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Background: Pulse wave velocity (PWV) in the pulmonary arteries (PA) is a marker of vascular stiffening. Currently, only phase-contrast (PC) MRI-based options exist to measure PA-PWV., Purpose: To test feasibility, repeatability, and correlation to clinical data of Phase-Resolved Functional Lung (PREFUL) MRI-based calculation of PA-PWV., Study Type: Retrospective., Subjects: 79 (26 female) healthy subjects (age range 19-78), 58 (24 female) patients with chronic obstructive pulmonary disease (COPD, age range 40-77), 60 (33 female) patients with suspected pulmonary hypertension (PH, age range 28-85)., Sequence: 2D spoiled gradient echo, 1.5T., Assessment: PA-PWV was measured from PREFUL-derived cardiac cycles based on the determination of temporal and spatial distance between lung vasculature voxels using a simplified (sPWV) method and a more comprehensive (cPWV) method including more elaborate distance calculation. For 135 individuals, PC MRI-based PWV (PWV-QA) was measured., Statistical Tests: Intraclass-correlation-coefficient (ICC) and coefficient of variation (CoV) were used to test repeatability. Nonparametric tests were used to compare cohorts. Correlation of sPWV/cPWV, PWV-QA, forced expiratory volume in 1 sec (FEV 1 ) %predicted, residual volume (RV) %predicted, age, and right heart catheterization (RHC) data were tested. Significance level α = 0.05 was used., Results: sPWV and cPWV showed no significant differences between repeated measurements (P-range 0.10-0.92). CoV was generally lower than 15%. COPD and PH patients had significantly higher sPWV and cPWV than healthy subjects. Significant correlation was found between sPWV or cPWV and FEV 1 %pred. (R = -0.36 and R = -0.44), but not with RHC (P-range -0.11 - 0.91) or age (P-range 0.23-0.89). Correlation to RV%pred. was significant for cPWV (R = 0.42) but not for sPWV (R = 0.34, P = 0.055). For all cohorts, sPWV and cPWV were significantly correlated with PWV-QA (R = -0.41 and R = 0.48)., Data Conclusion: PREFUL-derived PWV is feasible and repeatable. PWV is increased in COPD and PH patients and correlates to airway obstruction and hyperinflation., Level of Evidence: 3 TECHNICAL EFFICACY: Stage 2., (© 2024 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Segmental instillation of lipopolysaccharide (LPS) by bronchoscopy safely induces transient airway inflammation in human lungs. This model enables investigation of pulmonary inflammatory mechanisms as well as pharmacodynamic analysis of investigational drugs. The aim of this work was to describe the transcriptomic profile of human segmental LPS challenge with contextualization to major respiratory diseases. Pre-challenge bronchoalveolar lavage (BAL) fluid and biopsies were sampled from 28 smoking, healthy participants, followed by segmental instillation of LPS and saline as control. Twenty-four hours post instillation, BAL and biopsies were collected from challenged lung segments. Total RNA of cells from BAL and biopsy samples were sequenced and analysed for differentially expressed genes (DEGs). After challenge with LPS compared with saline, 6316 DEGs were upregulated and 241 were downregulated in BAL, but only one DEG was downregulated in biopsy samples. Upregulated DEGs in BAL were related to molecular functions such as "Inflammatory response" or "chemokine receptor activity", and upregulated pro-inflammatory pathways such as "Wnt-"/"Ras-"/"JAK-STAT" "-signaling pathway". Furthermore, the segmental LPS challenge model resembled aspects of the five most prevalent respiratory diseases chronic obstructive pulmonary disease (COPD), asthma, pneumonia, tuberculosis and lung cancer and featured similarities with acute exacerbations in COPD (AECOPD) and community-acquired pneumonia. Overall, our study provides extensive information about the transcriptomic profile from BAL cells and mucosal biopsies following LPS challenge in healthy smokers. It expands the knowledge about the LPS challenge model providing potential overlap with respiratory diseases in general and infection-triggered respiratory insults such as AECOPD in particular., (© 2024. The Author(s).)

Background: Bradykinin 1 receptor (B1R) signalling pathways may be involved in the inflammatory pathophysiology of chronic obstructive pulmonary disease (COPD). B1R signalling is induced by inflammatory stimuli or tissue injury and leads to activation and increased migration of pro-inflammatory cells. Lipopolysaccharide (LPS) lung challenge in man is an experimental method of exploring inflammation in the lung whereby interference in these pathways can help to assess pharmacologic interventions in COPD. BI 1026706, a potent B1R antagonist, was hypothesized to reduce the inflammatory activity after segmental lipopolysaccharide (LPS) challenge in humans due to decreased pulmonary cell influx., Methods: In a monocentric, randomized, double-blind, placebo-controlled, parallel-group, phase I trial, 57 healthy, smoking subjects were treated for 28 days with either oral BI 1026706 100 mg bid or placebo. At day 21, turbo-inversion recovery magnitude magnetic resonance imaging (TIRM MRI) was performed. On the last day of treatment, pre-challenge bronchoalveolar lavage fluid (BAL) and biopsies were sampled, followed by segmental LPS challenge (40 endotoxin units/kg body weight) and saline control instillation in different lung lobes. Twenty-four hours later, TIRM MRI was performed, then BAL and biopsies were collected from the challenged segments. In BAL samples, cells were differentiated for neutrophil numbers as the primary endpoint. Other endpoints included assessment of safety, biomarkers in BAL (e.g. interleukin-8 [IL-8], albumin and total protein), B1R expression in lung biopsies and TIRM score by MRI as a measure for the extent of pulmonary oedema., Results: After LPS, but not after saline, high numbers of inflammatory cells, predominantly neutrophils were observed in the airways. IL-8, albumin and total protein were also increased in BAL samples after LPS challenge as compared with saline control. There were no significant differences in cells or other biomarkers from BAL in volunteers treated with BI 1026706 compared with those treated with placebo. Unexpectedly, neutrophil numbers in BAL were 30% higher and MRI-derived extent of oedema was significantly higher with BI 1026706 treatment compared with placebo, 24 h after LPS challenge. Adverse events were mainly mild to moderate and not different between treatment groups., Conclusions: Treatment with BI 1026706 for four weeks was safe and well-tolerated in healthy smoking subjects. BI 1026706 100 mg bid did not provide evidence for anti-inflammatory effects in the human bronchial LPS challenge model., Trial Registration: The study was registered on January 14, 2016 at ClinicalTrials.gov (NCT02657408)., Competing Interests: Declaration of competing interest KH, MK, and TL are employees of Boehringer Ingelheim Pharma GmbH & Co. KG. WS and AG are employees of Boehringer Ingelheim International. JMH has received grants to his institution for clinical trial conduct and personal fees for consultancy from Boehringer Ingelheim Pharma GmbH & Co. KG. CG, JVC, PB, and MM have nothing to declare., (Copyright © 2023. Published by Elsevier Ltd.)

