Interstitial Lung Abnormalities in a CT Lung Cancer Screening Population: Prevalence and Progression Rate 1

Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at www.rsna.org/rsnarights. Gong Yong Jin, MD, PhD David Lynch, MD Ashish Chawla, MD Kavita Garg, MD Martin C. Tammemagi, DVM, MSc, PhD Hakan Sahin, MD, Shigeki Misumi, MD Keun Sang Kwon, MD, PhD Interstitial Lung Abnormalities in a CT Lung Cancer Screening Population: Prevalence and Progression Rate 1 Purpose: Materials and Methods: To determine the prevalence of interstitial lung abnormalities (ILAs) at initial computed tomography (CT) examination and the rate of progression of ILAs on 2-year follow-up CT images in a National Lung Screening Trial population studied at a single site. The study was approved by the institutional review board and informed consent was obtained from all participants. Image review for this study was HIPAA compliant. We reviewed the CT images of 884 cigarette smokers who underwent low-dose CT at a single site in the National Lung Screening Trial. CT findings were categorized as having no evidence of ILA, equivocal for ILA, or ILA. We categorized the type of ILA as nonfibrotic (ground-glass opacity, consolidation, mosaic attenuation), or fibrotic (ground glass with reticular pattern, reticular pattern, honeycombing). We evaluated the temporal change of the CT findings (no change, improvement, or progression) of ILA at 2-year follow-up. A x 2 with Fisher exact test or unpaired t test was used to determine whether smoking parameters were associated with progression of ILA at 2-year follow-up CT. Original Research n Thoracic Imaging 1 From the Departments of Radiology (G.Y.J.) and Preventive Medicine (K.S.K.), Chonbuk National University Medical School and Hospital, Institute of Medical Science, Research Institute of Clinical Medicine, 634-18 Keumam-Dong, Jeonju, Jeonbuk 561-712, South Korea; Department of Radiology, National Jewish Health, Denver, Colorado (D.L.); Department of Radiology, Sri Aurobindo Institute of Medical Sciences, Indore, India (A.C.); Department of Radiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado (K.G.); Department of Community Health Sciences, Brock University, St. Catharines, Ontario, Canada (M.C.T.); Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas (H.S.); and Department of Radiology, Tachikawa General Hospital, Nagaoka, Japan (S.M.). Received April 10, 2012; revision requested May 31; revision received September 7; accepted October 5; final version accepted January 14, 2013. Supported by research funds from Chonbuk National University and Chonbuk National University Hospital in 2010 and by the National Lung Screening Trial. Address correspondence to G.Y.J. (e-mail: gyjin@chonbuk.ac.kr). q RSNA, 2013 Results: Conclusion: The prevalence of ILA was 9.7% (86 of 884 participants; 95% confidence interval: 7.9%, 11.9%), with a further 11.5% (102 of 884 participants) who had findings equivocal for ILA. The pattern was fibrotic in 19 (2.1%), nonfibrotic in 52 (5.9%), and mixed fibrotic and nonfibrotic in 15 (1.7%) of the 86 participants with ILA. The percentage of current smokers (P =.001) and mean number of cigarette pack-years (P =.001) were significantly higher in those with ILA than those without. At 2-year follow-up of those with ILA (n = 79), findings of nonfibrotic ILA improved in 49% of cases and progressed in 11%. Fibrotic ILA improved in 0% and progressed in 37% of cases. ILA is common in cigarette smokers. Nonfibrotic ILA improved in about 50% of cases, and fibrotic ILA progressed in about 37%. q RSNA, 2013 Radiology: Volume 268: Number 2 August 2013 n radiology.rsna.org 563

