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new england
journal of medicine
The
established in 1812
May 12, 2016
vol. 374
no. 19
Clinical Significance of Symptoms in Smokers

with Preserved Pulmonary Function
Prescott G. Woodruff, M.D., R. Graham Barr, M.D., Dr.P.H., Eugene Bleecker, M.D., Stephanie A. Christenson, M.D.,
David Couper, Ph.D., Jeffrey L. Curtis, M.D., Natalia A. Gouskova, Ph.D., Nadia N. Hansel, M.D., Eric A. Hoffman, Ph.D.,
Richard E. Kanner, M.D., Eric Kleerup, M.D., Stephen C. Lazarus, M.D., Fernando J. Martinez, M.D., Robert Paine, III, M.D.,
Stephen Rennard, M.D., Donald P. Tashkin, M.D., and MeiLan K. Han, M.D., for the SPIROMICS Research Group*
a bs t r ac t
BACKGROUND
Currently, the diagnosis of chronic obstructive pulmonary disease (COPD) requires

a ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) of
less than 0.70 as assessed by spirometry after bronchodilator use. However, many
smokers who do not meet this definition have respiratory symptoms.
METHODS
We conducted an observational study involving 2736 current or former smokers and

controls who had never smoked and measured their respiratory symptoms using the
COPD Assessment Test (CAT; scores range from 0 to 40, with higher scores indicating greater severity of symptoms). We examined whether current or former smokers
who had preserved pulmonary function as assessed by spirometry (FEV1:FVC 0.70
and an FVC above the lower limit of the normal range after bronchodilator use)
and had symptoms (CAT score, 10) had a higher risk of respiratory exacerbations
than current or former smokers with preserved pulmonary function who were asymptomatic (CAT score, <10) and whether those with symptoms had different findings
from the asymptomatic group with respect to the 6-minute walk distance, lung
function, or high-resolution computed tomographic (HRCT) scan of the chest.
The authors affiliations are listed in the

Appendix. Address reprint requests to Dr.
Woodruff at the University of California at
San Francisco, Box 0130, Rm. HSE 1305, 513
Parnassus Ave., San Francisco, CA 94143, or
at [email protected].
*A complete list of the investigators in
the Subpopulations and Intermediate
Outcome Measures in COPD Study
(SPIROMICS) is provided in the Supplementary Appendix, available at NEJM.org.
N Engl J Med 2016;374:1811-21.
DOI: 10.1056/NEJMoa1505971
Copyright 2016 Massachusetts Medical Society.
RESULTS
Respiratory symptoms were present in 50% of current or former smokers with preserved pulmonary function. The mean (SD) rate of respiratory exacerbations among
symptomatic current or former smokers was significantly higher than the rates among
asymptomatic current or former smokers and among controls who never smoked (0.27
0.67 vs. 0.080.31 and 0.030.21 events, respectively, per year; P<0.001 for both comparisons). Symptomatic current or former smokers, regardless of history of asthma,
also had greater limitation of activity, slightly lower FEV1, FVC, and inspiratory capacity, and greater airway-wall thickening without emphysema according to HRCT
than did asymptomatic current or former smokers. Among symptomatic current or
former smokers, 42% used bronchodilators and 23% used inhaled glucocorticoids.
CONCLUSIONS
Although they do not meet the current criteria for COPD, symptomatic current or
former smokers with preserved pulmonary function have exacerbations, activity limitation, and evidence of airway disease. They currently use a range of respiratory medications without any evidence base. (Funded by the National Heart, Lung, and Blood
Institute and the Foundation for the National Institutes of Health; SPIROMICS
ClinicalTrials.gov number, NCT01969344.)
n engl j med 374;19
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n e w e ng l a n d j o u r na l
A Quick Take is
available at
NEJM.org
1812
mong the criteria that are needed to make a diagnosis of chronic obstructive pulmonary disease (COPD) are
deficits in the rate at which one can forcefully
exhale. Most experts consider a low ratio (<0.70)
of the forced expiratory volume in 1 second (FEV1)
to the forced vital capacity (FVC) after bronchodilator use to be a key diagnostic criterion.1
Once the diagnosis of COPD has been established, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) nomenclature grades
severity according to the degree to which the
measured FEV1 is lower than the patients predicted value. GOLD stage 1, indicating mild
disease, is defined as an FEV1 that is greater
than or equal to 80% of the predicted value;
GOLD stage 2, indicating moderate disease, as
an FEV1 that is greater than or equal to 50% and
less than 80% of the predicted value; GOLD
stage 3, indicating severe disease, as an FEV1
that is greater than or equal to 30% and less
than 50% of the predicted value; and GOLD
stage 4, indicating very severe disease, as an
FEV1 that is less than 30% of the predicted value.
However, some smokers who do not have
airflow obstruction those whose FEV1:FVC
after bronchodilator use is equal to or greater
than the conventionally accepted cutoff of 0.70
nonetheless report cough, sputum production, and shortness of breath; these symptoms
are suggestive of COPD.1-3 Furthermore, the
FEV1:FVC ratio can be insensitive to early airway
disease.4 A recent task-force document emphasized the need for additional research involving smokers with symptoms and normal lung
function.5
In the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS),
we hypothesized that many current or former
smokers who have respiratory symptoms despite
an FEV1:FVC of at least 0.70 after bronchodilator
use have clinical symptoms and findings that
are consistent with a chronic lower respiratory
disease similar to COPD. To test this hypothesis,
we focused on current or former smokers who
had respiratory symptoms at baseline despite
preserved pulmonary function as assessed by
spirometry (FEV1:FVC 0.70 and an FVC above
the lower limit of the normal range after bronchodilator use). We required an FVC above the
lower limit of the normal range in order to
minimize the misclassification of participants
n engl j med 374;19
of
m e dic i n e
with restrictive disease as having COPD. We then

