Clinical Course and Changes in High-Resolution Computed Tomography Findings in Patients with Idiopathic Pulmonary Fibrosis without Honeycombing
Clinical Course and Changes in High- Resolution Computed Tomography Findings in Patients with Idiopathic Pulmonary Fibrosis without Honeycombing
Hiroyoshi Yamauchi 0 1 2
Masashi Bando 0 1 2
Tomohisa Baba 0 2
Kensuke Kataoka 0 2
Yoshihito Yamada 0 2
Hiroshi Yamamoto 0 2
Atsushi Miyamoto 0 2
Soichiro Ikushima 0 2
Takeshi Johkoh 0 2
Fumikazu Sakai 0 2
Yasuhiro Terasaki 0 2
Akira Hebisawa 0 2
Yoshinori Kawabata 0 2
Yukihiko Sugiyama 0 1 2
Takashi Ogura 0 2
0 Abbreviations: ALAT, Latin American Thoracic Association; ATS, American Thoracic Society; DLco , diffusing capacity for carbon monoxide
1 Department of Medicine, Jichi Medical University , Tochigi , Japan , 2 Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center , Kanagawa , Japan , 3 Department of Respiratory Medicine and Allergy, Tosei General Hospital, Aichi, Japan, 4 Department of Respiratory Medicine, JR Tokyo General Hospital, East Japan Railway Company, Tokyo, Japan, 5 First Department of Internal Medicine, Shinshu University School of Medicine, Nagano, Japan, 6 Department of Respiratory Medicine, Toranomon Hospital , Tokyo , Japan , 7 Department of Respiratory Medicine, Japanese Red Cross Medical Center, Tokyo, Japan, 8 Department of Radiology, Kinki Central Hospital of Mutual Aid Association of Public School Teachers, Hyogo, Japan, 9 Department of Diagnostic Radiology, Saitama Medical University International Medical Center , Saitama , Japan , 10 Department of Analytic Human Pathology, Nippon Medical School , Tokyo , Japan , 11 Department of Clinical Research, National Hospital Organization Tokyo National Hospital , Tokyo , Japan , 12 Division of Diagnostic Pathology, Saitama Prefectural Cardiovascular and Respiratory Center , Saitama , Japan
2 Editor: Toby M Maher, Imperial College London , UNITED KINGDOM
Some patients with idiopathic pulmonary fibrosis (IPF) do not have honeycombing on highresolution computed tomography (HRCT) at their initial evaluation. The clinical course and sequential changes in HRCT findings in these patients are not fully understood. We reviewed the cases of 43 patients with IPF without honeycombing on initial HRCT from institutions throughout Japan. All patients were diagnosed with IPF based on a surgical lung biopsy. Multidisciplinary discussions were held five times between 2011 and 2014, to exclude alternative etiologies. We evaluated the sequential changes in HRCT findings in 30 patients with IPF. We classified these 30 patients into three groups based on their HRCT patterns and clarified the clinical characteristics and prognosis among the groups. The patterns of all 30 patients on initial HRCT corresponded to a possible usual interstitial pneumonia (UIP) pattern which was described in the 2011 International Statement. On long-term follow-up (71.0±38.7 standard deviation [SD] months), honeycombing was seen in 16 patients (53%, the HoneyCo group); traction bronchiectasis or cysts without honeycombing was observed in 12 patients (40%, the NoHoneyCo group), and two patients showed no
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: The authors received no specific funding
for this work.
Competing Interests: The authors have declared
that no competing interests exist.
interval change (7%, the NoChange group) on HRCT. The mean survival periods of the
HoneyCo and NoHoneyCo groups were 67.1 and 61.2 months, respectively (p = 0.76).
There are some patients with IPF whose conditions chronically progress without
ERS, European Respiratory Society; FVC, forced
vital capacity; HRCT, high-resolution computed
tomography; IPF, idiopathic pulmonary fibrosis;
JRS, Japanese Respiratory Society; NSIP,
nonspecific interstitial pneumonia; UIP, usual
honeycombing on HRCT. The appearance of honeycombing on HRCT during the follow-up
might not be related to prognosis.
