Introduction Prognostic biomarkers have been very elusive in the lung squamous cell carcinoma (SCC) and none is currently being used in the clinical setting. We aimed to identify and validate the clinical utility of a protein-based prognostic signature to stratify patients with early lung SCC according to their risk of recurrence or death. Methods Patients were staged following the new International Association for the Study of Lung Cancer (IASLC) staging criteria (eighth edition, 2018). Three independent retrospective cohorts of 117, 96 and 105 patients with lung SCC were analysed to develop and validate a prognostic signature based on immunohistochemistry for five proteins. Results We identified a five protein-based signature whose prognostic index (PI) was an independent and significant predictor of disease-free survival (DFS) (p<0.001; HR=4.06, 95% CI 2.18 to 7.56) and overall survival (OS) (p=0.004; HR=2.38, 95% CI 1.32 to 4.31). The prognostic capability of PI was confirmed in an external multi-institutional cohort for DFS (p=0.042; HR=2.01, 95% CI 1.03 to 3.94) and for OS (p=0.031; HR=2.29, 95% CI 1.08 to 4.86). Moreover, PI added complementary information to the newly established IASLC TNM 8th edition staging system. A combined prognostic model including both molecular and anatomical (TNM) criteria improved the risk stratification in both cohorts (p<0.05). Conclusion We have identified and validated a clinically feasible protein-based prognostic model that complements the updated TNM system allowing more accurate risk stratification. This signature may be used as an advantageous tool to improve the clinical management of the patients, allowing the reduction of lung SCC mortality through a more accurate knowledge of the patient's potential outcome.

Background To assess the relationship between lung cancer and emphysema subtypes. Objective Airflow obstruction and emphysema predispose to lung cancer. Little is known, however, about the lung cancer risk associated with different emphysema phenotypes. We assessed the risk of lung cancer based on the presence, type and severity of emphysema, using visual assessment. Methods Seventy-two consecutive lung cancer cases were selected from a prospective cohort of 3,477 participants enrolled in the Clinica Universidad de Navarra's lung cancer screening program. Each case was matched to three control subjects using age, sex, smoking history and body mass index as key variables. Visual assessment of emphysema and spirometry were performed. Logistic regression and interaction model analysis were used in order to investigate associations between lung cancer and emphysema subtypes. Results Airflow obstruction and visual emphysema were significantly associated with lung cancer (OR = 2.8, 95%CI: 1.6 to 5.2; OR = 5.9, 95%CI: 2.9 to 12.2; respectively). Emphysema severity and centrilobular subtype were associated with greater risk when adjusted for confounders (OR = 12.6, 95%CI: 1.6 to 99.9; OR = 34.3, 95%CI: 25.5 to 99.3, respectively). The risk of lung cancer decreases with the added presence of paraseptal emphysema (OR = 4.0, 95%CI: 3.6 to 34.9), losing this increased risk of lung cancer when it occurs alone (OR = 0.7, 95%CI: 0.5 to 2.6). Conclusions Visual scoring of emphysema predicts lung cancer risk. The centrilobular phenotype is associated with the greatest risk.

The CODEX index was developed and validated in patients hospitalized for COPD exacerbation to predict the risk of death and readmission within one year after discharge. Our study aimed to validate the CODEX index in a large external population of COPD patients with variable durations of follow-up. Additionally, we aimed to recalculate the thresholds of the CODEX index using the cutoffs of variables previously suggested in the 3CIA study (mCODEX).Individual data on 2,755 patients included in the COPD Cohorts Collaborative International Assessment Plus (3CIA+) were explored. A further two cohorts (ESMI AND EGARPOC-2) were added. To validate the CODEX index, the relationship between mortality and the CODEX index was assessed using cumulative/dynamic ROC curves at different follow-up periods, ranging from 3 months up to 10 years. Calibration was performed using univariate and multivariate Cox proportional hazard models and Hosmer-Lemeshow test.A total of 3,321 (87.8% males) patients were included with a meanSD age of 66.9 +/- 10.5 years, and a median follow-up of 1,064 days (IQR 25-75% 426-1643), totaling 11,190 person-years. The CODEX index was statistically associated with mortality in the short- (3 months), medium- (1 year) and long-term (10 years), with an area under the curve of 0.72, 0.70 and 0.76, respectively. The mCODEX index performed better in the medium-term (<1 year) than the original CODEX, and similarly in the long-term.In conclusion, CODEX and mCODEX index are good predictors of mortality in patients with COPD, regardless of disease severity or duration of follow-up.

BACKGROUND: Some interstitial lung diseases are associated with lung cancer. However, it is unclear whether asymptomatic interstitial lung abnormalities convey an independent risk. OBJECTIVE: The goal of this study was to assess whether interstitial lung abnormalities are associated with an increased risk of lung cancer. METHODS: Data from all participants in the National Lung Cancer Trial were analyzed, except for subjects with preexisting interstitial lung disease or prevalent lung cancers. The primary analysis included those who underwent low-dose CT imaging; those undergoing chest radiography were included in a confirmatory analysis. Participants with evidence of reticular/reticulonodular opacities, honeycombing, fibrosis, or scarring were classified as having interstitial lung abnormalities. Lung cancer incidence and mortality in participants with and without interstitial lung abnormalities were compared by using Poisson and Cox regression, respectively. RESULTS: Of the 25,041 participants undergoing low-dose CT imaging included in the primary analysis, 20.2% had interstitial lung abnormalities. Participants with interstitial lung abnormalities had a higher incidence of lung cancer (incidence rate ratio, 1.61; 95% CI, 1.301.99). Interstitial lung abnormalities were associated with higher lung cancer incidence on adjusted analyses (incidence rate ratio, 1.33; 95% CI, 1.07-1.65). Lung cancer-specific mortality was also greater in participants with interstitial lung abnormalities. Similar findings were obtained in the analysis of participants undergoing chest radiography. CONCLUSIONS: Asymptomatic interstitial lung abnormalities are an independent risk factor for lung cancer that can be incorporated into risk score models.