determined whether these symptomatic current
or former smokers with preserved pulmonary
function had a higher risk of respiratory exacerbations or abnormalities on a high-resolution
computed tomographic (HRCT) scan of the
chest or shorter 6-minute walk distances than
asymptomatic current or former smokers with
preserved pulmonary function.
Me thods
Participants and Study Design
In this multicenter observational study funded

by the National Heart, Lung, and Blood Institute,6 we enrolled 2736 participants from 2010
through 2015. The study included persons 40 to
80 years of age who were either healthy persons
who had never smoked (1 pack-year of tobaccosmoking history, FEV1:FVC 0.70 before bronchodilator use, an FVC that was equal to or above
the lower limit of the predicted normal range,7
and no known current lung disease or unstable
cardiovascular disease) or current or former
smokers who had a smoking history of more than
20 pack-years, regardless of whether they had a
clinical diagnosis of obstructive lung disease.
For this study, we categorized participants for
analysis using the GOLD staging system according to the results on spirometry,8 which we performed before and after four inhalations each of
albuterol at a dose of 90 g per inhalation and
ipratropium at a dose of 18 g per inhalation.
Current or former smokers who had a concomitant diagnosis of asthma were not excluded; instead, historical data on whether the participant
had a diagnosis of asthma were collected. We
quantified symptoms during a stable phase of
disease (>6 weeks after any exacerbation) using
the COPD Assessment Test (CAT), a validated
eight-question health-status instrument.9 CAT
scores range from 0 to 40, with higher scores
indicating greater severity of symptoms. In the
context of COPD, GOLD uses a CAT score of 10
or more as a threshold for more severe symptoms in consideration of treatment regimens.8
We obtained an exacerbation history prospectively (every 3 months) with the use of a structured questionnaire, and we defined exacerbations on the basis of the use of antibiotic
agents, systemic glucocorticoids, or a combination of both or a health care utilization event
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May 12, 2016

Symptoms in Smokers with Preserved Pulmonary Function
(office visit, hospital admission, or emergency

department visit for a respiratory flare-up). We
defined severe exacerbations as interactions that
led to hospitalization or an emergency department visit. Exacerbations were managed by the
participants usual providers, who were aware of
their patients enrollment in an observational
study. The study did not, however, provide guidance on management. Spirometric tracings were
independently reviewed.
All the participants underwent testing to
determine the distance walked in 6 minutes.10
From computed tomographic scans of the lung,
we measured the extent of emphysema and airway-wall thickness with the use of HRCT imaging and VIDA Diagnostics software. A threshold
of 950 Hounsfield units was used to define
emphysema; Pi10, defined as the square root of
the wall area of a theoretical circular cross section of an airway that is 10 mm in the lumenal
perimeter, was used to define airway-wall thickening.11
This study was not population-based, so we
recruited participants from the population at
each center by means of physician referral, advertisement in clinical areas, or self-referral at
the study website (www.spiromics.com). The research protocol was approved by the institutional review board at each participating institution, and all the participants provided written
informed consent.
Statistical Analysis
The investigators performed the data analysis

using SAS software, version 9.3 (SAS Institute).
We used one-way analysis of variance, the chisquare test, and the KruskalWallis test, as appropriate, for the comparisons of groups. P values
are two-sided, with Bonferroni-corrected pairwise
comparisons between individual groups (with
adjustment for the 10 comparisons that result
from comparisons across five groups). A P value
of less than 0.05 was considered to indicate statistical significance.
To control for potential confounders, we used
linear regression (for the 6-minute walk distance
and lung function) and logistic-regression models (for the bronchodilator response). We fit
proportional-means models for recurrent events
of exacerbations to accommodate differences in
follow-up time across participants.12 We defined
annualized exacerbation rates as the total number
n engl j med 374;19
of events per person, divided by the number of