Purpose: To examine the time-dependent diffusion of fluorinated ( 19 F) gas in human lungs for determination of surface-to-volume ratio in comparison to results from hyperpolarized 129 Xe and lung function testing in healthy volunteers and patients with chronic obstructive pulmonary disease., Methods: Diffusion of fluorinated gas in the short-time regime was measured using multiple gradient-echo sequences with a single pair of trapezoidal gradient pulses. Pulmonary surface-to-volume ratio was calculated using a first-order approximation of the time-dependent diffusion in a study with 20 healthy volunteers and 22 patients with chronic obstructive pulmonary disease. The repeatability after 7 days as well as the correlation with hyperpolarized 129 Xe diffusion MRI and lung function testing was analyzed., Results: Using 19 F diffusion MRI, the median surface-to-volume ratio is significantly decreased in chronic obstructive pulmonary disease patients (S/V = 126 cm -1 [87-144 cm -1 ]) compared with healthy volunteers (S/V = 164 cm -1 [160-84 cm -1 ], p < 0.0001). No significant difference was found between measurements within 7 days for healthy (p = 0.88, median coefficient of variation = 4.3%) and diseased subjects (p = 0.58, median coefficient of variation= 6.7%). Linear correlations were found with S/V from 129 Xe diffusion MRI (r = 0.85, p = 0.001) and the forced expiratory volume in 1 second (r = 0.68, p < 0.0001)., Conclusion: Examination of lung microstructure using time-dependent diffusion measurement of inhaled 19 F is feasible, repeatable, and correlates with established measurements., (© 2022 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Chronic obstructive pulmonary disease (COPD) is associated with airway inflammation and bacterial dysbiosis. The relationship between the airway microbiome and bronchial gene expression in COPD is poorly understood. We aimed to identify differences in the airway microbiome from bronchial brushings in patients with COPD and healthy individuals and to investigate whether any distinguishing bacteria are related to bronchial gene expression., Methods: For this 16S rRNA gene sequencing and host transcriptomic analysis, individuals aged 45-75 years with mild-to-moderate COPD either receiving or not receiving inhaled corticosteroids and healthy individuals in the same age group were recruited as part of the Emphysema versus Airways Disease (EvA) consortium from nine centres in the UK, Germany, Italy, Poland, and Hungary. Individuals underwent clinical characterisation, spirometry, CT scans, and bronchoscopy. From bronchoscopic bronchial brush samples, we obtained the microbial profiles using 16S rRNA gene sequencing and gene expression using the RNA-Seq technique. We analysed bacterial genera relative abundance and the associations between genus abundance and clinical characteristics or between genus abundance and host lung transcriptional signals in patients with COPD versus healthy individuals, and in patients with COPD with versus without inhaled corticosteroids treatment., Findings: Between February, 2009, and March, 2012, we obtained brush samples from 574 individuals. We used 546 of 574 samples for analysis, including 207 from healthy individuals and 339 from patients with COPD (192 with inhaled corticosteroids and 147 without). The bacterial genera that most strongly distinguished patients with COPD from healthy individuals were Prevotella (median relative abundance 33·5%, IQR 14·5-49·4, in patients with COPD vs 47·7%, 31·1-60·7, in healthy individuals; p<0·0001), Streptococcus (8·6%, 3·8-15·8, vs 5·3%, 3·0-10·1; p<0·0001), and Moraxella (0·05%, 0·02-0·14, vs 0·02%, 0-0·07; p<0·0001). Prevotella abundance was inversely related to COPD severity in terms of symptoms and positively related to lung function and exercise capacity. 446 samples had assessable RNA-seq data, 257 from patients with COPD (136 with inhaled corticosteroids and 121 without) and 189 from healthy individuals. No significant associations were observed between lung transcriptional signals from bronchial brushings and abundance of bacterial genera in patients with COPD without inhaled corticosteroids treatment and in healthy individuals. In patients with COPD treated with inhaled corticosteroids, Prevotella abundance was positively associated with expression of epithelial genes involved in tight junction promotion and Moraxella abundance was associated with expression of the IL-17 and TNF inflammatory pathways., Interpretation: With increasing severity of COPD, the airway microbiome is associated with decreased abundance of Prevotella and increased abundance of Moraxella in concert with downregulation of genes promoting epithelial defence and upregulation of pro-inflammatory genes associated with inhaled corticosteroids use. Our work provides further insight in understanding the relationship between microbiome alteration and host inflammatory response, which might lead to novel therapeutic strategies for COPD., Funding: EU Seventh Framework Programme, National Institute for Health Research., Competing Interests: Declaration of interests CEB reports grants from EvA Seventh Framework Programme (FP7), Airway Disease Predicting Outcomes through Patient Specific Computational Modelling (AirPROM) FP7, and UK National Institute for Health Research (NIHR), during the conduct of the study, and grants and personal fees from AstraZeneca, GlaxoSmithKline, Novartis, Chiesi, Mologic, 4DPharma, and Genentech; and personal fees from Sanofi and Regeneron, outside the submitted work. TW reports grants from the EU (#200506) and the German Ministry of Research and Education, during the conduct of the study. TG reports grants from the EU, during the conduct of the study, and personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and CSL Behring; grants and personal fees from Grifols; and grants from the German Centre for Lung Research, outside the submitted work. LZ-H reports grants from the European Commission, during the conduct of the study. JMH reports grants from EU FP7, during the conduct of the study, and personal fees from Boehringer Ingelheim, Merck, Novartis, and HAL; and grants from AstraZeneca, Novartis, Janssen Pharmaceutica, ALK, Boehringer Ingelheim, LETI Pharma, GlaxoSmithKline, Sanofi-Aventis, Astellas Pharma, and Allergopharma, outside the submitted work. IG reports grants from the European Commission, during the conduct of the study. IB reports grants from EU FP7, during the conduct of the study. DGP reports personal fees from Mereo BioPharma, and CSL Behring, outside the submitted work. DS reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Genentech, GlaxoSmithKline, Glenmark, Menarini, Mundipharma, Novartis, Peptinnovate, Pfizer, Pulmatrix, Theravance, and Verona, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is a destructive inflammatory disease and the genes expressed within the lung are crucial to its pathophysiology. We have determined the RNAseq transcriptome of bronchial brush cells from 312 stringently defined ex-smoker patients. Compared to healthy controls there were for males 40 differentially expressed genes (DEGs) and 73 DEGs for females with only 26 genes shared. The gene ontology (GO) term "response to bacterium" was shared, with several different DEGs contributing in males and females. Strongly upregulated genes TCN1 and CYP1B1 were unique to males and females, respectively. For male emphysema (E)-dominant and airway disease (A)-dominant COPD (defined by computed tomography) the term "response to stress" was found for both sub-phenotypes, but this included distinct up-regulated genes for the E-sub-phenotype (neutrophil-related CSF3R, CXCL1, MNDA) and for the A-sub-phenotype (macrophage-related KLF4, F3, CD36). In E-dominant disease, a cluster of mitochondria-encoded (MT) genes forms a signature, able to identify patients with emphysema features in a confirmation cohort. The MT-CO2 gene is upregulated transcriptionally in bronchial epithelial cells with the copy number essentially unchanged. Both MT-CO2 and the neutrophil chemoattractant CXCL1 are induced by reactive oxygen in bronchial epithelial cells. Of the female DEGs unique for E- and A-dominant COPD, 88% were detected in females only. In E-dominant disease we found a pronounced expression of mast cell-associated DEGs TPSB2, TPSAB1 and CPA3. The differential genes discovered in this study point towards involvement of different types of leukocytes in the E- and A-dominant COPD sub-phenotypes in males and females.