The classification of idiopathic interstitial lung diseases has been established (1 4), and the 5-year survival rate for patients with interstitial lung diseases varies depending on the pattern of disease. A usual interstitial pneumonia pattern is associated with median length of survival from time of diagnosis between 2.5 and 4.4 years (5), whereas nonspecific interstitial pneumonia and desquamative interstitial pneumonia/respiratory bronchiolitis-associated interstitial lung disease has a better response to treatment and a much better outcome (1,2). However, many of the reported cases of usual interstitial pneumonia are in patients who presented late in the course of their disease. Thus, with increasing interest in specific treatments for each Advances in Knowledge nn The prevalence of interstitial lung abnormality (ILA) in current or former smokers enrolled in a lung cancer screening trial was 9.7% (86 of 884 patients), and the pattern was fibrotic in 2.1% (19 of 884), nonfibrotic in 5.9% (52 of 884), and mixed fibrotic and nonfibrotic in 1.7% (15 of 884); the percentage of current smokers and mean number of cigarette pack-years were significantly higher in those with ILA than those without (P =.001). nn At the 2-year follow-up of patients with ILA, findings of nonfibrotic ILA improved in 49% (23 of 47) of cases, and progressed in 11% (five of 47); fibrotic ILA improved in no cases and progressed in 37% (seven of 19) (P,.001). nn The presence of ILA is associated with the level of cigarette consumption, and the percentage of current smokers and the median number of cigarette pack-years in participants with ILA was significantly higher than in those without ILA (68.6% vs 39.4%, and 59.9 vs 51.1, respectively; P,.001). interstitial lung disease, it would be useful to have an accurate estimate of prevalence, particularly in those with early or subclinical disease. The precise prevalence of interstitial lung diseases is not established, despite considerable progress in the diagnosis and classification of interstitial lung diseases. Previous (5 9) prevalence estimates for usual interstitial pneumonia varied from 0.003% to 0.089%, according to age, sex, and race. A recent population-based study for interstitial lung diseases in individuals aged 50 years or older revealed a prevalence of 0.063%. In an autopsy-based study, the prevalence of preclinical interstitial lung disease was estimated at 1.8% (2,6,7). However, this report was based on the clinical records, and there was no recorded review of computed tomographic (CT) images (5,8,9). CT imaging is quite accurate for characterization of disease patterns, particularly usual interstitial pneumonia. First-choice diagnosis by means of CT is correct in 75% 90% of patients with idiopathic pulmonary fibrosis (10 12). There is a clear relationship between cigarette smoking and several specific types of interstitial lung diseases (13). Recently, Sverzellati et al (14) reported that patterns of usual interstitial pneumonia and chronic interstitial pneumonia were identified Implication for Patient Care nn In our study, which included only participants with more than a 30 pack-year exposure, the median pack-years exposure was higher in those with fibrotic ILA (no ILA vs fibrotic ILA, 51.1 vs 63.3), and fibrotic ILA was closely correlated with the total exposure; also, in our study, fibrotic ILA was found in about 3.7% (33 of 884) of participants and progressed in about 37% (seven of 19) on 2-year follow-up CT images, and we recommend regular follow-up if fibrotic ILA is detected incidentally. in 0.3% and 3.8%, respectively, of a cohort of smokers included in a lung cancer screening population. Progression of the disease was observed in 25% of those with chronic interstitial pneumonia who underwent repeat CT after 3 years. These authors suggested that features of interstitial lung disease as they appear on CT images are common in a lung cancer screening population and should not be overlooked. CT-based screening studies for interstitial lung abnormality (ILA) of the general population are still few. The purposes of our study were to determine the prevalence of ILAs at initial CT examination and the rate of progression of ILAs on 2-year follow-up CT images in a National Lung Screening Trial population studied at a single site. Also, we evaluated whether progression of ILA at 2-year follow-up CT is related to smoking status. Materials and Methods Study Population The National Lung Screening Trial, sponsored by the National Cancer Institute, began in 2002. The aim of the National Lung Screening Trial was to Published online before print 10.1148/radiol.13120816 Content code: Radiology 2013; 268:563 571 Abbreviations: CI = confidence interval GGO = ground-glass opacity ILA = interstitial lung abnormality Author contributions: Guarantors of integrity of entire study, G.Y.J., K.S.K.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, G.Y.J., D.L., H.S.; clinical studies, G.Y.J., D.L., A.C., K.G., M.C.T., H.S.; statistical analysis, G.Y.J., M.C.T., K.S.K.; and manuscript editing, G.Y.J., D.L., K.G., M.C.T., H.S. Funding: This research was supported by the National Cancer Institute (contract N01-CN-25514). Conflicts of interest are listed at the end of this article. 564 radiology.rsna.org n Radiology: Volume 268: Number 2 August 2013