follow-up days for that person, multiplied by 365.
In additional analyses, we stratified the analysis according to smoking status (current or former), participants report of previous diagnosis
of COPD by a health provider (yes or no), and
asthma (never, during childhood, or ever). We
developed receiver-operating-characteristic curves
to determine the value of the CAT, the British
modified Medical Research Council (mMRC)
dyspnea questionnaire (scores range from 0 to 4,
with higher scores indicating more severe dyspnea),13 and the FEV1 to predict the risk of one
or more exacerbations versus none in the first
year of follow-up. We limited these receiveroperating-characteristic curve analyses to participants with at least 1 year of follow-up.
R e sult s
Characteristics of the Participants
We categorized current or former smokers into

four mutually exclusive groups. First, we categorized current or former smokers according to an
FEV1:FVC of 0.70 or more after bronchodilator
use and an FVC above the lower limit of the
normal range (preserved pulmonary function)
versus mild-to-moderate COPD (GOLD stage 1
or 2); then we subcategorized the members of
each of these two groups into participants with a
CAT score of 10 or more (symptomatic) or a CAT
score of less than 10 (asymptomatic)8 (Table 1).
We found that 50% of current or former smokers
with preserved pulmonary function had symptoms (Fig. 1) a prevalence of symptoms that
was slightly less than that among participants
with GOLD stage 1 or 2 COPD (65%, P<0.001)
but far greater than the prevalence among controls who never smoked (16%, P<0.001).
Symptomatic current or former smokers with
preserved pulmonary function had elevations in
all components of the CAT score (Fig. S1 in the
Supplementary Appendix, available with the full
text of this article at NEJM.org), were younger,
were more likely to be nonwhite or Hispanic,
had a higher body-mass index (BMI; the weight
in kilograms divided by the square of the height
in meters), and were more likely to be current
smokers, report symptoms of chronic bronchitis, and report a history of wheezing and asthma
(during childhood or ever) than those with lesser
symptoms (CAT score, <10) (Table 1). Because
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1813
The
of
m e dic i n e
Table 1. Characteristics of the Participants at Baseline.*

Characteristic
Never Smoked
Group A
(N = 199)
Current or Former Smokers

Preserved Pulmonary Function
Mild-to-Moderate COPD
Group B,
CAT <10
(N = 424)
Group C,
CAT 10
(N = 425)
Group D,
CAT <10
(N = 337)
Group E,
CAT 10
(N = 626)
9.9
21.1
21.1
16.8
31.1
Mean (yr)
56.410.2
61.99.5
59.39.9
67.97.1
64.98.2
Significant between-group difference
B, C, D, E
A, C, D, E
A, B, D, E
A, B, C, E
A, B, C, D
77/199 (39)
222/424 (52)
186/425 (44)
223/336 (66)
342/626 (55)
B, D, E
A, D
D, E
A, B, C, E
A, C, D
27/199 (14)
16/423 (4)
37/425 (9)
11/336 (3)
24/626 (4)
B, D, E
A, C
B, D, E
A, C
A, C
Percentage of overall study population

Age
Male sex
No. of participants/total no. (%)
Hispanic ethnic group
Race
No. of participants (%)
White
Nonwhite
137 (69)
331 (78)
248 (58)
292 (87)
513 (82)
62 (31)
93 (22)
177 (42)
45 (13)
113 (18)
D, E
C, D
B, D, E
A, C
A, B, C
28.55.0
27.84.8
29.75.3
27.14.6
28.25.4
B, D, E
A, C, E
C, D
0/196
181/422 (43)
251/419 (60)
83/331 (25)
272/617 (44)
C, D
B, D, E
B, C, E
C, D
Body-mass index
Mean
Current smoking
Extent of smoking
Mean pack-yr
41.520.9
45.826.4
49.523.8
54.126.7
B, C, D, E
A, D, E
A, E
A, B, E
A, B, C, D
4/196 (2)
23/417 (6)
133/408 (33)
27/326 (8)
191/604 (32)
C, E
C, E
A, B, D
C, E
A, B, D
27/198 (14)
137/422 (32)
291/421 (69)
152/334 (46)
476/623 (76)
B, C, D, E
A, C, D, E
A, B, D
A, B, C, E
A, B, D
0/197
45/412 (11)
173/399 (43)
168/320 (52)
485/603 (80)
C, D, E
B, E
B, E
B, C, D
10/195 (5)
30/420 (7)
114/419 (27)
50/330 (15)
161/611 (26)
C, D, E
C, D, E
A, B, D
A, B, C, E
A, B, D
Symptoms of chronic bronchitis

Wheezing
History of COPD
Any diagnosis of asthma
1814
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Table 1. (Continued.)
Characteristic
Never Smoked
Group A
(N = 199)
Current or Former Smokers