In 2000, the American Thoracic Society (ATS) and European Respiratory Society (ERS) in
collaboration with the American College of Chest Physicians published an international
consensus statement on the diagnosis and management of idiopathic pulmonary fibrosis (IPF) [
and since then accumulated data and observations of the radiological patterns of IPF have
contributed to new guidelines. IPF is characterized by progressive worsening of pulmonary
function and is associated with a poor prognosis [
]. Several retrospective longitudinal studies
suggest that the median survival of IPF patients is 3–5 years after diagnosis [
], which is a
worse rate than those of several types of cancer . The majority of patients with IPF show
slow but steady worsening (“slow progression”) [
], while the natural course of IPF appears to
be heterogeneous [
According to the 2011 ATS/ERS/Japanese Respiratory Society (JRS)/Latin American
Thoracic Association (ALAT) guideline, the diagnosis of IPF should be based on the findings
obtained using the combination of high-resolution computed tomography (HRCT) and
surgical lung biopsy with a formal multidisciplinary discussion among the treating pulmonologist,
radiologist, and pathologist [
]. If the patient’s HRCT findings meet the criteria for the usual
interstitial pneumonia (UIP) pattern— in which honeycombing is critical for making the
diagnosis of the UIP pattern — a surgical lung biopsy is unnecessary. This IPF guideline thus placed
great importance on honeycombing on HRCT. If honeycombing is absent, but the imaging
features otherwise meet the criteria for the UIP pattern, the imaging features are regarded as
representing a ‘possible UIP pattern,’ and the surgical lung biopsy pattern must be a UIP pattern
or a probable UIP pattern to make a definitive diagnosis of IPF [
]. However, the clinical
course and the sequential changes in HRCT findings of these IPF patients are not fully
understood. It is yet to be ascertained whether a possible UIP pattern progresses to a UIP pattern on
The purposes of the present study were to (1) retrospectively assess the sequential changes
in the HRCT pattern in IPF patients who did not show honeycombing on their initial HRCT,
and (2) clarify these patients’ clinical outcomes.
Patients and Methods
Institutional review board approval was obtained for this retrospective study (Bioethics
Committee for Clinical Research A, Jichi Medical University Hospital; A15-180). We reviewed the
cases of 43 patients with IPF without honeycombing on their initial HRCT from 14 institutions
throughout Japan. All patients underwent a surgical lung biopsy between 1991 and 2010 (S1
Table). The initial multidisciplinary discussions of the 43 cases were held at the 11th Tokyo
Diffuse Lung Research Meeting in 2011. Thirty-nine patients were histologically diagnosed as
showing a UIP pattern or a probable UIP pattern, and the other four patients were excluded
from the present study because they showed another histological pattern. Three years later, at
the 15th Tokyo Diffuse Lung Research Meeting in 2014, we evaluated the changes in the 39
patients’ HRCT findings, their serological findings, and the changes in pulmonary functions
such as forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLco). The
cases of eight patients were excluded due to a lack of sequential HRCT scans. One patient was
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Fig 1. Establishing the diagnosis of idiopathic pulmonary fibrosis (IPF) by multidisciplinary discussions.
excluded because the patient was considered to have anti-neutrophil cytoplasmic
antibodyassociated vasculitis instead of IPF. The series of procedures for patient accrual to the study is
shown in Fig 1. A final total of 30 patients were given the diagnosis of IPF in 2014, and their
cases were enrolled in this study.
The first study outcome was our classification of these 30 patients into three groups based
on their HRCT patterns. Our second goal was to clarify the clinical characteristics and
prognosis among these groups.
CT scan evaluation
We reviewed the 30 patients’ initial HRCT scans obtained several months before the surgical
biopsies. The initial HRCT scan findings in the patients without honeycombing were discussed
in 2011. All available HRCT images were independently evaluated by two chest radiologists
with 35 and 27 years of experience, respectively. The predominance of several pulmonary
abnormalities such as ground glass opacities, reticular shadows, honeycombing, traction
bronchiectasis and cysts was evaluated. The diagnoses based on HRCT findings of a possible UIP
pattern were based on the 2000 guidelines [
]. Final decisions regarding the findings and
diagnosis were reached by consensus. Any discrepancies were resolved by repeated
multidisciplinary discussions. The HRCT images of two representative patients with a possible UIP pattern
on HRCT are shown in Fig 2. Continuous follow-up HRCT images were obtained after 2011.
All available HRCT findings were also evaluated by the same pulmonary radiologists in 2014.
All patients had no honeycombing on the initial HRCT scans, and each patient underwent a
surgical lung biopsy between 1991 and 2010. The histological findings were discussed in 2011.
Tissue samples were scored by two thoracic pathologists with 37 and 33 years of experience,
respectively. Diagnoses from pathological findings were based on the 2011 ATS/ERS/JRS/
ALAT guidelines [
]. The histopathological features of a UIP pattern included evidence of
marked fibrosis/architectural distortion with or without honeycombing in a predominantly
subpleural/paraseptal distribution of patchy involvement of lung parenchyma by fibrosis, the
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Fig 2. HRCT images of two patients with representative HRCT scans, showing reticular abnormalities and/or subpleural irregularities without
presence of fibroblast foci, and the absence of features against a diagnosis of UIP or suggesting
an alternate diagnosis. The histopathological features of a probable UIP pattern allow the
absence of either patchy involvement or fibroblastic foci, but not both.
A p-value <0.05 was considered significant in all tests. Statistical analyses were performed
using SAS software ver. 5.0 (SAS Institute, Cary, NC, USA). The survival rates of the patients in
the three groups were compared using the log rank test and are shown as Kaplan-Meier curves.
We analyzed the interobserver variation of the existence of various abnormalities and HRCT
pattern using the kappa (κ) statistic. The interobserver agreement was classified as follows:
poor, κ = 0–0.20; fair, κ = 0.21–0.40; moderate, κ = 0.41–0.60; good, κ = 0.61–0.80; and
excellent, κ = 0.81–1.00.
The agreements of the two observers regarding the HRCT interpretation were good to excellent
(Kappa value >0.7). The patients’ characteristics are summarized in Table 1. All 30 patients
(22 men and eight women) were diagnosed with a possible UIP pattern on the initial HRCT
scan. They were also diagnosed with a UIP pattern or a probable UIP pattern based on the
initial histopathological evaluation. The mean age of the patients was 64.5 ± 6.3 standard
deviation (SD) years (range 50–79 years). The mean percentage of predicted values for FVC (%
FVC) and DLco (%DLco) were 88.3% and 80.4%, respectively.
All 30 patients with IPF were classified based on the sequential changes in HRCT. The
mean follow-up duration from the initial HRCT was 71.0 ± 38.7 (SD) months (range 16–138
months). We classified the patients into one of the following three groups: HoneyCo group;
NoHoneyCo group or NoChange group. The HoneyCo group was the patients in whom
honeycombing emerged on subsequent HRCT scans after the initial evaluation. The NoHoneyCo
group was patients in whom honeycombing did not emerge, but traction bronchiectasis or a
cyst emerged on subsequent HRCT scans after the initial evaluation. The NoChange group
included patients who did not have any significant changes on subsequent serial HRCT scans
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MRC: Medical Research Council
FVC % pred: A percentage of those predicted of Forced Vital Capacity
DLco % pred: A percentage of those predicted of diffusing capacity of the lungs for carbon monoxide
PaO2: Partial pressure of oxygen in arterial blood
KL-6: Krebs von den Lungen-6
SP-D: Surfactant protein D.
after the initial evaluation (Fig 3). Sixteen patients (53%) were classified into the HoneyCo
group, 12 (40%) into the NoHoneyCo group, and the remaining two patients (7%) were
classified into the NoChange group.