determine whether reduced-dose chest CT imaging would reduce mortality from lung cancer compared with chest radiograph in a high-risk population of current and former smokers (55 74 years of age, cigarette smokers with a history of at least 30 pack-years, and former smokers had to have quit smoking in the past 15 years) (15). Imaging studies were obtained at baseline and annually for 2 years. Our site examined 1846 participants who were randomized to CT. The study was approved by the institutional review board and image review for this study was compliant with the Health Insurance Portability and Accountability Act. From the population of 1846 participants who underwent baseline CT, we reviewed the CT images of 890 participants who were selected with random number generation. None of the participants indicated a history of lung fibrosis on questionnaire at enrollment. Of these, six participants had technically inadequate CT images, and these participants were excluded from our study. CT Scanning In this study, participants underwent imaging with 16 or 64 detector row CT scanners (Definition 16 or Sensation 64; Siemens Medical Solutions, Forchheim, Germany). Images were obtained during breath hold at full inspiration in the supine position. CT imaging parameters were as follows: tube voltage, 120 kvp; tube current, 40 80 ma. The images reviewed for this analysis were reconstructed by using a high-resolution reconstruction algorithm with contiguous 2-mm sections. The axial images were reviewed by using a Digital Imaging and Communications in Medicine viewer with a window level of 700 HU and a window width of 1500 1600 HU. Image Review Four experienced thoracic radiologists (A.C., 10 years of experience; D.L., 20 years of experience; H.S., 15 years of experience; S.M., 7 years of experience) interpreted CT images in this study. Initial training of all radiologists was performed with 20 cases that were not included in the study dataset. The study CT images were reviewed by using the sequential reading process developed by Washko et al (3,4). Briefly, the first radiologist would review the images and score as follows: score of 1, no evidence of ILA; score of 2, equivocal for ILA; or score of 3, ILA. CT images, including those images that were given a score of 2 or 3, and a random selection of approximately 20% of the normal images (score of 1) were provided to a second radiologist who was blinded to the initial interpretation. Finally, a third radiologist who was blinded to the interpretations of the previous readers provided a majority opinion on those images discordantly scored between the first two radiologists. Findings equivocal for ILA were defined as focal or unilateral groundglass opacity (GGO), focal or unilateral reticulation, and patchy GGO (,5% of the lung). ILA was defined as nondependent GGO that affected more than 5% of any lung zone, nondependent reticular abnormality, diffuse centrilobular nodularity with GGO, honeycombing, traction bronchiectasis, nonemphysematous cysts, or architectural distortion. Centrilobular nodularity alone was not considered to be evidence of ILA. In addition, the extent of CT findings (GGO, GGO with reticular abnormality, reticular abnormality, honeycombing, consolidation, and mosaic attenuation) in each case of ILA was scored by using a five-point scale (score of 0, absent; score of 1, 1% 25% involvement; score of 2, 26% 50% involvement; score of 3, 51% 75% involvement; score of 4, 76% 100% involvement) (1,12,16). If there was a discrepancy about the pattern of lung disease or CT diagnosis, these discrepancies were resolved by consensus. From the population of 884 participants who underwent baseline CT, 86 participants (9.7%) were found to have ILA. Of these participants, seven participants did not undergo 2-year follow-up CT. Thus, 79 participants with ILA at baseline CT had 2-year follow-up