Preserved Pulmonary Function
Mild-to-Moderate COPD
Group B,
CAT <10
(N = 424)
Group C,
CAT 10
(N = 425)
Group D,
CAT <10
(N = 337)
Group E,
CAT 10
(N = 626)
4/197 (2)
15/423 (4)
41/417 (10)
25/331 (8)
69/619 (11)
C, E
C, E
A, B
A, B
1/196 (1)
3/421 (1)
8/423 (2)
4/335 (1)
25/622 (4)
35/195 (18)
112/421 (27)
142/422 (34)
89/335 (27)
221/622 (36)
C, E
A, B, D
Childhood diagnosis of asthma

History of congestive heart failure
History of GERD
* Plusminus values are means SD. Group A included healthy controls who had never smoked, group B current or former smokers with preserved pulmonary function as assessed by spirometry who had a Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT)9
score of less than 10, group C current or former smokers with preserved pulmonary function with a CAT score of 10 or more, group D current or former smokers with COPD symptoms of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 or 2 (indicating
mild and moderate disease, respectively) and a CAT score of less than 10, and group E current or former smokers with COPD symptoms of
GOLD stage 1 or 2 and a CAT score of 10 or more. Scores on the CAT, a validated eight-question health-status instrument, range from 0 to
40, with higher scores indicating greater severity of symptoms. Data on age and body-mass index (the weight in kilograms divided by the
square of the height in meters) were missing for one participant in group D, and data on the extent of smoking were missing for one participant in group A and one in group E. GERD denotes gastroesophageal reflux disease.
P<0.05 for each pairwise comparison (vs. the group indicated) by one-way analysis of variance with Bonferroni correction for multiple comparisons across the five groups (10 comparisons) for continuous variables and by the chi-square test for categorical variables.
Race and ethnic group were self-reported.
our definition of symptoms was based on the

CAT score and included more than just cough
and sputum production, chronic bronchitis was
present in only 33% of symptomatic current or
former smokers (Table 1).
Current or former smokers with preserved
pulmonary function who were symptomatic were
also more likely than those who were asymptomatic to report a previous diagnosis of COPD
by a health professional (43% vs. 11%, P<0.001),
although the prevalence was lower than that
among symptomatic participants with GOLD
stage 1 or 2 COPD symptoms (80%, P<0.001).
Even after the exclusion of participants with an
FEV1:FVC of 0.70 or more but who nonetheless
had received a health professionals diagnosis of
COPD, symptoms remained more prevalent among
current or former smokers with preserved pulmonary function than among healthy controls
who had never smoked (38% vs. 16%, P<0.001).
n engl j med 374;19
Exacerbations and Activity Limitation
The median prospective follow-up time was 829

days (interquartile range, 494 to 1106). Whether
defined on the basis of the use of antibiotics, the
use of systemic glucocorticoids, the prescription
of either of these medications, any health care
utilization, or hospitalization or emergency department visits (severe exacerbations), the prospective rate of exacerbations was higher among
symptomatic current or former smokers with preserved pulmonary function than among asymptomatic current or former smokers or among
healthy controls who had never smoked (0.270.67
vs. 0.080.31 and 0.030.21 events, respectively,
per year; P<0.001 for both comparisons) (Fig. 2,
and Fig. S2 and Table S1 in the Supplementary
Appendix). The mean distance walked in 6 minutes was also shorter in symptomatic current or
former smokers with preserved pulmonary function (79.819.2% of the predicted value) than in
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1815
The
asymptomatic current or former smokers (89.3

18.8% of the predicted value) and in participants
with GOLD stage 1 or 2 COPD symptoms and a
CAT score of less than 10 (89.219.3% of the
predicted value) (Table S1 in the Supplementary
Appendix).
of
m e dic i n e
lung function (Table S2 in the Supplementary

Appendix).
To assess the effect of active smoking, we
performed analyses that were stratified according to current smoking status versus former
smoking status and found that symptoms (CAT
Airway Disease and Emphysema
Potential Confounders
Given the significant differences in age, race,

ethnic group, BMI, current smoking, and asthma
between current or former smokers with preserved pulmonary function who were symptomatic and those who were asymptomatic, we developed multivariate models that controlled for
these potential confounders of exacerbations as
well as for sex, history of congestive heart failure, and history of gastroesophageal reflux disease. We found that even after these potential
confounders were controlled for, symptomatic
current or former smokers with preserved pulmonary function had more frequent exacerbations than did asymptomatic current or former
smokers (Table 2). We also found persistent
differences in the 6-minute walk distance and in
1816
n engl j med 374;19
P<0.001
P<0.001
40
30
Baseline CAT Score
Symptomatic current or former smokers with

