Cardiopulmonar y Imaging • Original Research

Chung et al.
CT Findings, Radiologic-Pathologic Correlation, and Predictors
of Survival for Patients With IPAF

Cardiopulmonary Imaging
Original Research

CT Findings, Radiologic-Pathologic
Correlation, and Imaging
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Predictors of Survival for Patients

With Interstitial Pneumonia With
Autoimmune Features
Jonathan H. Chung1 OBJECTIVE. The objective of this study is to determine the CT findings and patterns of
Steven M. Montner 1 interstitial pneumonia with autoimmune features (IPAF) and to assess whether imaging can
Ayodeji Adegunsoye2 predict survival for patients with IPAF.
Cathryn Lee2 MATERIALS AND METHODS. The study included 136 subjects who met the criteria
Justin M. Oldham 3 for IPAF and had diagnostic-quality chest CT scans obtained from 2006 to 2015; a total of 74
of these subjects had pathologic samples available for review within 1 year of chest CT ex-
Aliya N. Husain 4
amination. CT findings and the presence of an usual interstitial pneumonitis (UIP) pattern of
Heber MacMahon1 disease were assessed, as was the UIP pattern noted on pathologic analysis. Analysis of chest
Imre Noth2 CT findings associated with survival was performed using standard univariate and multivari-
Rekha Vij2 ate Cox proportional hazards methods as well as the unadjusted log-rank test. Survival data
Mary E. Strek 2 were visually presented using the Kaplan-Meier survival curve estimator.
RESULTS. Most subjects with IPAF (57.4%; 78/136) had a high-confidence diagnosis of a
Chung JH, Montner SM, Adegunsoye A, et al.
UIP pattern on CT. Substantially fewer subjects (28.7%; 39/136) had a pattern that was incon-
sistent with UIP noted on CT. The presence of a UIP pattern on CT was associated with smok-
ing (p < 0.01), male sex (p < 0.01), and older age (p < 0.001). Approximately one-fourth of the
subjects had a nonspecific interstitial pneumonitis pattern on CT. Of interest, nearly one-tenth
of the subjects had a CT pattern that was most consistent with hypersensitivity pneumonitis
rather than the customary CT patterns ascribed to lung disease resulting from connective tis-
sue disease. Most subjects with a possible UIP pattern on CT (83.3%) had UIP diagnosed on
Keywords: connective tissue disease, CT, interstitial
the basis of pathologic findings. Focused multivariate analysis showed that honeycombing on
pneumonia with autoimmune features, survival, usual CT (hazard ratio, 2.17; 95% CI, 1.05–4.47) and pulmonary artery enlargement on CT (hazard
interstitial pneumonitis ratio, 2.08; 95% CI, 1.02–4.20) were independent predictors of survival.
CONCLUSION. IPAF most often presents with a UIP pattern on CT and is associated with
DOI:10.2214/AJR.16.17121
worse survival when concomitant honeycombing or pulmonary artery enlargement is present.
Received July 21, 2016; accepted after revision
t has been recognized that a sub- [1]. The proposed criteria include traditional

I
October 27, 2016.

1
stantial proportion of patients clinical and serologic features of CTD; mor-
Department of Radiology, University of Chicago
Medical Center, 5841 S Maryland Ave, Chicago, IL
with idiopathic interstitial pneu- phologic features consistent with CTD, as
60637. Address correspondence to J. H. Chung monia (IIP) have signs and determined from the subdomains of chest ra-
(jonherochung@uchicago.edu). symptoms suggestive of an underlying auto- diographic imaging and histopathologic
2
immune process but do not meet the defined analysis; and physiologic features identified
Section of Pulmonary/Critical Care, Department of
criteria for a specific connective tissue dis- from pulmonary function tests.
Medicine, University of Chicago Medical Center,
Chicago, IL. ease (CTD). The differences in interstitial The imaging patterns and prognostic sig-
lung disease (ILD) associated with diag- nificance of the IPAF classification have yet
3
Section of Pulmonary/Critical Care, Department of nosed or suspected CTD, compared with oth- to be fully defined. Previous studies of pa-
Medicine, University of California at Davis, er types of ILD, is an ongoing field of study. tients with disease classifications similar to
­Sacramento, CA.
A multisociety task force introduced new re- IPAF (e.g., lung-dominant CTD, undifferenti-
4
Department of Pathology, University of Chicago Medical search criteria for interstitial pneumonia ated CTD [UCTD]–associated ILD, and ILD
Center, Chicago, IL. with autoimmune features (IPAF), in an at- with autoimmune features) have shown differ-
tempt “to derive a uniform name and set of ing results that are likely related to differences
AJR 2017; 208:1229–1236 classification criteria for patients with IIP in the criteria for diagnosis [1–4]. One of the
0361–803X/17/2086–1229
and an autoimmune flavor” separate from pa- goals of the IPAF classification is to develop a
tients with ILD who do not have evidence of consistent platform from which to rigorously
© American Roentgen Ray Society autoimmune components or a defined CTD study this specific group of patients.

