Acute Exacerbation of Usual Interstitial Pneumonia After Resection of Lung Cancer

Transcription

1 Acute Exacerbation of Usual Interstitial Pneumonia After Resection of Lung Cancer Hiroaki Sugiura, MD, Atsuya Takeda, MD, PhD, Toshiko Hoshi, MD, PhD, Yoshinori Kawabata, MD, Koichi Sayama, MD, PhD, Masahiro Jinzaki, MD, PhD, and Sachio Kuribayashi, MD, PhD Department of Diagnostic Radiology and Division of Pulmonary Medicine, Keio University School of Medicine, Tokyo; Department of Radiology, Ofuna Chuo Hospital, Kanagawa; and Department of Radiology and Division of Diagnostic Pathology, Saitama Cardiovascular and Respiratory Center, Saitama, Japan Background. Acute exacerbation of usual interstitial pneumonia is one of the most life-threatening complications after resection of lung cancer. It is important to detect patients at high risk for acute exacerbation. The purpose of this study was to investigate the incidence of postoperative acute exacerbation and the importance of the finding of honeycombing in predicting the risk of it. Methods. From 992 consecutive pulmonary resections for lung cancer, the background lung was retrospectively assessed histologically. Preoperative chest computed tomographic images of those patients with histologically proven usual interstitial pneumonia were retrospectively reassessed and classified into three groups: typical honeycombing, possible honeycombing, and no honeycombing. Records of patients who experienced postoperative acute exacerbation were extracted from the clinical database, and the correlation between computed tomographic findings and incidence of acute exacerbation was analyzed. Results. Of the 992 lung cancer patients, 12 (1.2%) experienced postoperative acute exacerbation. Usual interstitial pneumonia was histologically confirmed in 249 patients, and 4.8% of them experienced postoperative acute exacerbation. No patient without usual interstitial pneumonia experienced it. Preoperative computed tomographic images were available in 205 of the 249 patients. Postoperative acute exacerbation developed in 13.6% of patients (6 of 44 patients) in the typical honeycombing group, 6.4% of patients (5 of 78 patients) in the possible honeycombing group, and 0% of patients (0 of 83 patients) in the no-honeycombing group. Compared with the no-honeycombing group, the incidence of acute exacerbation in the typical and possible honeycombing groups was significantly higher (p 0.001, p 0.025, respectively). Conclusions. Physicians should consider the finding of possible honeycombing, as well as typical honeycombing, a potential risk factor for acute exacerbation after pulmonary resection for lung cancer. (Ann Thorac Surg 2012;93:937 43) 2012 by The Society of Thoracic Surgeons Idiopathic pulmonary fibrosis (IPF) is a distinctive type of chronic fibrosing interstitial pneumonia of unknown cause that is associated with a histologic pattern of usual interstitial pneumonia (UIP) [1, 2]. Typically, IPF is a slowly progressive disease; however, some patients experience acute exacerbation (AE), which is a rapid deterioration of IPF [3]. Kitaichi and colleagues [4] first reported the histopathologic findings of AE as diffuse alveolar damage superimposed on a UIP pattern. In some patients, AE is the presenting manifestation of previously unrecognized IPF [5]. The 2-year incidence of AE of IPF has been reported at 9.6% in Korea [6]. The clinical course of IPF is difficult to predict, but it is increasingly recognized that AE plays a major role in the progression of this disease. The incidence of lung cancer is reported to be markedly higher among patients who have IPF compared with Accepted for publication Dec 2, Address correspondence to Dr Sugiura, Department of Diagnostic Radiology, Keio University School of Medicine, 35 Shinanomachi Shinjukuku, Tokyo , Japan; hsugiura@rad.med.keio.ac.jp. that of the general population [7]. During the treatment of lung cancer in patients with concurrent IPF, AE after pulmonary resection is one of the most important lifethreatening complications [8 10]. The incidence of postoperative lung injury and operative mortality are both reportedly higher in patients with IPF than in patients without IPF [10, 11]. It has also been suggested that AE of IPF may play a role in the pathophysiology of postoperative acute respiratory distress syndrome [8]. Therefore, it is important to identify these high-risk patients before pulmonary resection. On computed tomography (CT), honeycombing is the most important finding in the diagnosis of