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Interstitial Features at Chest CT Enhance

the Deleterious Effects of Emphysema in the
COPDGene Cohort
Samuel Y. Ash, MD, MPH  •  Rola Harmouche, PhD  •  James C. Ross, PhD  •  Alejandro A. Diaz, MD, MPH  • 
Farbod N. Rahaghi, MD, PhD  •  Gonzalo Vegas Sanchez-Ferrero, PhD  •  Rachel K. Putman, MD, MPH  • 
Gary M. Hunninghake, MD, MPH  •  Jorge Onieva Onieva, MSc  •  Fernando J. Martinez, MD, MS  • 
Augustine M. Choi, MD  •  Russell P. Bowler, MD, PhD  •  David A. Lynch, MD  •  Hiroto Hatabu, MD, PhD  • 
Surya P. Bhatt, MD  •  Mark T. Dransfield, MD  •  J. Michael Wells, MD  •  Ivan O. Rosas, MD  • 
Raul San Jose Estepar, PhD  •  George R. Washko, MD  •  for the COPDGene Investigators
From the Division of Pulmonary and Critical Care Medicine, Department of Medicine (S.Y.A., A.A.D., F.N.R., R.K.P., G.M.H., I.O.R., G.R.W.), Laboratory of Math-
ematics in Imaging, Department of Radiology (R.H., J.C.R., G.V.S., J.O.O., R.S.J.E.), and Department of Radiology (H.H.), Brigham and Women’s Hospital, 75 Francis
St, PBB CA-3, Boston, MA 02115; Department of Medicine, Weil Cornell Medical College, New York, NY (F.J.M., A.M.C.); Departments of Medicine (R.P.B.) and
Radiology (D.A.L.), National Jewish Health, Denver, Colo; and Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of
Alabama at Birmingham, Birmingham, Ala (S.P.B., M.T.D., J.M.W.). Received November 20, 2017; revision requested January 10, 2018; final revision received February
6, accepted February 6. Address correspondence to S.Y.A. (e-mail: syash@partners.org).
Study supported by the National Heart, Lung, and Blood Institute (R01 HL089897, R01 HL089856). The COPDGene study (NCT00608764) is also supported by
the COPD Foundation through contributions made to an Industry Advisory Board composed of AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, Pfizer,
Siemens, and Sunovion. Additional funding for this work includes the following National Institutes of Health grants: 5-T32-HL007633-30 (to S.Y.A. and R.K.P.), R01-
HL107246 (to R.H., J.O.O., R.S.J.E., and G.R.W.), R01-HL116933 (to R.H., J.C.R., J.O.O., R.S.J.E., and G.R.W.), R01-HL111024 (to G.M.H.), P01-HL114501
(to A.M.C., I.O.R., and G.R.W.) and R01-HL089856 (to J.C.R., D.A.L., R.S.J.E., and G.R.W.). G.R.W. supported by Boehringer Ingelheim. S.Y.A. supported by the
Pulmonary Fibrosis Foundation (the I.M. Rosenzweig Junior Investigator Award).
Conflicts of interest are listed at the end of this article.
See also the editorial by Grenier in this issue.

Radiology 2018; 288: 600–609 • https://doi.org/10.1148/radiol.2018172688 • Content codes:

Purpose:  To determine if interstitial features at chest CT enhance the effect of emphysema on clinical disease severity in smokers
without clinical pulmonary fibrosis.

Materials and Methods:  In this retrospective cohort study, an objective CT analysis tool was used to measure interstitial features
(reticular changes, honeycombing, centrilobular nodules, linear scar, nodular changes, subpleural lines, and ground-glass opacities)
and emphysema in 8266 participants in a study of chronic obstructive pulmonary disease (COPD) called COPDGene (recruited
between October 2006 and January 2011). Additive differences in patients with emphysema with interstitial features and in those
without interstitial features were analyzed by using t tests, multivariable linear regression, and Kaplan-Meier analysis. Multivariable
linear and Cox regression were used to determine if interstitial features modified the effect of continuously measured emphysema
on clinical measures of disease severity and mortality.

Results:  Compared with individuals with emphysema alone, those with emphysema and interstitial features had a higher percent-
age predicted forced expiratory volume in 1 second (absolute difference, 6.4%; P , .001), a lower percentage predicted diffusing
capacity of lung for carbon monoxide (Dlco) (absolute difference, 7.4%; P = .034), a 0.019 higher right ventricular–to–left ven-
tricular (RVLV) volume ratio (P = .029), a 43.2-m shorter 6-minute walk distance (6MWD) (P , .001), a 5.9-point higher
St George’s Respiratory Questionnaire (SGRQ) score (P , .001), and 82% higher mortality (P , .001). In addition, interstitial
features modified the effect of emphysema on percentage predicted Dlco, RVLV volume ratio, 6WMD, SGRQ score, and
mortality (P for interaction , .05 for all).

Conclusion:  In smokers, the combined presence of interstitial features and emphysema was associated with worse clinical disease
severity and higher mortality than was emphysema alone. In addition, interstitial features enhanced the deleterious effects of em-
physema on clinical disease severity and mortality.
© RSNA, 2018

Online supplemental material is available for this article.