AJR:208, June 2017 1229


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The main objective of the present study
is to document in detail the CT features of
IPAF, on the basis of a systematic review
of a large number of CT scans and corre-
sponding patient medical records at our
medical center. Given that most patients
with CTD-associated ILD (with the ex-
ception of rheumatoid arthritis) have mor-
phologic findings of nonspecific interstitial
pneumonia (NSIP), organizing pneumo-
nia, or both, and given that many CT find-
ings inconsistent with UIP [5] support the
diagnosis of IPAF, we expect that the CT
appearance would most often be inconsis-
tent with UIP. The second objective of this
study is to assess which, if any, CT find-
ings are predictive of survival for patients
with IPAF. Imaging findings have been
shown to predict survival in the setting of
IIP; however, in the setting of CTD, the sig-
nificance of imaging findings is less clear,
and in IPAF, it is unknown [6]. We hypoth-
esize that, similar to idiopathic ILD, the
presence of a UIP pattern and macroscop-
ic CT findings of pulmonary fibrosis (e.g.,
honeycombing, reticulation, and traction
bronchiectasis) would be associated with
decreased survival.
1230 AJR:208, June 2017
Chung et al.
A B
Materials and Methods
Subjects and Clinical Information
This retrospective study was HIPAA compli-
ant and was approved by our institutional review
board (number 14163-A).
The ILD research registry at the University of
Chicago Medical Center was used to identify adults
who were evaluated in the ILD clinic from 2006 to
2015. Patients with idiopathic pulmonary fibrosis,
unclassifiable IIP, biopsy-proven idiopathic NSIP,
and biopsy-proven organizing pneumonia were iden-
tified [5]. Patients who were given an interim diagno-
sis of UCTD-associated ILD on the basis of previous
criteria were also identified [2]. ILD was diagnosed
using a multidisciplinary approach. Follow-up was
censored on December 1, 2015. Subjects were ex-
cluded from the study if they had a known cause of
ILD, declined to provide informed consent, or did
not undergo the necessary tests (i.e., serologic as-
sessment, chest CT, or surgical lung biopsy) needed
to achieve a confident diagnosis of IPAF.
Of the 1045 patients in the ILD registry, 144
met the criteria for IPAF reported by Oldham et
al. [7]. Of these 144 patients, 136 had diagnos-
tic-quality chest CT scans available for review.
Oldham and colleagues reported the presenting
features of a cohort with IPAF from the clini-
cal pulmonary perspective, whereas in the pres-
A B
Fig. 1—75-year-old man with
interstitial pneumonia with
autoimmune features.
A and B, Axial (A) and coronal (B)
chest CT images show peripheral
and basilar predominant
distribution of pulmonary fibrosis
characterized by reticulation,
traction bronchiectasis, traction
bronchiolectasis, and subpleural
honeycombing consistent with
usual interstitial pneumonitis.
ent study, we report the specific CT findings for
IPAF as well as the CT findings associated with
the survival of patients with IPAF. Oldham and
colleagues analyzed survival mainly on the basis
of pathologic findings.
IPAF was diagnosed using the current research
guidelines, which comprise clinical, serologic, and
morphologic (i.e., imaging, pathologic, and phys-
iologic) features [8]. We obtained clinical data
from patients at their initial clinic visit, including
demographic characteristics, history, medication
use, physical examination findings, and laborato-
ry findings (which included findings from a com-
prehensive serologic assessment). Anti–clinically
amyopathic dermatomyositis-140 (melanoma dif-
ferentiation-associated protein 5) autoantibody and
anti–polymyositis/scleroderma antibodies were not
included in the routine evaluation of ILD at our
medical center; therefore, they could not be as-
sessed. Data from pulmonary function tests were
also assessed, including the percentage of predict-
ed forced vital capacity, the percentage of predicted
total lung capacity, and the percentage of predicted
diffusion capacity of the lung for carbon monoxide.
CT Evaluation
The earliest diagnostic-quality chest CT scan
obtained for each subject was scored. Studies from
Fig. 2—48-year-old woman
with interstitial pneumonia with
autoimmune features.
A and B, Axial (A) and coronal (B) chest
CT images show peripheral and basilar
predominant distribution of pulmonary
fibrosis characterized by reticulation,
traction bronchiectasis, and traction
bronchiolectasis without subpleural
honeycombing consistent with possible
usual interstitial pneumonitis pattern.
 CT Findings, Radiologic-Pathologic Correlation, and Predictors of Survival for Patients With IPAF
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outside hospitals were reviewed if their image ­quality
was adequate, resulting in a total of 18 of the 136 CT
evaluated scans originating from outside hospitals.
The criteria for determining whether an image was
of diagnostic quality included thin-section acquisi-
tion or reconstruction (< 2.0 mm) through the whole
thorax and absence of significant motion artifact
that obscured the lung parenchymal detail. High-
resolution CT was performed at our medical center
with the use of various scanners, including 16- and
64-MDCT scanners (­Brilliance, Philips Healthcare)
or a 256-MDCT scanner (­Brilliance iCT, Philips
Healthcare). Helical CT acquisition was performed
during full inspiration with the patient in the supine
position, with the use of a tube voltage of 120 kVp,
a tube current-time product of 220 mAs, and image
