(Chest. 2001;120:198-202.)
© 2001
American College of Chest Physicians
Centrilobular Nodules Correlate With Air Trapping in Diffuse Panbronchiolitis During Erythromycin Therapy*
Gen Yamada, MD;
Tomofumi Igarashi, MD;
Eiji Itoh, MD;
Hiroshi Tanaka, MD;
Kyuichiro Sekine, MD and
Shosaku Abe, MD
*
From the Third Department of Internal Medicine (Drs. Yamada, Itoh, Tanaka, and Abe), Sapporo Medical University, School of Medicine, Sapporo; the Department of Respiratory Medicine (Dr. Igarashi), Kushiro City General Hospital, Kushiro; and the Department of Respiratory Medicine (Dr. Sekine), Minami Ichijo Hospital, Sapporo, Japan.
Correspondence to: Gen Yamada, MD, Third Department of Internal Medicine, Sapporo Medical University, School of Medicine, Chuo-ku South 1 West 16, Sapporo, 060-8543 Japan; e-mail: gyamada{at}sapmed.ac.jp
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Abstract
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Background: Low-dose erythromycin therapy improves
airflow limitation and airway inflammation in patients with diffuse
panbronchiolitis (DPB). However, to our knowledge there has been no
study to determine whether physiologic improvement during erythromycin
therapy correlates with radiologic findings.
Study
objective: To clarify whether improvement in pulmonary function
correlates with specific changes on chest CT.
Design:
The relationship between five CT findings and five pulmonary function
parameters was evaluated before and 3 months after low-dose
erythromycin therapy in 24 patients with DPB retrospectively.
Results: After erythromycin therapy, the predicted
percentage of vital capacity (%VC; 87.0 ± 3.07% vs
98.9 ± 3.39%; p = 0.00006) and 50% of the maximum midexpiratory
flow rate of FVC (1.41 ± 0.26 L/s vs 1.61 ± 0.27 L/s; p = 0.03)
significantly increased, and the residual volume/total lung capacity
ratio (RV/TLC%; 44.5 ± 1.93% vs 40.7 ± 1.83%; p = 0.0019)
significantly decreased, but the FEV1 to FVC ratio and 25%
of the maximum expiratory flow rate of FVC did not. In five CT
findings, centrilobular nodules (3.7 ± 0.4 vs 1.5 ± 0.3;
p = 0.0001), peripheral bronchiolar wall thickness (3.8 ± 0.3 vs
2.6 ± 0.4; p = 0.0007), and peripheral bronchiolectasis
(2.8 ± 0.3 vs 2.2 ± 0.4; p = 0.0058) had significantly
improved, whereas low attenuation area and central bronchiectasis had
not. There were positive correlations of improved scores of
centrilobular nodules with improved %VC (r = 0.58,
p = 0.0062) and RV/TLC% (r = 0.64,
p = 0.0022).
Conclusions: Decreased air
trapping in DPB correlates with an improvement of centrilobular
nodules, which reflects the obstructive lesions of bronchioles during
the erythromycin therapy.
Key Words: air trapping • centrilobular nodules • CT • diffuse panbronchiolitis • pulmonary function test
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Introduction
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Diffuse
panbronchiolitis (DPB) is a progressive disease characterized by
chronic recurrent bronchiolitis and peribronchiolitis, affecting the
respiratory bronchiole. The characteristic pathologic features of DPB
are thickening of the respiratory bronchiolar wall with infiltration of
lymphocytes and plasma cells, consequently causing obstruction or
stenosis of respiratory bronchioles.1
2
Chest
radiography demonstrates mild-to-moderate overinflation in the
initial stage of the disease. With progression, small nodular shadows
and tramlines in the lower lung fields appear; in the advanced stage,
diffuse bronchiectasis occurs.3
DPB is common in East Asia, and human leukocyte antigen B54 is a
frequent halotype (63.2%), appearing in 11.4% of Japanese
patients.4
In the past, the prognosis of this disease was
poor and most patients suffered from continuous infection and died of
chronic respiratory failure in spite of combined antibiotic
administration. In 1987, it was first reported that low-dose (400 to
600 mg/d), long-term (at least 4 weeks) administration of erythromycin
was effective for DPB.5
Since then, erythromycin therapy
has been used in the treatment of patients with DPB,6
7
8
and it has been confirmed that erythromycin raised the survival rate
markedly.2
Although erythromycin therapy improves physiologic and radiographic
findings,5
6
7
it is unknown whether radiologic improvement
reflects pulmonary function in patients with DPB following erythromycin
therapy. In order to address this problem, we evaluated the radiologic
images on CT by using a scoring method and investigated the
relationship between CT findings and pulmonary function tests before
and 3 months after erythromycin therapy.
