time of follow-up (month, mean ± SD, range) 46 ± 21 (5-113) 41 ± 31 (5-146) >0.4
    Number of PFTs (mean ± SD, range) 2 ± 1 (2-6) 3 ± 2 (2-8) <10−3
    Interval between PFTs (month, mean ± SD, range) 33 ± 18 (5-73) 18 ± 20 (1-127) <10−6

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1
A total of 105 active smokers were enrolled in the study, including 46 individuals with normal history, physical, general laboratory tests, normal
posterior-anterior and lateral chest film, normal spirometry and lung volumes, but low diffusion capacity (DLCO) and 59 with normal spirometry,
lung volumes and diffusion capacity. All were followed over time with full lung function studies.
2
AA – African-American; E - European; H - Hispanic.
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3
Current smoking was verified at baseline by urine nicotine and its derivative cotinine; at subsequent visits for lung function testing, active
smoking status was verified by questionnaire.
4
Cough and sputum scores were each evaluated on a scale of 0-4: 0 = not at all; 1 = only with chest infections; 2 = a few days a month; 3 = several
days a wk; 4 - most days a wk.[31] MMRC = Modified Medical Research Council dyspnea scale.[32]
5
Chest high resolution computed tomography (HRCT); % emphysema at −950 Hounsfield Units (HU).
6
All individuals tested negative for HIV and had normal levels of αl-antitrypsin; ESR - erythrocyte sedimentation rate; IgE – immunoglobin E; CrP
– C-reactive protein; hepatitis C – hepatitis C serology.
7
Data available for 55 of 59 smokers with normal spirometry and DLCO and 45 of 46 smokers with normal spirometry but low DLCO.
8
Lung function parameters are presented as percent predicted except the FEV1/FVC ratio, which is presented as percent observed; VC – vital
capacity; FVC - forced vital capacity; FEV1 - forced expiratory volume in 1 second; TLC - total lung capacity; RV - residual volume; DLCO -
diffusion capacity; and VA – alveolar volume. The DLCO was corrected for hemoglobin and carboxyhemoglobin.[11]
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Table II

Progression to COPD in Active Smokers with Normal Spirometry/Low DLCO vs Active Smokers with
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1
Normal Spirometry/Normal DLCO

At end of evaluation period

2 % normal % with COPD
Group
Normal spirometry, normal DLCO 97% (57/59) 3% (2/59)
Normal spirometry, low DLCO 78% (36/46) 22% (10/46)
3 0.009
p value

1
Fifty-nine active smokers with normal spirometry/normal diffusion capacity, and 46 active smokers with normal spirometry/low diffusion
capacity (DLCO) were followed over time with full lung function studies to determine the rate of progression to COPD.
2
Individuals with normal spirometry, lung volumes and normal DLCO were followed for 45±20 months. Individuals with normal spirometry, lung
volumes but low DLCO were followed for 41±31months (p>0.4).
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3
Chi-square.
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