reconstruction with a 512 × 512 pixel image ma-
trix. Transverse (axial) images were reconstructed
contiguously at slice thicknesses of 1.0 mm and 3.0
mm, with the use of a standard lung kernel. Coro-
nal and sagittal images were reconstructed at a slice
thickness of 2.5 mm. End-expiratory phase helical
CT images were also obtained at a tube voltage of
120 kVp, a tube current-time product of 60 mA, and
contiguous reconstruction of 3-mm slices, as were
transverse 1-mm images (thickness, 1.2 × 10 mm)
obtained during full inspiration with the patient in
the prone position.
Chest CT scans were evaluated by consensus by
two dedicated thoracic radiologists who had 32 and
11 years of thoracic imaging experience and were
blinded to other data. CT scans were scored for
the presence of reticulation, honeycombing, trac-
tion bronchiectasis, air trapping or mosaic atten-
uation, and ground-glass opacity. The preponder-
ant distribution of lung disease was also scored in
zonal plane (i.e., diffuse, upper, middle, or lower)
and transverse plane (i.e., diffuse, bronchovascu-
lar, peripheral, or peripheral with subpleural spar-
ing). Reticulation, honeycombing, traction bron-
chiectasis, air trapping or mosaic attenuation, and
ground-glass opacity were scored as present or ab-
sent on CT; the percentage of lung involvement
AJR:208, June 2017 1231
A B
with regard to these categories was scored to the
nearest 5%. Multicompartment involvement [8]
was systematically evaluated on chest CT by as-
sessing the presence of pleural effusion or thicken-
ing, pericardial effusion or thickening, mosaic at-
tenuation in the absence of visible emphysema, and
nontraction bronchiectasis, as well as by determin-
ing the diameter of the pulmonary artery [9]. We
corrected mosaic attenuation for emphysema (as a
marker of substantial injury to the lungs caused by
smoking), given that small airways disease is com-
monly associated with smoking and may have con-
founded statistical analyses [10]. A threshold of 3.3
cm for pulmonary artery enlargement was used to
increase the specificity of this finding [11, 12].
As per guidelines, the level of confidence in a
CT diagnosis of IPAF relative to UIP was scored
as UIP, possible UIP, or inconsistent with UIP [5,
13–17] (Figs. 1–3). If the pattern noted on CT was
not definitely UIP, the readers also selected by con-
sensus the best overall alternative imaging-based
diagnosis, including the whole spectrum of IIP,
hypersensitivity pneumonitis (HP), sarcoidosis, ob-
literative bronchiolitis, asbestosis, silicosis, and cel-
lular bronchiolitis, with a level of confidence (i.e.,
possible, probable, or definite).
Histopathologic Evaluation and Radiologic-
Pathologic Correlation
For 74 of the 136 CT scans, a pathologic sample
was available for assessment within 1 year of the
scored CT scan. Pathologic samples from surgical
lung biopsies were reviewed by a pulmonary pa-
thologist with expertise in ILD, as reported else-
where [7]. The biopsy specimens were evaluated
for pathologic patterns of ILD, such as UIP, NSIP,
organizing pneumonia, lymphocytic interstitial
pneumonitis, and chronic HP, as well as for other
evidence of underlying autoimmune diseases
Statistical Analysis
CT findings were descriptively summarized
as mean (± SD) values or median (range) values,
Fig. 3—79-year-old woman
with interstitial pneumonia with
autoimmune features.
A and B, Axial (A) and coronal (B)
CT images show axially diffuse
and upper zone preponderant lung
disease characterized by ground-
glass opacity and reticulation
diagnostic of pattern inconsistent
with usual interstitial pneumonitis,
given degree of ground-glass opacity
and upper lung preponderance.
as appropriate. A two-tailed Fisher exact test or
chi-square test was used to compare proportions.
Mean values for continuous variables between
groups were compared using a two-tailed t (para-
metric) test or a Mann-Whitney U (nonparametric)
test. Analysis of chest CT findings associated with
survival was performed using standard univariate
and multivariate Cox proportional hazards meth-
odology as well as the unadjusted log-rank test.
Survival was visually presented using the Kaplan-
Meier survival curve estimator. Time from diag-
nosis to either death or lung transplantation was
used as the endpoint. The multivariate analysis of
survival included chest CT variables thought to af-
fect survival in biologically plausible independent
pathways; thus, only honeycombing (as the major
proxy for end-stage fibrosis), mosaic attenuation
(as a proxy for small airways disease), and ground-
glass opacity (as a proxy for pulmonary inflamma-
tion) were included. The analysis was adjusted for
the GAP (gender, age, and physiology [forced vital
capacity and diffused capacity of the lung for car-
bon monoxide]) score [18] and the positivity of the
clinical domain (i.e., clinical, serologic, and mor-
phologic), as defined for IPAF classification [8].
All statistical studies were performed using statis-
tical software (Stata, version 14, StataCorp).
Results
Near-equal numbers of men and women
were included in the study (50.7% of the pa-
tients were women). The mean patient age
was 63.5 ± 10.9 years.
CT Findings
The mean lung volume affected by ILD
was 22.5% ± 12.5%. Most subjects had basi-
lar (89.0%; 121/136) and peripheral (73.5%;
100/136) predominant disease distribution.
Diffuse distribution was the next most com-
mon pattern in both the zonal (8.7%) and axial
(15.1%) planes. Approximately 60.2% of sub-
jects had honeycombing on CT. In those with
 Chung et al.