Smalities in the lungs, including both airspace dilatation

moking results in a wide range of parenchymal abnor-
and alveolar destruction in the form of emphysema and in-
flammation and scarring in the form of interstitial changes
and fibrosis (1,2). The presence of emphysema on chest
CT scans has been repeatedly demonstrated to be associ-
ated with worse physiologic measures such as lung func-
tion and exercise capacity, as well as with higher mortality
(3–5). Meanwhile, subtle visually and objectively defined
interstitial features in smokers without clinical interstitial
lung disease (ILD) or fibrosis have been shown to be as-
sociated with lower lung volumes, reduced exercise capac-
ity, and higher mortality (6–11). These features typically
include reticular changes, honeycombing, centrilobular
nodules, linear scar, nodular changes, subpleural line, and
ground-glass opacities that occur in the absence of clinical
or radiologic ILD, and they are often visually described as
interstitial lung abnormalities (ILAs) (7,8,11). However,

Abbreviations
CI = confidence interval, COPD = chronic obstructive pulmonary dis-
ease, Dlco = diffusing capacity of lung for carbon monoxide, FEV1 =
forced expiratory volume in 1 second, FVC = forced vital capacity,
ILA = interstitial lung abnormality, ILD = interstitial lung disease, RVLV =
right ventricular to left ventricular, SGRQ = St George’s Respiratory
Questionnaire, 6MWD = 6-minute walk distance
Summary
Among ever-smokers without interstitial lung disease, objectively identi-
fied interstitial features at chest CT enhanced the deleterious effects of
emphysema on diffusing capacity, exercise capacity, quality of life, and
mortality.
Implications for Patient Care
nn Even in the absence of interstitial lung disease, smokers with
emphysema and interstitial features, such as reticular changes,
honeycombing, centrilobular nodules, linear scar, nodular changes,
subpleural lines, and ground-glass opacities, at chest CT have
worse clinical disease severity and mortality than those with em-
physema alone.
nn Beyond this additive effect, the presence of interstitial features
enhances the deleterious effects of emphysema, highlighting the im-
portance of identifying these subtle interstitial features and the role
of CT in assessing the severity of smoking-related lung disease.
nn Because smokers with interstitial features at chest CT have worse
emphysema-related outcomes, they may be those most likely to
benefit from interventions such as smoking cessation.
whether these interstitial features modify the effect of emphyse-
ma on outcomes is unknown. We hypothesized that in smokers
with emphysema, the additional presence of interstitial features
would be associated with worse physiologic measures, reduced
exercise capacity, worse quality of life, and higher mortality. In
addition, we hypothesized that interstitial features would en-
hance the deleterious effect of emphysema on these outcomes.
Materials and Methods
Patient Selection
We performed our retrospective cohort study using clinical and
radiologic data from a study of chronic obstructive pulmonary
disease (COPD) called the COPDGene study, which has been
described elsewhere (10,12–15). Briefly, 10 306 smokers aged
45–80 years with at least a 10–pack-year history and a small
number of never-smoking “healthy” individuals were enrolled
at 21 clinical study centers in the United States between Oc-
tober 2006 and January 2011 and underwent baseline testing
that included an extensive interview, volumetric non—contrast
material–enhanced thin-section CT of the chest, and spirom-
etry (12). Participants were excluded from enrollment in the
COPDGene study if their predominant lung condition was ei-
ther bronchiectasis or ILD on the basis of a review of clinical or
imaging findings, as detailed in Appendix E1 (online). Because
of their lack of clear spirometric definition and their highly
heterogeneous clinical and genetic characteristics, individuals
with a preserved ratio and impaired spirometry (PRISm)—de-
fined as a reduced forced expiratory volume in 1 second (FEV1)
in the setting of preserved FEV1 to forced vital capacity (FVC)
Radiology: Volume 288: Number 2—August 2018  n  radiology.rsna.org 601
Ash et al
ratio—were eligible to enroll in COPDGene, but data in these
individuals were analyzed separately (12,16). As shown in Fig-
ure E1 (online), we performed the analyses in our study in
a “baseline” group and in three predefined subgroups: those
with follow-up (mortality) information, those with ventricu-
lar volume measurements, and those with diffusing capacity
of lung for carbon monoxide (Dlco) measurements. Individu-
als were excluded from the baseline group if they were never
smokers; if they had PRISm; or if they did not have complete
baseline imaging and clinical information for all of the spiro-
metric, exercise capacity, and respiratory health–related quality
of life outcomes and covariates. Follow-up of the COPDGene
participants is ongoing, and for our study we excluded indi-
viduals from the mortality analyses who did not have current
follow-up information. The ventricular volume measurements
were obtained from prior work, and data in those individu-
als in whom the measurements could not be performed were
excluded from our study (14). Finally, Dlco was measured at
one COPDGene site (National Jewish Health, Denver, Colo)
in a sample of convenience, and only individuals with Dlco
measurements were included in our diffusing capacity analy-
ses (15). The baseline COPDGene data set used for our study
was generated on August 31, 2016. The mortality COPDGene
data set used for our study was generated on December 18,
2016, with back censoring as described in Appendix E1 (on-
line). The COPDGene study was approved by the institutional
review boards at all the centers, and our study was approved as
an ancillary study by the COPDGene Ancillary Study Com-
mittee and the Partners Institutional Review Board (Boston,
Mass). All of the participants in the COPDGene Study pro-
vided written informed consent and Health Insurance Porta-
bility and Accountability Act authorization. Additional details
regarding our study design and the COPDGene study design
are available in Appendix E1 (online).
CT Analyses
Two forms of objective CT analysis were performed in our
study: classification of the lung parenchyma and measurement
of the right ventricular and left ventricular volume. These
methods have been described previously and are described in
detail in Appendix E1 (online) (4,6,14).
A detailed description of the parenchymal analysis tool used
for this study is available in Appendix E1. Briefly, our approach
used the local tissue density histogram characteristics of a partic-
ular portion of lung tissue combined with that region’s distance
from the pleural surface to label that area as a particular tissue
subtype (4,6,13). By using this method, each portion of the lung
parenchyma was labeled as a particular radiologic tissue type.
These parenchymal tissue types included normal parenchyma;
emphysema, which was defined as centrilobular emphysema,
paraseptal emphysema, and panlobular emphysema; and inter-
stitial features, which were defined as reticular changes, honey-
combing, centrilobular nodules, linear scar, nodular changes,
subpleural line, and ground-glass opacities (Fig E2 [online]).
The aggregate volume of these radiologic tissue type volumes
were summed to the total CT lung volume for each patient, and
the radiologic tissue type volumes were expressed as a percentage
Interstitial Features at CT Modify the Effects of Emphysema in the COPDGene Cohort