preserved pulmonary function differed from asymptomatic current or former smokers in a range
of lung-function measures including FEV1 (percentage of predicted FEV1 after bronchodilator
use, 94.113.1% vs. 98.512.6%; P<0.001), FVC,
and inspiratory capacity. Current or former
smokers with preserved pulmonary function who
were symptomatic did not have a higher percentage of lung volume with emphysematous features
(hereafter referred to as percent emphysema)
than did those who were asymptomatic (1.62.2%
and 2.02.1%, respectively; P = 0.99) but did have
a greater Pi10 (3.730.09 vs. 3.700.09, P = 0.002),
a measure of airway-wall thickening on HRCT of
the chest. Current or former smokers with preserved pulmonary function who were symptomatic were more likely than those who were asymptomatic to have an increase in FVC after
bronchodilator use, according to the combined
criteria of an increase of at least 12% and a 200-ml
increase in FVC (8% vs. 2%, P = 0.003),14 but not
according to the criterion of percentage increase
in the FVC alone. For additional details on airway disease and emphysema, see Figures S3 and
S4 and Table S1 in the Supplementary Appendix.
20
10
Controls
Who Never
Smoked
Current or
Current or
Former
Former
Smokers with
Smokers with
Mild-to-Moderate
Preserved
COPD
Pulmonary
Function
Figure 1. Prevalence of Respiratory Symptoms,

According to Study Group.
Respiratory symptoms were assessed with the use of
the Chronic Obstructive Pulmonary Disease (COPD)
Assessment Test (CAT) in controls who had never
smoked, in current or former smokers with preserved
pulmonary function as assessed by spirometry (a ratio
of the forced expiratory volume in 1 second to the forced
vital capacity [FVC] of 0.70 after bronchodilator use
and an FVC above the lower limit of the normal range),
and in current or former smokers who had COPD
symptoms of Global Initiative for Chronic Obstructive
Lung Disease (GOLD) stage 1 or 2 (indicating mild
and moderate disease, respectively). Scores on the
CAT, a validated eight-question health-status instrument, range from 0 to 40, with higher scores indicating a greater severity of symptoms. The red line indicates the cutoff for more severe symptoms that is used
by GOLD (CAT score, 10). The horizontal line in the
boxes represents the median, and the bottom and top
of the boxes the 25th and 75th percentiles, respectively. I bars represent the upper adjacent value (75th percentile plus 1.5 times the interquartile range) and the
lower adjacent value (corresponding formula below the
25th percentile), and the dots outliers. P values were
adjusted with Bonferroni correction for multiple comparisons.
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Prospective Annualized Exacerbation Rate
1.6
Antibiotic
Glucocorticoid
Antibiotic or
glucocorticoid
Office or hospital
visit
Severe
Any
1.4
1.2
* *
*
0.8
0.6
0.0
* *
0.4
1.0
0.2
*
*
Controls Who Never

Smoked
Current or Former
Current or Former
Smokers with
Smokers with
Preserved Pulmonary Preserved Pulmonary
Function,
Function,
CAT10
CAT<10
Current or Former
Smokers with
Mild-to-Moderate
COPD,
CAT<10
Current or Former
Smokers with
Mild-to-Moderate
COPD,
CAT10
Figure 2. Prevalence of Symptoms and Risk of Respiratory Exacerbations, According to Study Group.
Prospective respiratory exacerbations were defined as respiratory events that were treated with antibiotics or oral
glucocorticoids, those associated with health care utilization (office visit, emergency department visit, or hospitalization), those that were considered to be severe exacerbations (i.e., that led to an emergency department visit or
hospitalization), or any exacerbation (any of the above). T bars indicate 1 SD. Asterisks indicate a P value of less
than 0.05, with Bonferroni correction for multiple comparisons, for the comparison with current or former smokers
with preserved pulmonary function and a CAT score of less than 10.
score, 10) were associated with elevations in all

components of the CAT score in both current
smokers and former smokers with preserved
pulmonary function. We also found higher rates
of exacerbations among symptomatic current
and former smokers with preserved pulmonary
function, regardless of current versus former
smoking status, than among asymptomatic current or former smokers or persons who had
never smoked. For details, see Figures S5 and S6
in the Supplementary Appendix.
Finally, we performed sensitivity analyses in
which we excluded participants who reported a
history of asthma (during childhood or ever).
These analyses showed that exacerbation rates
remained higher among current or former smokers with preserved pulmonary function who
were symptomatic than among those who were
asymptomatic (Tables S3 and S4 in the Supplementary Appendix).
score and risk of exacerbation in the first year of