The baseline characteristics among these three groups were not significantly different,
although the HoneyCo group had a tendency to have slightly low %FVC and %DLco values.
The values of FVC decline in the HoneyCo and NoHoneyCo groups were −274 ± 181 (SD) ml/
year (range −79 to −680 ml/year) and −395 ± 478 (SD) ml/year (range −101 to −1440 ml/year)
respectively, which are not significantly different (p = 0.92). Patients in the NoHoneyCo group
did not form honeycombing, but the long-term observation of serial HRCT images revealed
that their traction bronchiectasis or cysts progressed to an appearance suggestive of a
nonspecific interstitial pneumonia (NSIP) pattern or an appearance that was inconsistent with a UIP
pattern. The Kaplan-Meier survival curves of the three groups are shown in Fig 4. The mean
survivals of the HoneyCo group patients was 67.1 months, and that of the NoHoneyCo patients
was 61.2 months; the survival periods were not significantly different (p = 0.76).
The results of the present study showed that IPF patients who do not have honeycombing on
the initial HRCT scans can be classified patterns of the sequential changes in HRCT into three
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Fig 3. Representative HRCT scans from the three patient groups. HoneyCo: Honeycombing became evident on HRCT scan. NoHoneyCo: Traction
bronchiectasis or cysts became evident on HRCT scan. NoChange: No significant change in HRCT findings.
groups. One group of IPF patients showed the typical HRCT pattern of IPF; i.e., the appearance
of honeycombing. Another group showed an atypical HRCT pattern of IPF; i.e., the appearance
of traction bronchiectasis or cysts without honeycombing. Our analysis of the prognoses of
these two groups indicated that the presence or absence of honeycombing on HRCT during
the follow-up is not related to prognosis. Our third, small patient group showed stable findings
on HRCT, which can be expected to suggest a good prognosis.
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Fig 4. Kaplan-Meier survival curves where honeycombing appeared on subsequent HRCT scans after initial evaluation (n = 16, blue line, the
HoneyCo group), patients in whom honeycombing was not seen but traction bronchiectasis or cysts appeared on subsequent computed
tomography scans after initial evaluation (n = 12, green line, the NoHoneyCo group), and patients with no change in HRCT findings after
longterm follow-up (n = 2, yellow line, the NoChange group).
It was recently reported that some patients with IPF have little or no radiological evidence
of honeycombing at the time of diagnosis [
], but there have been no long-term longitudinal
studies of such patients. The clinical course and the sequential changes in HRCT findings of
these IPF patients are not fully understood, and it is yet to be ascertained whether a possible
UIP pattern progresses to a UIP pattern on HRCT. The present study was a first attempt to
observe temporal HRCT changes in these patients.
According to the 2011 international (ATS/ERS/JRS/ALAT) statement, the key finding on
HRCT to differentiate between possible UIP/IPF and a UIP/IPF pattern is the absence or
presence of honeycombing. Honeycombing is seen on HRCT as clusters of cystic spaces, typically
with diameters on the order of 3–10 mm with 1–3 mm wall thickness, but they may be up to 25
mm in diameter [
]. Previous studies examined the correlation between CT scan and
histologic findings in IPF patients. Schettino et al. reported that the honeycomb pattern shown on
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HRCT scans was correlated with that determined by histology (r = 0.71; p<0.01, kappa 0.3)
]. Kazerooni et al. reported that CT fibrosis scores, determined by the ratio of
honeycombing to the lobe, strongly correlate with pathology fibrosis scores [
The first major finding of the present study is that some possible UIP/IPF patients did not
develop a definite UIP/IPF pattern but developed traction bronchiectasis or cysts that finally
progressed to an appearance that was suggestive of NSIP or inconsistent with a UIP pattern on
HRCT. Although we were unable to find any studies in the literature in which possible UIP/
IPF patients developed an appearance suggestive of NSIP, there are some reports that NSIP
patients developed a UIP pattern on CT. Akira et al. reported that the HRCT appearance of
NSIP progressed to an appearance suggestive of IPF because ground-glass opacity and
consolidation decreased whereas the coarseness of fibrosis increased on the follow-up HRCT scans in
most NSIP patients [
]. Silva et al. reported that 28 percent of patients with initial HRCT
findings suggestive of NSIP progressed to findings suggestive of IPF [
Another research group reported their comparison between CT patterns and pathologic
diagnoses: Sumikawa et al. noted that 21 of 56 (38%) patients with an NSIP pattern at CT were
classified as having pathologic UIP; however, the sequential changes in HRCT findings of these
patients were not described in that study [
]. Though several past studies suggested that wider
honeycombing is one of the HRCT findings suggesting the diagnosis of IPF [
recent IPF guidelines might set a high value on HRCT patterns to diagnose IPF, honeycombing
on HRCT may not be essential for diagnosing IPF.
