Expiratory Air Trapping on Thoracic Computed Tomography A Diagnostic Subclassification

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1 Expiratory Air Trapping on Thoracic Computed Tomography A Diagnostic Subclassification Wallace T. Miller, Jr. 1, Jonathan Chatzkel 2, and Michael G. Hewitt 1 1 Department of Radiology, and 2 Medical School, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania Abstract Rationale: Multiple causes for air trapping as identified by expiratory computed tomography (CT) have been reported, but a unified evaluation schema has never been proposed. Objectives: It was our purpose to identify imaging features that would help distinguish etiologies of mosaic air trapping. Methods: Cases with the term air trapping in the radiology report in 2010 were identified by searching the Radiology Information System of an academic tertiary care center and associated community hospital. Medical records and CT examinations were reviewed for the causes of air trapping. Measurements and Main Results: Causes for moderate to severe air trapping could be identified in 201 of 230 (87.4%) cases and could be subdivided into those associated with bronchiectasis (76 of 201, 38%), those associated with interstitial lung disease (62 of 201, 31%), those associated with tree-in-bud opacities (5 of 201, 2%), and those with air trapping alone (58 of 201, 29%). When found with bronchiectasis, nontuberculous mycobacteria, cystic fibrosis, idiopathic bronchiectasis, and transplant-related bronchiolitis obliterans were the most common causes of air trapping. When found with interstitial lung disease, sarcoidosis, hypersensitivity pneumonitis, or unspecified interstitial lung disease were the most common cause of air trapping. When found in isolation, chronic bronchitis, asthma, bronchiolitis obliterans, and unspecified small airways disease were the most common causes of air trapping. Unusual conditions causing isolated air trapping included vasculitis and diffuse idiopathic neuroendocrine cell hyperplasia. Conclusion: A variety of conditions can cause air trapping. Associated imaging findings can narrow the differential diagnosis. Keywords: air trapping; asthma; chronic bronchitis; bronchiolitis obliterans; computed tomography (Received in original form November 11, 2013; accepted in final form March 24, 2014 ) Author Contributions: W.T.M. takes responsibility for the study as a whole. W.T.M. contributed to study design, data collection, data analysis, statistical analysis, and manuscript preparation. J.C. contributed to data collection, data analysis, and manuscript preparation. M.D.H. contributed to data collection and manuscript preparation. Correspondence and requests for reprints should be addressed to Wallace T. Miller, Jr., M.D., Associate Professor of Radiology, University of Pennsylvania Medical Center, Department of Radiology, 3400 Spruce Street, Philadelphia, PA wallacejr.miller@uphs.upenn.edu Ann Am Thorac Soc Vol 11, No 6, pp , Jul 2014 Copyright 2014 by the American Thoracic Society DOI: /AnnalsATS OC Internet address: The term air trapping indicates retention of inspired air during expiration. This term is applicable to a variety of obstructive lung diseases. In 1993, Webb and colleagues reported their experience with a new type of computed tomography (CT) called expiratory CT (1). A standard thoracic CT examination is performed with the patient holding his or her breath at deep inspiration while scanning the lung. Expiratory CT is performed with the patient holding his or her breath at end expiration while scanning the lung. Webb and colleagues showed that normal young men can retain air within individual or groups of secondary pulmonary lobules, a finding that they termed air trapping (1). These lobular areas of decreased attenuation represented hyperinflated lobules caused by obstruction of the supplying bronchioles and are specific for small airways diseases. This radiographic finding is compared with the more general meaning of air trapping as measured by pulmonary function tests, which includes a variety of obstructive lung diseases other than small airways disease. In fact, pulmonary function tests can be insensitive to the detection of small airways disease, with the forced expiratory flow in the midexpiratory phase reported as the most sensitive pulmonary function test measure of small airways disease (2). As a consequence, expiratory CT is among the more important tests to identify individuals with small airways disease. Reported causes of CT air trapping include chronic bronchitis (3 10), asthma (3 5, 11 14), bronchiolitis 874 AnnalsATS Volume 11 Number 6 July 2014