TABLE 1: Usual Interstitial
­Pneumonitis (UIP) ­Patterns
on CT Scans of 136
­Patients With ­Interstitial
­Pneumonia With
­Autoimmune ­Features
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subjects, who had a mean affected lung vol-
ume of 12.1%  ± 5.6%. Almost all subjects
had traction bronchiectasis (96.3%; 131/136),
with a mean affected lung volume of 11.4% ±
7.1%. Multicompartment involvement, as de-
fined by IPAF criteria, was common. Pleural
2). Nearly one-tenth of the subjects had an
imaging pattern that was most consistent
with HP, rather than the typical CT patterns
ascribed to CTD-associated ILD.
Men and smokers or former smokers had a
UIP pattern more often than the pattern that

CT UIP Pattern No. (%) of Patients effusion or thickening was present in 13.2% was inconsistent with UIP on chest CT (Table
UIP 70 (51.5)
of subjects (18/136), and pericardial effusion 3). Subjects with the UIP pattern on CT were
or thickening was present in 1.5% (2/136). also older than those with a pattern inconsis-
Possible UIP 19 (14.0)
Mosaic attenuation without CT evidence of tent with UIP on CT. No apparent difference
Inconsistent with UIP 47 (34.6) emphysema was present in 34.6% of subjects related to race was noted, although this may
(47/136), and pulmonary artery enlargement have been a function of limited power.
TABLE 2: CT Patterns for 136 was present in 27.2% (37/136).
Patients With I­ nterstitial CT and Pathologic Correlation
Pneumonia With Usual Interstitial Pneumonitis Pattern and The strongest agreement between CT and
­Autoimmune Features Diagnosis on CT pathologic findings, with regard to UIP diag-
No. (%) of Most subjects with IPAF had a UIP or pos- nosis, occurred when CT scans were scored as
CT Pattern Patients sible UIP pattern (65.4%; 89/136) on CT (Ta- having a UIP pattern (93.8% of these subjects
ble 1). A substantially smaller number of sub- had UIP diagnosed on the basis of pathologic
Usual interstitial pneumonitis 70 (51.5)
jects had a pattern inconsistent with UIP on findings). There was slightly lower agreement
NSIP 37 (27.2) CT (34.6%; 47/136). The most common CT between CT and pathologic findings when CT
Hypersensitivity pneumonitis 11 (8.1) finding (53.2%; 25/47) on CT scans with a scans were scored as having a possible UIP
NSIP organizing pneumonia 9 (6.6) pattern inconsistent with UIP was the pres- pattern on CT (83.3% of these subjects had
ence of a significant degree of ground-glass UIP diagnosed on the basis of pathologic find-
Organizing pneumonia 5 (3.7)
opacity. Nonbasilar predominant distribution ings), although this was not statistically differ-
Other 4 (2.9) of disease, nonperipheral predominant distri- ent when compared with CT scans with a UIP
Note—NSIP = nonspecific interstitial pneumonia. bution, or both distributions were noted on pattern on CT (Table 3). There was much low-
23.4% (11/47) of CT scans that showed a pat- er agreement between CT findings and patho-
honeycombing, the mean lung volume affect- tern inconsistent with UIP. logic findings when CT scans were scored
ed was 3.1%  ± 4.3%. Ground-glass opacity On the basis of the imaging pattern only, as having a pattern inconsistent with UIP (or