follow-up. Among current or former smokers
with preserved pulmonary function, the area
under the curve for the baseline CAT score and
the occurrence of any exacerbation in the first
year of follow-up was 0.68; the corresponding
area under the curve for the FEV1 after bronchodilator use was 0.59 (P = 0.05 for the comparison
of CAT score with FEV1 after bronchodilator
use). The sensitivity and specificity of the CAT
score for at least one exacerbation in the first
year of follow-up varied according to CAT-score
cutoff. A CAT score of 10 had 75% sensitivity
and 54% specificity for any exacerbation.
Defining preserved pulmonary function on
the basis of each participants lower limit of the
normal range for FEV1:FVC after bronchodilator
use or with the use of an FEV1:FVC cutoff of 0.65
did not significantly affect the association between the CAT score and any exacerbation (Fig. 3).
However, a definition that was based on a postEffect of FEV1:FVC and CAT-Score Cutoffs
bronchodilator FEV1:FVC cutoff of 0.75 led to
We performed receiver-operating-characteristic fewer participants being categorized as having
curve analyses of the association between CAT preserved pulmonary function (577 participants
n engl j med 374;19
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1817
1818
<0.001
* Results are from proportional-means models that modeled exacerbations as recurrent events. Model 1 was for the comparison of persons with a CAT score of less than 10 (reference
group) with those who had a CAT score of 10 or more. Model 2 included model 1 plus the potential confounders of body-mass index, current smoking status, age, sex, race, and ethnic
group. Model 3 included model 2 plus the potential confounders of self-reported coexisting conditions of congestive heart failure, GERD, and diagnosis of asthma at any time. Model 4
included model 2 plus the potential confounders of self-reported coexisting conditions of congestive heart failure, GERD, and diagnosis of asthma during childhood. CI denotes confidence interval.
<0.001
0.001
<0.001
2.80 (1.684.67)
11.50 (2.9345.21)
<0.001
2.37 (1.463.85)
<0.001
3.01 (1.795.08)
<0.001
11.99 (3.0447.37)
3.56 (2.185.83)
18.10 (4.77 68.67)

Severe
Leading to health care utilization
<0.001
2.20 (1.303.71)
<0.001
2.90 (1.655.09)
4.37 (2.168.84)
<0.001
6.00 (2.8712.56)
3.36 (1.965.77)
While taking antibiotic or
glucocorticoid
<0.001
7.22 (3.4914.93)
While taking glucocorticoid
<0.001
2.07 (1.233.49)
<0.001
2.72 (1.554.77)
2.40 (1.463.94)
<0.001
3.09 (1.825.27)
<0.001
3.19 (1.865.49)
While taking antibiotic
<0.001
3.62 (2.176.03)
Any
Relative Risk
(95% CI)
P Value
Relative Risk
(95% CI)
P Value
9.84 (2.4839.02)
2.72 (1.564.75)
0.003
<0.001
5.77 (2.7712.05)
<0.001
<0.001
2.56 (1.474.47)
0.006
<0.001
2.90 (1.714.90)
<0.001
<0.001
Relative Risk
(95% CI)
P Value
P Value
Relative Risk
(95% CI)
Model 4
Model 3
Model 2
Model 1
Exacerbation
Table 2. Risk of Exacerbations Associated with CAT Score of 10 or More, as Compared with a CAT Score of Less Than 10, among Current or Former Smokers with Preserved Pulmonary
Function.*
The
n engl j med 374;19
of
m e dic i n e
with the use of the 0.75 cutoff vs. 849 with the
use of the 0.70 cutoff) and weakened the association between the CAT score and exacerbation
(Fig. 3). Finally, on receiver-operating-characteristic curve analyses, the mMRC dyspnea score
was similar to the CAT score in its association
with any exacerbation over the first year of follow-up in current or former smokers with preserved pulmonary function. For details, see
Figures S7 and S8 and Table S5 in the Supplementary Appendix.
Use of Respiratory Medication
In the 3 months before enrollment in the study,

42% of symptomatic current or former smokers
with preserved pulmonary function had used
inhaled bronchodilators, as compared with 8%
of asymptomatic current or former smokers
(P<0.001), and 23% had used inhaled glucocorticoids (vs. 3%, P<0.001) (Table S1 in the Supplementary Appendix). In sensitivity analyses, we
excluded participants with any history of asthma
and found that 29% of symptomatic current or
former smokers with preserved pulmonary function used inhaled bronchodilators and 22% used
inhaled glucocorticoids.
Discussion
In this longitudinal study, we found that respiratory symptoms, as measured by the CAT instrument, were common in current or former smokers, despite FEV1:FVC and FVC values that were
in the range that is generally considered to be
normal. Current or former smokers with preserved pulmonary function and a CAT score of
10 or more were more likely than those with
lower CAT scores to have respiratory exacerbations, a shorter 6-minute walk distance, evidence
of occult airway disease characterized by slightly
lower lung function (e.g., with regard to FEV1,
FVC, and inspiratory capacity), and greater airwaywall thickening. In contrast, the percent emphysema was low and similar among current or
former smokers with preserved pulmonary function who were symptomatic and those who were
asymptomatic.
Our findings were robust even with adjustment
of the analyses for several important potential
confounders. Concomitant asthma can confound
CAT scores in current or former smokers.15 Although adults with a new diagnosis of COPD
nejm.org
May 12, 2016

FEV1:FVC Cutoff to Define Obstruction
Prospective Annualized Exacerbation Rate
0.6
0.65
LLN
0.70
0.75
*
*
*
0.5
*
0.4
0.3
*
*
0.2
0.1
0.0
Controls Who Never