Background: Free-breathing phase-resolved functional lung (PREFUL)-MRI may be useful for treatment monitoring in chronic obstructive pulmonary disease (COPD) patients with dyspnea. PREFUL test-retest reliability is essential for clinical application., Purpose: To measure the repeatability of PREFUL-MRI ventilation (V) and perfusion (Q) parameters., Study Type: Retrospective and prospective., Population: A total of 28 COPD patients and 57 healthy subjects., Field Strength/sequence: 1.5T MRI/2D spoiled gradient echo imaging., Assessment: V and Q lung parameter maps based on three coronal slices were obtained at baseline and after 14 days (COPD patients) or after a short pause outside the scanner (healthy subjects). Regional ventilation (RVent) and imaging flow volume loops by cross-correlation (ccVent) were quantified. Q was normalized to the signal of the main pulmonary artery (Q N ) and quantified (Q Quant ). Pulmonary pulse wave transit time (pPTT), voxel-by-voxel (regional), and whole lung (global) ventilation defect percentage based on RVent (VDP RVent ) and ccVent (VDP ccVent ), perfusion defect percentage (QDP), and ventilation/perfusion match based on RVent (VQM RVent ) and ccVent (VQM ccVent ) were calculated., Statistical Tests: Regional V and Q were analyzed globally for each subject. Each parameter's median of scans 1 and 2 were assessed by Wilcoxon sign rank test. A parameter's repeatability was analyzed by Bland-Altman analyses, coefficients of variation, intraclass correlation coefficients (ICC), and power calculations. The regional voxel repeatability was examined by calculating the Sørensen-Dice coefficient., Results: There was no bias and no significant differences between the first and second MRI for any parameters (P > 0.05). Coefficient of variation ranged from 2.26% (ccVent) to 19.31% (QDP), ICC from 0.93 (QDP) to 0.60 (pPTT), the smallest detectable difference was 0.002 ccVent. Regional comparison showed the highest overlap (84%) in VDP RVent in healthy voxels and the lowest (53%) in VDP ccVent defect voxels., Data Conclusion: V and Q PREFUL-MRI parameters were repeatable over two scan sessions in both healthy controls and COPD patients., Level of Evidence: 2 TECHNICAL EFFICACY STAGE: 2., (© 2020 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC. on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: We recently introduced a sputum cell quality score to rate how cell morphology, cellular debris and squamous cell contamination influence inflammatory cell identification during microscopic evaluation. However, sputum cell quality is generally not considered for the interpretation of sputum fluid phase biomarkers. Therefore, we compared the soluble protein concentrations between sputum samples with different cell quality. The impact of cell quality was compared to other factors potentially affecting soluble biomarker concentrations., Methods: A comprehensive sputum dataset from 154 clinically stable COPD patients was used to analyse the differences and the variability of sputum supernatant concentrations for 23 proteins between low, medium, and high sputum cell quality samples. A model was developed and tested to compare the impact of different factors on sputum supernatant protein levels., Results: Mean percentages of sputum macrophages, neutrophils, eosinophils, monocytes and lymphocytes showed no significant differences between low, medium and high cell quality levels. The mean percentage of squamous cells were lower, while total cell count/mL sputum and cell viability were significantly higher in sputum samples with higher cell quality. The concentrations of Interleukin-6, Interleukin-8 and Tumor Necrosis Factor Receptor 2 were significantly increased in sputum samples of higher cell quality. The variability of most protein concentrations declined with increasing cell quality levels. Sixteen proteins showed significantly negative correlations with the percentage of squamous cells. For 14 proteins we observed a positive correlation with cell number/mL sputum. Multiple regression analysis shows that generally less than 30% of the protein variability can be explained by the included factors., Conclusion: Sputum cell quality has a significant impact on some soluble biomarker concentrations in sputum supernatant. Sputum samples with low sputum cell quality show a higher variability of fluid phase proteins in comparison to medium and high sputum cell quality levels., Competing Interests: Dr Frederik Trinkmann reports personal fees from Actelion, Berlin Chemie, Boehringer Ingelheim, Chiesi, Novartis, Mundipharma, TEVA, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Roche, and Sanofi Aventis, outside the submitted work. Prof. Dr. Klaus F Rabe reports personal fees from Boehringer Ingelheim, AstraZeneca, Novartis, Chiesi, Teva, Sanofi & Regeneron, Berlin Chemie, GSK, and Orion Menarini, outside the submitted work. Prof. Dr. Marina Saetta reports grants from Chiesi Farmaceutici, outside the submitted work. Prof. Dr. Jens M Hohlfeld reports personal fees from Boehringer Ingelheim for consultancy and HAL for lecture fee, grants to my institution from AstraZeneca AB, Novartis, Janssen Pharmaceutica NV, ALK, Boehringer Ingelheim, LETI, GlaxoSmithKline, GSK, Astellas Pharma, Allergopharma, and Sanofi-Aventis, personal fees for consultancy from Merck & Co, Inc., lecture fee from Novartis, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2021 Pedersen et al.)

This exploratory, randomised, double-blind, double-dummy, multicentre, cross-over study explored the effect of 6 weeks of treatment with tiotropium/olodaterol (T/O) versus fluticasone propionate/salmeterol (F/S) on left ventricular filling in patients with chronic obstructive pulmonary disease with functional residual capacity (FRC) >120% predicted and postbronchodilator improvement of FRC ≥7.5%. Overall, 76 patients were randomised across nine sites. Treatment with T/O or F/S increased left ventricular end-diastolic volume index from baseline (adjusted mean change: T/O: 2.317 mL/m 2 , F/S: 2.855 mL/m 2 ), with no statistically significant difference between treatments. However, T/O resulted in a significantly greater reduction in lung hyperinflation versus F/S (FRC plethysmography absolute change from baseline: F/S: -0.329 L, T/O: -0.581 L)., Competing Interests: Ethics approval and patient consent: All studies included in this analysis were performed in accordance with the provisions of the Declaration of Helsinki (1996 version), the International Conference on Harmonisation Tripartite Guideline for Good Clinical Practice, applicable regulatory requirements and Boehringer Ingelheim Standard Operating Procedures. All patients provided written informed consent. This article does not report individual patient data; all data presented here are anonymised. The clinical trial protocols and the informed consent and patient information forms were reviewed and received approval/favourable opinion from a constituted local Institutional Review Board or an Independent Ethics Committee at each centre prior to the start of the study. This study was approved by Ethikkomission Medizinische Heidelberg under ID number AFmu-559/2016., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To investigate the diffusion of hyperpolarized 129 Xe in air spaces at short-time scales for determination of lung surface-to-gas-volume ratio in comparison to results from chemical shift saturation recovery, CT, and established clinical measures., Methods: A pulse sequence for measurement of time-dependent diffusion of 129 Xe in air spaces at short diffusion times was developed. Gas uptake into lung tissue was measured in the same breathhold using chemical shift saturation recovery spectroscopy in the short-time regime. The potential to obtain the surface-to-gas-volume ratio using a first-order and second-order approximation of the short-time expansion of time-dependent diffusion according to Mitra et al 11 and its diagnostic relevance were tested in a study with 9 chronic obstructive pulmonary diseases patients., Results: Surface-to-gas-volume ratios obtained from time-dependent diffusion were correlated with results from chemical shift saturation recovery, r = 0.840, P = .005 (first-order fits), and r = 0.923, P < .001 (second-order fits), and from CT results for second-order fits, r = 0.729, P = .026. Group means ± SD were 75.0 ± 15.5 cm -1 (first-order fits) and 122.3 ± 32.8 cm -1 (second-order fits) for time-dependent diffusion, 125.9 ± 43.3 cm -1 for chemical shift saturation recovery, and 159.5 ± 50.9 cm -1 for CT. Surface-to-gas-volume ratios from time-dependent diffusion with first-order fits correlated significantly with carbon monoxide diffusing capacity as percent of prediction, r = 0.724, P = .028., Conclusion: Time-dependent diffusion measurements of 129 Xe at short-time scales down to ~1 ms are feasible in chronic obstructive pulmonary patients and provide clinically relevant information on lung microstructure., (© 2020 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: There is an ongoing demand for easily accessible biomarkers that reflect the physiological and pathophysiological mechanisms of COPD. To test if an exercise challenge could help to identify clinically relevant metabolic biomarkers in COPD., Patients and Methods: We performed two constant-load exercise challenges separated by 4 weeks including smokers with COPD (n=23/19) and sex- and age-matched healthy smokers (n=23/20). Two hours after a standardized meal venous blood samples were obtained before, 5 mins after the start, at the end of submaximal exercise, and following a recovery of 20 mins. Data analysis was performed using mixed- effects model, with the metabolite level as a function of disease, time point and interaction terms and using each individual's resting level as reference., Results: Exercise duration was longer in healthy smokers but lactate levels were comparable between groups at all four time points. Glucose levels were increased in COPD. Glutamine was lower, while glutamate and arginine were higher in COPD. Branched-chain amino acids showed a stronger decline during exercise in healthy smokers. Carnitine and the acyl-carnitines C16 and C18:1 were increased in COPD. These metabolite levels and changes were reproducible in the second challenge., Conclusion: Higher serum glucose, evidence for impaired utilization of amino acids during exercise and a shift of energy metabolism to enhanced consumption of lipids could be early signs for a developing metabolic syndrome in COPD. In COPD patients, deviations of energy and nitrogen metabolism are amplified by an exercise challenge., Competing Interests: OH: no competing interest; DD: no competing interest; SR: employee of the sponsor of the study Nycomed during its conduct; TI: no competing interest; KW: reports grants from Biocrates Life Sciences, during the conduct of the study, contract research revenues from Altana during the conduct of the study, is a shareholder of Biocrates Life Sciences and a patent WO2007003343 issued, a patent WO2008145385 issued, and a patent WO2010139341 issued; CS: employee of the sponsor of the study Nycomed during its conduct; JH: received grants from Nycomed during the conduct of the study, personal fees from Boehringer Ingelheim, grants from AstraZeneca AB, grants from Novartis, grants from Janssen Pharmaceutica NV, grants from ALK, grants from Boehringer Ingelheim, grants from LETI, grants from GlaxoSmithKline, GSK, grants from Sanofi-Aventis, personal fees from Merck & Co, Inc., personal fees from Novartis, grants from Astellas Pharma, grants from Allergopharma, outside the submitted work., (© 2020 Holz et al.)