was present in 27.9% of subjects, for whom UIP was the single best diagnosis for approx- 50.0% UIP according to pathologic findings).
the mean lung volume affected was 15.9% ± imately one-half of the subjects, followed by When compared with the other CT categories,
17.1%. Air trapping was present in 10.3% of NSIP for one-quarter of the subjects (Table a statistically significant difference was noted
in the concordance of CT findings and patho-
TABLE 3: Demographic Characteristics of Patients With I­ nterstitial logic findings in subjects with a pattern incon-
­Pneumonia With Autoimmune Features Relative to sistent with UIP (p < 0.001).
High-­Confidence CT Diagnoses
Survival and CT Findings
Pattern Inconsistent With UIP on CT Univariate statistically significant CT
Characteristic (n = 47) UIP Pattern on CT (n = 70) p
findings that were associated with worse sur-
Smoker 19 (40.4) 42 (60.0) 0.041a vival included the percentage of reticulation
White race 31 (66.0) 51 (72.9) 0.537 (hazard ratio [HR], 1.04; 95% CI, 1.01–1.06),
Male 16 (34.0) 41 (58.6) 0.014a the presence of honeycombing (HR, 2.60;
95% CI, 1.33–5.07), mosaic attenuation cor-
Age (y), mean ± SD 59.4 ± 11.5 66.7 ± 9.5 < 0.001a
rected for the presence of emphysema (HR,
Note—Except where noted otherwise, data are number (%) of patients. UIP = usual interstitial pneumonitis.
aStatistically significant.
2.17; 95% CI, 1.19–3.95), and pulmonary ar-
tery enlargement (HR, 2.23; 95% CI, 1.22–
4.05) (Table 4). The UIP pattern on CT and
TABLE 4: Radiologic and Pathologic Correlation for Diagnosis of Usual the distribution of pulmonary fibrosis were
­Interstitial Pneumonitis (UIP)
not statistically significant predictors of sur-
No. of Patients With Pathologic Diagnosis vival. Corresponding Kaplan-Meier survival
Patients With UIP curves with log-rank test p values are shown
CT Diagnosis Not UIP UIP Diagnosis (%)
for the presence on CT of honeycombing,
Inconsistent with UIP 12 12 50.0 mosaic attenuation corrected for the pres-
Possible UIP 3 15 83.3 ence of emphysema, and pulmonary artery
UIP 2 30 93.8
enlargement in Figures 4, 5, and 6, respec-
tively. Focused multivariate analysis showed
Total 17 57
that only honeycombing (HR, 2.17; 95% CI,

1232 AJR:208, June 2017

 CT Findings, Radiologic-Pathologic Correlation, and Predictors of Survival for Patients With IPAF

100 100

75 75
Survival Rate (%)

Survival Rate (%)

50 50
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25 25

0 0
0 24 48 72 96 120 0 24 48 72 96 120
Time (mo) Time (mo)

Fig. 4—Survival of patients with interstitial pneumonia with autoimmune features
with honeycombing on CT versus those without honeycombing on CT. Kaplan-
Meier survival curves show that those with honeycombing on CT (dashed line) had
significantly worse survival than those without honeycombing on CT (solid line)
(p = 0.0092, log-rank test).
Fig. 5—Survival of patients with interstitial pneumonia with autoimmune features
with mosaic attenuation on CT versus those without mosaic attenuation on CT.
Kaplan-Meier survival curves show that patients with mosaic attenuation on
CT (dashed line) had significantly worse survival than those without mosaic
attenuation on CT (solid line) (p = 0.0092, log-rank test).