2 Table 1. Interobserver agreement of individual findings on 420 computed tomography scans Finding n (%) (N = 420) Kappa Air trapping 415 (98.6) Bronchiectasis 411 (97.9) Tree-in-bud 418 (99.5) opacity Centrilobular 420 (100) 1.00 nodules Bronchovascular 420 (100) 1.00 nodules Ground-glass 415 (98.6) opacity Reticulation 419 (99.8) Architectural distortion 420 (100) 1.00 obliterans (obliterative bronchiolitis, constrictive bronchiolitis) (3, 15 21), bronchiectasis (3 5, 22 28), sarcoidosis (5, 29 32), subacute and chronic hypersensitivity pneumonitis (5, 33, 34), and a variety of less common conditions (35 44). Prior reports are mostly composed of pictorial essays, review articles, or reports of preselected disease states. There are three studies of small cohorts of 40 to 49 patients with consecutive cases of air trapping (3 5). A large, comprehensive, unselected study of the relative frequency of causes of CT air trapping has not been published previously. Table 2. Associated imaging findings in 201 patients with proven cause of moderate/severe air trapping Finding Frequency Isolated air trapping* 53 (26) Airways findings Bronchiectasis 92 (46) Tree-in-bud opacities 47 (23) Interstitial findings Ground-glass opacity 24 (12) Architectural distortion 24 (12) Bronchovascular nodules 8 (4) Centrilobular nodules 2 (1) Reticulation/honeycombing 25 (13) Peripheral 13 (6) Peribronchiolar 14 (7) Diffuse 1 (0.5) *Air trapping was the only clinically significant imaging finding (excluding small nodules, nonspecific linear scars). Non tree-in-bud centrilobular nodules. Three patients with both peripheral and peribronchovascular reticulation/honeycombing. Methods Study Design The study was approved by the center s Institutional Review Board (IRB#7, Protocol #813882) and is Health Insurance Portability and Accountability Act compliant. Informed consent was waived due to the purely retrospective nature of the project. For inclusion into the study, we required the following: (1) the patient had a medical record at our institution, (2) the patient received a CT scan that imaged the entire lung, (3) the CT scan had adequate expiratory images to assess the severity of air trapping, and (4) the patient had moderate or severe air trapping identified on the CT examination. The study was performed at two affiliated university-based hospitals in the northeastern United States: a 725-bed academic tertiary care center and an urban 324-bed community hospital. The patient population consisted of an unselected mixture of both inpatients and outpatients. The Radiology Information System was searched for the term air trapping from January 1, 2010 to December 31, 2010, identifying a total of 1,295 examinations. We searched specifically for the term air trapping and not the less-specific term mosaic attenuation, because our radiologists have been trained to specifically identify air trapping when expiratory images are provided and explain the presence of a mosaic pattern. Per our inclusion criteria, incomplete or duplicate examinations (n = 348) were excluded, including 73 abdominal, neck, or airway examinations that did not include the entire lungs; 227 thoracic examinations without expiratory images; and 48 duplicate examinations. Of the 947 examinations with expiratory series, 383 had a report indicating no air trapping and were excluded. Furthermore, 141 examinations had poor-quality expiratory images preventing adequate evaluation for air trapping, and three patients had large pleural effusions or extensive lung consolidation that prevented accurate evaluation of air trapping, leaving 420 examinations that met our inclusion criteria. Inadequate expiratory examinations were defined as those in which a mosaic pattern was identified on inspiratory examinations, but the expiratory Table 3. Causes of moderate to severe air trapping with associated bronchiectasis in 76 patients with proven cause Cause Frequency (%) Atypical mycobacteria 23 (30) Diseases predisposing to airway infection Cystic fibrosis 18 (24) Allergic 2 (3)* bronchopulmonary aspergillosis Primary ciliary 1 (1) dyskinesia Panbronchiolitis 1 (1) Idiopathic bronchiectasis 11 (14) Bronchiolitis obliterans/ 11 (14) bronchiolitis obliterans syndrome Unspecified obstructive 3 (4) disease Asthma 2 (3)* Other 5 (7) x *One patient had both asthma and allergic bronchopulmonary aspergillosis. Excluding traction bronchiectasis. Eight lung transplants, one