Chronic obstructive pulmonary disease (COPD) is induced by cigarette smoking and characterized by inflammation of airway tissue. Since smokers with COPD have a higher risk of developing lung cancer than those without, we hypothesized that they carry more mutations in affected tissue. We called somatic mutations in airway brush samples from medium-coverage whole genome sequencing data from healthy never and ex-smokers (n = 8), as well as from ex-smokers with variable degrees of COPD (n = 4). Owing to the limited concordance of resulting calls between the applied tools we built a consensus, a strategy that was validated with high accuracy for cancer data. However, consensus calls showed little promise of representing true positives due to low mappability of corresponding sequence reads and high overlap with positions harbouring known genetic polymorphisms. A targeted re-sequencing approach suggested that only few mutations would survive stringent verification testing and that our data did not allow the inference of any difference in the mutational load of bronchial brush samples between former smoking COPD cases and controls. High polyclonality in airway brush samples renders medium-depth sequencing insufficient to provide the resolution to detect somatic mutations. Deep sequencing data of airway biopsies are needed to tackle the question.

Chronic obstructive pulmonary disease (COPD) primarily affects the lungs; however, cardiovascular conditions are among the most common extrapulmonary comorbidities. Besides shared risk factors such as cigarette smoking, pathophysiological connections between the lung and the heart have been identified as mediators of reduced cardiac output. Recent research has focused on hyperinflation of the lung as a pulmonary cause for heart dysfunction. Hyperinflation is a typical lung abnormality seen in COPD; it is characterized by increased residual volume, intrathoracic gas volume, and total lung capacity while vital capacity is decreased. The degree of hyperinflation with airway obstruction is inversely related to left ventricular filling, stroke volume, and cardiac output. The underlying mechanisms are assumed to be compression of the pulmonary veins and thus reduced preload of the left heart as well as decreased pulmonary microvascular blood flow due to compression of the pulmonary vasculature. Treatment with a dual bronchodilator antagonizes this detrimental lung-heart unbalance effectively: Pulmonary blood flow, left ventricular end-diastolic volume, and stroke volume increase in COPD patients without cardiac abnormalities. Similar effects, yet less pronounced, were reported with single bronchodilator therapy. Future work needs to investigate whether these promising findings can be reproduced in COPD patients with cardiovascular diseases.

Rationale: In the CLAIM study, dual bronchodilation with indacaterol/glycopyrronium (IND/GLY) significantly reduced hyperinflation, which translated into improved cardiac function, measured by left ventricular end-diastolic volume and cardiac output. Pulmonary microvascular blood flow (PMBF) is reduced in chronic obstructive pulmonary disease (COPD); however, the effect of reduced lung hyperinflation on PMBF remains unknown. Objectives: To determine the effect of lung deflation with IND/GLY on PMBF and regional pulmonary ventilation using magnetic resonance imaging (MRI) in hyperinflated patients with COPD. Methods: In this double-blind, randomized, two-period crossover study, gadolinium-enhanced MRI and phase-resolved functional lung MRI were used to measure PMBF and regional ventilation, respectively, in patients with COPD receiving IND/GLY versus placebo. Measurements and Main Results: Sixty-two patients were randomized to receive once-daily IND/GLY (110/50 μg) for 14 days, followed by 14 days of placebo, or vice versa. Treatment periods were separated by a 14-day washout. Sixty patients were included in the per-protocol analysis. MRI measurements showed significant improvements in total PMBF ( P  = 0.006) and regional PMBF ( P values for individual lobes were between 0.004 and 0.022) in response to IND/GLY versus placebo. Regional ventilation was also significantly improved with IND/GLY, as evidenced by a 12.4% increase versus placebo ( P  = 0.011), a 14.3% relative decrease in ventilation defect percentage of nonventilated/hypoventilated lung tissue (cutoff was defined as 0.075 regional ventilation; P  = 0.0002), and a 15.7% reduction in the coefficient of variation of regional ventilation compared with placebo ( P  < 0.0001). Conclusions: Pharmacologic intervention with IND/GLY improves pulmonary microvascular blood flow and regional ventilation in patients with COPD with hyperinflation. Clinical trial registered with www.clinicaltrials.gov (NCT02442206).

Purpose: To develop a novel technique for voxel-based mapping of lung microstructural parameters using hyperpolarized 129 Xe dissolved-phase MR imaging during saturation recovery., Methods: A pulse sequence using a highly undersampled stack-of-stars trajectory was developed, and low-rank plus sparse matrix decomposition was employed for reconstruction of regional 129 Xe uptake dynamics into lung tissue. In 4 healthy volunteers and 9 patients with chronic obstructive pulmonary disease, the technique was tested and compared to chemical shift saturation recovery spectroscopy in patients. Reproducibility of 129 Xe gas uptake imaging was assessed by computing coefficients of variation, and results were compared with other modalities., Results: Numerical simulations and results from in vivo measurements in patients with chronic obstructive pulmonary disease showed that septal wall thickness and surface-to-volume ratio can be measured with an accuracy close to spectroscopic measurements. The average of the microstructural parameters of the total lung volume showed good reproducibility (coefficient of variation wall thickness: 7.4% coefficient of variation surface-to-volume ratio: 7.5%) and correlated strongly with the findings of global chemical shift saturation recovery spectroscopy. Gravitational gradients of microstructural parameters and increased heterogeneity in chronic obstructive pulmonary disease patients were observed., Conclusion: A novel technique for mapping of regional lung microstructural parameters was introduced, and its feasibility was shown in healthy volunteers and chronic obstructive pulmonary disease patients., (© 2018 International Society for Magnetic Resonance in Medicine.)

Rationale and Objectives: To assess the repeatability of global and regional lung ventilation quantification in both healthy subjects and patients with chronic obstructive pulmonary disease (COPD) using fluorinated ( 19 F) gas washout magnetic resonance (MR) imaging in free breathing., Material and Methods: In this prospective institutional review board-approved study, 12 healthy nonsmokers and eight COPD patients were examined with 19 F dynamic gas washout MR imaging in free breathing and with lung function testing. Measurements were repeated within 2 weeks. Lung ventilation was quantified using 19 F gas washout time. Repeatability was analyzed for the total lung and on a regional basis using the coefficient of variation (COV) and Bland-Altman plots., Results: In healthy subjects and COPD patients, a good repeatability was found for lung ventilation quantification using dynamic 19 F gas washout MR imaging on a global (COV < 8%) and regional (COV < 15%) level. Gas washout time was significantly increased in the COPD group compared to the healthy subjects., Conclusion: 19 F gas washout MR imaging provides a good repeatability of lung ventilation quantification and appears to be sensitive to early changes of regional lung function alterations such as normal aging., (Copyright © 2018 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Purpose: To evaluate the reproducibility and regional variation of parameters obtained from localized 129 Xe chemical shift saturation recovery (CSSR) MR spectroscopy in healthy volunteers and patients with chronic obstructive pulmonary disease (COPD) and to compare the results to 129 Xe dissolved-phase MR imaging., Methods: Thirteen healthy volunteers and 10 COPD patients were scanned twice using 129 Xe dissolved-phase imaging, CSSR, and ventilation imaging sequences. A 16-channel phased-array coil in combination with the regularized spectral localization achieved by sensitivity heterogeneity (SPLASH) method was used to perform a regional analysis of CSSR data. Lung function and microstructural parameters were obtained using Patz model functions and their reproducibility was assessed., Results: The Patz model alveolar wall thickness parameter shows good reproducibility on a regional basis with a median coefficient of variation of 6.5% in healthy volunteers and 12.4% in COPD patients. Significant regional differences of lung function parameters derived from localized CSSR were found in healthy volunteers and correlations with spirometric indices were found., Conclusion: Localized 129 Xe CSSR provides reproducible estimates of alveolar wall thickness and is able to detect regional differences of lung microstructure., (© 2018 International Society for Magnetic Resonance in Medicine.)

Background: Inhalation of medications is the cornerstone in the treatment of patients with lung diseases. A variety of inhalation devices exists and each device has specific requirements to achieve optimum inhalation of the drug. The goal of this study was to establish a clear overview on performance requirements of standard inhalation devices that should be met by the patient's breathing power and to develop a new method to measure the individual performance data. Materials and Methods: An optimum and still acceptable required breathing power (P in watts) was calculated for each device with the aid of individual device flow rates (determined by a literature search) and the flow resistances (by measuring the pressure drop over the different inhalation devices). For the in vivo part of the study, peak inspiratory flow and peak inspiratory pressure drop were measured in 21 adult patients with asthma or chronic obstructive pulmonary disease and healthy volunteers and the peak inspiratory power (PIPO in watts) was calculated. Results: Nearly no power is needed to achieve optimum results when using pressurized metered dose inhalers. For dry powder inhalers, the required power depends on the specific inhalation device. Conclusions: Inhalation devices impose differing demands on the inspiratory breathing power of patients. To ensure adequate use of the different devices, a cheap and simple assessment of patients' PIPO may be one option.

Background: Ventilation-weighted Fourier decomposition-MRI (FD-MRI) has matured as a reliable technique for quantitative measures of regional lung ventilation in recent years, but has yet not been validated in COPD patients., Purpose/hypothesis: To compare regional fractional lung ventilation obtained by ventilation-weighted FD-MRI with dynamic fluorinated gas washout MRI ( 19 F-MRI) and lung function test parameters., Study Type: Prospective study., Population: Twenty-seven patients with chronic obstructive pulmonary disease (COPD, median age 61 [54-67] years) were included., Field Strength/sequence: For FD-MRI and for 19 F-MRI a spoiled gradient echo sequence was used at 1.5T., Assessment: FD-MRI coronal slices were acquired in free breathing. Dynamic 19 F-MRI was performed after inhalation of 25-30 L of a mixture of 79% fluorinated gas (C 3 F 8 ) and 21% oxygen via a closed face mask tubing using a dedicated coil tuned to 59.9 MHz. 19 F washout times in numbers of breaths ( 19 F-n breaths ) as well as fractional ventilation maps for both methods (FD-FV, 19 F-FV) were calculated. Slices were matched using a landmark driven algorithm, and only corresponding slices with an overlap of >90% were coregistered for evaluation., Statistical Tests: The obtained parameters were correlated with each other using Spearman's correlation coefficient (r)., Results: FD-FV strongly correlated with 19 F-n breaths on a global (r = -0.72, P < 0.0001) as well as on a lobar level and with lung function test parameters (FD-FV vs. FEV1, r = 0.76, P < 0.0001). There was a small systematic overestimation of FD-FV compared to 19 F-FV (mean difference -0.03 (95% confidence interval [CI]: -0.097; -0.045)., Data Conclusion: Regional ventilation-weighted Fourier decomposition-MRI is a promising noninvasive, radiation-free tool for quantification of regional ventilation in COPD patients., Level of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1534-1541., (© 2017 International Society for Magnetic Resonance in Medicine.)

Background: Pulmonary hyperinflation in chronic obstructive pulmonary disease (COPD) is associated with reduced biventricular end-diastolic volumes and increased morbidity and mortality. The combination of a long-acting β agonist (LABA) and a muscarinic antagonist (LAMA) is more effective in reducing hyperinflation than LABA-inhaled corticosteroid combination therapy but whether dual bronchodilation improves cardiac function is unknown., Methods: We did a double-blind, randomised, two-period crossover, placebo-controlled, single-centre study (CLAIM) at the Fraunhofer Institute of Toxicology and Experimental Medicine (Hannover, Germany), a specialty clinic. Eligible participants were patients aged at least 40 years with COPD, pulmonary hyperinflation (defined by a baseline residual volume >135% of predicted), a smoking history of at least ten pack-years, and airflow limitation (FEV 1 <80% predicted and post-bronchodilator FEV 1 : forced vital capacity <0·7). Patients with stable cardiovascular disease were eligible, but those with arrhythmias, heart failure, unstable ischaemic heart disease, or uncontrolled hypertension were not. We randomly assigned participants (1:1) to either receive a combined inhaled dual bronchodilator containing the LABA indacaterol (110 μg as maleate salt) plus the LAMA glycopyrronium (50 μg as bromide salt) once per day for 14 days, followed by a 14-day washout, then a matched placebo for 14 days, or to receive the same treatments in reverse order. The randomisation was done using lists and was concealed from patients and investigators. The primary endpoint was the effect of indacaterol-glycopyrronium versus placebo on left-ventricular end-diastolic volume measured by MRI done on day 1 (visit 4) and day 15 (visit 5) in treatment period 1 and on day 29 (visit 6) and day 43 (visit 7) in treatment period 2 in the per-protocol population. Left-ventricular end-diastolic volume was indexed to body surface area. Safety was assessed in all participants who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02442206., Findings: Between May 18, 2015, and April 20, 2017, we randomly assigned 62 eligible participants to treatment; 30 to indacaterol-glycopyrronium followed by placebo and 32 to placebo followed by indacaterol-glycopyrronium. The 62 randomly assigned patients were included in the intent-to-treat analysis. There were two protocol violations and therefore 60 were included in the per-protocol analysis. 57 patients completed both treatment periods. After indacaterol-glycopyrronium treatment, left-ventricular end-diastolic volume increased from a mean 55·46 mL/m 2 (SD 15·89) at baseline to a least-squares (LS) mean of 61·76 mL/m 2 (95% CI 57·68-65·84), compared with a change from 56·42 mL/m 2 at baseline (13·54) to 56·53 mL/m 2 (52·43-60·62) after placebo (LS means treatment difference 5·23 mL/m 2 [95% CI 3·22 to 7·25; p<0·0001]). The most common adverse events reported with indacaterol-glycopyrronium were cough (in nine patients [15%] of 59) and throat irritation (in seven [12%]). With placebo, the most common adverse events reported were headache (in five patients [8%] of 61) and upper respiratory tract infection (in four [7%]). Two patients had serious adverse events: one (2%) after indacaterol-glycopyrronium (endometrial cancer) and one (2%) after placebo (myocardial infarction); these were not thought to be treatment related. No patients died during the study., Interpretation: This is the first study to analyse the effect of LABA-LAMA combination therapy on cardiac function in patients with COPD and lung hyperinflation. Dual bronchodilation with indacaterol-glycopyrronium significantly improved cardiac function as measured by left-ventricular end-diastolic volume. The results are important because of the known association of cardiovascular impairment with COPD, and support the early use of dual bronchodilation in patients with COPD who show signs of pulmonary hyperinflation., Funding: Novartis Pharma GmbH., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: A subset of COPD-patients presents with eosinophilic airway inflammation. While treatment of asthmatic patients with the GATA3-specific DNAzyme SB010 attenuated sputum eosinophilia after allergen challenge, this specific treatment has not been evaluated in patients with COPD. Our objective was to evaluate the feasibility and safety of inhaled SB010 in COPD patients with sputum eosinophilia., Methods: We conducted a randomized, double-blind, placebo-controlled, multicentre clinical trial in COPD-patients with sputum eosinophilia (≥2.5% non-squamous cells). Patients inhaled 10 mg SB010 bid or matching placebo via the controlled inhalation system AKITA2 APIXNEB for 28 days. Endpoints included the feasibility of the study (primary), patient's safety, sputum eosinophils, F E NO, lung function, symptoms, and biomarkers. The study was registered in the German Clinical Trials Register: DRKS00006087., Results: One hundred thirty patients were screened, 23 patients were randomized (FEV 1 49.4 ± 11.5%; sputum eosinophils 8.0 ± 8.4%) and 19 patients completed the study (10 placebo, 9 SB010. After 28 days, SB010 decreased the relative sputum eosinophil count (p = 0.004) as compared to no changes in placebo-treated patients. F E NO, lung function, and symptoms were not affected significantly. We found an increase in blood IFN-γ (p = 0.02) and a trend to lower IL-5 levels in patients treated with SB010. SB010 was safe and well tolerated. Thirty five AEs (22 SB010, 13 placebo including 1 SAE) were observed with 3 AEs in each group judged to be possibly treatment-related., Conclusion: In patients with eosinophilic COPD, sputum eosinophils could be reduced by inhalation of SB010. Long-term studies are needed to demonstrate clinical efficacy.