100

75
Survival Rate (%)

50

25
Fig. 6—Survival of patients with interstitial pneumonia with autoimmune features
with pulmonary artery enlargement on CT versus those without pulmonary
0 artery enlargement on CT. Kaplan-Meier survival curves show that patients with
pulmonary artery enlargement of 3.3 cm or greater (dashed line) had significantly
0 12 24 36 48 60 72
Time (mo) worse survival than those with pulmonary artery enlargement of less than 3.3 cm
(solid line) (p = 0.0071, log-rank test).

1.05–4.47) and pulmonary artery enlarge-
ment (HR, 2.08; 95% CI, 1.02–4.20) were in-
dependent predictors of survival, but the per-
centage of reticulation and the presence of
mosaic attenuation corrected for emphysema
on CT were not (Table 5).
Discussion
The present study had five primary find-
ings. First, contrary to our initial hypothesis,
most subjects with IPAF had a UIP pattern
of pulmonary fibrosis on CT. Second, one of
10 subjects with IPAF had an imaging pat-
tern that was most consistent with HP. Third,
older age, smoking, and male sex were asso-
ciated with a UIP pattern. Fourth, a possi-
ble UIP pattern on CT is strongly associated
with UIP on pathologic analysis. Fifth, hon-
eycombing and pulmonary artery enlarge-
ment on CT were independent predictors of
survival for patients with IPAF.
In the current study, a UIP or possible UIP
pattern on CT was present in most subjects with
IPAF (65.4%). Recent evidence suggests that
most patients with a possible UIP pattern on CT
have UIP on pathologic analysis, as do those
with a UIP pattern on CT [13, 19–21]. Previous
studies of UCTD have shown that UIP is the
most common pattern, although NSIP is also
quite common, depending on the diagnostic cri-
teria used [2, 4, 22, 23]. In patients with CTD,
NSIP is the most common type of lung disease.
An exception to this rule is rheumatoid ar-
thritis, for which the UIP pattern is most com-
mon [24, 25]. The high prevalence of the UIP
pattern in patients with IPAF suggests that
these patients may mimic patients with rheu-
matoid arthritis with regard to their underly-
ing pathophysiologic profile and prognosis.
This subject is worthy of future investigation.
In our cohort, a history of smoking, older age,
and male sex were more likely characteristics
of patients with a UIP pattern of pulmonary
fibrosis, compared with patients with a pat-
tern inconsistent with UIP. For patients with
idiopathic pulmonary fibrosis, smoking, older
patient age, and male sex are major risk fac-
tors for the development of UIP [5]. Similar
phenomena may be present in patients with
IPAF and should be explored further.
The presence of autoimmune features
in patients with HP has only recently been
formally recognized; up to 15% of patients
with HP may have associated autoimmune
features [26]. In the present study, a similar
proportion of subjects with IPAF had a CT
pattern consistent with HP. Although not di-
agnostic of HP (which requires multidisci-
plinary discussion), our findings suggest that
there is relationship between autoimmunity
and HP, whether pathophysiologic or pheno-
typic. Only a small number of subjects ex-
posed to antigens known to cause HP have
significant ILD develop, implying the pres-
ence of an underlying genetic susceptibil-
ity. Inhaled substances may trigger auto-
immune disease in susceptible individuals,
because development of CTD has been re-
ported in individuals exposed to cigarette
smoke, silica, and coal dust, in addition to
dust and chemicals from the attacks on the
World Trade Center on September 11, 2001
[26–30]. Alternatively, although the CT ap-
pearance of IPAF has yet to be formally de-
fined, morphologic findings of HP may be
one of the phenotypes of IPAF. In addition,
there may be yet-undefined IPAF imaging
patterns, as has been suggested by the sub-
stantially small number of subjects whose
CT findings could not be classified into tra-
ditional UIP categories.