Smoked
Current or Former
Smokers,
FEV1:FVC
Specified Cutoff,
CAT<10
Current or Former
Smokers,
FEV1:FVC
Specified Cutoff,
CAT10
Current or Former
Smokers,
FEV1:FVC
<Specified Cutoff,
CAT<10
Current or Former
Smokers,
FEV1:FVC
<Specified Cutoff,
CAT10
Figure 3. Effect on Prospective Exacerbation Rates of Different FEV1:FVC Cutoffs to Define Preserved Pulmonary
Function.
Shown are the prospective annualized exacerbations rates of any exacerbation, according to different cutoffs of the
ratio of the forced expiratory volume in 1 second (FEV1) to the FVC. The definition of preserved pulmonary function
that was based on the lower limit of the normal range (LLN) for the FEV1:FVC or that used an FEV1:FVC cutoff of
0.65 did not significantly change the predictive value of the CAT score for any exacerbation. The definition that was
based on an FEV1:FVC cutoff of 0.75 weakened the predictive value of the CAT score for any exacerbation, although
the sample size was smaller with an FEV1:FVC cutoff of 0.75 than with a cutoff of 0.70 (577 vs. 849 persons). Asterisks
indicate a P value of less than 0.05, and the dagger a P value of 0.07, with Bonferroni correction for multiple comparisons, for the comparison with current or former smokers with a FEV1:FVC equal to or greater than the specified
cutoff and a CAT score of less than 10.
can occasionally receive an incorrect diagnosis

of asthma, we assessed the effect of asthma by
performing sensitivity analyses that controlled
for and then excluded persons on the basis of a
previous diagnosis of asthma (diagnosed during
childhood or ever). Because retrospective data
suggest that patients with COPD and coexisting
conditions may be at higher risk for symptoms
than those without coexisting conditions,16,17 we
also controlled for relevant coexisting conditions,
including congestive heart failure and gastroesophageal reflux disease.
Obesity can cause abnormal findings on spirometry and accentuate dyspnea.18,19 Extremely
obese persons (BMI, >40) were excluded from
this study. However, we also controlled for BMI
in multivariate analyses, and our findings persisted. Active cigarette smoking can cause cough
and sputum without apparent airway obstruction, a condition that has been termed simple
n engl j med 374;19
chronic bronchitis20 or nonobstructive chronic

bronchitis.2 However, our multivariate and stratified analyses indicate that current smoking
does not explain the elevated exacerbation rates
that we observed. Nonetheless, despite our efforts, it remains possible that other coexisting
conditions, such as undiagnosed cardiovascular
and metabolic abnormalities, could contribute to
symptoms and some respiratory exacerbations
in these persons, as they do in persons with
COPD.21,22 Clinical trials are needed to determine
whether maintenance therapy with bronchodilators or inhaled glucocorticoids will alleviate
symptoms and reduce the rate of respiratory
exacerbations in this group.
Our findings agree with and extend previously
published data, including studies that document
exacerbation-like events in smokers without airway obstruction23,24 and an association between an
increased percentage of lung that is affected by
nejm.org
May 12, 2016

1819
The
emphysema and increased mortality among persons without airway obstruction25 and a study that
previously challenged the notion of healthy
smokers by showing the presence of respiratory
symptoms, activity limitations, and abnormalities
on HRCT in smokers who did not have airway
obstruction.26 Our data add to these previous
publications by showing that chronic symptoms
precede the exacerbations, by showing that a
clinically useful tool (the CAT) can identify
smokers at risk for exacerbations, and by providing evidence for the type of lung disease these
symptomatic persons may have (airway disease
rather than emphysema).
Our results also raise the question of whether
the clinical definition of COPD should be adjusted or whether a new entity that includes the
population of patients with smoking-related
chronic pulmonary disease who do not meet the
standard criteria for airway obstruction should
be considered. Although these current or former
smokers with symptoms had spirometric results
at enrollment that are generally considered to be
normal, we do not know their best lung function. Thus, it is possible that had we been able
to obtain measurements of lung function in the
cohort of symptomatic participants in the years
before they were enrolled in the study, we would
have been able to compare the lung function at
enrollment with the lung function at an earlier
time point and show that obstruction had developed in these participants, even though they did
not meet spirometric criteria for airway obstruction at enrollment.
This study has an important limitation. We
did not enroll a random sample and cannot estimate the population prevalence of symptoms
of
m e dic i n e
among current or former smokers with preserved