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Materials and Methods
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Patients
All patients were recruited from Kushiro City General Hospital,
Sapporo Medical University Hospital, and Minami Ichijo Hospital during
the period from 1991 through 1997, and radiologic findings and clinical
information were evaluated retrospectively. Thirty-three patients
received a diagnosis of DPB during this period. The clinical diagnostic
criteria for DPB1
2
were as follows: (1) symptoms of
chronic cough, sputum, and dyspnea on exertion; (2) physical signs
consisting of coarse crackles, rhonchi, or wheezes on auscultation of
the chest; (3) bilateral fine nodular shadows, mainly in the lower lung
fields often with hyperinflation of the lungs on chest radiograph; (4)
FEV1 < 70% of predicted on pulmonary function
tests, and PaO2 < 80 mm Hg on blood
gas analysis; (5) elevated cold hemagglutinin titers > 64 times; (6)
history or coexistence of chronic paranasal sinusitis; and (7)
transbronchial lung biopsy specimens, if obtained, showing thickness of
the wall of respiratory bronchiole with infiltration of lymphocytes,
plasma cells, and foamy histiocytes expanding into the peribronchiolar
area.
Of the 33 patients, 24 patients (13 men and 11 women; age range, 30 to
84 years; mean ± SE age, 60 ± 3 years) underwent complete
pulmonary function tests and CT scans both before and 3 months after
erythromycin therapy.
Scoring Method of CT Findings
Chest CT scans were obtained on an SCT5000TH scanner (Shimazu;
Kyoto, Japan) or a TCT scanner (model 60A; Toshiba; Tokyo,
Japan) using 5-mm collimation at 10-mm intervals from the
sternal notch to below the diaphragm during breath-holding after deep
inspiration. The lungs were imaged at the window width of 1,500
Hounsfield units and the window level of - 700 Hounsfield units.
All CT images were independently reviewed and scored by three qualified
chest radiologists. Each CT score of the airway was based on five
findings: (1) low attenuation areas in the outer zone of the lungs; (2)
small nodules with a centrilobular distribution in both lower lungs;
(3) peripheral bronchiolar wall thickness; (4) peripheral
bronchiolectasis; and (5) central bronchiectasis. For each CT finding,
scores of 0 to 2 were given on the basis of the following grades:
0 = absent, 1 = sparsely or slightly existent, and 2 = dense or
clearly apparent (Fig 1
). The observers reviewed every CT image of all patients before and 3
months after erythromycin therapy. The CT score of each finding was
determined by the sum of the scores obtained from the three observers;
therefore, the highest possible value was 6 and the lowest was 0. We
calculated the CT score difference between before and after treatment
by the following formula:
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Figure 1.. CT scoring criteria of centrilobular nodules in
patients with DPB. Left: Centrilobular nodules are
absent (score 0). Center: Centrilobular nodules are
sparsely distributed within half of the area of the CT image (score 1).
Right: Centrilobular nodules appear densely in
more than half of the area of the CT image (score 2).
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CT scores = scores of before - scores of after
Pulmonary Function Tests
CT scans and pulmonary function tests using a spirometer
(Chestac 25; Chest; Tokyo, Japan) were performed on the same day. The
predicted percentage of vital capacity (%VC), the
FEV1 to FVC ratio
(FEV1/FVC%), the residual volume to total lung
capacity ratio (RV/TLC%), 50% of the maximum midexpiratory flow rate
of FVC (
50) and 25% of the maximum midexpiratory flow rate of
FVC (25), and the ratio of 50 to 25 were assessed.
The changes of %VC and RV/TLC% before and 3 months after erythromycin
therapy were calculated by the following formulas:
%VC = values of after - values of before
RV/TLC% = values of before - values of after
Statistical Analysis
All results were expressed as mean ± SE. Differences in each
CT score both before and 3 months after erythromycin therapy were
compared using the Wilcoxon signed-rank test. Differences in the
pulmonary function tests before and after erythromycin therapy were
compared using Student’s paired t test. Spearman’s rank
correlation test was used to assess the relationship between the score
difference in CT findings and the pulmonary function test parameters.
Differences and correlation were considered statistically significant
at p < 0.05.
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Results
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Changes of the CT Score
Three months of erythromycin therapy improved CT images in 22 of
24 patients with DPB, but not in the other 2 patients. No adverse
effects of erythromycin therapy appeared during this study. Every CT
score before and after erythromycin therapy is shown in Table 1
. Of the five CT findings, three were significantly decreased after
erythromycin therapy: centrilobular nodules (p = 0.0001), peripheral
bronchiolar wall thickness (p = 0.0007), and peripheral
bronchiolectasis (p = 0.0058). However, in the two patients with no
improvement, the CT score of centrilobular nodules increased after
erythromycin therapy: one score increased from 2 to 3, and the other
score increased from 3 to 4.