A second important finding of the present study is that was no significant difference in the
prognoses of the IPF patients who did or did not eventually form honeycombing as shown by
HRCT. The mean survival times of these patients were 67.1 and 61.2 months, respectively. IPF
has an unknown etiology and a very poor prognosis. Raghu et al. demonstrated that IPF
patients aged 65 years were living longer in 2011 than they were 10 years before [
], while a
2015 study showed that the median survival of IPF patients is 3–5 years from the time of
]. A baseline factor of “extent of honeycombing on HRCT” was associated with an
increased risk of mortality, although it is unknown whether the presence of these features
constitutes a subpopulation of patients with end-stage IPF, because of the variability in the natural
history of the disease [
Bando et al. reported that the median survival time of IPF patients in Japan from the initial
visit was 69 months [
], which is similar to our present findings. This might indicate that the
presence of honeycombing on the initial HRCT scan does not directly correlate with the
prognosis of IPF patients. A recent randomized, double-blind, placebo-controlled IPF study also
supported the results of the present study, showing that 298 IPF patients with honeycombing
on their initial HRCT had a −225.7 ml/yr decline in FVC values, whereas 125 patients without
honeycombing on HRCT had a −221.0 ml/yr decline in FVC; this difference was not significant
]. These two groups were placebo groups in the study, which might be equivalent to the
natural history of IPF [
Third, we found that a few patients with possible UIP/IPF did not progress over the
longterm follow-up. According to the 2011 international statement, the natural clinical course of
patients with IPF is variable, and the course can be described as “slow progression,”“stable,”
and”rapid progression,” [
] but the percentage of patients in each category is unclear. In the
present study, two of the 30 (7%) patients with possible UIP/IPF showed stable findings on
HRCT and were classified as the NoChange group.
This study had some limitations. It was retrospective and included only patients who
underwent a surgical biopsy. The decision whether or not to perform a surgical biopsy was made at
each institution, and this may have led to selection bias. In addition, we calculated the mean
survival time from the diagnosis of IPF, which also may have differed by each institution.
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Other factors that may affect the lungs such as smoking, dust inhalation and medications were
not taken into account in this study. It may also be difficult to draw any firm conclusions
because there were only 30 patients.
In conclusion, in our patients with pathologically proven UIP/IPF, the presence or absence
of honeycombing on HRCT was not related to prognosis. Although recent IPF guidelines state
that the HRCT pattern is a factor in making the diagnosis of IPF, honeycombing on HRCT
might not be essential to establish this diagnosis.
S1 Table. List of 43 patients in 2011.
We wish to acknowledge Dr. Y. Inoue, Dr. K. Sugino, Dr. A. Shiraki, and Dr. N. Awano for the
case registration from their respective institutions. We are also grateful to Dr. T. Takemura for
advice on the histological evaluation, Dr. H. Ishi for advice on the statistical analysis, and Dr.
Alan T. Lefor for advice on the English translation.
Funding acquisition: YS.
Writing – original draft: H. Yamauchi.
Writing – review & editing: MB.
Investigation: TB KK YY H. Yamamoto AM SI TJ FS YT AH YK.
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