Table 1: Baseline Clinical and Imaging Characteristics

Individuals without Individuals with

Characteristic Entire Cohort Interstitial Features Interstitial Features P Value
No. of participants
  Baseline cohort 8266 (100) 7197 (87.1) 1069 (12.2) …
  Diffusing capacity analysis 352 316 (90.0) 36 (10.2) …
  Ventricular geometry analysis 7407 6490 (87.6) 917 (12.4) …
  Mortality analysis 7253 6369 (87.8) 884 (12.2) …
  Follow-up analysis* 7253 (76.1) 6349 (76.4) 884 (73.8) …
  Age (y)† 59.8 6 9.1 59.7 6 9.0 60.8 6 9.4 .001
  No. of women 3757 (45.5) 3164 (44.0) 593 (55.5) ,.001
  No. of African Americans 2600 (31.5) 2069 (28.8) 531 (49.7) ,.001
Clinical characteristics
  Body mass index (kg/m2)† 28.4 6 5.9 28.2 6 5.9 29.6 6 6.2 ,.001
  No. of pack-years smoked 44.3 6 24.9 44.1 6 24.6 45.6 6 26.9 .086
  Currently smoking 4256 (51.5) 3650 (50.7) 606 (56.7 ,.001
  Percentage predicted FEV1† 77.7 6 26.6 77.8 6 27.0 76.8 6 23.8 .200
  Percentage predicted FVC† 89.4 6 17.9 89.8 6 18.0 87.0 6 17.5 ,.001
  Percentage predicted Dlco† 49.9 6 20.5 49.8 6 20.5 50.9 6 20.8 .764
  6MWD (m)† 417 (121 423.7 6 120.2 373.7 6 123.0 ,.001
  SGRQ score† 26.5 6 21.2 25.9 6 22.5 30.8 6 23.8 ,.001
Mortality analyses
  Duration of follow-up (y)† 6.3 6 1.4 6.4 6 1.4 6.2 6 1.6 ,.001
  Mortality rate 951 (13.1) 803 (12.6) 148 (16.7) .001
Objective analysis†
  Percentage of lung occupied by interstitial changes 5.9 6 4.5 4.5 6 2.3 14.8 6 5.5 …
  Percentage of lung occupied by emphysematous changes 10.2 6 17.1 10.7 6 17.7 6.9 6 12.1 ,.001
  RVLV volume ratio 0.51 6 0.10 0.51 6 0.10 0.51 6 0.10 .442
Note.—Unless otherwise specified, data are numbers of patients, with percentages in parentheses. Percentages may not add up to 100%
because of rounding. P values for comparison between individuals with and those without interstitial features were based on the t test for
continuous variables and the Fisher exact test for categoric variables. Dlco = diffusing capacity of lung for carbon monoxide, FEV1 = forced
expiratory volume in 1 second, FVC = forced vital capacity, SGRQ = St George’s Respiratory Questionnaire, 6MWD = 6-minute walk
distance, RVLV = right ventricular to left ventricular.
* Data in parentheses are mean lengths of follow-up in months.
†
Data are means 6 standard deviations.

of total lung volume (ie, percentage normal, percentage emphy-
sema, and percentage interstitial features).
The right ventricular–to–left ventricular (RVLV) volume ratio
measurement technique involved the use of a statistical model of
the heart’s surface developed from anatomic segmentations ob-
tained from individuals with a range of cardiac diseases and disor-
ders (14). From these surface-fitting models, measures of cardiac
morphology, including estimates of both the epicardial (wall and
chamber) and endocardial (chamber) volume of each ventricle,
can be extracted. For the analyses, the epicardial volumes were
used to calculate the RVLV volume ratio (ratio of right ventricular
epicardial volume to left ventricular epicardial volume) (14).
Definition of Disease
The percentage of lung occupied by emphysematous and inter-
stitial features was measured and analyzed both continuously
and as present versus absent (dichotomized). For the dichoto-
mized analyses, there are limited guidelines for what thresholds
to use to define the presence or absence of emphysema and
interstitial changes using objective CT analysis. Several stud-
ies (17,18) have used other techniques to determine normal
ranges of emphysema, but these have largely been limited to
non-smoking populations or to other forms of CT (eg, car-
diac). Others have suggested that 10% of the lung occupied by
emphysema is a reasonable, albeit arbitrary, threshold to define
the presence of disease (19–22). However, more recent work
in individuals with advanced interstitial disease suggests that
a threshold of 15% identifies those at a higher risk for decline
in lung function (2). Because we were specifically interested in
the interaction between emphysema and interstitial features,
we selected this latter threshold.
With regard to interstitial features, to our knowledge, there
is limited work identifying an objective threshold to define
early or mild interstitial features such as visually defined ILAs.
Although the visual definition of ILAs requires that they oc-
cupy more than 5% of any lung zone, previous work suggests
that when using the objective approach utilized in our study,
this threshold may be overly sensitive and nonspecific, result-
ing in a large percentage of the cohort being defined as having
interstitial features (7,11,13). Because of this, we selected 10%

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 Ash et al

Figure 1:  A–D, Representative axial CT images in individuals with and those without interstitial features but with simi-
lar percentages of lung occupied by emphysema show the effects of the presence of interstitial features. A, B, Images
in a 74-year-old man with interstitial features (percentage interstitial = 14.3%). The percentage of his lung occupied by
emphysema was 20.7%. His St George’s Respiratory Questionnaire (SGRQ) score was 48. His 6-minute walk distance
was 225 m. His right ventricular–to–left ventricular volume ratio was 0.75. He died during follow-up. C, D, Images in
a 73-year-old man without interstitial features (percentage interstitial = 6.1%). The percentage of his lung occupied by
emphysema was 20.5%. His SGRQ score was 53. His 6-minute walk distance was 480 m. His right ventricular–to–left
ventricular volume ratio was 0.61. He did not die during follow-up.

as the threshold for our study. Of note, this threshold resulted
in a prevalence of participants with interstitial features similar
to that reported in prior visual analyses of smokers (7,11).
Although these cutoffs were used in the primary analyses, to
evaluate the possibility that the observed associations were due
to the cutpoints selected, the interaction between emphysema
and interstitial features was also analyzed by using a contin-
uous-by-continuous interaction term. Details are available in
Appendix E1 (online).
between those with emphysema alone and those with emphy-
sema and interstitial features with regard to the following: the
percentage predicted FEV1, the percentage predicted FVC,
the percentage predicted Dlco, the 6-minute walk distance
(6MWD) in meters, the RVLV volume ratio, and the total
St George’s Respiratory Questionnaire (SGRQ) score (23).
Kaplan-Meier analysis, the log-rank test, and multivariable
Cox regression were used to determine if there was a difference
in mortality between these two groups.