Pulmonary Function Tests
The results of the pulmonary function tests are
demonstrated in Table 1
. %VC increased significantly (p = 0.00006)
from 87.0 ± 3.07% to 98.9 ± 3.39%, and RV/TLC% decreased
significantly (p = 0.0019) from 44.5 ± 1.93% to 40.7 ± 1.83%,
whereas 50 increased significantly (p = 0.03) from
1.41 ± 0.26 to 1.61 ± 0.27 L/min. However, there were no
significant differences in FEV1/FVC% and
25.
Relationship Between CT Scores and Pulmonary Function Tests
A moderately positive correlation between the decrease in
centrilobular nodules and the %VC (r = 0.58,
p = 0.0062) was found (Fig 2
). Moreover, a positive correlation between the decrease in
centrilobular nodules and the RV/TLC% (r = 0.64,
p = 0.0022) was disclosed (Fig 3
). No significant correlations were obtained between other CT scores and
pulmonary function tests.
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Discussion
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Erythromycin therapy has been established as a standard treatment
for DPB.5
6
7
8
More than 80% of patients with DPB show good
radiologic and physiologic responses to this therapy. In our study, 22
of 24 patients responded to erythromycin therapy, and this result was
consistent with previous reports.5
6
However, the
remaining two subjects were poor responders. Their clinical symptoms
and obstructive changes in pulmonary functions before erythromycin
therapy were more severe. Moreover, these two patients had more severe
airway lesions; their peripheral bronchiolar wall thickness scores were
6 and 4, respectively. Peripheral bronchiolectasis scores were 6 and 5,
and central bronchiectasis scores were 6 and 5, respectively. Moreover,
the centrilobular nodule scores also increased during erythromycin
therapy. These high CT scores before erythromycin therapy represented
an irreversible stage of the disease. Kudoh et al2
reported that the prognosis of patients with advanced DPB was poor in
spite of erythromycin therapy.
In our study, significant improvements were found in centrilobular
nodules, peripheral bronchiolar wall thickness, and peripheral
bronchiolectasis. Ichikawa et al9
demonstrated the
reversibility of airway lesions on CT in response to erythromycin
therapy. They reported a significant reduction in the extent of
centrilobular nodules, the periairway thickening, and the extent of
mucus plugging in conjunction with an improvement of the pulmonary
function tests. These results concur with those of our study. However,
they did not investigate the correlation between each CT finding and
each pulmonary function test.
We found a significant relationship between a decrease in
centrilobular nodules and an increase in both %VC and RV/TLC%.
These findings mean that there is an increase in the %VC but a
decrease in the RV/TLC%. Centrilobular nodules are pathologically
correlated with respiratory bronchiolitis and with peribronchiolar
inflammatory cell infiltration.3
9
10
These nodules
represent obstructive or stenotic changes in the respiratory
bronchioles in patients with DPB (Fig 4
). It is reasonable to suppose that erythromycin therapy improves these
abnormalities around respiratory bronchioles, which may cause air
trapping through a check valve mechanism.
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Figure 4.. Open-lung biopsy specimen in a patient with DPB
(40-year-old man). There is respiratory bronchiolitis with prominent
peribronchiolar inflammatory cell cuffing. These lesions cause
narrowing of the bronchiolar lumen (hematoxylin-eosin, original
x 100).
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The limitation of our study was that we evaluated only radiologic and
physiologic findings. The improvements in the radiologic abnormalities
were not documented because lung biopsy specimens were not obtained
before or after erythromycin therapy. Therefore, our interpretation of
the radiologic pathologic correlation depends on previously reported
results.10
We conclude that CT images of centrilobular
nodules in patients with DPB reflect air trapping and that they may be
a useful radiologic marker to assess the effect of low-dose
erythromycin therapy.
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Footnotes
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Abbreviations: DPB = diffuse
panbronchiolitis; FEV1/FVC% = FEV1 to FVC
ratio; RV/TLC% = residual volume to total lung capacity ratio;
25 = 25% of the maximum midexpiratory flow rate of FVC;
50 = 50% of the maximum midexpiratory flow rate of FVC;
%VC = predicted percentage of vital capacity
Received for publication July 12, 2000.
Accepted for publication December 14, 2000.
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References
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Homma, H, Yamanaka, A, Tanimoto, S, et al (1983) Diffuse panbronchiolitis: a disease of the transitional zone of the lung. Chest 83,63-69[Abstract/Free Full Text]
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Abstract
Introduction
