AJR 2003; 181:1539-1543
© American Roentgen Ray Society
Fibrosis of the Upper Lobes: A Newly Identified Late-Onset Complication After Lung Transplantation?
Eli Konen1,2,
Gordon L. Weisbrod1,
Smita Pakhale3,
TaeBong Chung1,
Narinder S. Paul1 and
Michael A. Hutcheon3
1 Department of Medical Imaging, Toronto General Hospital, University Health
Network, 200 Elizabeth St., Toronto, ON ES1-401C, Canada.
2 Present address: Department of Diagnostic Imaging, Chaim Sheba Medical Center,
Tel Hashomer 52621, Israel.
3 Toronto Lung Transplant Program, Toronto General Hospital, University Health
Network, Toronto ON ES1-401C, Canada.
Received May 5, 2003;
accepted after revision July 2, 2003.
Address correspondence to E. Konen
(konen{at}zahav.net.il).
Abstract
OBJECTIVE. The objective of this study was to describe the
high-resolution CT findings of a previously unreported rare complication
observed in seven patients who had undergone lung transplantation.
CONCLUSION. High-resolution CT findings suggestive of gradual
progressive lung fibrosis, predominantly in the upper lobes with relative
sparing of the basal segments, may represent a specific and rare type of
rejection of still unknown cause in lung transplant recipients.
Introduction
Lung transplant recipients are prone to a wide range of early- and
lateonset complications. Major long-term complications include the development
of bronchiolitis obliterans, opportunistic infections, organizing pneumonia,
recurrence of the primary disease, posttransplantation lymphoproliferative
disorder, and bronchogenic carcinoma
[1–6].
CT plays an important role in the diagnosis and follow-up of these
complications [3,
6,
7]. Between June 1, 1992, and
May 31, 2002, 391 patients underwent lung transplantation (double lung, 334;
single lung, 50; and heart–lung, seven) at our center. As a part of the
long-term follow-up of these patients, an annual high-resolution CT
examination was performed. From these follow-up CT scans, we identified seven
lung transplant recipients whose CT findings showed a gradual development of
parenchymal abnormalities that did not correspond radiologically or clinically
to any of the known complications encountered after lung transplantation. We
describe our retrospective assessment of the high-resolution CT, clinical, and
laboratory findings in these patients.
Materials and Methods
Between July 1, 2000, and June 30, 2002, we identified seven lung
transplant recipients (four female and three male patients) who were referred
to our department for a routine follow-up high-resolution CT examination of
the chest that revealed a unique pattern of lung parenchymal changes. Mean age
at the time of lung transplantation was 47.7 years (range, 13–67 years).
The indications for lung transplantation were chronic obstructive pulmonary
disease in three patients, pulmonary fibrosis in two patients, sarcoidosis in
one patient, and cystic fibrosis in one patient. Six patients had undergone
double lung transplantation, and one had undergone single lung
transplantation. A total of 44 high-resolution CT scans were available for
evaluation, a range of three to nine scans (mean, six scans) per patient. The
scans were obtained from 3 to 92 months after lung transplantation.
All of the high-resolution CT scans were retrospectively evaluated by two
chest radiologists: one, a staff-grade chest radiologist and the other, a
fellowship-trained chest radiologist. Both reviewers were unaware of any
clinical or laboratory data. All high-resolution CT scans obtained in 1997 or
later (n = 40) were evaluated on a PACS (picture archiving and
communication system) workstation (eFilm workstation 1.7.1, Merge eFilm,
Toronto, Canada), whereas earlier scans (n = 4) were assessed on
hard-copy films.
Both lungs were evaluated separately in three zones: upper lobes and right
middle lobe, superior segments of lower lobes, and basal segments of lower
lobes. Each zone was evaluated for the presence of the following
abnormalities: peripheral interstitial opacities (interlobular septal
thickening and coarse interstitial reticular opacities), traction
bronchiectasis, honeycombing, and architectural distortion. Interstitial
opacities and honeycombing were graded on a four-point scale: 0, no
significant abnormality; 1, abnormalities involving up to 25% of the lobar
volume; 2, abnormalities involving 26–50% of the lobar volume; and 3,
abnormalities involving more than 50% of the lobar volume. The severity of
traction bronchiectasis and architectural distortion was subjectively scored
using the following scale: 0, no bronchiectasis or distortion; 1, mild; 2,
moderate; and 3, severe. Evidence of pneumothorax was also recorded.
Serial volume assessments of the upper lobes were calculated on a
postprocessing workstation (CV Viewer, General Electric Medical Systems,
Milwaukee, WI) using a modification of a previously described method
[8]. The contours of the upper
lobes were manually traced, and the cross-sectional area was determined using
the region-of-interest function.