Statistical Analyses Effect modification.—Pearson correlation and univariable

The Student t test and Fisher exact test were used to determine
if there were baseline differences between individuals with and
those without interstitial features.
Additive effect.—Student t testing and multivariable linear
regression were used to determine if there was a difference
linear regression were used to determine the univariable as-
sociations between emphysema and continuous outcomes in
individuals with and those without interstitial features. An in-
teraction term was created to test for the interaction between
continuously measured emphysema and the presence or ab-
sence of interstitial features. As mentioned above and as de-

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Interstitial Features at CT Modify the Effects of Emphysema in the COPDGene Cohort

Figure 2:  Plots show association between percentage predicted forced expiratory volume in 1 second (FEV1) and emphysema in individuals
with and those without interstitial features. (a) Univariable additive effect of interstitial features and emphysema. SD = standard deviation. (b)
Interaction between interstitial features and emphysema. Interstitial features were defined as present if more than 10% of the lung was occupied by
interstitial features. For a, emphysema was defined as present if more than 15% of the lung was occupied by emphysematous features. Units for b
are (percentage predicted forced expiratory volume in 1 second)/(percentage emphysema). ∗ 5 P for interaction given for multivariable analysis,
which was additionally adjusted for age, sex, race, clinical center, current smoking status, number of pack-years smoked, and body mass index.

Figure 3:  Plots show association between percentage predicted forced vital capacity (FVC) and emphysema in individuals with and those with-
out interstitial features. (a) Univariable additive effect of interstitial features and emphysema. SD = standard deviation. (b) Interaction between
interstitial features and emphysema. Interstitial features were defined as present if more than 10% of the lung was occupied by interstitial features.
For a, emphysema was defined as present if more than 15% of the lung was occupied by emphysematous features. Units for b are (percentage
predicted forced vital capacity)/(percentage emphysema). ∗ = P for interaction given for multivariable analysis, which was additionally adjusted
for age, sex, race, clinical center, current smoking status, number of pack-years smoked, and body mass index.

tailed in Appendix E1 (online), an additional interaction term
was created to test for the interaction between continuously
measured emphysema and continuously measured interstitial
features. Multivariable linear and Cox regression were used to
determine whether the presence of interstitial features modi-
fied the effect of emphysema on the continuously measured
outcomes and mortality.
Multivariable linear regression analyses were adjusted for
age, sex, race, clinical center, current smoking status, num-
ber of pack-years smoked, body mass index, and percent-
age predicted FEV1, except for the spirometric measures,
which were not adjusted for percentage predicted FEV1. The
multivariable Cox regression analyses were adjusted for the
same covariates as the multivariable linear models as well
as for CT-measured total coronary calcium score calculated
by using previously described methods (24,25). All of the
variables were assessed by using the Schoenfeld residuals
method, and all satisfied the proportional hazards assump-
tion with the exception of current smoking status; therefore,
the adjusted Cox models were stratified according to current
smoking status (26).
The reported P values are two sided, P , .05 was considered to
indicate statistical significance, and all analyses were performed by
using SAS, version 9.4, or JMP, version 12 (Cary, NC).
Results
As shown in Table 1 the cohort was largely white, with a
mean age of 59.8 years, and it had a slight male predominance
(4509 [54.5%] of 8266). A total of 8266 participants had base-
line clinical and imaging data available, including spiromet-

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 Ash et al

Figure 4:  Plots show association between percentage predicted diffusing capacity of lung for carbon monoxide and emphysema in individu-
als with and those without interstitial features. (a) Univariable additive effect of interstitial features and emphysema. SD = standard deviation. (b)
Interaction between interstitial features and emphysema. Interstitial features were defined as present if more than 10% of the lung was occupied by
interstitial features. For a, emphysema was defined as present if more than 15% of the lung was occupied by emphysematous features. Units for b
are (percentage predicted diffusing capacity of lung for carbon monoxide)/(percentage emphysema). ∗ = P for interaction given for multivariable
analysis, which was additionally adjusted for age, sex, race, clinical center, current smoking status, number of pack-years smoked, body mass in-
dex, and percentage predicted forced expiratory volume in 1 second. There were 352 data points available for diffusing capacity analysis.

Figure 5:  Plots show association between right ventricular–to–left ventricular volume ratio in individuals with and those without interstitial fea-
tures. (a) Univariable additive effect of interstitial features and emphysema. SD = standard deviation. (b) Interaction between interstitial features
and emphysema. Interstitial features were defined as present if more than 10% of the lung was occupied by interstitial features. For a, emphysema
was defined as present if more than 15% of the lung was occupied by emphysematous features. Units for b are (right ventricular–to–left ventricular
volume ratio)/(percentage emphysema). ∗ = P for interaction given for multivariable analysis, which was additionally adjusted for age, sex, race,
clinical center, current smoking status, number of pack-years smoked, body mass index, and percentage predicted forced expiratory volume in 1
second. There were 7407 data points available for right ventricular–to–left ventricular volume ratio analysis.

