Silent Airway Mucus Plugs in COPD and Clinical Implications.

BACKGROUND: Airway mucus plugs are frequently identified on CT scans of patients with COPD with a smoking history without mucus-related symptoms (ie, cough, phlegm [silent mucus plugs]). RESEARCH QUESTION: In patients with COPD, what are the risk and protective factors associated with silent airway mucus plugs? Are silent mucus plugs associated with functional, structural, and clinical measures of disease? STUDY DESIGN AND METHODS: We identified mucus plugs on chest CT scans of participants with COPD from the COPDGene study. The mucus plug score was defined as the number of pulmonary segments with mucus plugs, ranging from 0 to 18, and categorized into three groups (0, 1-2, and ≥ 3). We determined risk and protective factors for silent mucus plugs and the associations of silent mucus plugs with measures of disease severity using multivariable linear and logistic regression models. RESULTS: Of 4,363 participants with COPD, 1,739 had no cough or phlegm. Among the 1,739 participants, 627 (36%) had airway mucus plugs identified on CT scan. Risk factors of silent mucus plugs (compared with symptomatic mucus plugs) were older age (OR, 1.02), female sex (OR, 1.40), and Black race (OR, 1.93) (all P values < .01). Among those without cough or phlegm, silent mucus plugs (vs absence of mucus plugs) were associated with worse 6-min walk distance, worse resting arterial oxygen saturation, worse FEV1 % predicted, greater emphysema, thicker airway walls, and higher odds of severe exacerbation in the past year in adjusted models. INTERPRETATION: Mucus plugs are common in patients with COPD without mucus-related symptoms. Silent mucus plugs are associated with worse functional, structural, and clinical measures of disease. CT scan-identified mucus plugs can complement the evaluation of patients with COPD.

Airway-Occluding Mucus Plugs and Mortality in Patients With Chronic Obstructive Pulmonary Disease.

Importance: Airway mucus plugs are common in patients with chronic obstructive pulmonary disease (COPD); however, the association of airway mucus plugging and mortality in patients with COPD is unknown. Objective: To determine whether airway mucus plugs identified on chest computed tomography (CT) were associated with increased all-cause mortality. Design, Setting, and Participants: Observational retrospective analysis of prospectively collected data of patients with a diagnosis of COPD in the Genetic Epidemiology of COPD cohort. Participants were non-Hispanic Black or White individuals, aged 45 to 80 years, who smoked at least 10 pack-years. Participants were enrolled at 21 centers across the US between November 2007 and April 2011 and were followed up through August 31, 2022. Exposures: Mucus plugs that completely occluded airways on chest CT scans, identified in medium- to large-sized airways (ie, approximately 2- to 10-mm lumen diameter) and categorized as affecting 0, 1 to 2, or 3 or more lung segments. Main Outcomes and Measures: The primary outcome was all-cause mortality, assessed with proportional hazard regression analysis. Models were adjusted for age, sex, race and ethnicity, body mass index, pack-years smoked, current smoking status, forced expiratory volume in the first second of expiration, and CT measures of emphysema and airway disease. Results: Among the 4483 participants with COPD, 4363 were included in the primary analysis (median age, 63 years [IQR, 57-70 years]; 44% were women). A total of 2585 (59.3%), 953 (21.8%), and 825 (18.9%) participants had mucus plugs in 0, 1 to 2, and 3 or more lung segments, respectively. During a median 9.5-year follow-up, 1769 participants (40.6%) died. The mortality rates were 34.0% (95% CI, 32.2%-35.8%), 46.7% (95% CI, 43.5%-49.9%), and 54.1% (95% CI, 50.7%-57.4%) in participants who had mucus plugs in 0, 1 to 2, and 3 or more lung segments, respectively. The presence of mucus plugs in 1 to 2 vs 0 and 3 or more vs 0 lung segments was associated with an adjusted hazard ratio of death of 1.15 (95% CI, 1.02-1.29) and 1.24 (95% CI, 1.10-1.41), respectively. Conclusions and Relevance: In participants with COPD, the presence of mucus plugs that obstructed medium- to large-sized airways was associated with higher all-cause mortality compared with patients without mucus plugging on chest CT scans.