CT images available for comparison. For these patients, two readers independently scored the extent of each finding on the CT image by using the five-point scale described above. The readers also did a side-by-side comparison of baseline and 2-year follow-up CT examinations of ILA participants to evaluate changes in follow-up findings on CT images (ie, no change, improvement, or progression) for nonfibrotic ILA (GGO, mosaic attenuation, and consolidation) and fibrotic ILA (GGO with reticular abnormality, reticular abnormality, and honeycombing). If there was a discrepancy regarding either the pattern of findings or the change in follow-up findings on CT images, these discrepancies were resolved by consensus. Statistical Analysis We evaluated demographic data for participants, and compared the demographic data with ILA and equivocal ILA to those without ILA for age, sex, smoking status (current or former), and total pack-year exposure by using an unpaired t test or a x 2 with Fisher exact test. Confidence intervals for proportions were prepared by using the binomial exact method. k value was calculated for agreement between first and second readers for the baseline read. A weighted k test was used to evaluate the agreement by two radiologists for the 2-year follow-up CT interpretation. Interobserver agreement was classified as poor (k = 0 0.20), fair (k = 0.21 0.40), moderate (k = 0.41 0.60), good (k = 0.61 0.80), or excellent (k = 0.81 1). Exact logistic regression models were used to assess the association between CT findings and demographic data (age, sex, smoking status, and pack-years) in participants with ILA on baseline CT; the corresponding odds ratios with 95% confidence interval (CI) were computed. An unpaired t test or a x 2 with Fisher exact test was used to compare overall progression of fibrotic ILA with nonfibrotic ILA and mixed fibrotic-nonfibrotic ILA at 2-year follow-up. The x 2 with Fisher exact test or unpaired t test was used to determine demographic data (age, sex, smoking type, or packyears) that were associated with progression of ILA at 2-year follow-up CT. CT findings at 2-year follow-up were categorized into two groups: improved Radiology: Volume 268: Number 2 August 2013 n radiology.rsna.org 565

Table 1 Demographic Data of Study Participants Characteristics Overall No ILA Equivocal ILA ILA P Value* Figure 1 No. of participants 884 696 (78.7) 102 (11.5) 86 (9.7) No. of men 524 (59.3) 401 (57.6) 61 (59.8) 62 (72.1).011 Age (y) 61.5 6 5.1 61.4 6 5.0 62.3 6 5.8 61.6 6 5.2.829 No. 55 59 years 37 (42.4) 297 (42.7) 43 (42.2) 35 (40.7) No. 60 69 years 416 (47.1) 327 (46.9) 43 (42.2) 46 (53.5) No. 70 75 years 93 (10.5) 72 (10.4) 16 (15.6) 5 (5.8) Smoking status.001 No. current 390 (44.1) 274 (39.4) 57 (55.9) 59 (68.6) No. former 49 (55.9) 422 (60.6) 45 (44.1) 27 (31.4),.001 Cigarette exposure (pack-years) 51.9 6 21.3 51.1 6 20.4 50.9 6 17.6 59.9 6 29.1.001 Note. Numbers in parentheses are percentages. Current = current smoker at baseline who was persistent at 2 years, or a former smoker at baseline who restarted smoking at 2 years. Former = former smoker at baseline who was not smoking at 2 years, or a current smoker at baseline who was not smoking at 2 years. * Comparison of demographic data of ILA with no ILA to equivocal ILA was performed by using an unpaired t test or x 2 with Fisher exact test. P,.05 indicates statistical significance. Mean 6 standard deviation or unchanged CT findings, or progression of any CT finding. A two-sided P value of.05 or less indicated a statistically significant difference. All analyses were performed with statistical software (SPSS 9.0; SPSS, Chicago, Ill) and scientific software (GraphPad; Graph- Pad Software, La Jolla, Calif). Results Demographic Data of Participants Table 1 shows the demographic data of the 884 participants. The participants studied consisted of 524 men and 360 women, with a mean age of 61.5 years 6 5.1 (range, 55 75 years). Observer agreement regarding the presence of ILA between first and second radiologists who interpreted the images on baseline was good (k = 0.60; 95% CI: 0.48, 0.72). No evidence of ILA was shown in 696 participants (78.7%; 95% CI: 75.9%, 81.4%); 102 participants (11.5%; 95% CI: 9.5%, 13.8%) were equivocal for ILA; and 86 participants (9.7%; 95% CI: 7.9%, 11.9%) had ILA. There were more men who had ILA than men who did not have ILA (P =.011). Also, the percentage of current smokers and the median number of cigarette pack-years in participants with ILA was significantly higher than in those without ILA (68.6% vs 39.4% and 59.9 vs 51.1, respectively; P,.001). Image Findings of ILA at Baseline and Follow-up CT Nonfibrotic findings (GGO, consolidation, and mosaic attenuation) were found in 52 of 884 participants (5.9%; 95% CI: 3.9%, 7.0%) (Fig 1); fibrotic findings (GGO with reticular, reticular, and/or honeycombing) were found in 19 participants (2.1%; 95% CI: 2.3%, 3.3%); 15 participants (1.7%; 95% CI: 0.7%, 2.5%) had mixed nonfibrotic and fibrotic abnormalities; and nonemphysematous cysts were found in 23 participants (2.6%; 95% CI: 1.7%, 3.9%). Interobserver agreement for the images of ILA at baseline and at follow-up CT was fair for GGO (k = 0.383; 95% CI: 0.159, 0.517); agreement was good for GGO with reticular abnormality (k = 0.667; 95% CI: 0.419, 0.935), reticular abnormality (k = 0.661; 95% CI, 0.039, 1.000), and honeycombing (k = 0.737; 95% CI: 0.387, 1.000). Table 2 shows the demographic features in participants without ILA, with nonfibrotic ILA, with fibrotic ILA, and in participants with mixed fibrotic with nonfibrotic ILA. The percentage of current smokers in those with nonfibrotic Figure 1: Low-dose chest CT images show GGO in 66-year-old man who is a current smoker with 30 pack-years of cigarette consumption. (a) Initial image at levels of left upper zones shows GGO. (b) Two years later, GGO in left upper lobe is improved on follow-up CT image. subtype (76.9% [40 of 52]) of ILA was significantly higher than in those without ILA (39.4% [274 of 696]) (P,.001). The median consumption of cigarette pack-years in the ILA group, regardless of subtype, was higher than in those with no ILA. Table 3 shows demographic features associated with ILAs 566 radiology.rsna.org n Radiology: Volume 268: Number 2 August 2013

Table 2 Comparison of Participant Demographic Data Nonfibrotic ILA* Fibrotic ILA* Mixed Nonfibrotic and Fibrotic ILA* Characteristics No ILA (n) Data P Value Data P Value Data P Value No. of participants 696 (78.7) 52 (60.5) 19 (22.1) 15, 17.4 No. of men 401 (57.6) 32 (61.5).579 17 (89.5),.001 10 (66.7),.001 Age (y) 61.4 6 5.0 60.4 6 4.6.015 63.8 6 5.8.033 63.5 6 5.2.058 No. 55 59 years 297 (42.7) 26 (50) 6 (31.6) 3 (20) No. 60 69 years 327 (46.9) 25 (48.1) 9 (47.4) 11 (73.3) No. 70 75 years 72 (10.4) 1 (1.9) 4 (21) 1 (6.7) Smoking status No. current 274 (39.4) 40 (76.9),.001 8 (42.1).810 10 (66.7).033 No. former 422 (60.6) 12 (23.1) 11 (57.9) 5 (33.3) Cigarette exposure (pack-years) 51.1 6 20.4 59.4 6 24.5.015 60.3 6 39.4.033 62.5 6 27.2.048 Note. Numbers in parentheses are percentages. Current = current smoker at baseline who was persistent at 2 years, or a former smoker at baseline who restarted smoking at 2 years. Former = former smoker at baseline who was not smoking at 2 years, or a current smoker at baseline who was not smoking at 2 years. * Total ILA: n = 86, 9.7% P value for comparison of each subgroup with the no ILA group, calculated with an unpaired t test or x 2 with Fisher exact test. P,.05 indicates statistical significance. Mean 6 standard deviation Table 3 Exact Logistic Regression Odds Ratios for Demographic Predictors of ILAs Detected at Baseline Association Parameter Nonfibrotic ILA Fibrotic ILA Pure GGO Consolidation Mosaic Attenuation GGO with Reticular Pure Reticular Honeycomb No. 32 9 40 12 9 9 Age 0.91 (0.82, 1.01) 1.06 (0.84, 1.34) 1.01 (0.92, 1.10) 1.14 (1.04, 1.26) 1.17 (1.04, 1.35) 1.17 (1.04, 1.35) Women 3.08 (0.74, 18.51) 0.82 (0, 5.94) 0.77 (0.26, 2.27) 0.22 (0.06, 0.69) 0.19 (0.01, 1.46) 0.19 (0.01, 1.46) Former smoker 0.43 (0.14, 1.40) 1.08 (0.02, 21.74) 0.38 (0.12, 1.12) 2.62 (0.89, 8.32) 3.74 (0.89, 17.02) 3.74 (0.89, 17.02) Cigarette exposure (pack-years) 0.99 (0.98, 1.01) 1.02 (0.99, 1.04) 1.00 (0.99, 1.02) 1.00 (0.98, 1.01) 0.98 (0.95, 1.01) 0.98 (0.95, 1.01) Note. Calculated with simple exact logistic regression test. Except where indicated, values are odds ratio; numbers in parentheses are 95% CIs. detected at baseline CT. According to the exact logistic regression model, the GGO with reticular pattern was