idiopathic, one rheumatoid arthritis. x One each of Swyer-James syndrome, chronic aspiration, chronic bronchitis, bronchiolitis obliterans with organizing pneumonia, childhood bronchopulmonary dysplasia. images were not performed in adequate expiration to determine whether the mosaic pattern was a result of air trapping or other causes. Inadequate expiration was identified if the trachea retained a circular cross-sectional appearance and the non air trapped portions of lung parenchyma failed to increase in attenuation with expiration. CT Analysis In normal expiratory CT, the lung attenuation increases as the proportion of air to tissue decreases with expiration of air. The Fleischner society defines air trapping as parenchymal areas with less than normal increase in attenuation and lack of volume reduction as seen on endexpiration CT scans (45). These areas appear as polygonal regions of low attenuation adjacent to areas of lung that have the normal increased attenuation with expiration. Two of the authors, one with 22 years and one with 1 year of subspecialty experience in thoracic imaging, independently reviewed the thoracic CT Miller, Jr., Chatzkel, and Hewitt: Air Trapping on Expiratory CT 875

3 Table 4. Causes of moderate to severe air trapping and interstitial abnormalities in 62 patients with proven cause Cause Frequency (%) Figure 1. Air trapping associated with bronchiectasis. This 28-year-old man had an acute exacerbation of cystic fibrosis. Expiratory computed tomography shows tram tracks and ring shadows indicating the presence of widespread bronchiectasis. There is also a mosaic pattern of attenuation (black arrows indicate lower-attenuation regions) indicative of severe air trapping. Sarcoidosis 18 (29) Unspecified 13 (21) Hypersensitivity 6 (10) pneumonitis Chronic beryllium 4 (6) disease Idiopathic pulmonary 3 (4) fibrosis Connective tissue 2 (3)* disease Nonspecific interstitial 2 (3) pneumonia Respiratory bronchiolitis 2 (3) interstitial lung disease Bronchiolitis obliterans/ 4 (6) bronchiolitis obliterans syndrome Chronic bronchitis 2 (3) Asthma 2 (3) Unspecified obstructive 2 (3) disease Organizing pneumonia 1 (2) Bronchial atresia 1 (2) examinations, blinded to the clinical history. Expiratory images were reviewed for the presence and severity of air trapping. Inspiratory series were evaluated for ancillary findings, including the presence of bronchiectasis, tree-in-bud opacities, non tree-in-bud centrilobular nodules, peribronchovascular (perilymphatic) nodules, reticulation, architectural distortion, and ground-glass opacities as defined by the Fleischner Society (45). Any differences in interpretation between the two reviewers were resolved by consensus after a second review of the CT examinations. We have defined isolated air trapping when air trapping was the only lung abnormality, excluding common, benign findings such as a few subcentimeter nodules or small focal scars. Air trapping was subdivided into mild (,25%), moderate (25 50%), and severe (.50%) air trapping based on a subjective estimation of the total lung volume of air-trapped lung. Previous reports have indicated that mild air trapping is commonly clinically asymptomatic (1, 45, 46), and therefore we excluded the 190 patients with mild air trapping from further analysis, leaving 230 individuals with moderate to severe air trapping. Proof of Diagnosis The electronic medical records were reviewed for the cause of air trapping, blinded to the CT interpretation. Of the 230 patients, 208 were evaluated by 1 of 42 board-certified pulmonologists working at our institution. We did not review the individual clinical data but assumed that International Statistical Classification of Disease and Related Health Problems, version 9, pulmonary-related diagnoses made by these pulmonologists met established criteria for disease. In 22 patients, the cause of air trapping was not investigated primarily because of other more pressing diseases, predominantly metastatic carcinoma. In seven cases, the pulmonologists failed to identify a cause for air trapping. These cases were also excluded from further review, leaving a total of 201 cases with a proven cause of moderate to severe air trapping. CT Protocols All patients received the same unenhanced CT protocol: Series 1: 1-mm contiguous spiral, deep inspiration viewed at 1-mm contiguous axial slices and 3-mm coronal reconstructions in lung windows; Series 2: 1-mm contiguous spiral, end expiration viewed at 1-mm contiguous axial slices and *Mixed connective tissue disease and polymyositis. Two bone marrow transplant, one lung transplant, and one Sjögren syndrome. 