ric data. Of these participants, 352 had percentage predicted
Dlco measurements available, 7407 had ventricular geometry
measurements available, and 7253 had mortality data available
(mean duration of follow-up, 6.3 years 6 1.5 [standard de-
viation]) (Table 1 and Fig E1 [online]). Those with interstitial
features were older, were more likely to be female, were more
likely to be African-American, had a higher body mass index,
lower lung function, a shorter 6MWD, and a higher SGRQ
score. Representative CT images in individuals with and those
without interstitial features who had similar amounts of em-
physema are shown in Figure 1.
Compared with those with emphysema alone, individuals
with both emphysema and interstitial features had a 6.4%
higher percentage predicted FEV1 (95% confidence inter-
val [CI]: 3.0%, 9.9%; P , .001), a 7.4% lower percentage
predicted Dlco (95% CI: 214.2%, 20.6%; P = .034), a
0.019 higher RVLV volume ratio (95% CI: 0.002, 0.037; P =
.029), a 43.2-m shorter 6MWD (95% CI: 258.7,227.7; P
, .001), and a 5.9-point higher SGRQ score (95% CI: 3.2,
8.7; P , .0001) (Figs 2–7, Table 2). In addition, as shown
in Figures 2–7 and Table 3, as compared with individuals
without interstitial features, in individuals with interstitial
features, the percentage of lung occupied by emphysema was
associated with a greater (more negative) effect on percentage
predicted Dlco (P for interaction = .013) and 6MWD (P for
interaction = .015), as well as a greater (more positive) effect

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Interstitial Features at CT Modify the Effects of Emphysema in the COPDGene Cohort

Figure 6:  Plots show association between 6-minute walk distance in individuals with and those without interstitial features. (a) Univariable addi-
tive effect of interstitial features and emphysema. SD = standard deviation. (b) Interaction between interstitial features and emphysema. Interstitial
features were defined as present if more than 10% of the lung was occupied by interstitial features. For a, emphysema was defined as present
if more than 15% of the lung was occupied by emphysematous features. Units for b are (meters)/(percentage emphysema). ∗ = P for interaction
given for multivariable analysis, which was additionally adjusted for age, sex, race, clinical center, current smoking status, number of pack-years
smoked, body mass index, and percentage predicted forced expiratory volume in 1 second.

Figure 7:  Plots show association between St George’s Respiratory Questionnaire total score in individuals with and those without interstitial fea-
tures. (a) Univariable additive effect of interstitial features and emphysema. SD = standard deviation. (b) Interaction between interstitial features
and emphysema. Interstitial features were defined as present if more than 10% of the lung was occupied by interstitial features. For a, emphysema
was defined as present if more than 15% of the lung was occupied by emphysematous features. Units for b are (St George’s Respiratory Question-
naire total score)/(percentage emphysema). ∗ = P for interaction given for multivariable analysis, which was additionally adjusted for age, sex,
race, clinical center, current smoking status, number of pack-years smoked, body mass index, and percentage predicted forced expiratory volume
in 1 second.

on RVLV volume ratio (P for interaction = .011) and SGRQ
score (P for interaction = .002).
Finally, the presence of both emphysema and interstitial
features was associated with an 82% greater mortality than em-
physema alone (hazard ratio, 1.82; 95% CI: 1.36, 2.43, P ,
.001) (Fig 8), and in individuals with interstitial features, the
percentage of lung occupied by emphysema was associated with
a greater effect (worsening) on mortality than in those with em-
physema alone (Table 4) (P for interaction = .037).
In the continuous-by-continuous interaction analyses, there
was evidence that the percentage of interstitial features modi-
fied the effect of emphysema with regard to percentage predicted
Dlco (P for interaction = .006), RVLV volume ratio (P for inter-
action , .001), 6MWD (P for interaction , .001), and SGRQ
score (P for interaction , .001) (Table E1 [online]). Evidence of
such interaction was present in the unadjusted continuous-by-
continuous mortality analysis but not in the adjusted analysis (P
for interaction = .004 and P for interaction = .180, respectively)
(Table E2 [online]).
Discussion
Among participants in the COPDGene cohort with emphy-
sema, the presence of interstitial features was associated with
worse physiologic measures, reduced exercise capacity, worse
respiratory health–related quality of life, and higher mortal-
ity. In addition, interstitial features intensified the effect of
emphysema on those outcomes. These findings suggest that
emphysema is more deleterious in patients with interstitial
features than in those with emphysema alone. Ever-smokers
with both high-attenuation features (interstitial features) and

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 Ash et al

Table 2: Comparison of Continuous Outcomes in Individuals with Emphysema Only versus Individuals with Emphy-
sema and Interstitial Features

Parameter Difference 95% CI P Value

Percentage predicted FEV1 6.4 3.0, 9.9 ,.001
Percentage predicted FVC 1.8 21.3, 5.0 .254
Percentage predicted Dlco 27.4 214.2, 20.6 .034
Right ventricular–to–left ventricular volume ratio 0.019 0.002, 0.037 .029
6-Minute walk distance (m) 243.2 258.7, 227.7 ,.001
St George's Respiratory Questionnaire total score 5.9 3.2, 8.7 ,.001
Note.—Outcomes are expressed as differences between individuals with emphysema and interstitial features compared with those with only
emphysema (eg, in patients with both emphysema and interstitial features, the mean 6-minute walk distance was 43.2 meters shorter than
in those with emphysema alone). All analyses were adjusted for age, sex, race, clinical center, current smoking status, number of pack-years
smoked, body mass index, and percentage predicted forced expiratory volume in 1 second (FEV1), except for the spirometric measures,
which were not adjusted for percentage predicted FEV1. CI = confidence interval, Dlco = diffusing capacity of lung for carbon monoxide,
FVC = forced vital capacity.