directly associated with age (odds ratio, 1.14; 95% CI: 1.04, 1.26) and inversely associated with women (odds ratio, 0.22; 95% CI: 0.06, 0.69). Of the 79 participants with ILA at baseline CT who underwent 2-year follow-up CT examination, 46.4% (37 of 79) were current smokers and 53.6% (42 of 79) were former smokers, with a median number of cigarette pack-years of 51.3 6 18.3 (range, 30 114). Table 4 shows the results of 2-year follow-up CT for participants with ILA (n = 79). ILA improved in 32.9% (26 of 79) of patients, was unchanged in 46.8% (37 of 79), and progressed in 20.3% (16 of 79). Findings of nonfibrotic ILA improved in 48.9% (23 of 47) (Fig 1) and progressed in 10.9% (five of 47), while findings of fibrotic ILA improved in no participants and progressed in 36.8% (seven of 19) (Figs 2, 3). On 2-year follow-up CT images, 16 (20.3%) participants had new nonfibrotic ILA findings compared with baseline CT, including mosaic attenuation (n = 14, 17.8%), GGO (n = 11, 13.9%), and consolidation (n = five, 6.3%). However, no participants with ILA on baseline CT images developed new fibrotic ILA findings at 2-year follow-up CT. Table 5 shows the association between demographic data and change in CT findings at 2-year follow-up CT in participants with ILA. None of demographic factors, including smoking status and pack-years, were associated with progression of CT findings. Discussion The National Lung Screening Trial showed that screening for lung cancer by using reduced-dose chest CT in a high-risk population reduced mortality from lung cancer by 20% compared with screening with chest radiographs. It is likely that this finding (17) will result in increased use of chest CT screening in current and former smokers who are high-risk. Our study suggested that Radiology: Volume 268: Number 2 August 2013 n radiology.rsna.org 567

ILA would be found in about 10% of participants within the National Lung Screening Trial population. Nonfibrotic findings (GGO, mosaic attenuation, or consolidation) on CT images were found in 7.2% (64 of 884) of participants, and fibrotic findings (GGO with reticular pattern, reticular pattern, and honeycombing) on CT images were found in 3.7% (33 of 884). Several studies have reported the prevalence of ILA in unselected populations of cigarette smokers. MacRedmond et al (18) identified idiopathic pulmonary fibrosis in 1.3% (six of 449) of smokers in a lung cancer screening study. Swensen et al (19) identified diffuse lung disease in 0.8% (nine of 1049) of participants in the Mayo Clinic Lung Cancer screening study. In a pilot study from the COPDGene study, Washko et al (3) identified ILA in 10% (10 of 100) of participants, and four of these participants had features suggestive of fibrosis (reticular abnormality or traction bronchiectasis). In a much larger study from the same group, the investigators found ILA on CT images in 8% (194 of 2416) of cigarette smokers (4). Most of the abnormalities in these participants were nonfibrotic, but 12 participants (0.4%) met American Thoracic Society and European Respiratory Society criteria for fibrotic ILA. The presence of ILA was associated with current smoking status and increased pack-years of smoking. In the Multicentric Italian Lung Detection CT screening study, Sverzellati et al (14) evaluated 700 cigarette smokers and found a usual interstitial pneumonia like pattern in two patients (0.3%), other chronic interstitial pneumonia (including some GGO) in 26 patients (3.8%), and a CT pattern consistent with respiratory bronchiolitis in 109 patients (15.7%). The overall prevalence of ILA in our study was quite similar to previous studies. When evaluating the lung parenchyma of cigarette smokers, it is important to distinguish between fibrotic and nonfibrotic forms of ILA. Nonfibrotic parenchymal abnormality, characterized primarily by GGO, most commonly represents respiratory bronchiolitis, Table 4 Changes in CT Findings at 2-year Follow-up in 79 Participants with ILA Figure 2 Findings at 2-year Follow-up Parameter No. Improved Same Progression Overall extent of abnormality* 26 (32.9) 37 (46.8) 16 (20.3) Nonfibrotic ILA 47 23 (48.9) 19 (40.2) 5 (10.9) Fibrotic ILA 19 0 12 (63.2) 7 (36.8) Mixed nonfibrotic and fibrotic ILA 13 3 (23.1) 6 (46.2) 4 (30.7) Individual CT findings