UIP; however, although honeycombing is almost specific for UIP [2, 12], it is not always present in patients with UIP. The purpose of this study was to investigate the incidence of postoperative AE of UIP in patients who underwent pulmonary resection for lung cancer in our institution and to assess the importance of honeycombing pattern on CT image in predicting the potential risk of AE by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 938 SUGIURA ET AL Ann Thorac Surg AE OF UIP AFTER RESECTION OF LUNG CANCER 2012;93: Material and Methods From 1993 to 2005 at Saitama Cardiovascular and Respiratory Center, a total of 992 consecutive pulmonary resections were performed to treat lung cancer, including 2 patients who each had repeat surgeries to treat metachronous lesions. Patients with histologically diagnosed resectable lung cancers were eligible for the study, and patients were not excluded only because of the severity of interstitial pneumonia (IP). A single pathologist (Y.K.) retrospectively reviewed histologic specimens from all eligible patients to identify those patients who had UIP pattern fibrosis throughout the resected lung, a finding that fulfilled the criteria of the American Thoracic Society/European Respiratory Society consensus classification (ATS/ERS) [13] and the IPF guidelines [2]. From the clinical database, we extracted the records of patients who had postoperative AE. These were reviewed to identify cases of postoperative AE of UIP, defined as acute, clinically significant respiratory deterioration after pulmonary resection in patients with underlying UIP. Proposed diagnostic criteria included sudden onset of respiratory failure, new bilateral radiographic opacities, and absence of infection or other identifiable etiology, such as pulmonary edema, drug-induced pneumonia, and so on [3]. Images from conventional preoperative chest CT scans with 5- to 10-mm collimation, and if available, thinsection CT scans with less than or equal to 2-mm collimation, were reviewed. Three CT scanners (CT 9800, HiSpeed Advantage, and LightSpeed 16; GE Healthcare, Milwaukee, WI) were used for this study. A single thoracic radiologist (H.S.) retrospectively evaluated the preoperative chest CT images. The whole lungs were surveyed for findings of IP, including tissue unrelated to the cancer location. Findings of IP included typical honeycombing, possible honeycombing, and others: reticulation, air space consolidation, and ground-glass opacity. Each term except possible honeycombing was based on the definition in the glossary of terms for thoracic imaging [12]. The definition of typical honeycombing on CT image was accumulation of cystic air spaces with thickened walls [12, 14] (Fig 1). The term possible honeycombing was used when the appearance of cysts corresponded neither to the definition of honeycombing nor to that of pulmonary emphysema, and included cysts with ill-defined or irregular walls (Fig 2B), scattered cystic air spaces superimposed on ground-glass opacity, and emphysematous change with some IP change (Figs 3A, 3B). To correlate the incidence of postoperative AE with CT image findings, patients were divided into three IP groups on the basis of their preoperative CT results: typical honeycombing group, possible honeycombing group, and no-honeycombing group (Fig 4). The ethics committee of Saitama Cardiovascular and Respiratory Center approved publication of this retrospective database review study; informed consent of each patient was not required. Fig 1. High-resolution computed tomography of the lung at the midlevel portion of the right lower lobe shows typical honeycombing pattern. Black arrows indicate an accumulation of cystic air spaces with thickened walls in the periphery of the lobe. The Cochran-Armitage trend test was used to compare the overall difference in the incidence of AE among the IP groups, the Mann-Whitney U test was performed to compare the differences between the incidence of AE and age, percentage of predicted vital capacity (%VC), forced expiratory volume in 1 second (FEV 1 ) to forced vital capacity (FVC) ratio, and smoking index, and Fisher s exact test was performed to compare the difference between the incidence of AE and sex. To compare the differences in age, %VC, FEV 1 /FVC ratio, and smoking index among the IP groups, one-way analysis of variance was used to investigate intergroup differences. When the overall differences were statistically significant, post hoc analyses were performed using Bonferroni adjustment. The Fisher s exact test with Bonferroni adjustment was then performed to compare each pair of IP groups. We performed separate Cochran- Mantel-Haenszel tests stratified by age, sex, %VC, FEV 1 / FVC ratio, and smoking index. For all tests, a probability value of less than 0.05 was considered significant. Statistical analyses were performed with SPSS Version 18.0 (SPSS, Inc, Chicago, IL) and SAS Version 9.2 (SAS Institute Inc, Cary, NC). Results Details on the number of lung cancer patients, their histologic findings, preoperative CT group, and whether