Results
The analysis of the sequential follow-up high-resolution CT scans is
summarized in Table 1. Initial
parenchymal abnormalities were noted on high-resolution CT scans obtained
18–72 months after lung transplantation (mean, 42 months). The earliest
parenchymal abnormalities noted were peripheral interstitial opacities,
ranging from interlobular septal thickening to coarse interstitial reticular
opacities (Figs. 1A,
1B,
1C,
2A,
2B,
2C,
3A,
3B,
3C). Some abnormalities were
associated with mild peripheral ground-glass opacities
(Fig. 2B). Traction
bronchiectasis, honeycombing, and architectural distortion all subsequently
developed and appeared contemporaneously (Figs.
1C,
2C, and
3C). In one patient who
underwent a single left lung transplantation, similar changes were noticed
mainly in the transplanted lung, whereas the native lung showed minimal
interval changes (Fig. 4A,
4B).
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TABLE 1 Average Scores for Abnormalities Seen on Follow-Up High-Resolution CT
Scans Obtained in Seven Patients After Lung Transplantation
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Fig. 1A. —72-year-old woman who underwent double lung transplantation 5
years earlier because of chronic obstructive pulmonary disease. Axial
high-resolution CT scan obtained 18 months after surgery at level of distal
trachea shows mild bronchial dilatation. Otherwise, no significant parenchymal
abnormalities are seen.
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Fig. 1B. —72-year-old woman who underwent double lung transplantation 5
years earlier because of chronic obstructive pulmonary disease. Axial
high-resolution CT scan obtained 17 months after A at level of aortic
arch shows interval appearance of extensive peripheral course reticular and
patchy ground-glass opacities (arrowheads), interlobular septal
thickening (short arrow), and associated severe dilatation of bronchi
(long arrow).
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Fig. 1C. —72-year-old woman who underwent double lung transplantation 5
years earlier because of chronic obstructive pulmonary disease. Axial
high-resolution CT scan obtained 19 months after B shows advancing
bilateral coarse opacities with cystic changes, architectural distortion, and
additional bilateral volume loss, all suggestive of lung fibrosis. Note
interval appearance of persistent right pneumothorax that occurred after open
lung biopsy. Arrow indicates surgical metal clip at site of lung biopsy.
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Fig. 2A. —38-year-old man who underwent double lung transplantation
necessitated by end-stage sarcoidosis. Axial high-resolution CT scan obtained
9 months after surgery at level of aortic arch shows no significant
parenchymal abnormalities.
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Fig. 2B. —38-year-old man who underwent double lung transplantation
necessitated by end-stage sarcoidosis. Axial high-resolution CT scan obtained
at same level 10 months after A shows interval appearance of bilateral
peripheral interstitial opacities (arrowheads) and interlobular
septal thickening (thin arrow), with associated bronchial dilatation.
Thick arrow indicates interlobar fissure.
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Fig. 2C. —38-year-old man who underwent double lung transplantation
necessitated by end-stage sarcoidosis. Axial high-resolution CT scan obtained
15 months after B shows interval anterior progression of interlobar
fissure (thick arrow), suggesting further volume loss of right upper
lobe. Note associated traction bronchiectasis (thin arrow).
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Fig. 3A. —20-year-old man who underwent double lung transplantation at
age of 13 for cystic fibrosis. Axial high-resolution CT scan obtained at level
of carina 43 months after transplantation shows normal lung parenchyma.
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Fig. 3B. —20-year-old man who underwent double lung transplantation at
age of 13 for cystic fibrosis. Axial high-resolution CT scan obtained at same
level as B 12 months later shows interval appearance of bilateral
diffuse peripheral interstitial opacities (arrowheads) and mild
septal thickening (arrow).
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Fig. 3C. —20-year-old man who underwent double lung transplantation at
age of 13 for cystic fibrosis. Axial high-resolution CT scan obtained at same
level as A and B 12 months after B shows further
reduction in lung volumes, bilateral course interstitial opacities with
associated traction bronchiectasis (thin arrows) and cystic changes
(thick arrow) suggestive of honeycombing. Note loculated pneumothorax
on left hemithorax (arrowheads).
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Fig. 4A. —60-year-old woman who underwent single (left) lung
transplantation at age 56 for interstitial pulmonary fibrosis. Axial
high-resolution CT image obtained at level of distal trachea 9 months after
surgery shows normal transplanted left lung. Diffuse fibrosis in native right
lung with volume loss causes shifting of mediastinum to right. Arrow indicates
interlobar fissure.
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Fig. 4B. —60-year-old woman who underwent single (left) lung
transplantation at age 56 for interstitial pulmonary fibrosis. Axial
high-resolution CT scan obtained at same level 35 months after A shows
interval appearance of subpleural reticular opacities mainly in left upper
lobe (arrowheads), associated with traction bronchiectasis (thin
arrow) and volume loss. Shift of mediastinum toward midline and interval
anterior progression of interlobar fissure (thick arrow) are seen.
Findings in right lung parenchyma remain mostly unchanged.