3-mm coronal reconstructions in lung windows. Images were obtained on a variety of scanners, including: Siemens Definition 64, Siemens Definition AS, Siemens, Siemens Sensation 64, Siemens Sensation Cardiac, Siemens Volume Zoom (Siemens Medical Systems, Forcheim, Germany). Images were reviewed on a picture archiving system (PACS; GE Centricity, Milwaukee, WI). Results The interobserver agreement for individual CT findings between reviewers is listed in Table 1. Percent agreement ranged from a low of 97.9% (411 of 420 examinations) to a high of 100% (420 of 420 examinations). Kappa statistics were considered to be very good to perfect, ranging from to All subsequent statistics are based on the consensus review. The 947 high-resolution examinations represented 6.99% (947 of 13,540) of thoracic CT scans performed at our institution in The quality of the 876 AnnalsATS Volume 11 Number 6 July 2014

4 Table 5. Causes of isolated moderatesevere air trapping in 58 patients with a proven cause Cause Frequency (%) Figure 2. Air trapping associated with interstitial lung disease. This 65-year-old woman had a long history of severe dyspnea due to sarcoidosis and was being evaluated for lung transplantation. Imagefromanexpiratorycomputedtomography scan shows air trapping (black arrows), peribronchovascular honeycombing (white arrow), and multiple calcified lymph nodes (black arrowheads) typical of advanced sarcoidosis. expiratory series was not adequate to accurately evaluate air trapping in 14.9% (141 of 947). Of 803 adequate examinations, 383 (47.6%) had no air trapping, 190 (23.7%) had mild (,25%) air trapping, 156 (19.4%) had moderate (25 50%) air trapping, and 74 (9.2%) had severe (.50%) air trapping. Ancillary imaging findings are listed in Table 2. Patients with moderate to severe air trapping could be divided into four subgroups based on their ancillary CT findings: (1) associated with bronchiectasis, (2) associated with interstitial lung disease, (3) associated with tree-in-bud opacities, and (4) isolated air trapping. These groups had differing causes for air trapping. In 89 (44%) patients, air trapping was associated with bronchiectasis. In 13 cases, the bronchiectasis was associated with interstitial lung disease and represented traction bronchiectasis (6 sarcoidosis, 4 unspecified, 2 idiopathic pulmonary fibrosis, 1 mixed connective tissue disorder). Causes of the remaining 76 (38%) patients with nontraction bronchiectasis and air trapping are listed in Table 3. Atypical mycobacteria (23 of 76, 30%), cystic fibrosis (18 of 76, 24%), idiopathic bronchiectasis (11 of 76, 14%), and bronchiolitis obliterans/ bronchiolitis obliterans syndrome (11 of 76, 14%) accounted for the majority of causes (Figure 1). In 62 (31%) patients, air trapping was associated with interstitial lung disease. Causes of air trapping in patients with interstitial lung disease are listed in Table 4 and were most commonly sarcoidosis (18 of 62, 29%), hypersensitivity pneumonitis (6 of 62, 10%), and an undiagnosed interstitial lung disease (13 of 62, 21%) (Figure 2). There was isolated air trapping in 58 (29%) patients, listed in Table 5. Chronic bronchitis (16 of 58, 28%), asthma (15 of 58, 26%), and bronchiolitis obliterans (13 of 58, 22%) accounted for the majority of patients with isolated air trapping (Figures 3 and 4). The remaining patients had a mixture of unclassified obstructive diseases, interstitial diseases, and other uncommon conditions (Figures 5 and 6). Finally, five (2%) patients had air trapping with associated tree-in-bud opacities but without bronchiectasis. Four of these cases were lung transplant recipients diagnosed with bronchiolitis obliterans syndrome. The fifth patient had a clinical diagnosis of asthma. Discussion Obstruction of small airways is a common finding on CT examinations of the thorax. In our population, 52.4% had air trapping, a frequency similar to other studies (46, 47). However, mild air trapping is commonly asymptomatic, and only when moderate or severe is it likely to have Obstructive disease 51 (88) Chronic bronchitis 16 (27) Asthma 15 (26) Bronchiolitis obliterans/ 13 (22) bronchiolitis obliterans syndrome Rheumatoid arthritis 1 (2) Idiopathic 1 (2) Bone marrow transplant 3 (5) Lung transplant* 8 (14) Chronic obstruction, 7 (12) unclassified Interstitial disease 4 (7) Sarcoidosis 1 (2) Chronic beryllium disease 2 (3) Unspecified 1 (2) Other 3 (5) Vasculitis