Purpose To quantify regional lung ventilation in patients with chronic obstructive pulmonary disease (COPD) by using free-breathing dynamic fluorinated (fluorine 19 [ 19 F]) gas magnetic resonance (MR) imaging. Materials and Methods In this institutional review board-approved prospective study, 27 patients with COPD were examined by using breath-hold 19 F gas wash-in MR imaging during inhalation of a normoxic fluorinated gas mixture (perfluoropropane) and by using free-breathing dynamic 19 F gas washout MR imaging after inhalation of the gas mixture was finished for a total of 25-30 L. Regional lung ventilation was quantified by using volume defect percentage (VDP), washout time, number of breaths, and fractional ventilation (FV). To compare different lung function parameters, Pearson correlation coefficient and Fisher z transformation were used, which were corrected for multiple comparisons with the Bonferroni method. Results Statistically significant correlations were observed for all evaluated lung function test parameters compared with median and interquartile range of 19 F washout parameters. An inverse linear correlation of median number of breaths (r = -0.82; P < .0001) and median washout times (r = -0.77; P < .0001) with percentage predicted of forced expiratory volume in 1 second (FEV 1 ) was observed; correspondingly median FV (r = 0.86; P < .0001) correlated positively with percentage predicted FEV 1 . Comparing initial with late phase, median VDP of all subjects decreased from 49% (25th-75th percentile, 35%-62%) to 6% (25th-75th percentile, 2%-10%; P < .0001). VDP at the beginning of the gas wash-in phase (VDP initial ) significantly correlated with percentage predicted FEV 1 (r = -0.74; P = .0028) and FV (r = 0.74; P = .0002). Median FV was significantly increased in ventilated regions (11.1% [25th-75th percentile, 6.8%-14.5%]) compared with the defect regions identified by VDP initial (5.8% [25th-75th percentile, 4.0%-7.4%]; P < .0001). Conclusion Quantification of regional lung ventilation by using dynamic 19 F gas washout MR imaging in free breathing is feasible at 1.5 T even in obstructed lung segments. © RSNA, 2017 Online supplemental material is available for this article.

There is increasing evidence that breath volatile organic compounds (VOC) have the potential to support the diagnosis and management of inflammatory diseases such as COPD. In this study we used a novel breath sampling device to search for COPD related VOCs. We included a large number of healthy controls and patients with mild to moderate COPD, recruited subjects at two different sites and carefully controlled for smoking. 222 subjects were recruited in Hannover and Marburg, and inhaled cleaned room air before exhaling into a stainless steel reservoir under exhalation flow control. Breath samples (2.5 l) were continuously drawn onto two Tenax(®) TA adsorption tubes and analyzed in Hannover using thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS). Data of 134 identified VOCs from 190 subjects (52 healthy non-smokers, 52 COPD ex-smokers, 49 healthy smokers, 37 smokers with COPD) were included into the analysis. Active smokers could be clearly discriminated by higher values for combustion products and smoking related VOCs correlated with exhaled carbon monoxide (CO), indicating the validity of our data. Subjects from the study sites could be discriminated even after exclusion of cleaning related VOCs. Linear discriminant analysis correctly classified 89.4% of COPD patients in the non/ex-smoking group (cross validation (CV): 85.6%), and 82.6% of COPD patients in the actively smoking group (CV: 77.9%). We extensively characterized 134 breath VOCs and provide evidence for 14 COPD related VOCs of which 10 have not been reported before. Our results show that, for the utilization of breath VOCs for diagnosis and disease management of COPD, not only the known effects of smoking but also site specific differences need to be considered. We detected novel COPD related breath VOCs that now need to be tested in longitudinal studies for reproducibility, response to treatment and changes in disease severity.

Due to its high sensitivity, compact size and low cost ion mobility spectrometry (IMS) has the potential to become a point-of-care breath analyzer. Therefore, we developed a prototype of a compact, closed gas loop IMS with gas chromatographic (GC) pre-separation and high resolving power of R  =  90. In this study, we evaluated the performance of this GC-IMS under clinical conditions in a COPD study to find correlations between VOCs (10 ppbv to 1 ppmv) and COPD. Furthermore, in order to investigate possible correlations between ultra-low concentrated breath VOCs (0.1 pptv to 1 ppbv) and COPD, a modified mass spectrometer (MS) with atmospheric pressure chemical ionization (APCI) and GC pre-separation (GC-APCI-MS) was used. The GC-IMS has been used in 58 subjects (21 smokers with moderate COPD, 12 ex-smokers with COPD, 16 healthy smokers and 9 non-smokers). GC-APCI-MS data were available for 94 subjects (21 smokers with moderate COPD, 25 ex-smokers with COPD, 25 healthy smokers and 23 non-smokers). For 44 subjects, a comparison between GC-IMS and GC-APCI-MS data could be performed. Due to service intervals, subject availability and corrupt data, patient numbers were different for GC-APCI-MS and GC-IMS measurements. Using GC-IMS, three VOCs have been found showing a significant difference between healthy controls and patients with COPD. In the GC-APCI-MS data, we only observed one distinctive VOC, which has been identified as 2-pentanone. This proof-of-principle study shows the potential of our high-resolution GC-IMS in the clinical environment. Due to different linear dynamic response ranges, the data of GC-IMS and GC-APCI-MS were only comparable to a limited extent.

There is an ongoing demand for easily accessible biomarkers related to pathophysiological processes in chronic obstructive pulmonary disease (COPD). Short-term intense exercise is known to increase the peripheral blood levels of cytokines. Therefore, we tested the potential and the repeatability of an exercise challenge to amplify seven serum biomarkers (interleukin 6 [IL6], C-reactive protein [CRP], myeloperoxidase [MPO], leukotriene B4, soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, and von Willebrand factor [VWF]) in smokers with and without COPD. Twenty-three smokers with moderate COPD (GOLD 2) and 23 sex- and age-matched healthy smokers underwent up to 30-minute submaximal, constant-load exercise (75% of maximum work load) on two occasions separated by 4 weeks (second challenge n=19/20). Serum samples were obtained before, 5 minutes after the start, at the end of exercise (maximum 30 minutes or until exhaustion), and after additional 20 minutes of rest. The median (interquartile range) exercise time until exhaustion in the two challenges was 10.0 (4.0) minutes and 10.0 (8.0) minutes in smokers with COPD and 22.0 (16.0) minutes and 26.5 (14.5) minutes in healthy smokers. The exercise challenge significantly increased the serum concentrations of IL6 and VWF, but decreased the concentrations of MPO. Healthy smokers showed a significantly greater increase (at the end of exercise compared to before exercise) in IL6 (P=0.01) and a larger decline (P=0.03) in MPO. The overall profile of the serum markers during the exercise challenge was shown to be repeatable in the second challenge. In summary, intense load exercise is capable of changing the concentration of inflammatory and endothelial function markers. Especially, the decline in the level of MPO, a marker closely related to cardiovascular risk, appears to be of clinical interest, as the exercise-induced decline might be related to the beneficial effects of physical activity in general.

Background: Human breath contains small particles that might be useful for the noninvasive diagnosis of lung disease. In this study, the impact of airway obstruction on particle emission was investigated., Methods: Particle number flux and particle size distribution were measured for healthy nonsmokers (n=16), healthy smokers (n=13), patients with chronic obstructive pulmonary disease (n=28, GOLD stage I-IV), and patients with asthma before and after methacholine challenge (n=10). The measurements were carried out using a condensation nucleus counter (TSI 3760) and a laser spectrometer (PMT LASAIR II-110)., Results: Particle number per breath showed high intrasubject reproducibility. However, there was a large intersubject variability in the number of emitted particles on the order of two magnitudes, with no influence of airway obstruction on emission level. Methacholine-induced airway obstruction, in subjects with allergic asthma, did not change the number of exhaled particles, when compared with prechallenge values. For the droplet size distribution averaged per breath, there was no difference between healthy subjects and subjects with airway obstruction., Conclusions: Airway obstruction does not change the number flux or size distribution of particles in exhaled breath. The high intersubject variability of particle emission supports the concept of online determination of aerosol properties (primarily number flux, during exhaled breath) during breath condensate sampling to properly normalize the results of biochemical analysis. As high dilution and variable dilution are the main challenges of biomarker assessment in exhaled breath condensate, this normalization procedure would significantly add to the value of the technique.