3 Ann Thorac Surg SUGIURA ET AL 2012;93: AE OF UIP AFTER RESECTION OF LUNG CANCER 939 Fig 2. Lung cancer in the right upper lobe with possible honeycombing finding in the background lung. Preoperative thin-section computed tomographic image shows (A) primary lung cancer in the periphery of the right upper lobe, and (B) thin-walled cystic change (black arrow) superimposed on ground-glass opacities and reticular opacities in the periphery of the right lower lobe. (C) Photomicrograph with hematoxylin and eosin staining shows patchy bands of fibrosis in the background tissue of the right upper lobe. Structural remodeling and fibroblastic foci are present both along the subpleural surface and within the parenchyma, findings that fulfill the pathologic criteria of usual interstitial pneumonia pattern. Magnification 2. Size bar: 5 mm. (D) High-resolution computed tomographic image of the right lower lung 7 days after right upper lobectomy shows acute exacerbation of usual interstitial pneumonia, with a pattern of diffuse heterogeneous ground-glass opacities. they experienced postoperative AE are shown in the study flow chart (Fig 5). Of the 992 lung cancer patients, 249 (25.1%) had histologically confirmed evidence of UIP pattern lesions in the resected background lung. The incidence of postoperative AE was 1.2% (12 of 992 patients) of the total lung cancer patients and 4.8% (12 of 249 patients) of the lung cancer patients with UIP. None of the patients who did not have histologic UIP pattern lesions exhibited postoperative AE. Table 1 provides a summary of the age, sex, smoking history, type of operation, and tumor pathology data for the 205 patients for whom both the clinical data and preoperative CT scans were available. Table 2 shows the details of 11 postoperative AE cases. Among the 205 patients with UIP, 11 patients (5.4%) experienced postoperative AE, and 8 patients (3.9%) died within 3 months after pulmonary resection. Acute exacerbation was considered the cause of death for 5 patients. The causes of death for the other 3 patients were pulmonary hemorrhage 2 months after surgery, severe infectious pneumonia several days after surgery, and tachycardia and dyspnea of unknown cause with clinical features that did not correspond to a diagnosis of AE. On the basis of preoperative CT image findings in the subjects with histologically confirmed UIP, the IP groups of typical honeycombing, possible honeycombing, and no-honeycombing consisted of 44 (21%), 78 (38%), and 83 (40%) patients, respectively. Table 3 summarizes the data for the three IP groups. Postoperative AE of UIP developed in 13.6% (6 of 44 patients) of the typical honeycombing group, 6.4% (5 of 78 patients) of the possible honeycombing group, and 0% (0 of 83 patients) of the nohoneycombing group (Fig 6). The overall difference in the incidence of AE among the three IP groups was statistically significant (p 0.001). Compared with the no-honeycombing group, the incidence of postoperative AE in the typical honeycombing group and that in the possible honeycombing group was significantly higher (p 0.001, p 0.025, respectively). The incidence of AE in the typical honeycombing group was higher than that in the possible honeycombing group; however, the difference was not statistically significant (p 0.201). All the differences between the incidence of AE and age (p 0.322), sex (p 0.261), %VC (p 0.399), FEV 1 /FVC ratio (p 0.990), and smoking index (p 0.649) were not significant. The overall differences in age, FEV 1 /FVC ratio, and smoking index among the three IP groups were statistically significant (p 0.011, p 0.012, p 0.001, respectively), but that in %VC was not (p 0.079). From the intergroup difference analysis, the mean age of the typical honeycombing group was significantly lower than that of the no-honeycombing group (p 0.008). The FEV 1 /FVC ratio of the possible honeycombing group was lower than the no-honeycombing and the typical honeycombing groups (p 0.030, p 0.009, respectively).