pulmonary function. Indeed, some participants
may have volunteered for this study because of
symptoms. Neither point invalidates the central
conclusion that some smokers with symptoms
have exacerbations that are suggestive of COPD
and that these persons are being treated as if
they had COPD even though they do not meet
the current criteria for a diagnosis of COPD.
In conclusion, respiratory symptoms and exacerbations are common in current or former
smokers who have spirometric values that are
generally considered to be within the normal
range. Many of these patients are already being
treated with respiratory medications despite a
lack of data from clinical trials. This finding
suggests that the current use of spirometry to
define who should receive a diagnosis of COPD
may not adequately cover the breadth of symptomatic smoking-related lung disease. Clinical
trials that are directed at this large and understudied population may provide better insight
into appropriate treatment strategies for these
patients.
Supported by grants (HHSN2682009000019C, HHSN268200900013C, HHSN268200900013C, HHSN268200900014C,
HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, and
HHSN268200900020C) from the National Heart, Lung, and
Blood Institute of the National Institutes of Health and by the
Foundation for the National Institutes of Health through contributions made to an external advisory board that includes members from AstraZeneca, Bellerophon Therapeutics, BoehringerIngelheim Pharmaceuticals, Chiesi Farmaceutici, Forest
Research Institute, GlaxoSmithKline, Grifols Therapeutics,
Ikaria, Nycomed, Takeda Pharmaceutical, Novartis Pharmaceuticals, Regeneron Pharmaceuticals, and Sanofi.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Susan Murray, Sc.D., for statistical advice.
Appendix
The authors affiliations are as follows: the Cardiovascular Research Institute (P.G.W., S.C.L.) and the Department of Medicine, Division
of Pulmonary, Critical Care, Sleep, and Allergy (P.G.W., S.A.C., S.C.L.), University of California at San Francisco, San Francisco; the
Departments of Medicine and Epidemiology, Columbia University Medical Center (R.G.B.), and the Department of Medicine, WeillCornell Medical College (F.J.M.) both in New York; the Department of Medicine, Center for Genomics and Personalized Medicine Research, Wake Forest University, Winston-Salem (E.B.), and the Department of Biostatistics, University of North Carolina at Chapel Hill,
Chapel Hill (D.C., N.A.G.) both in North Carolina; the Section of Pulmonary and Critical Care Medicine, Medical Service, Veterans
Affairs Ann Arbor Healthcare System (J.L.C.), and the Department of Medicine, Division of Pulmonary and Critical Care Medicine,
University of Michigan (J.L.C., M.K.H.) both in Ann Arbor; the Department of Medicine, Division of Pulmonary and Critical Care
Medicine, Johns Hopkins University School of Medicine, Baltimore (N.N.H.); the Department of Radiology, University of Iowa Carver
College of Medicine, Iowa City (E.A.H.); the Department of Medicine, University of Utah Hospitals and Clinics, Salt Lake City (R.E.K.,
R.P.); the Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles (E.K., D.P.T.);
the Department of Medicine, University of Nebraska Medical Center, Omaha (S.R.); and the Clinical Discovery Unit, AstraZeneca, Cambridge, United Kingdom (S.R.).
1820
n engl j med 374;19
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May 12, 2016

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Copyright 2016 Massachusetts Medical Society.
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new england

May 12, 2016

Clinical Significance of Symptoms in Smokers

Currently, the diagnosis of chronic obstructive pulmonary disease (COPD) requires

We conducted an observational study involving 2736 current or former smokers and

The authors affiliations are listed in the

May 12, 2016

The New England Journal of Medicine

with restrictive disease as having COPD. We then

In this multicenter observational study funded

May 12, 2016

The New England Journal of Medicine

Symptoms in Smokers with Preserved Pulmonary Function

(office visit, hospital admission, or emergency

The investigators performed the data analysis

of events per person, divided by the number of

We categorized current or former smokers into

May 12, 2016

The New England Journal of Medicine

Table 1. Characteristics of the Participants at Baseline.*

Current or Former Smokers

Significant between-group difference

Percentage of overall study population

Symptoms of chronic bronchitis

n engl j med 374;19

May 12, 2016

The New England Journal of Medicine

Symptoms in Smokers with Preserved Pulmonary Function

Current or Former Smokers

Childhood diagnosis of asthma

our definition of symptoms was based on the

n engl j med 374;19

Exacerbations and Activity Limitation

The median prospective follow-up time was 829

May 12, 2016

The New England Journal of Medicine

asymptomatic current or former smokers (89.3

lung function (Table S2 in the Supplementary

Airway Disease and Emphysema

Given the significant differences in age, race,

n engl j med 374;19

Baseline CAT Score

Symptomatic current or former smokers with

Figure 1. Prevalence of Respiratory Symptoms,

May 12, 2016

The New England Journal of Medicine

Symptoms in Smokers with Preserved Pulmonary Function

Prospective Annualized Exacerbation Rate

Controls Who Never

score, 10) were associated with elevations in all

score and risk of exacerbation in the first year of

May 12, 2016

The New England Journal of Medicine

18.10 (4.77 68.67)

Leading to health care utilization

n engl j med 374;19

In the 3 months before enrollment in the study,

May 12, 2016

The New England Journal of Medicine

Symptoms in Smokers with Preserved Pulmonary Function