Background: Tiotropium is generally well tolerated; however, there has been debate whether antimuscarinics, particularly tiotropium administered via Respimat(®) Soft Mist(™) Inhaler, may induce cardiac arrhythmias in a vulnerable subpopulation with cardiovascular comorbidity. The aim of this study was to provide evidence of the cardiac safety of tiotropium maintenance therapy., Methods: Combined analysis of Holter electrocardiogram (ECG) data from clinical trials of tiotropium in chronic obstructive pulmonary disease (COPD). Trials in the Boehringer Ingelheim clinical trials database conducted between 2003 and 2012, involving tiotropium HandiHaler(®) 18 μg and/or tiotropium Respimat(®) (1.25-, 2.5-, 5.0- and 10-μg doses) were reviewed. All trials involving Holter-ECG monitoring during this period were included in the analysis. Men and women aged ≥ 40 years with a smoking history of ≥ 10 pack-years, and a clinical diagnosis of COPD were included. Holter ECGs were evaluated for heart rate (HR), supraventricular premature beats (SVPBs), ventricular premature beats (VPBs) and pauses. Quantitative and categorical end-points were derived for each of the Holter monitoring days., Results: Four trials (n = 727) were included in the analysis. Respimat(®) (1.25-10 μg) or HandiHaler(®) (18 μg) was not associated with changes in HR, SVPBs, VPBs and pauses compared with placebo or the pretreatment baseline period. In terms of cardiac arrhythmia end-points, there was no evidence for an exposure-effect relationship., Conclusions: In this analysis, tiotropium maintenance therapy administered using Respimat(®) (1.25-10 μg) or HandiHaler(®) (18 μg) once daily for periods of up to 48 weeks was well tolerated with no increased risk of cardiac arrhythmia in patients with COPD., (© 2014 The Authors. International Journal of Clinical Practice Published by John Wiley & Sons Ltd.)

The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 µg compared to powder 18 µg and assess dose-dependency of tiotropium solution pharmacodynamics in comparison to placebo. In total 154 patients with chronic obstructive pulmonary disease (COPD) were included in this multicenter, randomized, double-blind within-solution (1.25, 2.5, 5 µg, and placebo), and open-label powder 18 µg, crossover study, including 4-week treatment periods. Primary end points were peak plasma concentration (Cmax,ss ), and area under the plasma concentration-time profile (AUC0-6h,ss ), both at steady state. The pharmacodynamic response was assessed by serial spirometry (forced expiratory volume in 1 second/forced vital capacity). Safety was evaluated as adverse events and by electrocardiogram/Holter. Tiotropium was rapidly absorbed with a median tmax,ss of 5-7 minutes postdosing for both devices. The gMean ratio of solution 5 µg over powder 18 µg was 81% (90% confidence interval, 73-89%) for Cmax,ss and 76% (70-82%) for AUC0-6h,ss , indicating that bioequivalence was not established. Dose ordering for bronchodilation was observed. Powder 18 µg and solution 5 µg were most effective, providing comparable bronchodilation. All treatments were well tolerated with no apparent relation to dose or device. Comparable bronchodilator efficacy to powder18 µg at lower systemic exposure supports tiotropium solution 5 µg for maintenance treatment of COPD., (© 2013 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

Background: The aim of this study was to test whether repeatable biomarkers collected from serum, bronchoalveolar lavage (BAL) and sputum of healthy smokers and smokers with COPD would have a prognostic value with respect to the decline in lung function over a 5 year period., Methods: In 2006/2007 we had repeatedly collected serum, BAL and sputum of 23 healthy smokers and 24 smokers with COPD (GOLD II) and analysed a panel of more than 100 different parameters. In 2012 we reinvited these subjects to assess the change in lung function to enable the investigation of the potential prognostic value of the 2006/2007 markers and to determine the long-term repeatability of selected blood and serum markers. In this follow-up study we performed body-plethysmography, a blood gas analysis and collected blood and urine samples. The change in lung function was compared with 67 markers from BAL, sputum, serum and whole blood that were shown in the 2006/2007 assessment to be repeatable over a 6 week period., Results: We were able to recruit 13 (54%) smokers with COPD and 11 (48%) former healthy smokers that participated in the 2006/2007 study. The decline in lung function was larger in COPD smokers; five of them changed to GOLD III, one to GOLD IV. Two healthy smokers changed to GOLD I. Blood cells, serum von Willebrand factor and alpha-1-antitrypsin showed a good repeatability over 5 years. In COPD smokers a weak correlation between 2006/2007 sputum markers of neutrophilic inflammation and the 5 year change in FEV1/FVC was found., Conclusions: Our data suggests that inter-individual and group differences are maintained over a five year period. Despite the large panel of markers available for this analysis, a potential prognostic value appears to exist only for some sputum inflammatory markers. If these data can be confirmed in larger COPD cohorts, it would emphasize the value of sputum markers in clinical trials and support the assumption that an anti-inflammatory treatment can have long term benefits in COPD.

The EvA study is a European Union-funded project under the Seventh Framework Programme (FP7), which aims at defining new markers for chronic obstructive pulmonary disease (COPD) and its subtypes. The acronym is derived from emphysema versus airway disease, indicating that the project targets these two main phenotypes of the disease. The EvA study is based on the concept that emphysema and airway disease are governed by different pathophysiological processes, are driven by different genes and have differential gene expression in the lung. To define these genes, patients and non-COPD controls are recruited for clinical examination, lung function analysis and computed tomography (CT) of the lung. CT scans are used to define the phenotypes based on lung density and airway wall thickness. This is followed by bronchoscopy in order to obtain samples from the airways and the alveoli. These tissue samples, along with blood samples, are then subjected to genome-wide expression and association analysis and markers linked to the phenotypes are identified. The population of the EvA study is different from other COPD study populations, since patients with current oral glucocorticoids, antibiotics and exacerbations or current smokers are excluded, such that the signals detected in the molecular analysis are due to the distinct inflammatory process of emphysema and airway disease in COPD.

Background: Spirometry is regarded as the gold standard for the diagnosis of COPD, yet the condition is widely underdiagnosed. Therefore, additional screening methods that are easy to perform and to interpret are needed. Recently, we demonstrated that low frequency ultrasound (LFU) may be helpful for monitoring lung diseases. The objective of this study was to evaluate whether LFU can be used to detect air trapping in COPD. In addition, we evaluated the ability of LFU to detect the effects of short-acting bronchodilator medication., Methods: Seventeen patients with COPD and 9 healthy subjects were examined by body plethysmography and LFU. Ultrasound frequencies ranging from 1 to 40 kHz were transmitted to the sternum and received at the back during inspiration and expiration. The high pass frequency was determined from the inspiratory and the expiratory signals and their difference termed ΔF. Measurements were repeated after inhalation of salbutamol., Results: We found significant differences in ΔF between COPD subjects and healthy subjects. These differences were already significant at GOLD stage 1 and increased with the severity of COPD. Sensitivity for detection of GOLD stage 1 was 83% and for GOLD stages worse than 1 it was 91%. Bronchodilator effects could not be detected reliably., Conclusions: We conclude that low frequency ultrasound is cost-effective, easy to perform and suitable for detecting air trapping. It might be useful in screening for COPD., Trial Registration: ClinicalTrials.gov: NCT01080924.

Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory disease, primarily affecting the airways. Stable biomarkers characterizing the inflammatory phenotype of the disease, relevant for disease activity and suited to predict disease progression are needed to monitor the efficacy and safety of drug interventions. We therefore analyzed a large panel of markers in bronchoalveolar lavage, bronchial biopsies, serum and induced sputum of 23 healthy smokers and 24 smoking COPD patients (GOLD II) matched for age and gender. Sample collection was performed twice within a period of 6 weeks. Assays for over 100 different markers were validated for the respective matrices prior to analysis. In our study, we found 51 markers with a sufficient repeatability (intraclass correlation coefficient >0.6), most of these in serum. Differences between groups were observed for markers from all compartments, which extends (von-Willebrand-factor) and confirms (e.g. C-reactive-protein, interleukin-6) previous findings. No correlations between lung and serum markers were observed, including A1AT. Airway inflammation defined by sputum neutrophils showed only a moderate repeatability. This could be improved, when a combination of neutrophils and four sputum fluid phase markers was used to define the inflammatory phenotype.In summary, our study provides comprehensive information on the repeatability and interrelationship of pulmonary and systemic COPD-related markers. These results are relevant for ongoing large clinical trials and future COPD research. While serum markers can discriminate between smokers with and without COPD, they do not seem to sufficiently reflect the disease-associated inflammatory processes within the airways.

Background: The evaluation of exhaled breath profiles by electronic nose (eNose) is considered as a promising non-invasive diagnostic tool, and the discrimination of breathprints between patients with COPD and asthma has been reported. The aim of this study was to assess, whether exhaled breath profile analysis can detect the inflammatory airway response induced by ozone inhalation., Methods: In a randomized double-blind, cross-over study 14 healthy ozone-responsive subjects were exposed to 250 ppb ozone and filtered room air for 3h with intermittent exercise. Blood biomarkers, exhaled NO, exhaled CO, and breathprints (Cyranose 320(®)) were assessed prior and at 3 time points up to 24h post exposure. Induced sputum was collected at baseline and 3h post exposure. Multivariate analysis of eNose data was performed using transformed and normalized datasets., Results: Significantly increased numbers of sputum and blood neutrophils were observed after ozone, whereas the eNose signals showed no differences between exposures and no correlation with neutrophilic airway inflammation. However, independent of ozone exposure, sensor data correlated with serum SP-D levels and to a smaller extent with blood neutrophil numbers., Conclusions: Exhaled breath profiles as measured by the Cyranose 320(®) did not reflect airway responses to ozone. This suggests that exhaled volatiles did not change with ozone challenges or that the changes were below the detection limits. Conversely, the correlation of eNose signals with blood neutrophils and serum SP-D, i.e. markers of systemic inflammation and lung permeability, suggested that the Cyranose 320(®) can detect volatile organic compounds of systemic origin., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Pulmonary surfactant protein D (SP-D) is considered as a candidate biomarker for the functional integrity of the lung and for disease progression, which can be detected in serum. The origin of SP-D in serum and how serum concentrations are related to pulmonary concentrations under inflammatory conditions is still unclear., Methods: In a cross-sectional study comprising non-smokers (n=10), young--(n=10), elderly smokers (n=20), and smokers with COPD (n=20) we simultaneously analysed pulmonary and serum SP-D levels with regard to pulmonary function, exercise, repeatability and its quaternary structure by native gel electrophoresis. Statistical comparisons were conducted by ANOVA and post-hoc testing for multiple comparisons; repeatability was assessed by Bland-Altman analysis., Results: In COPD, median (IQR) pulmonary SP-D levels were lower (129(68) ng/ml) compared to smokers (young: 299(190), elderly: 296(158) ng/ml; p<0.01) and non-smokers (967(708) ng/ml; p<0.001). The opposite was observed in serum, with higher concentrations in COPD (140(89) ng/ml) as compared to non-smokers (76(47) ng/ml; p<0.01). SP-D levels were reproducible and correlated with the degree of airway obstruction in all smokers. In addition, smoking lead to disruption of the quaternary structure., Conclusions: Pulmonary and serum SP-D levels are stable markers influenced by smoking and related to airflow obstruction and disease state. Smaller subunits of pulmonary SP-D and the rapid increase of serum SP-D levels in COPD due to exercise support the translocation hypothesis and its use as a COPD biomarker., Trial Registration: no interventional trial.

Rationale: Epidermal growth factor receptor (EGFR) activation is implicated in mucin hypersecretion in chronic obstructive pulmonary disease (COPD)., Objectives: To investigate the safety and efficacy of an inhaled EGFR antagonist (BIBW 2948) in COPD., Methods: Multicenter, double-blind, placebo-controlled trial of 4 weeks of treatment with two doses of BIBW 2948 (15 and 30 mg twice a day) on safety and mucin-related outcomes in 48 patients with COPD. The effect of BIBW 2948 on EGFR activation in airway epithelial cells was assessed using an ex vivo assay. Efficacy measures included the volume of mucin in the airway epithelium (Vs mu,bala) in bronchial biopsies and the expression of mucin genes in bronchial brushings., Measurements and Main Results: Inhaled BIBW 2948 induced a dose-related inhibition of EGFR internalization (reflecting decreased EGFR activation) in epithelial cells from treated subjects. However, BIBW 2948 was associated with a dose-related increase in adverse events, including reversible liver enzyme elevation (n = 2), and reduction in FEV(1). The changes in mucin stores and mucin gene expression were not significantly different in the pooled BIBW 2948 group versus placebo (volume of mucin per surface area of basal lamina = 0.22 +/- 7.11 vs. 0.47 +/- 8.06 microm(3)/microm(2); P = 0.93). However, in the 30 mg twice a day group, the reduction in epithelial mucin stores was greatest in subjects with the greatest degree of EGFR inhibition (Pearson r = 0.98; 95% confidence interval, 0.71-0.99)., Conclusions: Four-week treatment with BIBW 2948 did not significantly decrease epithelial mucin stores and was poorly tolerated in patients with COPD. Ex vivo analyses suggest that higher doses may be more effective at both EGFR inhibition and decreases in mucin stores but that adverse events should be expected. Clinical trial registered with www.clinicaltrials.gov (NCT00423137).

Background and Objective: Chronic obstructive pulmonary disease (COPD) is one of the most common causes of chronic morbidity and mortality. The "Burden of Obstructive Lung Disease" (BOLD) initiative was established as an international study collecting data about the prevalence of COPD. The Medical University of Hanover took part in this study collecting data representative for Germany., Methods: 683 individuals aged = 40 years from the city and region of Hannover were included in the study. On the basis of standardized questionnaires data were collected on general health, physical and mental capability, smoking habits and occupational exposure to dust. All participants performed spirometry before and after inhalation of salbutamol., Results: The prevalence of COPD, GOLD (Global Health Initiative on Obstructive Lung Disease) severity stage = I, was 13.2% (GOLD stage I: 7.4%; GOLD stage II: 5.0%, GOLD stage III or IV: 0.8%). There was a marked increase of the prevalence of COPD depending on age and smoking habits. The percentage of active smokers in the sample was 20.6 %. Among younger participants the percentage of female smokers was noticeable higher than in older subjects. Although clinical symptoms of COPD, GOLD stage = III correlated with disease severity, only persons with COPD reported reduced physical capability., Conclusion: COPD is a highly prevalent disease. With regard to the increasing life expectancy and the change of smoking habits of the population, a further increase of morbidity and mortality due to COPD must be expected, especially in women.

Chronic obstructive pulmonary disease (COPD) is one of the most common chronic diseases worldwide, and its morbidity and mortality are still increasing. Thus, it is expected that, globally, COPD will be the third most common cause of death by 2020. Moreover, COPD leads to enormous health-economic costs (i. e., outpatient and inpatient treatment, inability to work). Nevertheless, the prevalence of COPD is underestimated also in Germany. This is partly because often, the disease is symptomatic only in its advanced stages and as a result it is not diagnosed until late. In addition, the therapeutic effects on the long-term course and the progression of the disease are limited. Therefore, a much deeper understanding of the manifold and complex pathomechanisms of this pathomorphologically varied disease is needed before new therapeutic strategies can be developed. The aim of this review is to discuss current concepts of the pathophysiology of COPD and their scientific bases. The authors will concentrate mainly on a differentiated description of the pathomechanisms which cause chronic obstructive bronchiolitis and obstructive pulmonary emphysema.