4 940 SUGIURA ET AL Ann Thorac Surg AE OF UIP AFTER RESECTION OF LUNG CANCER 2012;93: Fig 3. Lung cancer in the left upper lobe with possible honeycombing finding in the background lung. (A, B) Preoperative thin-section computed tomographic image of the left upper lobe shows well-demarcated primary lung cancer and cysts with slightly thicker walls than in the surrounding emphysematous regions, a finding that suggests some fibrotic change superimposed on emphysematous change (black arrows). Intermingled cysts and ground-glass opacities are present in the periphery of the right lower lobe (arrowheads). These cystic changes were classified as possible honeycombing. (C) Photomicrograph with hematoxylin and eosin staining shows subpleural, chronic, interstitial pneumonia with emphysematous change. Although no bands of dense fibrosis were observed and the cyst walls were rather thin, this lesion was considered as fulfilling the histologic criteria of usual interstitial pneumonia pattern and was interpreted as usual interstitial pneumonia with thin-wall honeycombing. Magnification 2. Size bar: 5 mm. (D) High-resolution computed tomographic image of the right lung shows acute exacerbation of usual interstitial pneumonia 8 days after left upper lobectomy, with a pattern of ground-glass opacities. Compared with the no-honeycombing group, the smoking indices in the possible honeycombing and typical honeycombing groups were significantly higher (p 0.001, p 0.001, respectively). All the stratified analyses consistently showed significant associations between the IP groups and the incidence of AE, by age (p 0.001), sex (p 0.002), %VC (p 0.001), FEV 1 /FVC ratio (p 0.001), and smoking index (p 0.001). Fig 4. Preoperative thin-section computed tomographic image of the lower lung lobes at the apex of the diaphragm in a patient with usual interstitial pneumonia shows diffuse ground-glass opacities and reticulation bilaterally, primarily in a peripheral dominant distribution. Neither typical nor possible honeycombing is present. Comment The incidence of postoperative lung injury, as well as operative mortality, is reportedly higher in patients with IPF than in patients without IPF [10, 11]. Chida and associates [8] reported that acute respiratory distress syndrome developed after thoracotomy in 8.8% of patients who had IP findings on preoperative chest CT but in only 0.4% of patients without IP findings (p 0.001). In addition, 73% of patients with postoperative acute respiratory distress syndrome had IP findings on their preoperative chest CT images. It was suggested, from these data, that postoperative acute respiratory distress syndrome might be in some way associated with AE of IPF. Although the etiology of AE is unknown, several risk factors of AE have been reported. The incidence of AE after pulmonary resection for lung cancer is as high as 20% [8, 9]. The risk of this type of AE has not been clearly linked to the level of pulmonary function derangement [6], age, or smoking history, but appears to be higher in

5 Ann Thorac Surg SUGIURA ET AL 2012;93: AE OF UIP AFTER RESECTION OF LUNG CANCER 941 Fig 5. Flow chart of patients in the study shows the number of lung cancer patients, those who had usual interstitial pneumonia (UIP) pattern in the background lung, patients for whom preoperative computed tomographic (CT) images were available, and their computed tomographic results classification group. The number in the brackets in each box represents the number of patients who experienced postoperative acute exacerbation. men [3]. In the current study, there were no significant correlations between the incidence of AE and age, sex, pulmonary function (%VC, FEV 1 /FVC ratio), and smoking index. Even less-invasive procedures such as bronchoscopy, bronchoalveolar lavage, transbronchial lung biopsy, and surgical lung biopsy have been reported to cause AE [15 18]. The incidence of postoperative AE in the current study, 1.2% overall and 4.8% in patients with UIP, was lower than in previous reports [8, 9, 19]. Two factors may have contributed to this result. One is that some lung cancer Table 1. Operational and Pathologic Data of Patients Variable No. of Patients Age, years (range, median) 50 85, 71 Men/women 182/23 Smokers/nonsmokers/unknown (%) 188/12/5 (92%/6%/2%) Smoking index of smokers (pack-years) a Types of operation Lobectomy 174 Bilobectomy 11 Pneumonectomy 20 Number of cancers (excluding metachronous cancer) One 192 Two 10 Three 3 Pathologic classification of lung cancer SqCC 126 Adenocarcinoma 71 Others (including 4 cases of SCC) 27 a Average standard deviation. SCC small cell carcinoma; SqCC squamous cell carcinoma. patients with severe IP were excluded from this study because there was no indication for surgical resection at our institution. The second is that more patients with subclinical IP were included in this study, because the diagnosis of UIP was not based on the preoperative chest CT findings but on the histopathologic diagnosis of UIP in the resected lung. The official ATS/ERS/JRS/ALAT guidelines for IPF diagnosis and management were recently published [2]. One of the most important changes is that IPF can be