Eosinophilic granulomatosis with polyangiitis Granulomatosis with polyangiitis Diffuse idiopathic neuroendocrine cell hyperplasia 1 (2) 1 (2) 1 (2) Air trapping as the only diffuse pulmonary finding (allow nonspecific scar, few small nodules, pleural thickening/effusion). *Four bilateral and four single lung transplants. Diffuse idiopathic neuroendocrine cell hyperplasia. a clinical significance (1, 46, 47). Therefore, we limited our study to patients who semiquantitatively had greater than 25% of the lung volume air trapped. A wide variety of diseases have been reported to cause air trapping (3 44). Our study indicates that the etiology of air trapping can be subdivided based on the presence or absence of two additional findings: bronchiectasis and interstitial lung disease. Bronchiectasis is a known cause of air trapping (3 5, 22 28) and accounted for 38% (76 of 201) of our cases. In our population, the cause of bronchiectasis was most often nontuberculous mycobacterial infection, cystic fibrosis, and idiopathic bronchiectasis, but occasionally it was due to a variety of other disorders, including primary ciliary dyskinesia, allergic bronchopulmonary aspergillosis, Swyer- James syndrome, and chronic aspiration (Figure 1). Other reports have also noted Miller, Jr., Chatzkel, and Hewitt: Air Trapping on Expiratory CT 877

5 Figure 3. Isolated air trapping due to asthma. This 54-year-old woman presented with dyspnea and wheezing. Image from an expiratory computed tomography scan shows severe air trapping (white arrows) without other finding. air trapping and bronchiectasis in patients with immunodeficiency states (23, 24). It seems likely that bronchiectasis is a direct cause of air trapping, and any potential cause of bronchiectasis can also lead to air trapping. Thus, the differential diagnosis of air trapping, when associated with bronchiectasis, should be based on the usual differential diagnosis of bronchiectasis. Thirty-one percent (62 of 210) of our cases were associated with interstitial lung disease, most commonly sarcoidosis and hypersensitivity pneumonitis, which are the interstitial diseases most frequently associated with air trapping in the literature (29 34) (Figure 2). Chronic beryllium disease accounted for 6% (4 of 62) of interstitial diseases causing air trapping in our population because our institution has one of the few laboratories that specializes in testing for beryllium hypersensitivity. Beryllium exposure can cause an interstitial lung Figure 4. Isolated air trapping due to bronchiolitis obliterans. This 62-year-old woman with rheumatoid arthritis developed slowly progressive dyspnea and hypoxia. Expiratory computed tomography image shows severe air trapping (black arrows) without other imaging findings. Biopsy was diagnostic of bronchiolitis obliterans. disease that is pathologically identical to sarcoidosis, and therefore it is not surprising that it might cause air trapping on expiratory CT. In 21% of cases with interstitial lung disease, the cause was unspecified. These patients had common imaging features: peribronchovascular or peripheral reticulation often with architectural distortion, findings typical of chronic hypersensitivity pneumonitis (34). It is our belief that many of these cases represent undiagnosed hypersensitivity pneumonitis. Seven patients had interstitial diseases that are not typically associated with air trapping, including idiopathic pulmonary fibrosis, connective tissue diseases, and idiopathic nonspecific interstitial pneumonia. We suspect that these individuals had undiagnosed small airways disease in addition to their interstitial lung disease. Furthermore, 10 patients with small airways diagnoses had interstitial abnormalities on their CT scans. We suspect that these patients had undiagnosed interstitial disorders in addition to their small airways disease. Isolated air trapping was most often due to chronic bronchitis, asthma, or bronchiolitis obliterans (Figures 3 and 4). Asthma and chronic bronchitis are the two most common causes of small airways disease in general practice, so it was not surprising that they would be two of the most common causes of isolated air trapping, However, the relatively rare condition, bronchiolitis obliterans, had a similar frequency to asthma and chronic bronchitis in our population. This large number of cases of bronchiolitis obliterans/ bronchiolitis obliterans syndrome is primarily due to lung and bone marrow transplant patients that accounted for 26 of 32 (81%) of cases in our series. If we excluded transplant-related cases from the total, then chronic bronchitis would have accounted for 34% (16 of 47), asthma for 32% (15 of 47), unspecified small airways disease for 15% (7 of 47), and bronchiolitis obliterans for 4% (2 of 47) of patients with isolated air trapping. It is interesting to note that 15% (7 of 47) of patients with isolated air trapping had an otherwise imaging occult interstitial lung disease or other rare causes of air trapping. The interstitial diseases were sarcoidosis, hypersensitivity pneumonitis, and unspecified interstitial lung disease. The 878 AnnalsATS Volume 11 Number 6 July 2014