Table 3: Effect of Interaction between Emphysema (Measured Continuously) and Interstitial Features (Present vs
Absent) on Continuous Outcomes

Percentage Emphysema (Effect Presence of Interstitial Features Interaction: Percentage Emphysema with
per 1% Increase) (Present vs Absent) Presence of Interstitial Features

Effect Effect Effect P for

Parameter Estimate 95% CI P Value Estimate 95% CI P Value Estimate 95% CI Interaction
Percentage 20.90 20.93, 20.87 ,.001 23.81 25.29, 22.32 ,.001 0.05 20.05, 0.15 .335
  predicted FEV1
Percentage 20.36 20.38, 20.33 ,.001 23.63 24.83, 22.43 ,.001 0.06 20.02, 0.14 .156
  predicted FVC
Percentage 20.33 20.41, 20.25 ,.001 23.33 29.70, 3.05 .305 20.39 20.70, 20.08 .013
  predicted Dlco
RVLV volume 0.0005 0.0003, 0.0007 ,.001 0.002 20.006, 0.010 .691 0.0007 0.0001, 0.0012 .011
 ratio
6MWD (m) 23.41 23.94, 22.87 ,.001 251.93 274.62, 229.24 ,.001 21.90 23.43, 20.38 .015
SGRQ total score 0.17 0.14, 0.20 ,.001 1.60 0.30, 2.90 .016 0.14 0.05, 0.23 .002
Note.—Interstitial features were defined as present if more than 10% of the lung was occupied by interstitial features. All analyses were
adjusted for age, sex, race, clinical center, current smoking status, number of pack-years smoked, body mass index, and percentage predicted
forced expiratory volume in 1 second (FEV1), except for the spirometric measures, which were not adjusted for percentage predicted FEV1.
CI = confidence interval, Dlco = diffusing capacity of lung for carbon monoxide, FVC = forced vital capacity, RVLV = right ventricular to left
ventricular, SGRQ = St George’s Respiratory Questionnaire, 6MWD = 6-minute walk distance.

low-attenuation features (emphysema) at chest CT may be

Figure 8:  Graph shows survival in individuals with emphysema only
compared with that in those with both emphysema and interstitial fea-
tures. Numbers on x-axis = number surviving at each time point.
those most susceptible to the effects of chronic smoke-related
injury and may be most likely to benefit from smoking cessa-
tion and pharmacologic treatment.
The relationship between emphysema and worse outcomes
in COPD is well established and has been demonstrated by
using both densitometric and more advanced approaches for
the quantification of disease (4,5,19,27). Higher-attenuating
findings on chest radiographs and at CT are also highly preva-
lent in smokers with COPD and smokers without COPD. For
instance, a set of radiographic findings termed the “dirty chest”
has long been reported in patients with COPD (28). These
lesions seen on chest radiographs represent both airway abnor-
malities, such as increased airway wall thickness, and subtle
interstitial changes that have been sometimes termed ILAs
(11,28,29). Prior work (6,7,9–11,30) has demonstrated that
the visual or objective presence of these ILAs on the CT images

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Interstitial Features at CT Modify the Effects of Emphysema in the COPDGene Cohort
Table 4: Effect of the Interaction between Emphysema
and the Presence of Interstitial Features on Mortality
Parameter Hazard Ratio 95% CI P Value
Percentage of lung 1.008 1.004, 1.012 ,.001
 occupied by emphysema
(effect per 1% increase)
Presence of interstitial 1.542 1.200, 1.982 .001
  features (present vs absent)
Interaction term: percentage 1.011 1.001, 1.022 .037
 emphysema with presence
of interstitial features
Note.—Interstitial features were defined as present if more
than 10% of the lung was occupied by interstitial features. All
analyses were adjusted for age, sex, race, clinical center, current
smoking status, number of pack-years smoked, body mass index,
percentage predicted forced expiratory volume in 1 second, and
coronary calcium score. CI = confidence interval.
of smokers are associated with lower lung volumes, reduced
exercise capacity, and higher mortality in multiple cohorts.
However, their effect on the relationship between emphysema
and outcomes is unknown.
At the other end of the parenchymal disease spectrum, a
similar question exists of whether the presence of emphysema
modifies the effect of advanced fibrosis on outcomes such as
mortality and lung function decline. Although some studies
have shown the combination of diseases to be associated with
higher mortality compared with that in patients with idio-
pathic pulmonary fibrosis, other studies have shown a similar
or even improved survival of those with combined disease
(31–37). However, in general, when there has been an as-
sociation between combined disease and adverse outcomes,
the relationship has been additive. That is, the rate of adverse
outcomes expected is based on the total amount of lung oc-
cupied by either disease, without any effect modification of
one on the other (2).
In our study, we have shown that this may not be the case,
and that the presence of nonspecific interstitial features at chest
CT in patients with emphysema is not only associated with an
additive effect on physiologic measures such as Dlco, ancil-
lary findings associated with pulmonary hypertension such as
the RVLV volume ratio, exercise capacity, respiratory health–re-
lated quality of life, and mortality but also enhances the effect
of emphysema on those outcomes. These findings suggest that
high-attenuating features of smoking-related disease at CT may
represent a greater susceptibility to chronic smoking-related lung
injury and to the deleterious effects of that injury.
One strength of our study that may explain why we were
able to identify these relationships was the use of both additive
analyses and interaction terms to evaluate the effect of the pres-
ence of interstitial features on their impact on the relationship
between emphysema, mortality, and other clinical measures of
disease severity. In addition to the effect modification discussed
above, this approach revealed other subtle but clinically rel-
evant findings. For instance, in the additive analyses in patients
with emphysema, the additional presence of interstitial features
was associated with a higher percentage predicted FEV1 but
608 radiology.rsna.org  n  Radiology: Volume 288: Number 2—August 2018
no difference in percentage predicted FVC. Clinically, this re-
sults in the pseudonormalization of the FEV1/FVC ratio seen
in patients with combined pulmonary fibrosis and emphysema,
which makes spirometry alone nonsensitive to these clinically
relevant findings (38). This highlights the role of CT in assessing
smoking-related lung disease.
It should be stressed that the interstitial features detected us-
ing our automated approach are likely not, in all cases, the true
radiographic correlates of actual histopathologic fibrosis, but
rather are better thought of as subclinical imaging indexes of tis-
sue destruction, inflammation, and parenchymal remodeling in
response to smoke exposure (4,6,39). Further work is needed
that utilizes emphysema- and fibrosis-specific biomarkers, as well
as those related to inflammation and tissue remodeling, to help
determine whether the individuals at the highest risk are those
with more evidence of parenchymal inflammation, fibrosis, or
destruction. Our study did have several other limitations as well.
The cohort studied excluded those with a diagnosis of ILD, poten-
tially limiting the extension of these findings to those with more
advanced interstitial disease (12). In addition, a limited number
of participants had certain data available. For instance, Dlco was
available in only 4.3% of participants, potentially limiting the
interpretation of those findings. Both a limitation and a strength
of this work was the use of an automated detection algorithm
to identify emphysematous and interstitial features. Although
we ultimately hope to make this technique widely available and
implemented it using a widely available and open-source image-
processing tool (3D Slicer), it remains experimental, limiting its
widespread use (40). This approach did allow us to analyze a
large number of CT images and to measure CT features con-
tinuously, but although we have shown this technique to have
reasonable sensitivity and specificity for the detection of visually
defined ILAs, it does not provide precisely the same results as
visual analysis (4,6,13). Of note in this regard is the role of the
cutpoints selected to define the presence of emphysema and in-
terstitial features. As with any dichotomization of a continuous
variable, there is concern of a threshold effect such that the re-
sults are due to the cutpoint selected. As shown in Appendix E1
(online), the majority of the associations between emphysema
features, interstitial features, and outcomes were present in both
the dichotomized analyses and the continuous-by-continuous
analyses, suggesting that the findings were not cutpoint related.
Of note, the mortality findings in the continuous-by-continuous
analyses were statistically significant only in the unadjusted anal-
yses. Although this may be due to the high degree of collinearity
between the continuous-by-continuous interaction term and the
continuous measures of emphysema and interstitial features, we
cannot exclude a possible biologic or artifactual threshold effect
for mortality in particular.
In summary, in our large study utilizing automated CT
analysis, in those smokers with emphysema, the presence of
interstitial features was associated not only with worse physi-
ologic measures, respiratory health–related quality of life, and
higher mortality, but also with an intensified deleterious effect
of emphysema on those same outcomes. Further work is needed
to better understand the nature of this interaction and what its
underlying pathophysiologic mechanisms might be, but it does