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The upper and middle lobes were affected first and to the greatest degree
in all seven patients, followed by the superior segments of the lower lobes;
the basal segments remained relatively spared
(Table 1). Computed volumetric
calculations comparing the initial and last high-resolution CT scans showed a
mean interval decrease of 45% in the volume of the upper lobes (range,
25–66%) (Table 2).
Decreased volume showed no significant predilection for occurring in either
lung. An associated pneumothorax was noted on at least one scan of five (71%)
of the seven patients (Figs. 1C
and 3C). In two patients, the
pneumothorax appeared 4 years after transplantation (one patient had a
persistent asymptomatic pneumothorax after an open lung biopsy and later
developed an additional spontaneous pneumothorax); in the remaining three
patients, the pneumothorax appeared 5–6 years after transplantation.
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TABLE 2 Comparison of Volumes of Upper Lobes on First and Last Available
High-Resolution CT Scans in Seven Lung Transplant Recipients
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After the initial radiologic changes were noted, all patients presented
clinically with progressive limitation in exercise tolerance and shortness of
breath. In all patients, pulmonary function tests showed a progressively
restrictive pattern compared with the postoperative baseline test. In three
patients, this pattern was accompanied by a mild obstructive defect. Careful
microbiologic evaluation did not reveal any specific causative agent. Repeated
transbronchial biopsies in all patients and open lung biopsy in one patient
revealed nonspecific inflammation and fibrotic changes.
Discussion
The high-resolution CT findings for seven lung transplant recipients were
suggestive of progressive upper lobe fibrosis. Although the ages, indications
for lung transplantation, and clinical findings of the patient population were
diverse, the pattern of gradual high-resolution CT changes was strikingly
similar. The initial findings were suggestive of an interstitial lung disease
but are nonspecific; these findings include interlobular septal thickening and
gradual development of coarse reticular opacities, occasionally associated
with mild peripheral ground-glass opacities (Figs.
1B,
2B, and
3B). This pattern suggests an
early mechanism of interstitial inflammation that might already be accompanied
by elements of interstitial fibrosis, and the pathologic findings obtained in
the patients support this explanation. Within a few months, more specific
findings for pulmonary fibrosis appeared, including traction bronchiectasis,
honeycombing, and architectural distortion of the lung parenchyma (Figs.
1C,
2C,
3C, and
4B). The changes primarily
affected the upper lobes and later, to a lesser degree, the superior segments
of the lower lobes, whereas the basal segments were minimally involved
(Table 1). The parenchymal
findings were associated with a significant reduction in lung volume, which
was most striking in the upper lobes, with an average volume loss of 45%
(Table 2). An associated
pneumothorax was noted on at least one scan in five of our seven patients
(Fig. 3C); the pneumothorax was
usually small and loculated, producing minimal, if any, symptoms.
Neither the clinical, laboratory, nor pathologic findings were specific or
helpful in determining a common pathophysiologic process in this group of
patients. Also, none of the patients was treated with a pulmonary cytotoxic
drug. The associated clinical picture was one of progressive dyspnea, with the
results of pulmonary function tests suggestive of obstructive and restrictive
patterns and pathologic analysis showing nonspecific inflammation and
fibrosis. Upper lobe changes and fibrosis might be caused by mycobacterial
infection; however, repeated microbiologic studies showed no evidence of such
infection. Recurrence of the native disease, including recurrent pulmonary
fibrosis, is a well-known complication in patients after lung transplantation
and is most frequently reported in patients with sarcoidosis
[3]. However, such recurrence
would explain the radiologic findings in only one of our patients who
underwent a lung transplantation because of end-stage lung disease resulting
from sarcoidosis. Recurrent disease in two other patients, who previously had
interstitial lung disease, would be expected to appear mainly in the lower
lobes, not in the apices of the lungs, as observed in this cohort.
A literature search revealed one article with a lung transplant recipient
whose radiologic images were identical to those seen in our patients
[9]. Volume loss was described
generally as part of the spectrum of CT findings in patients with lung
rejection, with no emphasis of the upper lobe predominance. Whether this
particular pattern of predominantly upper lobe fibrosis represents an
expression of lung rejection is unknown; the causative mechanism has not been
identified. The fact that such changes affected mainly the transplanted lung
in a patient who underwent single lung transplantation (Fig.
4A,
4B) further suggests the
hypothesis of lung rejection, as opposed to another bilateral systemic
disease. A heightened awareness of this condition among thoracic radiologists
and respirologists who follow up lung transplant recipients might lead to a
better understanding of this specific and rare pattern.
In conclusion, we have described the high-resolution CT findings in seven
lung transplant recipients who showed a unique pattern of progressively
advancing pulmonary fibrosis that appeared initially in the upper lobes, and
later, less prominently, in the superior segments of the lower lobes, with a
relative sparing of the basal segments. Clinical, laboratory, microbiologic,
and pathologic studies in our patients did not reveal any specific finding
that could explain a common mechanism in this group of patients. Further
investigation involving a larger number of lung transplant recipients with
similar radiologic findings might shed more light on this rare type of lung
rejection.
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Abstract
Introduction