Idiopathic pulmonary fibrosis is more strongly associated with coronary artery disease than chronic obstructive pulmonary disease.

INTRODUCTION: Previous studies have shown that the population attributable risk of low forced expiratory volume in one second (FEV1) for coronary artery disease (CAD) is substantial. FEV1 can be low either because of airflow obstruction or ventilatory restriction. It is not known if low FEV1 arising from spirometric obstruction or restriction are differently associated with CAD. METHODS: We analyzed high resolution computed tomography (CT) scans acquired at full inspiration in lifetime non-smoker adults with no lung disease (controls) and those with chronic obstructive pulmonary disease enrolled in the Genetic Epidemiology of COPD (COPDGene) study. We also analyzed CT scans of adults with idiopathic pulmonary fibrosis (IPF) from a cohort of patients attending a quaternary referral clinic. Participants with IPF were matched 1:1 by FEV1 %predicted to adults with COPD and 1:1 by age to lifetime non-smokers. Coronary artery calcium (CAC), a surrogate for CAD, was measured by visual quantification on CT using the Weston score. Significant CAC was defined as Weston score ≥7. Multivariable regression models were used to test the association of the presence of COPD or IPF with CAC, with adjustment for age, sex, body-mass-index, smoking status, hypertension, diabetes mellitus, and hyperlipidemia. RESULTS: We included 732 subjects in the study; 244 with IPF, 244 with COPD, and 244 lifetime non-smokers. The mean (SD) age was 72.6 (8.1), 62.6 (7.4), and 67.3 (6.6) years, and median (IQR) CAC was 6 (6), 2 (6), and 1 (4), in IPF, COPD, and non-smokers, respectively. On multivariable analyses, the presence of COPD was associated with higher CAC compared to non-smokers (adjusted regression coefficient, ß = 1.10 ± SE0.51; P = 0.031). The presence of IPF was also associated with higher CAC compared to non-smokers (ß = 03.43 ± SE0.41; P < 0.001). The adjusted odds ratio for having significant CAC was 1.3, 95% CI 0.6 to 2.8; P = 0.53 in COPD and 5.6, 95% CI 2.9 to 10.9; P < 0.001 in IPF, compared to non-smokers. In sex stratified analyses, these associations were mainly noted in women. CONCLUSION: Adults with IPF displayed higher coronary artery calcium than those with COPD after accounting for age and lung function impairment.

Cardiac computed tomographic evaluation of coronary artery calcification: A review.

Vascular calcification is most commonly due to atherosclerosis. It has been well documented that absence of coronary calcification on a chest CT (CCT) is associated with low cardiovascular events and good prognosis. High CT calcium scores often result in a higher incidence of cardiovascular events and worse survival. In asymptomatic patients with an intermediate risk for coronary artery disease, numerous studies have shown Coronary Calcium Scoring (CCS) has prognostic relevance and incremental prognostic value over conventional risk stratification. CT detected calcium score plays important role in patient management. This article will review various CT based coronary artery calcium scoring methods.

An Updated Comparison of Conventional Coronary Angiography With Cardiac Magnetic Resonance Imaging to Diagnose the Origin and Proximal Course of Anomalous Coronary Arteries.

BACKGROUND: Anomalous coronary arteries (ACAs) may present increased risk for adverse cardiac events. We sought to evaluate the accuracy of conventional coronary angiography (CCA), as it is currently used in clinical practice, compared with expert interpretation and cardiac magnetic resonance imaging (CMR) in determining the site of origin and proximal course of ACAs. METHODS: Fifty consecutive patients without concomitant congenital heart disease, who were referred for CMR to diagnose the course of an ACA, were retrospectively evaluated. Original CCA reports were reviewed. Angiography images were available in all patients and were interpreted by 2 experts blinded to the prior interpretation and CMR results. The accuracy of interpretation in each group was then compared to the current gold standard of CMR. RESULTS: Identification of the site of origin (ie, aortic sinus) by referring angiographers was similar to that of expert angiographers (sensitivity, 89% vs 98%, respectively; P=.10). However, referring angiographers were less likely to correctly identify the proximal course as compared with expert angiographers (sensitivity, 27% vs 98%, respectively; P<.001). CONCLUSIONS: As it is used in current practice, CCA does not provide sufficient diagnostic accuracy for identifying the proximal course of an ACA. Review by expert angiographers added sensitivity, improving the accuracy to nearly 100%. Expert consultation may be nearly as accurate as advanced imaging, and should be considered in cases of ACA in which there is diagnostic uncertainty.

Correlation of Computed Tomography Test Bolus Dynamics and Conventional Computed Tomography Parameters With Pulmonary Vascular Resistance in Patients With Pulmonary Arterial Hypertension.

OBJECTIVE: Pulmonary vascular resistance (PVR) is a measurement obtained with invasive right heart catheterization (RHC) that is commonly used for management of patients with pulmonary arterial hypertension (PAH). Computed tomography pulmonary angiography (CTPA) is also done as part of the workup for PAH in some cases. The aim of our study was to assess the correlation of contrast dynamic changes in the main pulmonary artery (MPA) on CTPA with PVR obtained with RHC. METHODS: This is an IRB-approved retrospective study performed in two separate institutions (Medical College of Wisconsin and University of Alabama) between January 2010 and December 2013. During CTPA done as test bolus, serial images are acquired at the level of MPA after intravenous injection of contrast to determine timing of the CT acquisition. Since the PVR changes with the degree of PAH, we hypothesize that will be reflected in the contrast kinetics in MPA. A correlation of standard CT metrics (MPA diameter, right pulmonary artery [PA] diameter, left PA diameter, MPA/aorta ratio, and right ventricle/left ventricle [RV/LV] ratio) and dynamic (full width at half maximum) CTPA parameters in patients with known PAH was performed with PVR obtained from RHC done within 30 days. Statistical analysis was performed by Pearson correlation coefficient. RESULTS: Among 221 patients in our database, 37 patients fulfilled the selection criteria. There was a strong correlation between full width half maximum (FWHM) and mean pulmonary artery pressure (mPAP) (r=0.69, p value<0.00001), PVR (r=0.8, p value<0.00001) and indexed PVR (PVRI) (r=0.75, p value<0.00001). CONCLUSION: FWHM obtained from CTPA strongly correlates with RHC parameters and is potentially more helpful than static measurements for follow-up of patients with known PAH to assess response to treatment or progression.

Airway remodeling in ferrets with cigarette smoke-induced COPD using µCT imaging.

Structural changes to airway morphology, such as increased bronchial wall thickness (BWT) and airway wall area, are cardinal features of chronic obstructive pulmonary disease (COPD). Ferrets are a recently established animal model uniquely exhibiting similar clinical and pathological characteristics of COPD as humans, including chronic bronchitis. Our objective was to develop a microcomputed tomography (µCT) method for evaluating structural changes to the airways in ferrets and assess whether the effects of smoking induce changes consistent with chronic bronchitis in humans. Ferrets were exposed to mainstream cigarette smoke or air control twice daily for 6 mo. µCT was conducted in vivo at 6 mo; a longitudinal cohort was imaged monthly. Manual measurements of BWT, luminal diameter (LD), and BWT-to-LD ratio (BWT/LD) were conducted and confirmed by a semiautomated algorithm. The square root of bronchial wall area (√WA) versus luminal perimeter was determined on an individual ferret basis. Smoke-exposed ferrets reproducibly demonstrated 34% increased BWT (P < 0.001) along with increased LD and BWT/LD versus air controls. Regression indicated that the effect of smoking on BWT persisted despite controlling for covariates. Semiautomated measurements replicated findings. √WA for the theoretical median airway luminal perimeter of 4 mm (Pi4) was elevated 4.4% in smoke-exposed ferrets (P = 0.015). Increased BWT and Pi4 developed steadily over time. µCT-based airway measurements in ferrets are feasible and reproducible. Smoke-exposed ferrets develop increased BWT and Pi4, changes similar to humans with chronic bronchitis. µCT can be used as a significant translational platform to measure dynamic airway morphological changes.

Luminal Plugging on Chest CT Scan: Association With Lung Function, Quality of Life, and COPD Clinical Phenotypes.

BACKGROUND: Mucous exudates occluding the lumen of small airways are associated with reduced lung function and mortality in subjects with COPD; however, luminal plugs in large airways have not been widely studied. We aimed to examine the associations of chest CT scan-identified luminal plugging with lung function, health-related quality of life, and COPD phenotypes. METHODS: We randomly selected 100 smokers without COPD and 400 smokers with COPD from the COPDGene Study. Luminal plugging was visually identified on inspiratory CT scans at baseline and 5-year follow-up. The relationships of luminal plugging to FEV1, St. George's Respiratory Questionnaire (SGRQ) score, emphysema on CT scan (defined as the percentage of low attenuation area < 950 Hounsfield units [%LAA-950]), and chronic bronchitis were assessed using linear and logistic multivariable analyses. RESULTS: Overall, 111 subjects (22%) had luminal plugging. The prevalence of luminal plugging was higher in subjects with COPD than those without COPD (25% vs 10%, respectively; P = .001). In subjects with COPD, luminal plugging was significantly associated with FEV1 % predicted (estimate, -6.1; SE, 2.1; P = .004) and SGRQ score (estimate, 4.9; SE, 2.4; P = .04) in adjusted models. Although luminal plugging was associated with log %LAA-950 (estimate, 0.43; SE, 0.16; P = .007), its relationship with chronic bronchitis did not reach statistical significance (P = .07). Seventy-three percent of subjects with COPD with luminal plugging at baseline had it 5 years later. CONCLUSIONS: In subjects with COPD, CT-identified luminal plugging is associated with airflow obstruction, worse health-related quality of life, and emphysema phenotype. This imaging feature may supplement the current clinical assessment of chronic mucus hypersecretion in COPD.

Centrilobular emphysema and coronary artery calcification: mediation analysis in the SPIROMICS cohort.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with a two-to-five fold increase in the risk of coronary artery disease independent of shared risk factors. This association is hypothesized to be mediated by systemic inflammation but this link has not been established. METHODS: We included 300 participants enrolled in the SPIROMICS cohort, 75 each of lifetime non-smokers, smokers without airflow obstruction, mild-moderate COPD, and severe-very severe COPD. We quantified emphysema and airway disease on computed tomography, characterized visual emphysema subtypes (centrilobular and paraseptal) and airway disease, and used the Weston visual score to quantify coronary artery calcification (CAC). We used the Sobel test to determine whether markers of systemic inflammation mediated a link between spirometric and radiographic features of COPD and CAC. RESULTS: FEV1/FVC but not quantitative emphysema or airway wall thickening was associated with CAC (p = 0.036), after adjustment for demographics, diabetes mellitus, hypertension, statin use, and CT scanner type. To explain this discordance, we examined visual subtypes of emphysema and airway disease, and found that centrilobular emphysema but not paraseptal emphysema or bronchial thickening was independently associated with CAC (p = 0.019). MMP3, VCAM1, CXCL5 and CXCL9 mediated 8, 8, 7 and 16% of the association between FEV1/FVC and CAC, respectively. Similar biomarkers partially mediated the association between centrilobular emphysema and CAC. CONCLUSIONS: The association between airflow obstruction and coronary calcification is driven primarily by the centrilobular subtype of emphysema, and is linked through bioactive molecules implicated in the pathogenesis of atherosclerosis. TRIAL REGISTRATION: ClinicalTrials.gov: Identifier: NCT01969344 .