Nonfibrotic ILA GGO 32 13 (40.6) 9 (28.1) 10 (31.3) Mosaic attenuation 40 0 37 (92.5) 3 (7.5) Consolidation 9 2 (22.3) 7 (66.7) 0 Mixed nonfibrotic and fibrotic ILA GGO 5 3 (60) 0 2 (40) Mosaic attenuation 4 0 4 (100) 0 Consolidation 1 0 1 (100) 0 GGO with reticular abnormality 7 0 4 (57.1) 3 (42.9) Pure reticular abnormality 2 0 2 (100) 0 Honeycombing 5 0 5 (100) 0 Fibrotic ILA GGO with reticular abnormality 12 0 5 (41.7) 7 (58.3) Pure reticular abnormality 9 0 5 (55.6) 4 (44.4) Honeycombing 9 0 5 (55.6) 4 (44.4) Note. Numbers in parentheses are percentages. * One-way analysis of variance with Kruskal-Wallis test used to compare overall progression of fibrotic ILA with nonfibrotic ILA and mixed nonfibrotic and fibrotic ILA at 2-year follow-up. The progression of fibrotic ILA was statistically significant compared with nonfibrotic ILA at 2-year follow-up (P,.001). Figure 2: Low-dose chest CT images show progression of GGO at level of base of right lower lung in 69-year-old male current smoker with 60 pack-years of cigarette consumption. (a) Initial image shows diffuse GGO. (b) Follow-up CT image 2 years later shows increase in GGO. 568 radiology.rsna.org n Radiology: Volume 268: Number 2 August 2013

Figure 3 Figure 3: Low-dose chest CT images show usual interstitial pneumonia findings in 68-year-old male former smoker with 61.5 pack-years of cigarette consumption. (a) Initial image at levels of lower zones shows reticular pattern, honeycombing, and GGO that involves mainly peripheral lung regions and bases. (b) Follow-up CT image 2 years later shows progression of reticulation and honeycombing in predominantly peripheral and basal distribution. Table 5 Comparison of Demographic Data (Age and Pack-Years) with Change in CT Findings at 2-year Follow-up of Participants with ILA or respiratory bronchiolitis interstitial lung disease, and is frequently reversible at follow-up imaging. Prognosis Change at 2-year follow-up CT Variables Same or Improved* Progression P Value Mean age (y) 61.4 62.1.55 Sex Men 29 (36.7) 27 (34.2).70 Women 13 (16.5) 10 (12.6) Smoking status Current 30 (37.9) 24 (30.4).53 Former 12 (15.7) 13 (16.5) Cigarette exposure (pack-years, mean) 54.8 66.4.09 Note. Numbers in parentheses are percentages. Current = current smoker at baseline who was persistent at 2 years, or a former smoker at baseline who restarted smoking at 2 years. Former = former smoker at baseline who was not smoking at 2 years, or a current smoker at baseline who was not smoking at 2 years. * n = 42 (53.2%) n = 37 (46.8%) Unpaired t test was used to compare same or improvement of ILA with progression of ILA at 2-year follow-up. P,.05 indicates statistically significant difference. of respiratory bronchiolitis interstitial lung disease is very good, with 75% of patients surviving more than 7 years in one study (20). Fibrotic reticular abnormality most likely represents some form of idiopathic interstitial pneumonia (nonspecific interstitial pneumonia or usual interstitial pneumonia). Progression of this pattern is common, and was seen in 37% (seven of 19) of participants in our study. However, the prognosis of this relatively early fibrotic abnormality is likely to be better than the typical prognosis of clinically diagnosed idiopathic pulmonary fibrosis, which is associated with a median survival from time of diagnosis of 2.5 to 4.4 years (1,2,5). The most common smoking-related lung disease is respiratory bronchiolitis, found at histologic analysis in virtually all cigarette smokers who are dying of incidental causes (21,22), usually asymptomatic, and not usually associated with pulmonary fibrosis. Respiratory bronchiolitis, characterized by poorly defined centrilobular nodularity, is commonly seen on chest CT images, particularly in heavy smokers (22,23). In the current study, we did not consider centrilobular nodularity alone to be sufficient evidence for ILA. In some cigarette smokers, when respiratory bronchiolitis becomes extensive enough to cause symptoms and physiologic impairment, it is called respiratory bronchiolitis interstitial lung disease (24), and is usually associated with CT findings of GGO and centrilobular nodularity (25 27). We postulate that the areas of GGO identified on CT images in 70% (56 of 79) of participants in our study