diagnosed by using only high-resolution CT findings when no cause of interstitial lung disease has been identified, which eliminates the need for surgical biopsy [2]. Usual IP is characterized on high-resolution CT image by the presence of bilateral, predominantly basal or subpleural distribution of reticular patterns, associated with honeycombing or traction bronchiectasis [13]. Among these findings, honeycombing is critical for making a definitive diagnosis and is considered specific for pulmonary fibrosis [2]. It is emphasized that the term honeycombing should be used strictly because it may directly lead to diagnosis and impact patient care [12]. However, the honeycombing finding may include a wide and confusing spectrum of pulmonary changes. In this study, we cautiously restricted the typical honeycombing finding to the definition as described in the glossary of terms for thoracic imaging [12], that is, accumulation of cystic air spaces with thickened wall, which looks like a honeycomb [14]. In addition, we introduced the term possible honeycombing to describe changes that did not fulfill the criteria of honeycombing, and included cystic changes superimposed on IP findings and IP findings superimposed on emphysematous change when the features did not correspond to the criteria of pulmonary emphysema. Both types of changes were included in one group

6 942 SUGIURA ET AL Ann Thorac Surg AE OF UIP AFTER RESECTION OF LUNG CANCER 2012;93: Table 2. Cases of Postoperative Acute Exacerbation of Usual Interstitial Pneumonia Patient No. Age (y) Sex Smoking Index (pack-years) Operation Pathology Onset of AE (postoperative day) Outcome Typical honeycombing 1 54 M 14 Lobectomy Adenocarcinoma 3 Survived 2 73 M 59 Lobectomy SqCC 7 Dead 3 66 M 40 Lobectomy Adenocarcinoma 35 Dead 4 70 M 45 Lobectomy Adenocarcinoma 5 Survived 5 59 M 35 Lobectomy SqCC 6 Survived 6 75 M 52 Lobectomy LCNEC 20 Dead Possible honeycombing 7 62 M 40 Bilobectomy SCC 11 Survived 8 65 M 56 Lobectomy Adenocarcinoma 14 Dead 9 78 M 49 Lobectomy SqCC 8 Dead M 77 Lobectomy Adenocarcinoma 7 Survived M 25 Lobectomy SqCC 6 Survived Median, range 70, , , 3 35 AE acute exacerbation; LCNEC large cell neuroendocrine carcinoma; SCC small cell carcinoma; SqCC squamous cell carcinoma. because they resembled and were often hard to distinguish from each other. In the current study, 6.4% of the patients in the possible honeycombing group experienced postoperative AE, which was less frequent than in the typical honeycombing group (13.6%), but the difference was not statistically significant (p 0.201). The results of the current study suggest that any honeycomb changes on preoperative CT images may be important in prediction of postoperative AE of UIP. Although the finding of typical honeycombing is critical in the diagnosis of UIP, the finding of possible honeycombing on chest CT images may be associated with the histologic pattern of UIP, which has a potential risk for developing AE. However, in patients with lung cancer whose chest CT images have some IP findings without either typical or possible honeycombing changes, UIP may be identified histologically, but the risk of postoperative AE is statistically significantly lower than in patients with typical or possible honeycombing. The limitation of this study was that we did not investigate the results of preoperative CT images of lung cancer patients without histologic UIP lesions. In patients whose IP lesions were located in lobes other than that of the primary lung cancer, the UIP lesion would not be detected histologically in the resected lung, even if the preoperative CT showed obvious IP changes. However, in the current study, the rigorous diagnostic criteria of histologically confirmed UIP were used for inclusion in the study. In summary, among the consecutive 992 patients who underwent pulmonary resection to treat lung cancer, we classified the preoperative CT results of the 205 patients who had histologically confirmed UIP into three groups: typical honeycombing, possible honeycombing, and no Table 3. Computed Tomographic Classification and Pulmonary Function Tests, Smoking Index, Type of Operation, and Postoperative Acute Exacerbation Variable Typical Honeycombing Possible Honeycombing No-Honeycombing Total Age (y) a Sex (men/women) 40/4 75/3 67/16 182/23 %VC FEV 1 /FVC ratio b,c Smoking index (pack-years) d,e Operation (Lob/2 Lob/Pn) 39/3/2 69/3/6 66/5/12 174/11/20 Postoperative AE (%) 6 (13.6%) 5 (6.4%) 0 (0.0%) f,g 11 (5.4%) Total 44 (21.5%) 78 (38.0%) 83 (40.5%) 205 a Comparison between No-honeycombing and Typical honeycombing, p b Comparison between No-honeycombing and Possible honeycombing, p c Comparison between No-honeycombing and Typical honeycombing, p d Comparison between Nohoneycombing and Typical honeycombing, p e Comparison between No-honeycombing and Possible honeycombing, p f Comparison between No-honeycombing and Typical honeycombing, p g Comparison between No-honeycombing and Possible honeycombing, p AE acute exacerbation; FEV 1 /FVC ratio ratio of forced expiratory volume in 1 second to forced vital capacity; Lob lobectomy; Pn pneumonectomy; %VC percentage of predicted vital capacity.