Airway fractal dimension predicts respiratory morbidity and mortality in COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by airway remodeling. Characterization of airway changes on computed tomography has been challenging due to the complexity of the recurring branching patterns, and this can be better measured using fractal dimensions. METHODS: We analyzed segmented airway trees of 8,135 participants enrolled in the COPDGene cohort. The fractal complexity of the segmented airway tree was measured by the Airway Fractal Dimension (AFD) using the Minkowski-Bougliand box-counting dimension. We examined associations between AFD and lung function and respiratory morbidity using multivariable regression analyses. We further estimated the extent of peribronchial emphysema (%) within 5 mm of the airway tree, as this is likely to affect AFD. We classified participants into 4 groups based on median AFD, percentage of peribronchial emphysema, and estimated survival. RESULTS: AFD was significantly associated with forced expiratory volume in one second (FEV1; P < 0.001) and FEV1/forced vital capacity (FEV1/FVC; P < 0.001) after adjusting for age, race, sex, smoking status, pack-years of smoking, BMI, CT emphysema, air trapping, airway thickness, and CT scanner type. On multivariable analysis, AFD was also associated with respiratory quality of life and 6-minute walk distance, as well as exacerbations, lung function decline, and mortality on longitudinal follow-up. We identified a subset of participants with AFD below the median and peribronchial emphysema above the median who had worse survival compared with participants with high AFD and low peribronchial emphysema (adjusted hazards ratio [HR]: 2.72; 95% CI: 2.20-3.35; P < 0.001), a substantial number of whom were not identified by traditional spirometry severity grades. CONCLUSION: Airway fractal dimension as a measure of airway branching complexity and remodeling in smokers is associated with respiratory morbidity and lung function change, offers prognostic information additional to traditional CT measures of airway wall thickness, and can be used to estimate mortality risk. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00608764. FUNDING: This study was supported by NIH K23 HL133438 (SPB) and the COPDGene study (NIH Grant Numbers R01 HL089897 and R01 HL089856). The COPDGene project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, Siemens, Sunovion and GlaxoSmithKline.

Visual Estimate of Coronary Artery Calcium Predicts Cardiovascular Disease in COPD.

BACKGROUND: COPD is associated with cardiovascular disease (CVD), and coronary artery calcification (CAC) provides additional prognostic information. With increasing use of nongated CT scans in clinical practice, this study hypothesized that the visual Weston CAC score would perform as well as the Agatston score in predicting prevalent and incident coronary artery disease (CAD) and CVD in COPD. METHODS: CAC was measured by using Agatston and Weston scores on baseline CT scans in 1,875 current and former smokers enrolled in the Genetic Epidemiology of COPD (COPDGene) study. Baseline cardiovascular disease and incident cardiac events on longitudinal follow-up were recorded. Accuracy of the CAC scores was measured by using receiver-operating characteristic analysis, and Cox proportional hazards analyses were used to estimate the risk of incident cardiac events. RESULTS: CAD was reported by 133 (7.1%) subjects at baseline. A total of 413 (22.0%) and 241 (12.9%) patients had significant CAC according to the Weston (≥ 7) and Agatston (≥ 400) scores, respectively; the two methods were significantly correlated (r = 0.84; P < .001). Over 5 years of follow-up, 127 patients (6.8%) developed incident CVD. For predicting prevalent CAD, c-indices for the Weston and Agatston scores were 0.78 and 0.74 and for predicting incident CVD, they were 0.62 and 0.61. After adjustment for age, race, sex, smoking pack-years, FEV1, percent emphysema, and CT scanner type, a Weston score ≥ 7 was associated with time to first acute coronary event (hazard ratio, 2.16 [95% CI, 1.32 to 3.53]; P = .002), but a Agatston score ≥ 400 was not (hazard ratio, 1.75 [95% CI, 0.99-3.09]; P = .053). CONCLUSIONS: A simple visual score for CAC performed well in predicting incident CAD in smokers with and without COPD. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.

Paratracheal Paraseptal Emphysema and Expiratory Central Airway Collapse in Smokers.

RATIONALE: Expiratory central airway collapse is associated with respiratory morbidity independent of underlying lung disease. However, not all smokers develop expiratory central airway collapse, and the etiology of expiratory central airway collapse in adult smokers is unclear. Paraseptal emphysema in the paratracheal location, by untethering airway walls, may predispose smokers to developing expiratory central airway collapse. OBJECTIVES: To evaluate whether paratracheal paraseptal emphysema is associated with expiratory central airway collapse. METHODS: We analyzed paired inspiratory and expiratory computed tomography scans from participants enrolled in a multicenter study (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) of smokers aged 45 to 80 years. Expiratory central airway collapse was defined as greater than or equal to 50% reduction in cross-sectional area of the trachea during expiration. In a nested case-control design, participants with and without expiratory central airway collapse were included in a 1:2 fashion, and inspiratory scans were further analyzed using the Fleischner Society criteria for presence of centrilobular emphysema, paraseptal emphysema, airway wall thickening, and paratracheal paraseptal emphysema (maximal diameter ≥ 0.5 cm). RESULTS: A total of 1,320 patients were included, 440 with and 880 without expiratory central airway collapse. Those with expiratory central airway collapse were older, had higher body mass index, and were less likely to be men or current smokers. Paratracheal paraseptal emphysema was more frequent in those with expiratory central airway collapse than control subjects (16.6 vs. 11.8%; P = 0.016), and after adjustment for age, race, sex, body mass index, smoking pack-years, and forced expiratory volume in 1 second, paratracheal paraseptal emphysema was independently associated with expiratory central airway collapse (adjusted odds ratio, 1.53; 95% confidence interval, 1.18-1.98; P = 0.001). Furthermore, increasing size of paratracheal paraseptal emphysema (maximal diameter of at least 1 cm and 1.5 cm) was associated with greater odds of expiratory central airway collapse (adjusted odds ratio, 1.63; 95% confidence interval, 1.18-2.25; P = 0.003 and 1.77; 95% confidence interval, 1.19-2.64; P = 0.005, respectively). CONCLUSIONS: Paraseptal emphysema adjacent to the trachea is associated with expiratory central airway collapse. The identification of this risk factor on inspiratory scans should prompt further evaluation for expiratory central airway collapse. Clinical trial registered with ClinicalTrials.gov (NCT 00608764).

Signs of Gas Trapping in Normal Lung Density Regions in Smokers.

RATIONALE: A substantial proportion of subjects without overt airflow obstruction have significant respiratory morbidity and structural abnormalities as visualized by computed tomography. Whether regions of the lung that appear normal using traditional computed tomography criteria have mild disease is not known. OBJECTIVES: To identify subthreshold structural disease in normal-appearing lung regions in smokers. METHODS: We analyzed 8,034 subjects with complete inspiratory and expiratory computed tomographic data participating in the COPDGene Study, including 103 lifetime nonsmokers. The ratio of the mean lung density at end expiration (E) to end inspiration (I) was calculated in lung regions with normal density (ND) by traditional thresholds for mild emphysema (-910 Hounsfield units) and gas trapping (-856 Hounsfield units) to derive the ND-E/I ratio. Multivariable regression analysis was used to measure the associations between ND-E/I, lung function, and respiratory morbidity. MEASUREMENTS AND MAIN RESULTS: The ND-E/I ratio was greater in smokers than in nonsmokers, and it progressively increased from mild to severe chronic obstructive pulmonary disease severity. A proportion of 26.3% of smokers without airflow obstruction had ND-E/I greater than the 90th percentile of normal. ND-E/I was independently associated with FEV1 (adjusted ß = -0.020; 95% confidence interval [CI], -0.032 to -0.007; P = 0.001), St. George's Respiratory Questionnaire scores (adjusted ß = 0.952; 95% CI, 0.529 to 1.374; P < 0.001), 6-minute-walk distance (adjusted ß = -10.412; 95% CI, -12.267 to -8.556; P < 0.001), and body mass index, airflow obstruction, dyspnea, and exercise capacity index (adjusted ß = 0.169; 95% CI, 0.148 to 0.190; P < 0.001), and also with FEV1 change at follow-up (adjusted ß = -3.013; 95% CI, -4.478 to -1.548; P = 0.001). CONCLUSIONS: Subthreshold gas trapping representing mild small airway disease is prevalent in normal-appearing lung regions in smokers without airflow obstruction, and it is associated with respiratory morbidity. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