suggest that the combination of high- and low-density changes
at chest CT in response to cigarette smoke exposure may indi-
cate a particularly high susceptibility to chronic smoking-related
diseases and their associated outcomes.
Author contributions: Guarantors of integrity of entire study, S.Y.A., G.V.S.,
G.M.H., G.R.W.; study concepts/study design or data acquisition or data analysis/
interpretation, all authors; manuscript drafting or manuscript revision for impor-
tant intellectual content, all authors; manuscript final version approval, all authors;
agrees to ensure any questions related to the work are appropriately resolved, all
authors; literature research, S.Y.A., G.M.H., S.P.B., J.M.W., G.R.W.; clinical stud-
ies, S.Y.A., G.M.H., F.J.M., D.A.L., H.H., M.T.D., G.R.W.; experimental studies,
S.Y.A., R.H., J.C.R., F.N.R., G.V.S., G.M.H., J.M.W., I.O.R., R.S.J.E., G.R.W.;
statistical analysis, S.Y.A., J.C.R., R.K.P., G.M.H., J.O.O., F.J.M., G.R.W.; and
manuscript editing, S.Y.A., A.A.D., F.N.R., G.V.S., R.K.P., G.M.H., F.J.M.,
A.M.C., D.A.L., H.H., S.P.B., M.T.D., J.M.W., I.O.R., R.S.J.E., G.R.W.
Disclosures of Conflicts of Interest: For financial and nonfinancial disclo-
sures by the authors, please see Appendix E1 (online).
References
1. Auerbach O, Garfinkel L, Hammond EC. Relation of smoking and age to findings
in lung parenchyma: a microscopic study. Chest 1974;65(1):29–35.
2. Cottin V, Hansell DM, Sverzellati N, et al. Effect of emphysema extent on serial lung
function in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med
2017;196(9):1162–1171.
3. Goddard PR, Nicholson EM, Laszlo G, Watt I. Computed tomography in pulmo-
nary emphysema. Clin Radiol 1982;33(4):379–387.
4. Castaldi PJ, San José Estépar R, Mendoza CS, et al. Distinct quantitative computed
tomography emphysema patterns are associated with physiology and function in
smokers. Am J Respir Crit Care Med 2013;188(9):1083–1090.
5. Müller NL, Staples CA, Miller RR, Abboud RT. “Density mask.” An objective method
to quantitate emphysema using computed tomography. Chest 1988;94(4):782–787.
6. Ash SY, Harmouche R, Putman RK, et al. Clinical and genetic associations of objec-
tively identified interstitial changes in smokers. Chest 2017;152(4):780–791.
7. Putman RK, Hatabu H, Araki T, et al. Association between interstitial lung abnor-
malities and all-cause mortality. JAMA 2016;315(7):672–681.
8. Hunninghake GM, Hatabu H, Okajima Y, et al. MUC5B promoter polymorphism
and interstitial lung abnormalities. N Engl J Med 2013;368(23):2192–2200.
9. Doyle TJ, Washko GR, Fernandez IE, et al. Interstitial lung abnormalities and re-
duced exercise capacity. Am J Respir Crit Care Med 2012;185(7):756–762.
10. Washko GR, Hunninghake GM, Fernandez IE, et al. Lung volumes and emphysema
in smokers with interstitial lung abnormalities. N Engl J Med 2011;364(10):897–906.
11. Washko GR, Lynch DA, Matsuoka S, et al. Identification of early interstitial lung
disease in smokers from the COPDGene Study. Acad Radiol 2010;17(1):48–53.
12. Regan EA, Hokanson JE, Murphy JR, et al. Genetic epidemiology of COPD
(COPDGene) study design. COPD 2010;7(1):32–43.
13. Ash SY, Harmouche R, Ross JC, et al. The objective identification and quantification
of interstitial lung abnormalities in smokers. Acad Radiol 2017;24(8):941–946.
14. Rahaghi FN, Vegas-Sanchez-Ferrero G, Minhas JK, et al. Ventricular geometry from
non-contrast non-ECG-gated CT scans: an imaging marker of cardiopulmonary dis-
ease in smokers. Acad Radiol 2017;24(5):594–602.
15. Nambu A, Zach J, Schroeder J, et al. Relationships between diffusing capacity for
carbon monoxide (DLCO), and quantitative computed tomography measurements
and visual assessment for chronic obstructive pulmonary disease. Eur J Radiol
2015;84(5):980–985.
16. Wan ES, Castaldi PJ, Cho MH, et al. Epidemiology, genetics, and subtyp-
ing of preserved ratio impaired spirometry (PRISm) in COPDGene. Respir Res
2014;15(1):89.
Radiology: Volume 288: Number 2—August 2018  n  radiology.rsna.org 609
Ash et al
17. Hoffman EA, Ahmed FS, Baumhauer H, et al. Variation in the percent of emphyse-
ma-like lung in a healthy, nonsmoking multiethnic sample: the MESA lung study.
Ann Am Thorac Soc 2014;11(6):898–907.
18. Oelsner EC, Carr JJ, Enright PL, et al. Per cent emphysema is associated with respi-
ratory and lung cancer mortality in the general population: a cohort study. Thorax
2016;71(7):624–632.
19. Schroeder JD, McKenzie AS, Zach JA, et al. Relationships between airflow obstruc-
tion and quantitative CT measurements of emphysema, air trapping, and airways in
subjects with and without chronic obstructive pulmonary disease. AJR Am J Roent-
genol 2013;201(3):W460–W470.
20. Zach JA, Newell JD Jr, Schroeder J, et al. Quantitative computed tomography of the
lungs and airways in healthy nonsmoking adults. Invest Radiol 2012;47(10):596–602.
21. Lee JH, Cho MH, McDonald ML, et al. Phenotypic and genetic heterogene-
ity among subjects with mild airflow obstruction in COPDGene. Respir Med
2014;108(10):1469–1480.
22. Mets OM, van Hulst RA, Jacobs C, van Ginneken B, de Jong PA. Normal range
of emphysema and air trapping on CT in young men. AJR Am J Roentgenol
2012;199(2):336–340.
23. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of
health status for chronic airflow limitation. The St. George’s Respiratory Question-
naire. Am Rev Respir Dis 1992;145(6):1321–1327.
24. Shemesh J, Henschke CI, Shaham D, et al. Ordinal scoring of coronary artery calci-
fications on low-dose CT scans of the chest is predictive of death from cardiovascular
disease. Radiology 2010;257(2):541–548.
25. Budoff MJ, Nasir K, Kinney GL, et al. Coronary artery and thoracic calcium on non-
contrast thoracic CT scans: comparison of ungated and gated examinations in patients
from the COPD Gene cohort. J Cardiovasc Comput Tomogr 2011;5(2):113–118.
26. Schoenfeld D. Partial residuals for the proportional hazards regression model.
Biometrika 1982;69(1):239–241.
27. Han MK, Kazerooni EA, Lynch DA, et al. Chronic obstructive pulmonary disease
exacerbations in the COPDGene study: associated radiologic phenotypes. Radiology
2011;261(1):274–282.
28. Gückel C, Hansell DM. Imaging the ‘dirty lung’--has high resolution computed
tomography cleared the smoke? Clin Radiol 1998;53(10):717–722.
29. Kirchner J, Goltz JP, Lorenz F, Obermann A, Kirchner EM, Kickuth R. The “dirty
chest”--correlations between chest radiography, multislice CT and tobacco burden.
Br J Radiol 2012;85(1012):339–345.
30. Podolanczuk AJ, Oelsner EC, Barr RG, et al. High attenuation areas on chest com-
puted tomography in community-dwelling adults: the MESA study. Eur Respir J
2016;48(5):1442–1452.
31. Jankowich MD, Rounds SIS. Combined pulmonary fibrosis and emphysema syn-
drome: a review. Chest 2012;141(1):222–231.
32. Todd NW, Jeudy J, Lavania S, et al. Centrilobular emphysema combined with pul-
monary fibrosis results in improved survival. Fibrogenesis Tissue Repair 2011;4(1):6.
33. Sugino K, Ishida F, Kikuchi N, et al. Comparison of clinical characteristics and prog-
nostic factors of combined pulmonary fibrosis and emphysema versus idiopathic
pulmonary fibrosis alone. Respirology 2014;19(2):239–245.
34. Doherty MJ, Pearson MG, O’Grady EA, Pellegrini V, Calverley PM. Cryptogenic
fibrosing alveolitis with preserved lung volumes. Thorax 1997;52(11):998–1002.
35. Jankowich MD, Rounds S. Combined pulmonary fibrosis and emphysema alters
physiology but has similar mortality to pulmonary fibrosis without emphysema. Hai
2010;188(5):365–373.
36. Kurashima K, Takayanagi N, Tsuchiya N, et al. The effect of emphysema on lung
function and survival in patients with idiopathic pulmonary fibrosis. Respirology
2010;15(5):843–848.
37. Cottin V. Combined pulmonary fibrosis and emphysema: bad and ugly all the same?
Eur Respir J 2017;50(1):1700846.
38. Cottin V. The impact of emphysema in pulmonary fibrosis. Eur Respir Rev
2013;22(128):153–157.
39. Ostridge K, Williams N, Kim V, et al. Distinct emphysema subtypes defined by
quantitative CT analysis are associated with specific pulmonary matrix metallopro-
teinases. Respir Res 2016;17(1):92.
40. Fedorov A, Beichel R, Kalpathy-Cramer J, et al. 3D Slicer as an image comput-
ing platform for the Quantitative Imaging Network. Magn Reson Imaging
2012;30(9):1323–1341.