Background Plasma metabolomics profile (PMP) in COPD has been associated with clinical characteristics, but PMP's relationship to survival has not been reported. We determined PMP differences between patients with COPD who died an average of 2 years after enrollment (Non-survivors, NS) compared to those who survived (S) and also with age matched controls (C). Methods We studied prospectively 90 patients with severe COPD and 30 controls. NS were divided in discovery and validation cohorts (30 patients each) and the results compared to the PMP of 30 S and C. All participants completed lung function tests, dyspnea scores, quality of life, exercise capacity, BODE index, and plasma metabolomics by liquid and gas chromatography / mass spectometry (LC/MS, LC/MS2, GC/MS). Statistically, we used Random Forest Analysis (RFA) and Support Vector Machine (SVM) to determine metabolites that differentiated the 3 groups and compared the ability of metabolites vs. clinical characteristics to classify patients into survivors and non-survivors. Results There were 79 metabolites statistically different between S and NS [p < 0.05 and false discovery rate (q value) < 0.1]. RFA and SVM classification of COPD survivors and non-survivors had a predicted accuracy of 74 and 85% respectively. Elevation of tricyclic acid cycle intermediates branched amino acids depletion and increase in lactate, fructose and xylonate showed the most relevant differences between S vs. NS suggesting alteration in mitochondrial oxidative energy generation. PMP had similar predictive power for risk of death as information provided by clinical characteristics. Conclusions A plasma metabolomic profile characterized by an oxidative energy production difference between survivors and non-survivors was observed in COPD patients 2 years before death.

Purpose Lung cancer risk models optimise screening by identifying subjects at highest risk, but none of them consider emphysema, a risk factor identifiable on baseline screen. Subjects with a negative baseline low-dose CT (LDCT) screen are at lower risk for subsequent diagnosis and may benefit from risk stratification prior to additional screening, thus we investigated the role of radiographic emphysema as an additional predictor of lung cancer diagnosis in participants with negative baseline LDCT screens of the National Lung Screening Trial. Methods Our cohorts consist of participants with a negative baseline (T0) LDCT screen (n=16 624) and participants who subsequently had a negative 1-year follow-up (T1) screen (n=14 530). Lung cancer risk scores were calculated using the Bach, PLCOm2012 and Liverpool Lung Project models. Risk of incident lung cancer diagnosis at the end of the study and number screened per incident lung cancer were compared between participants with and without radiographic emphysema. Results Radiographic emphysema was independently associated with nearly double the hazard of lung cancer diagnosis at both the second (T1) and third (T2) annual LDCT in all three risk models (HR range 1.9-2.0, p<0.001 for all comparisons). The number screened per incident lung cancer was considerably lower in participants with radiographic emphysema (62 vs 28 at T1 and 91 vs 40 at T2). Conclusion Radiographic emphysema is an independent predictor of lung cancer diagnosis and may help guide decisions surrounding further screening for eligible patients.

BACKGROUND: Smoking is a recognized risk factor for osteoporosis. Trabecular bone score (TBS) is a novel texture parameter to evaluate bone microarchitecture. TBS and their main determinants are unknown in active and former smokers. OBJECTIVE: To assess TBS in a population of active or former smokers with and without Chronic Obstructive Pulmonary Disease (COPD) and to determine its predictive factors. METHODS: Active and former smokers from a pulmonary clinic were invited to participate. Clinical features were recorded and bone turnover markers (BTMs) measured. Lung function, low dose chest Computed Tomography scans (LDCT), dual energy absorptiometry (DXA) scans were performed and TBS measured. Logistic regression analysis explored the relationship between measured parameters and TBS. RESULTS: One hundred and forty five patients were included in the analysis, 97 (67.8%) with COPD. TBS was lower in COPD patients (median 1.323; IQR: 0.13 vs 1.48; IQR: 0.16, p = 0.003). Regression analysis showed that a higher body mass index (BMI), younger age, less number of exacerbations and a higher forced expiratory volume-one second (FEV1%) was associated with better TBS (ß = 0.005, 95% CI:0.000-0.011, p = 0.032; ß = -0.003, 95% CI:-0.007(-)-0.000, p = 0.008; ß = -0.019, 95% CI:-0.034(-)-0.004, p = 0.015; ß = 0.001, 95% CI:0.000-0.002, p = 0.012 respectively). The same factors with similar results were found in COPD patients.

Introduction: The Spanish COPD guidelines (GesEPOC) have been recently modified. The aim of this study is to assess this revision and evaluate the prognosis of patients according to the new classification of severity. Methods: A total of 700 COPD patients (83.9% men) were prospectively followed up for a mean period of 5 years in tertiary hospitals in Spain and the USA. Anthropometric data, lung function tests, dyspnea (according to the mMRC scale), BODE and Charlson index were collected. We calculated mortality at 5 years following the risk criteria proposed by the new GesEPOC. Results: Mean age was 66 +/- 9.6 years and mean FEV1% was 59.7 +/- 20.2. The proportion of patients in the low-risk group was 40.43%. Patients in the high-risk group had a significantly higher BODE index than those in the low-risk group (2.92 +/- 0.66 vs. 0.52 +/- 1.91, p < 0.001), while the Charlson index score was similar in both groups. Mortality at 60 months was significantly higher in the high-risk group (31.7% vs. 15.5%, p < 0.001). Dyspnea and FEV1% were also independent predictors of mortality (p < 0.001), and neither was inferior to the risk classification proposed by GesEPOC. Conclusions: The new severity index proposed by GesEPOC accurately predicts 5-year mortality. However, dyspnea and FEV1% have the same strength in predicting mortality. (C) 2018 SEPAR. Published by Elsevier Espana, S.L.U. All rights reserved.

Background Aging is an important risk factor for most chronic diseases. Patients with COPD develop more comorbidities than non-COPD subjects. We hypothesized that the development of comorbidities characteristically affecting the elderly occur at an earlier age in subjects with the diagnosis of COPD. Methods and findings We included all subjects carrying the diagnosis of COPD (n = 27,617), and a similar number of age and sex matched individuals without the diagnosis, extracted from the 727,241 records of individuals 40 years and older included in the EpiChron Cohort (Aragon, Spain). We compared the cumulative number of comorbidities, their prevalence and the mortality risk between both groups. Using network analysis, we explored the connectivity between comorbidities and the most influential comorbidities in both groups. We divided the groups into 5 incremental age categories and compared their comorbidity networks. We then selected those comorbidities known to affect primarily the elderly and compared their prevalence across the 5 age groups. In addition, we replicated the analysis in the smokers' subgroup to correct for the confounding effect of cigarette smoking. Subjects with COPD had more comorbidities and died at a younger age compared to controls. Comparison of both cohorts across 5 incremental age groups showed that the number of comorbidities, the prevalence of diseases characteristic of aging and network's density for the COPD group aged 56-65 were similar to those of non-COPD 15 to 20 years older. The findings persisted after adjusting for smoking. Conclusion Multimorbidity increases with age but in patients carrying the diagnosis of COPD, these comorbidities are seen at an earlier age.

Rationale: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) document has modified the grading system directing pharmacotherapy, but how this relates to the previous one from 2015 and to comorbidities, hospitalizations, and mortality risk is unknown. Objectives: The aim of this study was to evaluate the changes in the GOLD groups from 2015 to 2017 and to assess the impact on severity, comorbidities, and mortality within each group. Methods: We prospectively enrolled and followed, for a mean of 5 years, 819 patients with chronic obstructive pulmonary disease (84% male) in clinics in Spain and the United States. We determined anthropometrics, lung function (FEV1%), dyspnea score (modified Medical Research Council scale), ambulatory and hospital exacerbations, and the body mass index, obstruction, dyspnea, and exercise capacity (BODE) and Charlson indexes. We classified patients by the 2015 and 2017 GOLD ABCD system, and compared the differential realignment of the same patients. We related the effect of the reclassification in BODE and Charlson distribution as well as chronic obstructive pulmonary disease and all-cause mortality between the two classifications. Measurements and Main Results: Compared with 2015, the 2017 grading decreased by half the proportion of patients in groups C and D(20.5% vs. 11.2% and 24.6% vs. 12.9%; P < 0.001). The distribution of Charlson also changed, whereas group D was higher than B in 2015, they become similar in the 2017 system. In 2017, the BODE index and risk of death were higher in B and D than in A and C. The mortality risk was better predicted by the 2015 than the 2017 system. Conclusions: Compared with 2015, the GOLD ABCD 2017 classification significantly shifts patients from grades C and D to categories A and B. The new grading system equalizes the Charlson comorbidity score in all groups and minimizes the differences in BODE between groups B and D, making the risk of death similar between them.

Single nucleotide polymorphisms (SNPs) may modulate individual susceptibility to carcinogens. We designed a genome-wide association study to characterize individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced non-small cell lung cancer (NSCLC), and we validated our results. We hypothesized that this strategy would enrich the frequencies of the alleles that contribute to the observed traits. We genotyped 2.37 million SNPs in 95 extreme phenotype individuals, that is: heavy smokers that either developed NSCLC at an early age (extreme cases); or did not present NSCLC at an advanced age (extreme controls), selected from a discovery set (n=3631). We validated significant SNPs in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNPs were validated: rs12660420 (p(combined)=5.66x10(-5); ORcombined=2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (p(combined)=1.02x10(-4); ORcombined=2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early-stage NSCLC. PDE10A and ATP10D mRNA expressions correlated with survival in 821 stage I-II NSCLC patients (p=0.01 and p<0.0001). PDE10A protein expression correlated with survival in 149 patients with stage I-II NSCLC (p=0.002). In conclusion, we validated two variants associated with extreme phenotypes of high and low risk of developing tobacco-induced NSCLC. Our findings may allow to identify individuals presenting high and low risk to develop tobacco-induced NSCLC and to characterize molecular mechanisms of carcinogenesis and resistance to develop NSCLC.

Background: External validations and comparisons of prognostic models or scores are a prerequisite for their use in routine clinical care but are lacking in most medical fields including chronic obstructive pulmonary disease (COPD). Our aim was to externally validate and concurrently compare prognostic scores for 3-year all-cause mortality in mostly multimorbid patients with COPD. Methods: We relied on 24 cohort studies of the COPD Cohorts Collaborative International Assessment consortium, corresponding to primary, secondary, and tertiary care in Europe, the Americas, and Japan. These studies include globally 15,762 patients with COPD (1871 deaths and 42,203 person years of follow-up). We used network meta-analysis adapted to multiple score comparison (MSC), following a frequentist two-stage approach; thus, we were able to compare all scores in a single analytical framework accounting for correlations among scores within cohorts. We assessed transitivity, heterogeneity, and inconsistency and provided a performance ranking of the prognostic scores. Results: Depending on data availability, between two and nine prognostic scores could be calculated for each cohort. The BODE score (body mass index, airflow obstruction, dyspnea, and exercise capacity) had a median area under the curve (AUC) of 0.679 [1st quartile-3rd quartile = 0.655-0.733] across cohorts. The ADO score (age, dyspnea, and airflow obstruction) showed the best performance for predicting mortality (difference AUC(ADO) - AUC(BODE) = 0.015 [95% confidence interval (CI) = - 0.002 to 0.032]; p = 0.08) followed by the updated BODE (AUCBODE updated - AUCBODE = 0.008 [95% CI = -0.005 to +0.022]; p = 0.23). The assumption of transitivity was not violated. Heterogeneity across direct comparisons was small, and we did not identify any local or global inconsistency. Conclusions: Our analyses showed best discriminatory performance for the ADO and updated BODE scores in patients with COPD. A limitation to be addressed in future studies is the extension of MSC network meta-analysis to measures of calibration. MSC network meta-analysis can be applied to prognostic scores in any medical field to identify the best scores, possibly paving the way for stratified medicine, public health, and research.

In this prospective observational study of COPD patients with mild to moderate airflow limitation, PAE was the best predictor of long-term survival along with age.

Background: The stability of the new GOLD 2017 COPD staging is unknown, as well as the frequency of individual transitions in COPD stages beyond one year. Methods: All COPD participants in the CHAIN cohort were re-analysed according to GOLD 2017 up to five years of follow-up. Their individual changes within COPD stages were aggregated into cohort-wide Markov chains; group stability was evaluated using joinpoint regression. Results: At baseline, 959 COPD patients were distributed according to GOLD 2017 stages as 37.7% in A, 38.3% B, 8.2% C, and 15.7% D. The group proportion of patients in each stage was maintained from years one to five. However, we found significant changes between stages at the individual patient level, especially in the more severe stages. The probability of a patient remaining in the same GOLD 2017 COPD stage for two consecutive years ranged during the five years of follow-up for stage C from 16% to 31% per year, while for D from 23% to 43% per year, indicating substantial variation either increasing or decreasing severity for the vast majority of patients. Conclusions: We conclude that group stability observed in COPD staging according to GOLD 2017 recommendations is paired with a large variability at the individual patient level.

BACKGROUND: The clinical characteristics of patients with emphysema but without airway limitations remain unknown. The goal of this study was to compare the clinical features of current and former smokers without airflow limitation who have radiologic emphysema on chest CT scans vs a control group of current and ex-smokers without emphysema. METHODS: Subjects enrolled had anthropometric characteristics recorded, provided a medical history, and underwent low-dose chest CT scanning. The following parameters were also evaluated: pulmonary function tests including diffusion capacity for carbon monoxide (D-LCO), the modified Medical Research Council dyspnea score, COPD assessment test (CAT), and 6-min walk test (6MWT). Acomparison was conducted between those with and withoutCT-confirmedemphysema. RESULTS: Of the 203 subjects, 154 had emphysema, and 49 did not. Adjusted group comparisons revealed that a higher proportion of patients with emphysema according to low-dose chest CT scanning had an abnormal DLCO value (< 80%) (46% vs 19%; P = .02), a decrease in percentage of oxygen saturation > 4% during the 6MWT (8.5% vs 0; P = .04), and an altered quality of life (CAT score >= 10) (32% vs 14%; P = .01). A detailed analysis of the CAT questionnaire items revealed that more patients with emphysema had a score >= 1 in the "chest tightness" (P = .05) and "limitation when doing activities at home" (P < .01) items compared with those with no emphysema. They also experienced significantly more exacerbations in the previous year (0.19 vs 0.04; P = .02). CONCLUSIONS: A significant proportion of smokers with emphysema according to low-dose chest CT scanning but without airway limitation had alterations in their quality of life, number of exacerbations, DLCO values, and oxygen saturation during the 6MWT test.

Objective: To describe the evidence- and experience-based expert consensus on the use of single-agent bronchodilators in patients with stable mild-moderate chronic obstructive pulmonary disease (COPD). Methods: Using Delphi methodology, a panel of 7 respiratory medicine experts was established, who, in the first nominal group meeting defined the scope, users, and document sections. The panel drew up 14 questions on the use of single-agent bronchodilators in patients with mild-moderate stable COPD to be answered with a systematic review of the literature. The results of the review were discussed in a second nominal group meeting and 17 statements were generated. Agreement/disagreement with the statements was tested among16 different experts including respiratory medicine experts and primary care physicians. Statements were scored from 1 (total disagreement) to 10 (total agreement). Agreement was considered if at least 70% voted >= 7. The level of evidence and grade of recommendation of the systematic literature review was assessed using the Oxford Centre for Evidence-based Medicine levels. Results: A total of 12 of the 17 statements were selected. Specific statements were generated on different profiles of patients with stable mild-moderate COPD in whom single-agent bronchodilators could be prescribed. Conclusions: These statements on the use of single-agent bronchodilators might improve the outcomes and prognosis of patients with stable mild-moderate COPD. (C) 2017 SEPAR. Published by Elsevier Espafia, S.L.U. All rights reserved.

Background: Chronic Obstructive Pulmonary Disease (COPD) is an independent risk factor for cardiovascular (CV) disease, one of the most frequent causes of death in COPD patients. The goal of the present study was to evaluate the prognostic value of non-invasive CV risk markers in COPD patients. Methods: CV risk was prospectively evaluated in 287 COPD patients using non-invasive markers including the Framingham score, the Systematic Coronary Risk Evaluation (SCORE) charts, coronary arterial calcium (CAC), epicardial adipose tissue (EAT), as well as clinical, biochemical and physiological variables. The predictive power of each parameter was explored using CV events as the main outcome. Results: During a median follow up of 65 months (ICR: 36-100), 44 CV events were recorded, 12 acute myocardial infarctions (27.3%), 10 ischemic heart disease/angina (22.7%), 12 peripheral artery disease events requiring surgery (27.3%) and 10 strokes (22.7%). A total of 35 CV deaths occurred during that period. Univariable analysis determined that age, hypertension, CRP, total Cholesterol, LDL-Cholesterol, Framingham score and CAC were independently associated with CV events. Multivariable analysis identified CAC as the best predictor of CV events (HR; 95%CI: 1.32; 1.19-1.46, p < 001). Conclusions: In COPD patients attending pulmonary clinics, CAC was the best independent non-invasive predictor of CV events. This tool may help evaluate the risk for a CV event in patients with COPD. Larger studies should reproduce and validate these findings.

A major drawback of lung cancer screening programs is the high frequency of false-positive findings on computed tomography (CT). We investigated the accuracy of selective 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (FDG) Positron Emission Tomography/Computed Tomography (PET/CT) scan in assessing radiologically indeterminate lung nodules detected in lung cancer screening. Methods: FDG PET/CT was performed to characterize 64 baseline lung nodules >10 mm and 36 incidence nodules detected on low-dose CT screening in asymptomatic current or former smokers (83 men, age range 40¿83 years) at high risk for lung cancer. CT images were acquired without intravenous contrast. Nodules were analyzed by size, density, and metabolic activity and visual scored on a 5-point scale for FDG uptake. Nodules were classified as negative for malignancy when no FDG uptake was observed, or positive when focal uptake was observed in the visual analysis, and the maximum standardized uptake value (SUVmax) was measured. Final diagnosis was based on histopathological evaluation or at least 24 months of follow-up. Results: A total of 100 nodules were included. The prevalence of lung cancer was 1%. The sensitivity, specificity, NPV and PPV of visual analysis to detect malignancy were 84%, 95%, 91%, and 91%, respectively, with an accuracy of 91% (AUC 0.893). FDG PET/CT accurately detected 31 malignant tumors (diameters 9¿42 mm, SUVmax range 0.6¿14.2) and was falsely negative in 6 patients. With SUVmax threshold

The experience in Spain's longest lung cancer screening program is comparable to what has been described in the rest of Europe, and confirms the feasibility and efficacy of lung cancer screening using LDCT.

Therapies that are safe, effective, and not vulnerable to developing resistance are highly desirable to counteract bacterial infections. Host-directed therapeutics is an antimicrobial approach alternative to conventional antibiotics based on perturbing host pathways subverted by pathogens during their life cycle by using host-directed drugs. In this study, we identified and evaluated the efficacy of a panel of host-directed drugs against respiratory infection by nontypeable Haemophilus influenzae(NTHi). NTHi is an opportunistic pathogen that is an important cause of exacerbation of chronic obstructive pulmonary disease (COPD). We screened for host genes differentially expressed upon infection by the clinical isolate NTHi375 by analyzing cell whole-genome expression profiling and identified a repertoire of host target candidates that were pharmacologically modulated. Based on the proposed relationship between NTHi intracellular location and persistence, we hypothesized that drugs perturbing host pathways used by NTHi to enter epithelial cells could have antimicrobial potential against NTHi infection. Interfering drugs were tested for their effects on bacterial and cellular viability, on NTHi-epithelial cell interplay, and on mouse pulmonary infection. Glucocorticoids and statins lacked in vitroand/or in vivoefficacy. Conversely, the sirtuin-1 activator resveratrol showed a bactericidal effect against NTHi, and the PDE4 inhibitor rolipram showed therapeutic efficacy by lowering NTHi375 counts intracellularly and in the lungs of infected mice. PDE4 inhibition is currently prescribed in COPD, and resveratrol is an attractive geroprotector for COPD treatment. Together, these results expand our knowledge of NTHi-triggered host subversion and frame the antimicrobial potential of rolipram and resveratrol against NTHi respiratory infection.

Rationale: Lung cancer (LC) screening using low-dose chest computed tomography is now recommended in several guidelines using the National Lung Screening Trial (NLST) entry criteria (age, 55-74; ¿30 pack-years; tobacco cessation within the previous 15 yr for former smokers). Concerns exist about their lack of sensitivity. Objectives: To evaluate the performance of NLST criteria in two different LC screening studies from Europe and the United States, and to explore the effect of using emphysema as a complementary criterion. Methods: Participants from the Pamplona International Early Lung Action Detection Program (P-IELCAP; n = 3,061) and the Pittsburgh Lung Screening Study (PLuSS; n = 3,638) were considered. LC cumulative frequencies, incidence densities, and annual detection rates were calculated in three hypothetical cohorts, including subjects whometNLST criteria alone, those withcomputed tomography-detected emphysema, and those who met NLST criteria and/or had emphysema. Measurements and Main Results: Thirty-six percent and 59% of P-IELCAP and PLuSS participants, respectively, met NLST criteria. Among these, higher LC incidence densities and detection rates were observed. However, applying NLST criteria to our original cohorts would miss asmany as 39% of all LC. Annual screening of subjects meeting either NLST criteria or having emphysema detected most cancers (88% and 95% of incident LC of P-IELCAP and PLuSS, respectively) despite reducing the number of screened participants by as much as 52%. Conclusions: LC screening based solely on NLST criteria could miss a significant number of LC cases. Combining NLST criteria and emphysema to select screening candidates results in higher LC detection rates and a lower number of cancers missed.

The COPD-LUCSS is a good predictor of LC risk in patients with COPD participating in LC screening programs. Validation in two different populations adds strength to the findings.

Nontypeable Haemophilus influenzae (NTHI) is an opportunistic pathogen that is an important cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). COPD is an inflammatory disease of the airways, and exacerbations are acute inflammatory events superimposed on this background of chronic inflammation. Azithromycin (AZM) is a macrolide antibiotic with antibacterial and anti-inflammatory properties and a clinically proven potential for AECOPD prevention and management. Relationships between AZM efficacy and resistance by NTHI and between bactericidal and immunomodulatory effects on NTHI respiratory infection have not been addressed. In this study, we employed two pathogenic NTHI strains with different AZM susceptibilities (NTHI 375 [AZM susceptible] and NTHI 353 [AZM resistant]) to evaluate the prophylactic and therapeutic effects of AZM on the NTHI-host interplay. At the cellular level, AZM was bactericidal toward intracellular NTHI inside alveolar and bronchial epithelia and alveolar macrophages, and it enhanced NTHI phagocytosis by the latter cell type. These effects correlated with the strain MIC of AZM and the antibiotic dose. Additionally, the effect of AZM on NTHI infection was assessed in a mouse model of pulmonary infection. AZM showed both preventive and therapeutic efficacies by lowering NTHI 375 bacterial counts in lungs and bronchoalveolar lavage fluid (BALF) and by reducing histopathological inflammatory lesions in the upper and lower airways of mice. Conversely, AZM did not reduce bacterial loads in animals infected with NTHI 353, in which case a milder anti-inflammatory effect was also observed. Together, the results of this work link the bactericidal and anti-inflammatory effects of AZM and frame the efficacy of this antibiotic against NTHI respiratory infection.

Background: The new Global Initiative for Chronic Obstructive Lung Disease (GOLD) update includes airflow limitation, history of COPD exacerbations, and symptoms to classify and grade COPD severity. We aimed to determine their distribution in 11 well-defined COPD cohorts and their prognostic validity up to 10 years to predict time to death. Methods: Spirometry in all 11 cohorts was postbronchodilator. Survival analysis and C statistics were used to compare the two GOLD systems by varying time points. Results: Of 3,633 patients, 1,064 (33.6%) were in new GOLD patient group A (low risk, less symptoms), 515 (16.3%) were B (low risk, more symptoms), 561 (17.7%) were C (high risk, less symptoms), and 1,023 (32.3%) were D (high risk, more symptoms). There was great heterogeneity of this distribution within the cohorts (¿2, P < .01). No differences were seen in the C statistics of old vs new GOLD grading to predict mortality at 1 year (0.635 vs 0.639, P = .53), at 3 years (0.637 vs 0.645, P = .21), or at 10 years (0.639 vs 0.642, P = .76). Conclusions: The new GOLD grading produces an uneven split of the COPD population, onethird each in A and D patient groups, and its prognostic validity to predict time to death is no different than the old GOLD staging based in spirometry only.

From an initial sample of 410 (SG) and 735 (CG) patients we were able to match 333 patients from each group. At the same follow-up time lung cancer incidence density was 1.79/100 person-years in the SG and 4.14/100 person-years in the CG (p = 0.004). The most frequent histological type was adenocarcinoma in both SG and CG (65% and 46%, respectively), followed by squamous cell carcinoma (25% and 37%, respectively). Eighty percent of lung cancers in the SG (16/20) were diagnosed in stage I, and all of CG cancers (35/35) were in stage III or IV. Mortality incidence density from lung cancer (0.08 vs. 2.48/100 person-years, p < 0.001) was lower in the SG.

BACKGROUND: There is a medical need for diagnostic biomarkers in lung cancer. We evaluated the diagnostic performance of complement activation fragments. METHODS: We assessed complement activation in four bronchial epithelial and seven lung cancer cell lines. C4d, a degradation product of complement activation, was determined in 90 primary lung tumors; bronchoalveolar lavage supernatants from patients with lung cancer (n = 50) and nonmalignant respiratory diseases (n = 22); and plasma samples from advanced (n = 50) and early lung cancer patients (n = 84) subjects with inflammatory lung diseases (n = 133), and asymptomatic individuals enrolled in a lung cancer computed tomography screening program (n = 190). Two-sided P values were calculated by Mann-Whitney U test. RESULTS: Lung cancer cells activated the classical complement pathway mediated by C1q binding that was inhibited by phosphomonoesters. Survival was decreased in patients with high C4d deposition in tumors (hazard ratio [HR] = 3.06; 95% confidence interval [CI] = 1.18 to 7.91). C4d levels were increased in bronchoalveolar lavage fluid from lung cancer patients compared with patients with nonmalignant respiratory diseases (0.61 ± 0.87 vs 0.16 ± 0.11 µg/mL; P < .001). C4d levels in plasma samples from lung cancer patients at both advanced and early stages were also increased compared with control subjects (4.13 ± 2.02 vs 1.86 ± 0.95 µg/mL, P < 0.001; 3.18 ± 3.20 vs 1.13 ± 0.69 µg/mL, P < .001, respectively). C4d plasma levels were associated with shorter survival in patients at advanced (HR = 1.59; 95% CI = 0.97 to 2.60) and early stages (HR = 5.57; 95% CI = 1.60 to 19.39). Plasma C4d levels were reduced after surgical removal of lung tumors (P < .001) and were associated with increased lung cancer risk in asymptomatic individuals with (n = 32) or without lung cancer (n = 158) (odds ratio = 4.38; 95% CI = 1.61 to 11.93). CONCLUSIONS: Complement fragment C4d may serve as a biomarker for early diagnosis and prognosis of lung cancer.

Guidelines recommend defining chronic obstructive pulmonary disease (COPD) by airflow obstruction and other factors, but no studies have evaluated the ability of existing multicomponent indices to predict mortality up to 10 years. We conducted a patient-based pooled analysis. Survival analysis and C statistics were used to determine the best COPD index/indices according to several construct variables and by varying time-points. Individual data of 3633 patients from 11 COPD cohorts were collected, totalling the experience of 15 878 person-years. Overall, there were 1245 death events within our cohorts, with a Kaplan¿Meier survival of 0.963 at 6 months, which was reduced to 0.432 at 10 years. In all patients, ADO (age, dyspnoea and forced expiratory volume in 1 s), BODE (body mass index, airflow obstruction, dyspnoea and exercise capacity) and e-BODE (BODE plus exacerbations) were the best indices to predict 6-month mortality. The ADO index was the best to predict 12-month (C statistic 0.702), 5-year (C statistic 0.695) and 10-year mortality (C statistic 0.698), and was significantly better than BODE (all p<0.05). The best indices to predict death by C statistics when adjusting by age were e-BODE, BODEx (substitution of exacerbations for exercise capacity) and BODE. No index predicts short-term survival of COPD well. All BODE modifications scored better than ADO after age adjustment. The ADO and BODE indices are overall the most valid multicomponent indices to predict time to death in all COPD patients.

Current or former smokers expressing a well-defined disease characteristic such as emphysema, has a specific plasma cytokine profile. This includes a decrease of cytokines mainly implicated in activation of apoptosis or decrease of immunosurveillance. This information should be taken into account when evaluated patients with tobacco respiratory diseases

Introducción El presente trabajo describe el método y la organización del trabajo del estudio COPD History Assessment in SpaiN (CHAIN), cuyo objetivo principal es evaluar a largo plazo la historia natural de una cohorte de pacientes con enfermedad pulmonar obstructiva crónica (EPOC) desde un punto de vista multidimensional y la identificación de fenotipos clínicos comparándola con otra cohorte control sin EPOC. Pacientes y método CHAIN es un estudio observacional multicéntrico de cohortes prospectivas realizado en 36 hospitales españoles. Ambas cohortes se seguirán durante un periodo de 5 años con visitas completas cada 12 meses y controles telefónicos cada 6 meses para valorar las exacerbaciones y el estado vital del sujeto. El periodo de reclutamiento de casos se realizó entre el 15 de enero de 2010 y el 31 de marzo de 2012. En cada visita anual se recoge información sobre: a) aspectos clínicos (situación socioeconómica, datos antropométricos, comorbilidades, tabaquismo, clínica respiratoria, exacerbaciones, calidad de vida, escala ansiedad-depresión, actividades de la vida diaria, tratamientos); b) función respiratoria (espirometría, gasometría arterial, hiperinsuflación, difusión, presiones respiratorias); c) índice BODE (variable principal del estudio); d) función muscular periférica, y e) analítica sanguínea (incluida IgE y factores de riesgo cardiovascular). Además, se creará una seroteca para la futura determinación de biomarcadores. Los datos de los pacientes son anonimizados en una base de datos con un acceso jerárquico para garantizar la seguridad en los accesos a la información. El estudio CHAIN aportará información sobre la progresión de la EPOC y establecerá una red de investigadores para futuros proyectos relacionados con la enfermedad.

Rationale: Patients with chronic obstructive pulmonary disease (COPD) are afflicted by comorbidities. Few studies have prospectively evaluated COPD comorbidities and mortality risk. Objectives: To prospectively evaluate COPD comorbidities and mortality risk. Methods: We followed 1,664 patients with COPD in five centers for a median of 51 months. Systematically, 79 comorbidities were recorded. We calculated mortality risk using Cox proportional hazard, and developed a graphic representation of the prevalence and strength of association to mortality in the form of a ¿comorbidome.¿ A COPD comorbidity index (COPD specific comorbidity test [COTE]) was constructed based on the comorbidities that increase mortality risk using a multivariate analysis. We tested the COTE index as predictor of mortality and explored whether the COTE index added predictive information when used with the validated BODE index. Measurements and Main Results: Fifteen of 79 comorbidities differed in prevalence between survivors and nonsurvivors. Of those, 12 predicted mortality and were integrated into the COTE index. Increases in the COTE index were associated with an increased risk of death from COPD-related (hazard ratio [HR], 1.13; 95% confidence interval, 1.08¿1.18; P < 0.001) and non¿COPD-related causes (HR, 1.18; 95% confidence interval, 1.15¿1.21; P < 0.001). Further, increases in the BODE and COTE were independently associated with increased risk of death. A COTE score of greater than or equal to 4 points increased by 2.2-fold the risk of death (HR, 2.26¿2.68; P < 0.001) in all BODE quartile. Conclusions: Comorbidities are frequent in COPD and 12 of them negatively influence survival. A simple disease-specific comorbidities index (COTE) helps assess mortality risk in patients with COPD.

Background: The relationship between serum biomarkers and clinical expressions of COPD is limited. We planned to further describe this association using markers of inflammation and injury and repair. Methods: We studied lung function, comorbidities, exercise tolerance, BODE index, and quality of life in 253 COPD patients and recorded mortality over three years. Serum levels of Interleukins 6,8 and 16, tumor necrosis factor alpha (TNF alpha) [inflammatory panel], vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP-9)[injury and repair panel] and pulmonary and activation-regulated chemokine (PARC/CCL-18) and monocyte chemotactic protein 1 (MCP-1/CCL2) [chemoattractant panel] were measured. We related the pattern of the biomarker levels to minimal clinically important differences (MCID) using a novel visualization method [ObServed Clinical Association Results (OSCAR) plot]. Results: Levels of the inflammatory markers IL-6, TNF alpha were higher and those of injury and repair lower (p < 0.01) with more advanced disease (GOLD 1 vs. 4). Using the OSCAR plot, we found that patients in the highest quartile of inflammatory and lowest quartile of injury and repair biomarkers level were more clinically compromised and had higher mortality (p < 0.05). Conclusions: In COPD, serum biomarkers of inflammation and repair are distinctly associated with important clinical parameters and survival.

Phenotypic characterization of patients with COPD may have potential prognostic and therapeutic implications. Available information on the relationship between emphysema and the clinical presentation in patients with COPD is limited to advanced stages of the disease. The objective of this study was to describe emphysema presence, severity, and distribution and its impact on clinical presentation of patients with mild to moderate COPD. METHODS: One hundred fifteen patients with COPD underwent clinical and chest CT scan evaluation for the presence, severity, and distribution of emphysema. Patients with and without emphysema and with different forms of emphysema distribution (upper/lower/core/peel) were compared. The impact of emphysema severity and distribution on clinical presentation was determined. RESULTS: Fifty percent of the patients had mild homogeneously distributed emphysema (1.84; 0.76%-4.77%). Upper and core zones had the more severe degree of emphysema. Patients with emphysema were older, more frequently men, and had lower FEV(1)%, higher total lung capacity percentage, and lower diffusing capacity of the lung for carbon monoxide. No differences were found between the clinical or physiologic parameters of the different emphysema distributions. CONCLUSIONS: In patients with mild to moderate COPD, although the presence of emphysema has an impact on physiologic presentation, its severity and distribution seem to have little impact on clinical presentation.

Objective: The objective of our study was to investigate whether fluorodeoxyglucose (FDG) positron emission tomography scanning uptake impacts the yield of transbronchial needle aspiration (TBNA). Methods: We carried out a retrospective analysis of data from 140 consecutive patients (178 lymph nodes) undergoing positron emission tomography-computed tomography scanning and subsequent TBNA with rapid onsite cytologic evaluation of the specimen. Patient and lymph node characteristics, including nodal station, size, FDG uptake, number of passes with the needle, sample adequacy, and the final diagnosis were recorded. Results: The diagnostic yield of TBNA was 75%. Themean short axis lymph node diameter was 18.7+/-9 mm and mean maximum standardized uptake value (SUVmax) was 7.7+/-4. The diagnostic yield depended on the lymph node size [odds ratio (OR)=1.07 (1.00-1.14); P=0.04], clinical suspicion of malignancy [OR=5.13 (1.95-13.52); P=0.001], malignant diagnosis [OR=4.91 (1.71-14.09); P=0.003], and FDG uptake [for SUVmax cutoff of 3.0: OR=33.8 (9.2-124); P<0.001]. Only clinical suspicion of cancer [OR=6.2 (2.2-17.2); P=0.001] and FDG uptake [for SUVmax cutoff of 3.0: OR=33.8 (9.2-123.8); P<0.001] remained significant on multivariate analysis. Receiver operating characteristic curves combining 3 key variables (lymph node size, clinical suspicion of malignancy, and SUVmax) showed an area of 0.83 under the curve for a 2.5 SUVmax cutoff and 0.84 for a 3.0 cutoff. Conclusions: FDG uptake is the single most important variable impacting the TBNA yield. TBNA of lymph nodes with an SUVmax less than 3.0 is rarely diagnostic.

Rationale: Little is known about the clinical factors associated with the development of lung cancer in patients with chronic obstructive pulmonary disease (COPD), although airway obstruction and emphysema have been identified as possible risk factors. Objectives: To explore incidence, histologic type, and factors associated with development of lung cancer diagnosis in a cohort of outpatients with COPD attending a pulmonary clinic. Methods: A cohort of 2,507 patients without initial clinical or radiologic evidence of lung cancer was followed a median of 60 months (30-90). At baseline, anthropometrics, smoking history, lung function, and body composition were recorded. Time to diagnosis and histologic type of lung cancer was then registered. Cox analysis was used to explore factors associated with lung cancer diagnosis. Measurements and Main Results: A total of 215 of the 2,507 patients with COPD developed lung cancer (incidence density of 16.7 cases per 1,000 person-years). The most frequent type was squamous cell carcinoma (44%). Lung cancer incidence was lower in patients with worse severity of airflow obstruction. Global Initiative for Chronic Obstructive Lung Disease Stages I and II, older age, lower body mass index, and lung diffusion capacity of carbon monoxideless than 80% were associated with lung cancer diagnosis. Conclusions: Incidence density of lung cancer is high in outpatients with COPD and occurs more frequently in older patients with milder airflow obstruction (Global Initiative for Chronic Obstructive Lung Disease Stages I and II) and lower body mass index. A lung diffusion capacity of carbon monoxide less than 80% is associated with cancer diagnosis. Squamous cell carcinoma is the most frequent histologic type. Knowledge of these factors may help direct efforts for early detection of lung cancer and disease management.

Background: The 6-minute walk distance (6MWD) has been useful in the evaluation of men with COPD. Little is known about 6MWD in women with the disease. Objectives: Using healthy women as a reference, to evaluate the factors that help determine 6MWD in women with COPD. To explore if the 350 meters threshold differentiates survival in women as it does in men. Methods: Healthy women (n = 164) and with COPD (n = 223) were included in the study. Age, pack-years history, smoking status, comorbidities (Charlson Index), BMI, MRC dyspnea, spirometry and 6MWD were recorded in all participants and PaO(2) and IC/TLC in COPD women. The patients were prospectively followed and deaths registered. Factors predicting 6MWD were determined by multiple regression analysis. ROC analysis was used to calculate the best threshold value for the 6MWD with mortality as gold standard. Kaplan-Meier curves compared survival of patients that walked more or less than 350 m by age categories. Results: The 6MWD is decreased in women with COPD. Values decrease with age and GOLD stages. Age, BMI, smoking status, comorbidities, MRC and FEV(1%) are statistical significant predictors of 6MWD. A 350 m cut-off value has a good sensitivity and specificity to predict (73% and 80% respectively) and differentiate survival (p < 0.001 for log rank comparisons) in these patients. Conclusions: In women with COPD, the 6MWD decreases with age and GOLD stages. A 350 m distance is a valid threshold to differentiate survival. Further studies in different settings should confirm our findings.

The 6-min walk distance (6MWD) predicted values have been derived from small cohorts mostly from single countries. The aim of the present study was to investigate differences between countries and identify new reference values to improve 6MWD interpretation. We studied 444 subjects (238 males) from seven countries (10 centres) ranging 40¿80 yrs of age. We measured 6MWD, height, weight, spirometry, heart rate (HR), maximum HR (HRmax) during the 6-min walk test/the predicted maximum HR (HRmax % pred), Borg dyspnoea score and oxygen saturation. The mean±sd 6MWD was 571±90 m (range 380¿782 m). Males walked 30 m more than females (p<0.001). A multiple regression model for the 6MWD included age, sex, height, weight and HRmax % pred (adjusted r2 = 0.38; p<0.001), but there was variability across centres (adjusted r2 = 0.09¿0.73) and its routine use is not recommended. Age had a great impact in 6MWD independent of the centres, declining significantly in the older population (p<0.001). Age-specific reference standards of 6MWD were constructed for male and female adults. In healthy subjects, there were geographic variations in 6MWD and caution must be taken when using existing predictive equations. The present study provides new 6MWD standard curves that could be useful in the care of adult patients with chronic diseases.

Rationale: Chronic obstructive pulmonary disease (COPD) is thought to result in rapid and progressive loss of lung function usually expressed as mean values for whole cohorts. Objectives: Longitudinal studies evaluating individual lung function loss and other domains of COPD progression are needed. Methods: We evaluated 1,198 stable, well-characterized patients with COPD (1,100 males) recruited in two centers (Florida and Tenerife, Spain) and annually monitored their multidomain progression from 1997 to 2009. Patients were followed for a median of 64 months and up to 10 years. Their individual FEV1 (L) and BODE index slopes, expressed as annual change, were evaluated using regression models for repeated measures. A total of 751 patients with at least three measurements were used for the analyses. Measurements and Main Results: Eighteen percent of patients had a statistically significant FEV1 slope decline (¿86 ml/yr; 95% confidence interval [CI], ¿32 to ¿278 ml/yr). Higher baseline FEV1 (relative risk, 1.857; 95% CI, 1.322¿2.610; P < 0.001) and low body mass index (relative risk, 1.071; 95% CI, 1.035¿1.106; P < 0.001) were independently associated with FEV1 decline. The BODE index had a statistically significant increase (0.55, 0.20¿1.37 point/yr) in only 14% of patients and these had more severe baseline obstruction. Concordance between FEV1 and BODE change was low (¿ Cohen, 16%). Interestingly, 73% of patients had no significant slope change in FEV1 or BODE. Only the BODE change was associated with mortality in patients without FEV1 progression. Conclusions: The progression of COPD is very heterogeneous. Most patients show no statistically significant decline of FEV1 or increase in BODE. The multidimensional evaluation of COPD should offer insight into response to COPD management.

La prevalencia de la enfermedad pulmonar obstructiva crónica (EPOC) se está incrementando en todo el mundo, fundamentalmente a expensas del aumento en las mujeres. En los países desarrollados, la EPOC en la mujer es consecuencia, principalmente, de la exposición al humo de tabaco, y en los países en vías de desarrollo, a la inhalación de los productos de combustión de la biomasa. El infradiagnóstico de la EPOC es más común en las mujeres, ya que ha sido, clásicamente, asociada al sexo masculino. Además, la enfermedad presenta aspectos diferenciales en las mujeres como son: mayor expresión de los aspectos perceptivos (disnea y calidad de vida relacionada con la salud), elevada prevalencia de desnutrición, alta prevalencia de ansiedad y depresión y un patrón de distribución del enfisema diferente al de los varones. Una mejor caracterización fenotípica de la EPOC en la mujer nos permitirá abordar, de modo apropiado, su impacto en el sistema sanitario y diseñar estrategias terapéuticas más individualizadas.

Objectives To evaluate the feasibility of using automatic quantitative analysis of breath hold gated micro-CT images to detect and monitor disease in a mouse model of chronic pulmonary inflammation, and to compare image-based measurements with pulmonary function tests and histomorphometry. Material and methods Forty-nine A/J mice were used, divided into control and inflammation groups. Chronic inflammation was induced by silica aspiration. Fourteen animals were imaged at baseline, and 4, 14, and 34 weeks after silica aspiration, using micro-CT synchronized with ventilator-induced breath holds. Lung input impedance was measured as well using forced oscillation techniques. Five additional animals from each group were killed after micro-CT for comparison with histomorphometry. Results At all time points, micro-CT measurements show statistically significant differences between the two groups, while first differences in functional test parameters appear at 14 weeks. Micro-CT measurements correlate well with histomorphometry and discriminate diseased and healthy groups better than functional tests. Conclusion Longitudinal studies using breath hold gated micro-CT are feasible on the silica-induced model of chronic pulmonary inflammation, and automatic measurements from micro-CT images correlate well with histomorphometry, being more sensitive than functional tests to detect lung damage in this model.

Rationale: Microalbuminuria (MAB), a marker of endovascular dysfunction, is a predictor of cardiovascular events and all-cause mortality in the general population. There is evidence of vascular dysfunction in patients with chronic obstructive pulmonary disease (COPD). Objectives: To assess the prevalence and relationship of MAB with clinical and physiological parameters in stable patients with COPD. Methods: We measured urinary albumin rate (urinary albumin to creatinine ratio: UACR), smoking history, arterial blood pressure, gas exchange, body mass index, lung function, BODE index (body mass index, airflow obstruction, dyspnea, exercise performance), and comorbidity index in 129 patients with stable COPD and 51 smokers with normal spirometry without known cardiovascular disease. MAB levels were compared between groups. A multivariate analysis was performed to determine the best determinants of MAB levels. Measurements and Main Results: MAB was higher in patients with COPD than in control smokers (8 [5th¿95th percentile (P5¿95), 2.9¿113] vs. 4.2 [P5¿95, 1.8¿22.7] mg/g, P < 0.001]). The difference remained significant even after using the standard pathologic threshold (MAB, 30¿299 mg/g in women and 20¿299 mg/g in men; 24% in patients with COPD vs. 6% in control smokers; P = 0.005). In patients with COPD, there was a negative correlation between PaO2 and MAB (r = ¿0.40, P < 0.001). Using multivariate analysis, MAB was only associated with the PaO2 (relative risk, 0.934; 95% confidence interval, 0.880¿0.992; P < 0.001) and with the systolic arterial blood pressure (relative risk, 1.034; 95% confidence interval, 1.011¿1.057; P = 0.003). Conclusions: MAB is frequent in patients with COPD and is associated with hypoxemia independent of other cardiovascular risk factors. Further studies are necessary to investigate whether MAB could be an early simple biomarker of cardiovascular compromise in patients with COPD.