The relationship of cancer characteristics and patient outcome with time to lung cancer diagnosis after an abnormal screening CT.

PURPOSE: The National Lung Screening Trial (NLST) demonstrated a reduction in lung cancer and all-cause mortality with low-dose CT (LDCT) screening. The aim of our study was to examine the time to diagnosis (TTD) of lung cancer in the LDCT arm of the NLST and assess its relationship with cancer characteristics and survival. METHODS: The subjects (N = 462) with a positive baseline screen and subsequent lung cancer diagnosis within 3 years were evaluated by data and image review to confirm the baseline abnormality. The cases were analysed for the relationship between TTD and imaging features, cancer type, stage and survival for 7 years from baseline screen. RESULTS: Cancer was judged to be present at baseline in 397/462 cases. The factors that showed significant association (p value trend less than 0.05) with longer TTD included smaller nodule size, pure ground glass nodules (GGNs), smooth/lobulated margins, stages I/II, adenocarcinoma, and decreasing lung cancer mortality. The logistic regression model for lung cancer death showed significant inverse relationships with size less than 20 mm (OR = 0.32), pure GGNs (OR = 0.24), adenocarcinoma (OR = 0.57) and direct relationship with age (OR = 1.4). CONCLUSION: TTD after a positive LDCT screen in the NLST showed a strong association with imaging features, stage and mortality. KEY POINTS: • NLST observed variable time to lung cancer diagnosis from positive baseline screen. • Time to diagnosis was associated with imaging features, cancer type and stage. • In univariate but not multivariate analysis, longer TTD correlated with decreased mortality.

Interval lung cancer after a negative CT screening examination: CT findings and outcomes in National Lung Screening Trial participants.

OBJECTIVES: This study retrospectively analyses the screening CT examinations and outcomes of the National Lung Screening Trial (NLST) participants who had interval lung cancer diagnosed within 1 year after a negative CT screen and before the next annual screen. METHODS: The screening CTs of all 44 participants diagnosed with interval lung cancer (cases) were matched with negative CT screens of participants who did not develop lung cancer (controls). A majority consensus process was used to classify each CT screen as positive or negative according to the NLST criteria and to estimate the likelihood that any abnormalities detected retrospectively were due to lung cancer. RESULTS: By retrospective review, 40/44 cases (91%) and 17/44 controls (39%) met the NLST criteria for a positive screen (P < 0.001). Cases had higher estimated likelihood of lung cancer (P < 0.001). Abnormalities included pulmonary nodules ≥4 mm (n = 16), mediastinal (n = 8) and hilar (n = 6) masses, and bronchial lesions (n = 6). Cancers were stage III or IV at diagnosis in 32/44 cases (73%); 37/44 patients (84%) died of lung cancer, compared to 225/649 (35%) for all screen-detected cancers (P < 0.0001). CONCLUSION: Most cases met the NLST criteria for a positive screen. Awareness of missed abnormalities and interpretation errors may aid lung cancer identification in CT screening. KEY POINTS: • Lung cancer within a year of a negative CT screen was rare. • Abnormalities likely due to lung cancer were identified retrospectively in most patients. • Awareness of error types may help identify lung cancer sooner.