predominantly represented areas of respiratory bronchiolitis interstitial lung disease. However, some of the GGO may have represented desquamative interstitial pneumonia. Desquamative interstitial pneumonia is a less common entity than respiratory bronchiolitis interstitial lung disease. Previous studies (27,28) have suggested that the CT findings of respiratory bronchiolitis interstitial lung disease are at least partially reversible, which would account for the fact that GGO improved at follow-up in 41% (13 of 32) of participants in our study. Cigarette smoking is also a risk factor for development of fibrotic lung Radiology: Volume 268: Number 2 August 2013 n radiology.rsna.org 569

abnormality. Baumgartner et al (29) reported that, compared with those who had never smoked, individuals who had smoked had an odds ratio of 1.6 for the diagnosis of idiopathic pulmonary fibrosis. The prevalence of idiopathic pulmonary fibrosis increased with packyears of smoking, with an odds ratio of 2.3 in smokers with 21 40 pack-years exposure. In our study, which included only participants with more than 30 pack-year smoking exposure, the median pack-years cigarette smoke exposure was higher in those with fibrotic ILA, again suggesting that cigarette smoking is an important risk factor for lung fibrosis. The pattern of subpleural reticular abnormality is a relatively common finding in asymptomatic elderly individuals. Copley et al (30) prospectively performed prone thinsection CT in volunteers with no known respiratory disease, who were older than 75 years or younger than 55 years. They found mild subpleural basal reticular pattern in 24 of 40 asymptomatic participants older than 75 years (independent of smoking history), but in none of 16 participants younger than 55 years. This is consistent with the finding in our study that the CT finding of fibrotic abnormality was associated with higher mean age. However, in at-risk populations, such as families affected with pulmonary fibrosis, smokers with chronic obstructive pulmonary disease, and patients with inflammatory lung disease, this CT finding of fibrotic abnormality might be associated with reductions in lung volume, functional limitations, and increased pulmonary symptoms (31). The fact that 37% (seven of 19) of individuals with this pattern showed progression over 2-year follow-up in our study suggested that this should not necessarily be dismissed as an incidental abnormality. Our study does have some limitations. Because CT imaging was only performed in the supine position, dependent attenuation may have obscured some early ILA. This is the primary reason for the relatively large number of participants with findings equivocal for ILA. The reduced-dose CT technique may result in decreased sensitivity to GGO (32). The reading technique was associated with fair to good agreement for various patterns of abnormality, and required resolution of some cases by consensus. Clinical or physiologic correlations of imaging abnormalities were not available, and we do not have treatment information. Because histologic confirmation of the presence or pattern of parenchymal abnormality was not possible, precise diagnoses cannot be provided. The relatively small number of patients precludes accurate analysis of factors associated with progression in the subgroup with fibrotic ILA. In conclusion, ILA was found in about 10% (86 of 884) of lung cancer screening participants. Nonfibrotic ILA, found in about 6% (52 of 884) of participants, and improved in about 50% (23 of 47) of cases at the 2-year follow up CT. Fibrotic ILA, found in about 2% (19 of 884), did not improve, and progressed in about 37% (seven of 19) at 2-year follow up CT. The presence of ILA is associated with current smoking status and with the total amount of cigarette consumption. Disclosures of Conflicts of Interest: G.Y.J. Financial activities related to the present article: grant money paid to institution by Chonbuk National University and Chonbuk National University Hospital in 2010. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. D.L. Financial activities related to the present article: grant money paid by the National Cancer Institute; grant money paid to institution by Siemens. 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