AJR:208, June 2017 1233

 Chung et al.

TABLE 5: Cox Unadjusted and Adjusted Analyses of Prognostic Features Noted on High-Resolution CT Examinations
of Patients With Interstitial Pneumonia With Autoimmune Features
Unadjusted Analysis (n = 136) Adjusted Analysisa (n = 136)
Variable HR p 95% CI HR p 95% CI
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Honeycomb pattern 2.60 0.005 1.33–5.07 2.17 0.037 1.05–4.47

Reticulation (% involvement) 1.04 0.001 1.01–1.06 1.01 0.386 0.98–1.05
Multicompartment features
Mosaic attenuation excluding emphysemab 2.17 0.011 1.19–3.95 1.79 0.117 0.87–3.70
Pulmonary artery enlargementc 2.23 0.009 1.22–4.05 2.08 0.043 1.02–4.20
UIP patternd
Possible UIP 0.99 0.982 0.36–2.73
Definite UIP 1.57 0.172 0.82–2.98
Mosaic attenuation 1.63 0.102 0.91–2.94
Ground-glass opacities 0.99 0.968 0.52–1.88
Axial distribution of fibrosise
Peripheral 1.40 0.575 0.43–4.56
Peripheral with subpleural sparing 0.32 0.325 0.03–3.09
Diffuse 1.29 0.722 0.32–5.17
Pleural or pericardial effusion or thickening 1.77 0.146 0.82–3.81
Note—HR = hazard ratio, UIP = usual interstitial pneumonitis. Statistically significant values are shown in boldface type.
a Adjusted for age, sex, forced vital capacity, diffusing capacity of the lung for carbon monoxide, and presence of clinical domain.
bFor multicompartment features, with patients with a history of smoking excluded, univariate analysis revealed an HR of 1.83 (p = 0.047).
cWith use of a pulmonary artery diameter cutoff of 33 mm.
dCompared with pattern inconsistent with UIP.
eCompared with central distribution, bronchovascular distribution, or both.

Multiple previous studies in different clin-
ical settings have shown that a CT pattern
that is suggestive of UIP but does not meet
strict criteria for UIP is almost always asso-
ciated with a UIP pattern on pathologic anal-
ysis [14, 19, 20, 31]. In 96 patients with his-
tologically proven UIP or NSIP, Flaherty et
al. [14] showed that all 11 patients with prob-
able UIP on HRCT (defined as CT findings
consistent with UIP except for the absence
of basilar distribution) had UIP diagnosed
on pathologic analysis. Another study, which
was part of a larger genomewide association
study, showed that, in 82.4% of cases, proba-
ble UIP (defined as CT findings suggestive of
UIP but with honeycombing absent) was as-
sociated with a UIP diagnosis on pathologic
analysis [13]. In two separate studies of idio-
pathic pulmonary fibrosis, Raghu et al. [20]
and Yagihashi et al. [19] found that 94.0%
of 84 subjects and 93.8% of 64 subjects, re-
spectively, who met CT criteria for possible
UIP had UIP confirmed on the basis of his-
tologic findings. These findings suggest that
these cases may not require biopsy for accu-
rate diagnosis. Current guidelines direct pa-
tients with a possible UIP pattern on CT to
undergo surgical lung biopsy for more de-
finitive diagnosis. Given the morbidity and
mortality risks associated with surgical lung
biopsy performed for patients with ILD, an
alternative pathway that minimizes the num-
ber of patients sent for surgical lung biopsy
is attractive. Our data and previous studies
suggest that, rather than have patients with
a possible UIP pattern on CT undergo biop-
sy, such patients could be managed like those
with a high-confidence UIP pattern on CT.
The ramifications of the IPAF classifica-
tion with regard to survival have yet to be
fully delineated. Studies evaluating prog-
nostic factors in UCTD (or similar designa-
tions) have suggested that patients with auto-
immune interstitial pneumonias who do not
meet strict criteria for a defined CTD likely
have a survival rate similar to that of patients
with idiopathic pulmonary fibrosis and may
have worse survival than those with defined
CTD [2–4]. In the current study, the pres-
ence of honeycombing on CT was indepen-
dently associated with worse survival, which
supports the well-accepted relationship be-
tween disease severity and poor survival in
patients with pulmonary fibrosis [6, 32]. On
the other hand, the absence of a survival dif-
ference relative to CT classification of UIP
was somewhat unexpected. NSIP is associ-
ated with survival superior to that associated
with UIP in the idiopathic setting [33, 34].
Therefore, one would expect patients with a
high-confidence UIP pattern on CT to have
worse survival than patients with a pattern
inconsistent with UIP on CT.
However, previous studies suggest that
the clinical significance of the UIP pattern
in the setting of CTD is less certain. In a
heterogeneous group of subjects with CTD,
no significant difference in survival was
noted between patients with CTD-related
NSIP and UIP [35]. Bouros et al. [36] noted
little difference in the survival of patients
with systemic sclerosis–related ILD with
NSIP, compared with those with UIP (91%
vs 82%, respectively).
Conversely, a small study of patients with
rheumatoid arthritis showed that patients
with UIP have worse survival than those with
NSIP, on the basis of pathologic findings, al-
though the much higher prevalence of smok-
ing among patients with UIP, compared with
patients with NSIP, may have been a con-
founding factor [37]. An imaging-based study
of patients with rheumatoid arthritis showed
that patients with a definite UIP pattern on

