Comparison of pulmonary CT findings and serum KL-6 levels in patients with cryptogenic organizing pneumonia
Abstract
The aim of this study was to retrospectively compare high-resolution CT findings among cryptogenic organizing pneumonia (COP) patients with normal and elevated serum KL-6 levels. Chest CT scans performed between April 1999 and April 2007 in 20 COP patients with a normal KL-6 level and 17 COP patients with an elevated KL-6 level were evaluated retrospectively by two chest radiologists. The CT findings in the COP patients with either a normal or an elevated KL-6 level mainly consisted of consolidation (n = 17 and n = 13, respectively) followed by ground-glass opacity (n = 11 and n = 13, respectively). Traction bronchiectasis and architectural distortion were significantly more frequent in patients with an elevated KL-6 level than in those with normal levels (n = 7 and n = 1, and n = 13 and n = 3, respectively) (p = 0.0077 and p = 0.00017, respectively). In follow-up CT scans, a relapse within 1 year after initial treatment with steroids, performed in 16 patients with a normal KL-6 level and 16 with an elevated KL-6 level, occurred in 2 (12.5%) patients with a normal KL-6 level and in 6 (37.5%) with an elevated KL-6 level. The frequency of relapse in patients with an elevated KL-6 level was higher than in those with a normal KL-6 level; however, no significant difference between the two groups was observed (p = 0.103). In conclusion, CT findings of traction bronchiectasis and architectural distortion in COP patients are associated with increased serum KL-6 levels, which might be related to a relapse after treatment.
KL-6 is a mucin-like high molecular weight glycoprotein and is expressed in Type II pneumocytes and respiratory bronchiolar epithelial cells in the normal lung [1, 2]. Serum levels of KL-6 are elevated in various respiratory and non-respiratory conditions, including breast and pancreatic cancers [3, 4] and diabetes mellitus [5]. However, most attention has focused on KL-6 as a diagnostic and prognostic tool in respiratory diseases.
Serum and bronchoalveolar lavage fluid levels of KL-6, first described by Kohno et al in 1985 [6], are raised in patients with interstitial pneumonia [1, 2, 7]. Several investigators have also reported that KL-6 is a useful serum marker to confirm the diagnosis and aid in the long-term management of patients with diffuse pulmonary diseases, particularly interstitial lung diseases. Patients with idiopathic pulmonary fibrosis (IPF) or non-specific interstitial pneumonia (NSIP) show significantly elevated KL-6 levels [8].
However, to the best of our knowledge, no consensus has been reached on whether serum KL-6 levels are elevated in patients with cryptogenic organizing pneumonia (COP). Moreover, there is no radiological report comparing high-resolution CT (HRCT) findings between patients with an elevated KL-6 level and those with a normal KL-6 level. Thus, we aimed to retrospectively evaluate and compare pulmonary CT findings between patients with an elevated KL-6 level and those with a normal KL-6 level.
Methods and materials
Patients
37 patients with known serum KL-6 levels who underwent HRCT between April 1999 and April 2007 at one of our 5 institutions, and in whom COP had been histologically diagnosed, were included in the study. HRCT scans were performed within 3 days of the measurement of KL-6 levels, and surgical biopsy and transbronchial lung biopsy were performed within 21 days and 5 days, respectively, after the CT scans.
Our study included 20 COP patients (7 men, 13 women; age range, 21–75 years; mean age, 51.5 years) with a normal KL-6 level (106–460 U ml–1; mean, 282.1 U ml–1) in whom transbronchial lung biopsy (n = 7) or both surgical and transbronchial lung biopsy (n = 13) had been performed; and 17 COP patients (9 men, 8 women; age range, 42–74 years; mean age, 56.5 years) with an elevated KL-6 level (502–3500 U ml–1; mean, 1206.3 U ml–1) in whom surgical lung biopsy (n = 1), transbronchial lung biopsy (n = 5), or both surgical and transbronchial lung biopsy (n = 11) had been performed. The ethical review boards of the institutions that contributed the cases to this study did not require approval or informed consent for the retrospective review of the patient records and images.
Patients with other idiopathic interstitial pneumonias were excluded from the study. Moreover, patients with all other known cases of interstitial pneumonia (i.e. connective tissue disease, pneumoconiosis, sarcoidosis, hypersensitivity pneumonitis or drug-induced pneumonitis), those diagnosed with concurrent infectious diseases by serological tests and by clinical and pathological findings, and those with malignancy or diabetes mellitus were also excluded.
COP was diagnosed on the basis of histological findings and clinical history. The clinical findings in all patients were subsequently reviewed by four chest radiologists to ensure that all cases fulfilled the diagnostic criteria recommended by American Thoracic Society and the European Respiratory Society [9].
Treatment was initiated with 0.5–1 mg kg–1day–1 prednisone for 4–8 weeks, which then tapered to about 0.25–0.5 mg kg–1day–1 over the ensuing 4–8 weeks in 16 patients with a normal KL-6 level and 16 with an elevated KL-6 level.
CT examinations
HRCT images were obtained at the end of inspiration and in a supine position. The scanning protocol consisted of the reconstruction of 1 mm collimation sections with a high spatial frequency algorithm at 10 mm intervals. Images were captured at window settings allowing the viewing of the lung parenchyma (window level, −600 HU (Hounsfield units) to −700 HU; window width, 1200–1500 HU) and the mediastinum (window level, 20–40 HU; window width, 400 HU). All initial scans were evaluated. In all patients, follow-up CT scans were obtained at 7–183 days (mean, 35 days) after the initial scan. A total of 143 CT scans were performed, and intravenously administered contrast material was used for 58 CT of these.
CT image interpretation
Images were reviewed independently in random order by 2 chest radiologists (with 19 years and 11 years of experience in chest CT image interpretation, respectively). The observers were unaware of the KL-6 levels and the clinical information. An average of 2 sessions per week was reserved for reviewing the CT scans, with a total of about 60 sessions.
CT images were assessed for the following radiological patterns: ground-glass opacity, consolidation, nodules, interlobular septal thickening, traction bronchiectasis, intralobular reticular opacity, reversed halo sign, subpleural linear opacity, architectural distortion, enlarged hilar/mediastinal lymph node(s) (>1 cm in diameter of the short axis) and pleural effusion. Areas of ground-glass opacity were defined as hazy increases in attenuation without obscuration of vascular markings [10, 11]. Areas of consolidation were defined as areas of increased attenuation causing obscuration of normal lung markings [10, 11]. Interlobular septal thickening was defined as abnormal widenings of interlobular septa [11]. Intralobular reticular opacity was considered present when interlacing line shadows were separated by a few millimetres [10, 11]. Traction bronchiectasis was defined as irregular bronchial dilatation within the surrounding areas showing parenchymal abnormalities. Reversed halo signs were defined as central ground-glass opacities surrounded by denser air-space consolidation of crescentric and ring-shaped areas [12]. Subpleural linear opacity was defined as a thin curvilinear opacity from the pleural surface paralleling the pleura [10, 11]. Architectural distortion was considered present when bronchi, pulmonary vessels, or interlobular fissures or septa were abnormally displaced [11].
The distribution of the parenchymal disease was also noted. If the main lesion was predominantly located in the inner third of the lung, the disease was classified as having a central distribution. Conversely, if the lesion was located predominantly in the outer third of the lung, the disease was classified as having a peripheral distribution. If the lesions showed no predominant distribution, the disease was classified as having a random distribution. If the lesions were along the bronchovascular bundle, the disease was classified as having a peribronchial distribution. In addition, zonal predominance was classified as “upper”, “lower” or “random”. An upper lung zone predominance was considered when most abnormalities were seen in the upper level to the tracheal carina, whereas a lower zone predominance referred to most abnormalities being below the upper zone. When abnormalities showed no definite zonal predominance, the lung disease was classified to have a random distribution.
Measurement of KL-6 levels
Serum KL-6 levels were measured within 3 days of the initial CT scans and before steroid treatment using a sandwich-type enzyme-linked electrochemiluminescence immunoassay (ECLIA) kit (Picolumi KL-6; Sanko Junyaku Co, Tokyo). The recommended cut-off value was determined at 500 U ml–1 according to the levels reported in healthy individuals [6]. The assay was performed by technicians unaware of the clinical information related to the samples.
Statistical analysis
Statistical analyses of the incidence of symptoms and laboratory data were conducted using the Fisher exact test and the χ2 test. Mean age comparison was conducted using a Student's t-test.
Results
CT patterns
The frequencies of CT findings are summarized in Table 1. Of the 20 patients with a normal KL-6 level, consolidation (n = 17, 85%) (Figure 1) was observed most frequently, followed by ground-glass opacity (n = 11, 55%) (Figure 1) and subpleural linear opacity (n = 5, 25%). Intralobular reticular opacity (n = 4, 20%) (Figure 1), nodules (n = 3, 15%) (Figure 2), architectural distortion (n = 3, 15%), reversed halo signs (n = 2, 10%) (Figure 2), interlobular septal thickening (n = 1, 5%) (Figure 1) and traction bronchiectasis (n = 1, 5%) were also observed. A combination of consolidation and ground-glass opacity (n = 9, 45%) was seen most frequently (Figure 1), followed by consolidation and subpleural linear opacity (n = 3, 15%). Consolidation was often irregularly confluent. Some ground-glass opacity was detected in areas surrounding consolidation or in areas without consolidation.
Of the 17 patients with an elevated KL-6 level, ground-glass opacity (Figures 3 and 4), consolidation (Figures 4 and 5) and architectural distortion (Figures 3, 4 and 5) were observed most frequently (n = 13, 76.5%, respectively). Traction bronchiectasis (n = 7, 41.1%) (Figures 3 and 4) and intralobular reticular opacity (n = 5, 29.4%) (Figure 3) were also observed. A combination of ground-glass opacity and architectural distortion (Figure 3), and that of consolidation and architectural distortion (Figures 4 and 5), were seen most frequently (n = 13 and n = 13, respectively).
The CT findings of architectural distortion and traction bronchiectasis in patients with an elevated KL-6 level were observed significantly more frequently than in patients with a normal KL-6 level (p = 0.00017 and p = 0.0077, respectively).
Distribution of the disease
Among the patients with a normal KL-6 level, abnormal findings were predominantly seen in peripheral lungs (n = 11) (Figures 1 and 2). Nine patients showed a random distribution of the disease, and nine had a peribronchial distribution. Conversely, in patients with an elevated KL-6 level, abnormal findings were predominantly classified in the random distribution group (n = 10) (Figure 3), followed by peripheral distribution (n = 7) (Figures 4 and 5). However, there was no statistically significant difference in distribution between groups. In both groups, there were no patients showing a predominantly central distribution.
In patients with a normal KL-6 level, the predominant zonal distribution was the lower zone in 10 patients and had a random distribution in 7 patients. Conversely, in patients with an elevated KL-6 level, the predominant zonal distribution had a random distribution in 11 patients and was classified as the lower distribution in 4 patients. However, there were no statistically significant differences between the two groups.
Effusion and lymph nodes
Bilateral pleural effusions were found in one patient with a normal KL-6 level (Figure 1), and unilateral pleural effusion was found in one patient with an elevated KL-6 level.
Mediastinal and/or hilar lymph node enlargement was observed in one patient with an elevated KL-6 level. Enlarged lymph nodes were found at the paratracheal, tracheobronchial and subcarinal regions. There were no enlarged lymph nodes in patients with a normal KL-6 level.
Follow-up study
Abnormal findings improved in all 32 patients who underwent steroid treatment. Of the five patients who did not undergo treatment, abnormal findings were improved on follow-up CT scans in three with a normal KL-6 level; in the remaining two, consolidation newly appeared on follow-up CT scans. With regard to the responses to steroid treatment, no significant difference was observed between the two groups.
However, relapse within 1 year after initial treatment with steroid treatment occurred in 2 (12.5%) patients with a normal KL-6 level and in 6 (37.5%) with an elevated KL-6 level. The frequency of relapse in patients with an elevated KL-6 level was higher than for those with a normal KL-6 level; however, no significant difference was observed between the two groups (p = 0.103).
Discussion
In lung tissues from patients with interstitial lung diseases, including those with IPF and radiation pneumonitis, the majority of cells stained by a KL-6 monoclonal antibody (mAb) have been identified as regenerating Type II pneumocytes [1, 13]. Therefore, Kohno et al [1, 13] speculated that the increased serum KL-6 level in patients with interstitial pneumonitis was derived from damaged or regenerating epithelial cells in the lower respiratory tract, and thus the KL-6 amount reflects tissue damage in the parenchymal cells of peripheral lung tissues. They also speculated that the changes in KL-6 concentration might give useful information for assessing the state of peripheral lung tissues in various inflammatory interstitial lung diseases.
Recently, serum KL-6 has been proven to be a useful marker for the differential diagnosis of interstitial lung diseases and the evaluation of disease activity. It also appears to serve as a useful marker of IPF, collagen vascular disease-associated interstitial pneumonitis, hypersensitivity pneumonitis, sarcoidosis, alveolar proteinosis and Pneumocystis jiroveci pneumonia [1, 7, 14–18].
Ishii et al [8] reported that mean serum concentrations of KL-6 were significantly higher in patients with usual interstitial pneumonia and NSIP than in healthy volunteers. With regard to patients with COP, elevated KL-6 levels were observed in four of eight patients. There are a few Japanese reports on KL-6 levels in patients with COP [19, 20]; however, there are no other English reports on serum KL-6 levels in patients with COP.
We retrospectively reviewed 37 patients with COP; with regard to the frequency of elevated KL-6 levels in COP patients, our result was similar to that of the previous report [8].
Histopatholigically, the proliferation of Type II pneumocytes is one of the common characteristics of IPF and collagen vascular disease [1, 2]. In addition, there is a mild-to-moderate interstitial infiltration in the organized regions usually associated with a modest Type II cell proliferation [21]. Iwashita et al [22] reported that the number of Type II pneumocytes was significantly higher in COP patients than in control groups. Therefore, it is not difficult to understand how serum KL-6 levels might be elevated in COP patients.
COP usually responds spectacularly well to steroid treatment and typically runs a benign course. However, relapses can occur when steroids are tapered or stopped [23]. In our study, abnormal findings improved with steroid treatment in all patients, and there were no significant differences between the two groups. Conversely, relapses were observed in 8 of the 32 patients (25%) with steroid treatment, a level similar to previous reports [23]. The frequency of relapse in patients with an elevated KL-6 level was higher than in those with a normal KL-6 level; however, no significant difference was observed between the two groups (p = 0.103).
Moreover, to the best of our knowledge, there is no radiological report comparing the HRCT findings in patients with an elevated KL-6 level and those with a normal KL-6 level. In our study, CT findings in COP patients consisted mainly of consolidation with a predominantly peripheral and/or random distribution. Our results were similar to those of previous reports [24, 25]. The prevalence of traction bronchiectasis and nodules were lower than those in previous reports [12, 25]. These differences might be due to elapsed time since the onset of COP; however, this remains unclear.
Correlative studies using CT and histopathology showed that the areas of consolidation and nodules on CT corresponded histopathologically to the typical features of organizing pneumonia, including granulation tissues. Ground-glass opacity histopathologically corresponds to the areas of alveolar septal inflammation [26, 27]. In the reversed halo sign, central ground-glass opacity histopathologically corresponds to the areas of alveolar septal inflammation, whereas the ring-shaped consolidation corresponds to the area of organizing pneumonia within the distal air space [28]. Interlobular septal thickening can be attributed to infiltration into the interstitium of mononuclear cells [29].
Our study showed that there were no significant differences in the frequencies of consolidation, ground-glass opacity, reversed halo sign or interlobular septal thickening between the two groups. Conversely, traction bronchiectasis and architectural distortion were (significantly) observed more frequently in patients with an elevated KL-6 level than in those with a normal KL-6 level (p = 0.0077 and p = 0.00017, respectively). Traction bronchiectasis and architectural distortion are considered to represent the organization and fibrosis of the lungs around the bronchi [30, 31]. Therefore, our results showed that an increased KL-6 level in COP patients whose CT scans mainly consisted of architectural distortion and traction bronchiectais might be caused by an increase in KL-6 production by the regeneration of alveolar Type II pneumocytes and/or an enhanced permeability following the destruction of the air–blood barrier in the affected lungs.
In addition, it has been reported that a reticular pattern on CT is associated with atypical pathological findings, including the presence of interstitial thickening and fibrosis in addition to classic features of organizing pneumonia [27]. In our cases, the frequency of intralobular reticular opacity in patients with an elevated KL-6 level was greater than that in patients with a normal KL-6 level. However, no significant difference between the two groups was observed. This might be due to the cut-off value of 500 U ml–1 or mild interstitial fibrosis associated with Type II cell proliferation.
Finally, there were several limitations to our study. Firstly, we undertook a retrospective study and CT image interpretation was performed by consensus. Secondly, the number of patients in the study was small (n = 37) and, more importantly, surgical lung biopsy was not performed in all patients. However, in all patients, histological and clinical features fulfilled the diagnostic criteria recommended by American Thoracic Society and the European Respiratory Society [9]. Thirdly, the (i) CT scans, (ii) measurement of KL-6 levels and (iii) histological specimens were not obtained on the same days. In addition, our study lacked a pathological correlation with specific CT findings, such as consolidation, traction bronchiectasis and architectural distortion. Fourthly, the relationship between the extent of abnormal findings and KL-6 levels was not evaluated. Finally, the HRCT images were obtained at several institutions using various protocols.
In summary, HRCT findings of traction bronchiectasis and architectural distortion were associated with elevated serum KL-6 levels, which might reflect interstitial fibrosis resulting from the regeneration of alveolar Type II pneumocytes and/or an enhanced permeability following the destruction of the air–blood barrier.
There were no significant differences between the two groups with regard to steroid treatment responses. However, the frequency of relapse was higher in patients with an elevated KL-6 level than in those with a normal KL-6 level.
Images from a 64-year-old woman (KL-6 level, 205 U ml–1). (a) Transverse CT scan (1 mm section thickness) obtained at the level of the tracheal carina shows consolidation (arrows), ground-glass opacity and intralobular reticular opacity with a peripheral distribution. Interlobular septal thickening is also present (arrowheads). (b) Transverse CT scan (1 mm section thickness) obtained at the level of the lower lobes shows consolidation (black arrows) with a peripheral distribution. Note the presence of bilateral pleural effusion (white arrows). Images from a 75-year-old woman (KL-6 level, 315 U ml–1). (a) Transverse CT scan (1 mm section thickness) obtained at the level of the right lower lobe shows a reversed halo sign with a peripheral distribution (arrow). (b) Transverse CT scan (1 mm section thickness) obtained at the level of the right hemidiaphragm shows nodules (arrows). Images from a 66-year-old man (KL-6 level, 1,165 U ml–1). (a,b) Transverse CT scans (1 mm section thickness) obtained at the level of the division of the right lower lobe bronchus show ground-glass opacity, intralobular reticular opacity, traction bronchiectasis (arrows) and architectural distortion with a random distribution. Image from a 52-year-old woman (KL-6 level, 1001 U ml–1). Transverse CT scan (1 mm section thickness) obtained at the level of the diaphragm shows ground-glass opacity, consolidation and architectural distortion with a peripheral distribution. Note the presence of nodules (arrows) and traction bronchiectasis (arrowheads). Images from a 69-year-old woman (KL-6 level, 1882 U ml–1). (a) Transverse CT scans (1 mm section thickness) obtained 1 cm above the tracheal carina and (b) at the level of the tracheal carina show consolidation (arrows) and architectural distortion with a peripheral distribution.
 |
References
1 Kohno N, Kyoizumi S, Awaya Y, Fukuhara H, Yamakido M, Akiyama M. New serum indicator of interstitial pnuemonitis activity: sialyated carbohydrate antigen KL-6. Chest 1989;96:68–73.
2 Kobayashi J, Kitamura S. KL-6: A serum marker for interstitial pneumonia. Chest 1995;108:311–5.
3 Ogawa Y, Ishikawa T, Ikeda K, Nakata B, Sawada T, OgisawaK,et al. Evaluation of serum KL-6, a mucin-like glycoprotein, as a tumor marker for breast cancer. Clin Cancer Res 2000;6:4069–72.
4 Kohno N, Inoue Y, Hamada H, Fujioka S, Fujino S, Yokoyama A, et al. Difference in sero-diagnostic values among KL-6-associated mucins classified as cluster 9. Int J Cancer Suppl 1994;8:81–3.
5 Takahashi T, Takamura K, Sakaue S, Ishii J, Yokouchi H, Nasuhara Y. Elevated serum KL-6 concentrations in patients with diabetes mellitus. J Diabetes Complications 2002;16:352–8.
6 Kohno N, Akiyama M, Kyoizumi S, Hakoda M, Kobuke K, Yamakido M. Detection of soluble tumor-associated antigens in sera and effusions using novel monoclonal antibodies, KL-3 and KL-6, against lung adenocarcinoma. Jpn J Clin Oncol 1988;18:203–16.
7 Kohno N, Awaya Y, Oyama T, Yamakido M, Akiyama M, Inoue Y, et al. KL-6, a mucin-like glycoprotein, in bronchoalveolar lavage fluid from patients with interstitial lung disease. Am Rev Respir Dis 1993;148:637–42.
8 Ishii H, Mukae H, Kadota J, Kaida H, Nagata T, Abe K, et al. High serum concentrations of surfactant protein A in usual interstitial pneumonia compared with non-specific interstitial pneumonia. Thorax 2003;58:52–7.
9 American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias: this joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002;165:277–304.
10 Webb WR, Muller NL, Naidich DP. High-resolution computed tomography findings of lung disease. In: High-resolution CT of the lung, 3rd edn. Philadelphia, PA: Lippincott Williams & Wilkins, 2001; 71–192.
11 Austin JH, Muller NL, Friedman PJ, Hansell DM, Naidich DP, Remy-Jardin M, et al. Glossary of terms for CT of the lungs: recommendations of the Nomenclature Committee of the Fleischner Society. Radiology 1996;200:327–31.
12 Kim SJ, Lee KS, Ryu YH, Yoon YC, Choe KO, Kim TS, et al. Reversed halo sign in high-resolution CT of cryptogenic organizing pneumonia: diagnostic implications. AJR Am J Roentgenol 2003;180:1251–4.
13 Hamada H, Kohno N, Akiyama M, Hiesfs K. Monitoring of serum KL-6 antigen in a patients with radiation pneumonia. Chest 1992;101:858–60.
14 Kohno N, Hamada H, Fujioka S, Hiwada K, Yamakido M, Akiyama M. Circulating antigen KL-6 and lactate dehydrogenase for monitoring irradiated patients with lung cancer. Chest 1992;102:117–22.
15 Kohno N, Yokoyama A, Hirasawa Y,Kondo K, Fujino S, Abe M, et al. Comparative studied of circulating KL-6, type III protocollagen N-terminal peptide and type IV collagen 7S in patients with interstitial pneumonitis and alveolar pneumonia. Respir Med 1997;91:558–61.
16 Takahashi T, Munakata M, Suzuki I, Kawakami Y. Serum and bronchoalveolar fluid KL-6 levels in patients with pulmonary alveolar proteiosis. Am J Respir Crit Care Med 1998;158:1294–8.
17 Yokoyama A, Kohno N, Hamada H, Sakatani M, Ueda E, Kondo K, et al. Circulation KL-6 predicts the outcome of rapidly progressive idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998;158:1680–4.
18 Hamada H, Kohno N, Yokoyama A, Hirasawa Y, Hiwada K,Sakatani M, et al. KL-6 as a serologic indicator of pneumocystis carinii pneumonia in immunocompromised hosts. Intern Med 1998;37:307–10.
19 Inoue T, Tanaka E, Sakuramoto M, Minakuchi M, Maeda Y, Maniwa K, et al. A case of cryptogenic organizing pneumonia accompanied by large bullae. Nihon Kokyuki Gakkai Zasshi 2006;44:517–21.
20 Katayama H, Yokoyama A, Hamada H, Irita J, Kadowaki T, Ito R, et al. Successful treatment of bronchiolitis obliterans organizing pneumonia with cyclosporin and steroids. Nihon Kokyuki Gakkai Zasshi 2003;41:551–5.
21 Colby TV. Pathological approach to idiopathic interstitial pneumonias: useful points for clinicians. Breathe 2004;1:43–9.
22 Iwashita T, Kadota J, Naito S, Kaida H, Ishimatsu Y, Miyazaki M, et al. Involvement of collagen-binding heat shock protein 47 and procollagen type I synthesis in idiopathic pulmonary fibrosis: contribution of type II pneumocytes to fibrosis. Hum Pathol 2000;31:1498–505.
23 Lazor R, Vandevenne A, Pelletier A, Leclerc P, Court-Fortune I, Cordier JF. Cryptogenic organizing pneumonia. Characteristics of relapses in a series of 48 patients. Am J Respir Crit Care Med 2000;162:571–7.
24 Lee KS, Kulling P, Hartman TE, Muller NL. Cryptogenic organizing pneumonia: CT findings in 43 patients. AJR Am J Roentgenol 1994;162:543–6.
25 Arakawa H, Kurihara Y, Niimi H, Nakajima Y, Johkoh T Nakamura H. Bronchiolitis obliterans with organizing pneumonia versus chronic eosinophilic pneumonia: high-resolution CT findings in 81 patients. AJR Am J Roentgenol 2001;176:1053–8.
26 Nishimura K, Itoh H. High-resolution computed tomographic features of bronchiolitis obliterans organizing pneumonia. Chest 1992;102:26S–31S.
27 Bouchardy LM, Kuhlman JE, Ball WC, Hruban RH, Askin FB, Siegelman SS. CT findings in bronchiolitis obliterans organizing pneumonia (BOOP) with radiographic, clinical, and histologic correlation. J Comput Assist Tomogr 1993;17:352–7.
28 Voloudaki AE, Bouros DA, Froudarakis ME, Datseris GE, Apostolaki EG, Gourtsoyiannis NC. Crescentic and ring-shaped opacities CT features in two cased of bronchiolitis obliterans organizing pneumonia (BOOP). Acta Radiol 1996;37:889–92.
29 Akira M, Yamamoto S, Sakatani M. Bronchiolitis obliterans organizing pneumonia manifesting as multiple large nodules or masses. AJR Am J Roentgenol 1998;170:291–5.
30 Remy-Jardin M, Giraud F, Remy J, Copin MC, Gosselin B, Duhamel A. Importance of ground-glass attenuation in chronic diffuse infiltrative lung disease: pathologic-CT correlation. Radiology 1993;189:693–8.
31 Westcott JL, Cole SR. Traction bronchiectasis in end-stage pulmonary fibrosis. Radiology 1986;161:665–9.