6 Figure 5. Isolated air trapping due to granulomatosis with polyangiitis. This 64-year-old woman with a history of granulomatosis with polyangiitis had recurrent dyspnea. The examination was normal except for moderate air trapping (black arrows) identified on the expiratory computed tomography scan. other unusual diseases causing air trapping were: (1) Churg Strauss vasculitis, (2) granulomatosis with polyangiitis, and (3) diffuse idiopathic neuroendocrine cell hyperplasia (Figures 5 and 6). Other reports have also identified some unusual causes of air trapping, including: silicosis (35), diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (36), b-thalassemia (37), HIV infection (39), tracheobronchomalacia (40, 41), toxic inhalation (42), pulmonary embolism (43), and relapsing polychondritis (44). Therefore, in symptomatic patients with isolated air trapping who do not appear to meet standard criteria for chronic bronchitis or asthma and do not have the appropriate clinical presentation for Figure 6. Isolated air trapping due to diffuse idiopathic neuroendocrine cell hyperplasia. This 59-year-old woman had the subacute onset of incapacitating dyspnea. The examination was normal except for severe air trapping (black arrows) found on expiratory computed tomography. Surgical lung biopsy was diagnostic of diffuse neuroendocrine cell hyperplasia. bronchiolitis obliterans, a variety of unusual etiologies should be considered. The primary limitation to this study is the retrospective nature of the research. We did not review the data establishing the clinical diagnoses but relied on the evaluations of subspecialty pulmonologists to establish the causes of air trapping. It is possible that some individuals were misdiagnosed or had multiple superimposed causes for imaging findings, leading to a misclassification or information bias. As with any single-institution study, the relative frequencies of causes reflect the patient composition of our institution and those patients more likely to receive CT scans. Patients with asthma and chronic bronchitis are frequently managed without CT scans and are likely underrepresented in our study population. As we have previously noted, our large lung and bone marrow transplantation population and our cystic fibrosis clinic likely increased the representation of bronchiolitis obliterans and cystic fibrosis as causes of air trapping in our study. We also have an active interstitial lung disease clinic, including a specialized beryllium-exposed population, and therefore the proportion of cases of air trapping due to interstitial lung disease may have been inflated. Due to these limitations, our results can only be considered preliminary. The relative frequencies of causes of air trapping in other settings will be dependent on the patient population being evaluated. It is likely that the rank order of causes of air trapping in this study is close to the rank order of causes of air trapping in the general population. However, the specific relative frequency is likely biased by the particular population served at our institution. In conclusion, air trapping is a common finding on thoracic CT, and the etiology is influenced by associated imaging findings. When seen with bronchiectasis, usual causes of bronchiectasis should be considered, such as atypical mycobacterial infection, cystic fibrosis, idiopathic bronchiectasis, and transplant-related bronchiolitis obliterans. Air trapping seen with interstitial lung disease is most often secondary to sarcoidosis or hypersensitivity pneumonitis. Air trapping seen in isolation is most often due to chronic bronchitis, asthma, and bronchiolitis obliterans. Isolated air trapping in patients without chronic bronchitis, asthma, or bronchiolitis obliterans can be due to a wide variety of Miller, Jr., Chatzkel, and Hewitt: Air Trapping on Expiratory CT 879

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