1234 AJR:208, June 2017

 CT Findings, Radiologic-Pathologic Correlation, and Predictors of Survival for Patients With IPAF
CT had worse survival, compared with pa-
tients without this CT pattern (median surviv-
al, 3.2 vs 6.6 years, respectively) [25]. Sim-
ilarly, Solomon et al. [24] showed that, for
patients with rheumatoid arthritis, the pres-
ence of the UIP pattern on CT was associated
Downloaded from www.ajronline.org by 125.167.114.159 on 05/24/21 from IP address 125.167.114.159. Copyright ARRS. For personal use only; all rights reserved
with worse survival than was presence of the
NSIP pattern on CT, although this finding did
not persist after multivariate analysis.
Our results also suggest that pulmonary
artery size on CT is independently associ-
ated with worse survival for patients with
IPAF. Pulmonary hypertension is a known
manifestation of CTDs and has poor prog-
nostic ramifications [38]. Extensive literature
exists that documents the strong correlation
between pulmonary artery size on CT and
pulmonary hypertension [12, 39]. The most
likely theory for our result is that pulmonary
artery size is associated with pulmonary hy-
pertension, which is, in turn, associated with
poor prognosis. This theory could not be for-
mally tested because of the observational na-
ture of the present study. However, little, if
any, correlation exists between CT pulmo-
nary artery measurements and pulmonary
hypertension in the setting of pulmonary fi-
brosis, particularly if pulmonary fibrosis is
more severe, possibly because of alterations
in mediastinal structures secondary to un-
derlying chronic pulmonary pathologic find-
ings [11, 40, 41]. Therefore, considering alter-
native pathophysiologic mechanisms would
be prudent. The ratio of pulmonary artery
size to aorta size on CT has been strongly as-
sociated with acute exacerbations in a large
cohort with chronic obstructive pulmonary
disease with external validation [42]. In the
setting of chronic lung disease, enlargement
of the pulmonary artery on CT may signal
an increased likelihood for pulmonary exac-
erbations and, eventually, pulmonary-related
death, although this is speculative.
The limitations of the present study in-
clude its retrospective design and its rela-
tively small number of subjects, which may
have limited the power of the study. Howev-
er, the total number of subjects is on par with
the number of subjects in other single-center
studies of CTD-related ILD. Also, there was
some heterogeneity in CT acquisition param-
eters, given that some of the CT scans were
not performed at our medical center. We ad-
dressed this issue by only scoring CT scans
from outside hospitals, which could be accu-
rately analyzed for findings of pulmonary fi-
brosis. Finally, this study was performed at a
tertiary medical center specializing in the di-
AJR:208, June 2017 1235
agnosis and treatment of ILD; therefore, our
results may not be generalizable to the com-
munity setting.
This study shows that a UIP pattern was
present on CT for most subjects with IPAF
and that it was more common among those
with known risk factors for idiopathic pul-
monary fibrosis (e.g., older age, smoking his-
tory, and male sex). A possible UIP pattern
on CT was almost always associated with
UIP on pathologic analysis. Also, a HP pat-
tern on CT was not rare in our cohort with
IPAF, which implies the possible presence of
a relationship between autoimmunity and HP.
Further research regarding CT phenotypes in
the setting of IPAF will be necessary to deter-
mine the significance of this finding. Final-
ly, honeycombing and pulmonary artery en-
largement on CT are independent predictors
of poor survival for patients with IPAF.
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