7 Ann Thorac Surg SUGIURA ET AL 2012;93: AE OF UIP AFTER RESECTION OF LUNG CANCER 943 Fig 6. Comparison of the incidence of postoperative acute exacerbation in each computed tomographic classification group. honeycombing. This study showed that AE developed in 13.6% of patients who had typical honeycombing on chest CT, and 6.4% of patients with possible honeycombing; however, AE did not develop in the nohoneycombing group. Therefore, physicians should consider the finding of possible honeycombing as well as typical honeycombing on the preoperative chest CT image as a potential risk factor for the development of AE of UIP after lung resection. In patients with lung cancer whose chest CT images have some IP findings without either typical or possible honeycombing changes, UIP may be identified histologically, but the risk for developing AE is statistically significantly lower than in patients with typical or possible honeycombing. The authors would like to thank Dr Takayuki Abe and Dr Li-Yu Lin for statistical support. References 1. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000;161(2 Pt 1): Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/ JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183: Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2007;176: Kitaichi M. Pathologic features and the classification of interstitial pneumonia of unknown etiology. Bull Chest Dis Res Inst Kyoto Univ 1990;23: Parambil JG, Myers JL, Ryu JH. Histopathologic features and outcome of patients with acute exacerbation of idiopathic pulmonary fibrosis undergoing surgical lung biopsy. Chest 2005;128: Kim DS, Park JH, Park BK, Lee JS, Nicholson AG, Colby T. Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features. Eur Respir J 2006;27: Hubbard R, Venn A, Lewis S, Britton J. Lung cancer and cryptogenic fibrosing alveolitis. A population-based cohort study. Am J Respir Crit Care Med 2000;161: Chida M, Ono S, Hoshikawa Y, Kondo T. Subclinical idiopathic pulmonary fibrosis is also a risk factor of postoperative acute respiratory distress syndrome following thoracic surgery. Eur J Cardiothorac Surg 2008;34: Hyzy R, Huang S, Myers J, Flaherty K, Martinez F. Acute exacerbation of idiopathic pulmonary fibrosis. Chest 2007; 132: Kumar P, Goldstraw P, Yamada K, et al. Pulmonary fibrosis and lung cancer: risk and benefit analysis of pulmonary resection. J Thorac Cardiovas Surg 2003;125: Watanabe A, Higami T, Ohori S, Koyanagi T, Nakashima S, Mawatari T. Is lung cancer resection indicated in patients with idiopathic pulmonary fibrosis? J Thorac Cardiovasc Surg 2008;136: , 1363.e Hansell DM, Bankier AA, MacMahon H, McLoud TC, Muller NL, Remy J. Fleischner Society: glossary of terms for thoracic imaging. Radiology 2008;246: 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 Am J Respir Crit Care Med 2002;165: Akira M, Kozuka T, Yamamoto S, Sakatani M. Computed tomography findings in acute exacerbation of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2008;178: Hiwatari N, Shimura S, Takishima T, Shirato K. Bronchoalveolar lavage as a possible cause of acute exacerbation in idiopathic pulmonary fibrosis patients. Tohoku J Exp Med 1994;174: Suga T, Sugiyama Y, Ohno S, Kitamura S. [Two cases of IIP which developed acute exacerbation after bronchoalveolar lavage.] Nihon Kyobu Shikkan Gakkai Zasshi 1994; 32: Kondoh Y, Taniguchi H, Kitaichi M, et al. Acute exacerbation of interstitial pneumonia following surgical lung biopsy. Respir Med 2006;100: Tasaka S, Kanazawa M, Komune Y, et al. [Acute exacerbation of subacute interstitial pneumonia after thoracoscopic lung biopsy.] Nihon Kokyoki Gakkai Zasshi 1998; 36: Takenaka K, Yoshimura A, Okano T, et al. Acute exacerbation of idiopathic interstitial pneumonia complicated by lung cancer, caused by treatment for lung cancer. Jpn J Lung Cancer 1999;39: