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Background The Global initiative for chronic Obstructive Lung Disease (GOLD) defines COPD as a fixed post-bronchodilator ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) below 0.7. Age-dependent cut-off values below the lower fifth percentile (LLN) of this ratio derived from the general population have been proposed as an alternative. We wanted to assess the diagnostic accuracy and prognostic capability of the GOLD and LLN definition when compared to an expert-based diagnosis. Methods In a prospective cohort study, 405 patients aged ≥ 65 years with a general practitioner's diagnosis of COPD were recruited and followed up for 4.5 (median; quartiles 3.9; 5.1) years. Prevalence rates of COPD according to GOLD and three LLN definitions and diagnostic performance measurements were calculated. The reference standard was the diagnosis of COPD of an expert panel that used all available diagnostic information, including spirometry and bodyplethysmography. Results Compared to the expert panel diagnosis, 'GOLD-COPD' misclassified 69 (28%) patients, and the three LLNs misclassified 114 (46%), 96 (39%), and 98 (40%) patients, respectively. The GOLD classification led to more false positives, the LLNs to more false negative diagnoses. The main predictors beyond the FEV1/FVC ratio for an expert diagnosis of COPD were the FEV1 % predicted, and the residual volume/total lung capacity ratio (RV/TLC). Adding FEV1 and RV/TLC to GOLD or LLN improved the diagnostic accuracy, resulting in a significant reduction of up to 50% of the number of misdiagnoses. The expert diagnosis of COPD better predicts exacerbations, hospitalizations and mortality than GOLD or LLN. Conclusions GOLD criteria over-diagnose COPD, while LLN definitions under-diagnose COPD in elderly patients as compared to an expert panel diagnosis. Incorporating FEV1 and RV/TLC into the GOLD-COPD or LLN-based definition brings both definitions closer to expert panel diagnosis of COPD, and to daily clinical practice.

We compared interexamination variability of CT lung nodule volumetry with six currently available semi-automated software packages to determine the minimum change needed to detect the growth of solid lung nodules. We had ethics committee approval. To simulate a follow-up examination with zero growth, we performed two low-dose unenhanced CT scans in 20 patients referred for pulmonary metastases. Between examinations, patients got off and on the table. Volumes of all pulmonary nodules were determined on both examinations using six nodule evaluation software packages. Variability (upper limit of the 95% confidence interval of the Bland-Altman plot) was calculated for nodules for which segmentation was visually rated as adequate. We evaluated 214 nodules (mean diameter 10.9 mm, range 3.3 mm–30.0 mm). Software packages provided adequate segmentation in 71% to 86% of nodules (p < 0.001). In case of adequate segmentation, variability in volumetry between scans ranged from 16.4% to 22.3% for the various software packages. Variability with five to six software packages was significantly less for nodules ≥8 mm in diameter (range 12.9%-17.1%) than for nodules <8 mm (range 18.5%-25.6%). Segmented volumes of each package were compared to each of the other packages. Systematic volume differences were detected in 11/15 comparisons. This hampers comparison of nodule volumes between software packages.

Abstract Rationale Pulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering. Objectives To complete a genome-wide association study (GWAS) for the percentage of emphysema-like lung on computed tomography in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung/SNP Health Association Resource (SHARe) Study, a large, population-based cohort in the United States. Methods We determined percent emphysema and upper-lower lobe ratio in emphysema defined by lung regions less than −950 HU on cardiac scans. Genetic analyses were reported combined across four race/ethnic groups: non-Hispanic white (n = 2,587), African American (n = 2,510), Hispanic (n = 2,113), and Chinese (n = 704) and stratified by race and ethnicity. Measurements and Main Results Among 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 × 10−8) and PPT2 (rs10947233; P = 3.2 × 10−8), both of which replicated in an additional 6,023 individuals of European ancestry. Both single-nucleotide polymorphisms were previously implicated as genes influencing lung function, and analyses including lung function revealed independent associations for percent emphysema. Among Hispanics, we identified a genetic locus for upper-lower lobe ratio near the α-mannosidase–related gene MAN2B1 (rs10411619; P = 1.1 × 10−9; minor allele frequency [MAF], 4.4%). Among Chinese, we identified single-nucleotide polymorphisms associated with upper-lower lobe ratio near DHX15 (rs7698250; P = 1.8 × 10−10; MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10−8; MAF, 2.6%), which acts on α-linked mannose. Among African Americans, a locus near a third α-mannosidase–related gene, MAN1C1 (rs12130495; P = 9.9 × 10−6; MAF, 13.3%) was associated with percent emphysema. Conclusions Our results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to α-mannosidase may influence risk of emphysema.

SP-D, YKL-40, CCL18 and CA 15-3 are pulmonary markers that have been extensively investigated in different chronic pulmonary diseases. However, in acute pulmonary diseases, such as community-acquired pneumonia (CAP), little is known about the course of these markers and their relationship with the aetiological agent. The aim of this study was to investigate the course of these four markers in CAP and to study influence of disease severity, aetiology and antibiotic use prior to admission on their course. We included 291 adult patients hospitalised with CAP and 20 healthy controls. Measurements were performed in serum of day 0, 2, and 4, and at least 30 days after admission. Our most important results were: 1) At all time-points, including 30 days after admission, YKL-40 and CCL18 levels were higher in CAP patients compared to healthy controls; and 2) Patients with CAP caused by an intracellular, atypical bacterium had lower YKL-40 and especially CCL18 levels on and during admission in comparison with other or unknown CAP aetiology. Our findings suggest that these pulmonary markers could be useful to assess CAP severity and, especially YKL-40 and CCL18 by helping predict CAP caused by atypical pathogens.

Background Lung cancer screening CT scans might provide valuable information about air trapping as an early indicator of smoking-related lung disease. We studied which of the currently suggested measures is most suitable for detecting functionally relevant air trapping on low-dose computed tomography (CT) in a population of subjects with early-stage disease. Methods This study was ethically approved and informed consent was obtained. Three quantitative CT air trapping measures were compared against a functional reference standard in 427 male lung cancer screening participants. This reference standard for air trapping was derived from the residual volume over total lung capacity ratio (RV/TLC) beyond the 95th percentile of predicted. The following CT air trapping measures were compared: expiratory to inspiratory relative volume change of voxels with attenuation values between −860 and −950 Hounsfield Units (RVC −860 to −950 ), expiratory to inspiratory ratio of mean lung density (E/I-ratio MLD ) and percentage of voxels below −856 HU in expiration (EXP −856 ). Receiver operating characteristic (ROC) analysis was performed and area under the ROC curve compared. Results Functionally relevant air trapping was present in 38 (8.9 %) participants. E/I-ratio MLD showed the largest area under the curve (0.85, 95 % CI 0.813–0.883), which was significantly larger than RVC −860 to −950 (0.703, 0.657–0.746; p  < 0.001) and EXP −856 (0.798, 0.757–0.835; p  = 0.002). At the optimum for sensitivity and specificity, E/I-ratio MLD yielded an accuracy of 81.5 %. Conclusions The expiratory to inspiratory ratio of mean lung density (E/I-ratio MLD ) is most suitable for detecting air trapping on low-dose screening CT and performs significantly better than other suggested quantitative measures.

Introduction YKL-40 is a novel biomarker in diseases with inflammation, fibrosis and tissue remodelling. Previously, circulating YKL-40 was shown to be elevated in patients with idiopathic pulmonary fibrosis (IPF) and was associated with survival. Objective To compare YKL-40 serum levels between IPF and other interstitial pneumonias such as non-specific interstitial pneumonia (NSIP), smoking-related interstitial lung disease (SR-ILD) and cryptogenic organising pneumonia (COP). Materials and Methods Serum YKL-40 levels were measured in 124 healthy controls and 315 patients. Serial measurements were available in 36 patients with IPF and 6 patients with COP. Results Serum YKL-40 levels were elevated in all patient groups compared to controls ( p  < 0.0001), and highest levels were found in the most fibrotic diseases, which showed worst prognosis. Conclusion YKL-40 is highly elevated in fibrotic interstitial pneumonias and may reflect the degree of activity of the fibrogenic process. Remarkably, levels remain high in IPF, but can decrease in other interstitial pneumonias, which appears to be related to a better prognosis.

Background Increased airway wall thickness (AWT) and parenchymal lung destruction bothcontribute to airflow limitation. Advances in computed tomography (CT)post-processing imaging allow to quantify these features. The aim of thisDutch population study is to assess the relationships between AWT, lungfunction, emphysema and respiratory symptoms. Methods AWT and emphysema were assessed by low-dose CT in 500 male heavy smokers,randomly selected from a lung cancer screening population. AWT was measuredin each lung lobe in cross-sectionally reformatted images with an automatedimaging program at locations with an internal diameter of 3.5 mm, andvalidated in smaller cohorts of patients. The 15 th percentilemethod (Perc15) was used to assess the severity of emphysema. Informationabout respiratory symptoms and smoking behavior was collected byquestionnaires and lung function by spirometry. Results Median AWT in airways with an internal diameter of 3.5 mm(AWT 3.5 ) was 0.57 (0.44 - 0.74) mm. Median AWT in subjectswithout symptoms was 0.52 (0.41-0.66) and in those with dyspnea and/orwheezing 0.65 (0.52-0.81) mm (p<0.001). In the multivariate analysisonly AWT 3.5 and emphysema independently explained 31.1%and9.5%of the variance in FEV 1 %predicted, respectively,after adjustment for smoking behavior. Conclusions Post processing standardization of airway wall measurements provides areliable and useful method to assess airway wall thickness. Increased airwaywall thickness contributes more to airflow limitation than emphysema in asmoking male population even after adjustment for smoking behavior.

We aimed to study the association between lung function decline and quantitative computed tomography (CT) air trapping. Current and former heavy smokers in a lung cancer screening trial underwent volumetric low-dose CT in inspiration and expiration. Spirometry was obtained at baseline and after 3 years. The expiratory to inspiratory ratio of mean lung density (E/I-ratioMLD) was used to quantify air trapping. CT emphysema was defined as voxels in inspiratory CT below -950 Hounsfield Unit. Linear mixed modeling was used to determine the association between CT air trapping and lung function. We included 985 subjects with a mean age of 61.3 years. Independent of CT emphysema, CT air trapping was significantly associated with a reduction in forced expiratory volume in one second (FEV1) and the ratio of FEV1 over the forced vital capacity (FEV1/FVC); FEV1 declines with 33 mL per percent increase in CT air trapping, while FEV1/FVC declines 0.58% per percent increase (both p<0.001). CT air trapping further elicits accelerated loss of FEV1/FVC (additional 0.24% reduction per percent increase; p = 0.014). In a lung cancer screening cohort, quantitatively assessed air trapping on low-dose CT is independently associated with reduced lung function and accelerated decline of FEV1/FVC.

There is increasing evidence that structural lung changes may be present before the occurrence of airflow limitation as assessed by spirometry. This study investigated the prevalence of computed tomography (CT) quantified emphysema, airway wall thickening and gas trapping according to classification of airflow limitation (FEV1/FVC <70% and/or < the lower limit of normal (LLN)) in (heavy) smokers. A total number of 1,140 male former and current smokers participating in a lung cancer screenings trial (NELSON) were included and underwent chest CT scanning and spirometry. Emphysema was quantified by the 15(th) percentile, air way wall thickening by the square root of wall area for a theoretical airway with 10mm lumen perimeter (Pi10) and gas trapping by the mean lung density expiratory/inspiratory (E/I)-ratio. Participants were classified by entry FEV1/FVC: group 1>70%; group 2<70% but >LLN; and group 370% but FEV1 <80% predicted, were excluded. Multivariate regression analysis correcting for covariates was used to asses the extent of emphysema, airway wall thickening and gas trapping according to three groups of airflow limitation. Mean (standard deviation) age was 62.5 (5.2) years and packyears smoked was 41.0 (18.0). Group 2 subjects when compared to group 1 had a significantly lower 15(th) percentile, -920.6 HU versus -912.2 HU; a higher Pi10, 2.87 mm versus 2.57 mm; and a higher E/I-ratio, 88.6% versus 85.6% (all p<0.001). Subjects with an FEV1/FVC<70%, but above the LLN, have a significant greater degree of structural lung changes on CT compared to subjects without airflow limitation.

The passage of carbon monoxide (CO) through the alveolocapillary membrane and into the plasma and intraerythrocytic compartments determines the diffusing capacity of the lung for CO (Dlco) as defined by the Roughton and Forster equation. On the other hand, the single-breath diffusing capacity of the lung for nitric oxide (Dlno) is thought to represent the true membrane diffusing capacity because of its very high affinity for hemoglobin (Hb) and its independence from pulmonary capillary blood volume. Therefore, the Dlno/Dlco ratio can be used to differentiate between thickened alveolocapillary membranes (both Dlno and Dlco are decreased, and the Dlno/Dlco ratio is normal) and decreased perfusion of ventilated alveoli (the Dlno less decreased than the Dlco; therefore, the Dlno/Dlco ratio is high) in patients with pulmonary disease. We measured the combined values of Dlco and Dlno in 41 patients with diffuse parenchymal lung disease (DPLD), 26 patients with pulmonary arterial hypertension (PAH), and 71 healthy subjects. The Dlco (corrected to the standard Hb value) was lowered in the DPLD group (64% of predicted) and in the PAH group (64% of predicted), and was normal in the control group (105% of predicted). The Dlno/Dlco ratio in patients with PAH (4.98) was significantly higher than that in patients with DPLD (4.56) and in healthy subjects (4.36). The Dlno/Dlco ratio is significantly higher in patients with PAH than in healthy subjects, although this ratio cannot be applied as a screening test to discriminate between patients with DPLD and PAH as the overlap between these groups is too large.