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Mustafa Abdo,1 Frederik Trinkmann,2,3 Anne-Marie Kirsten,4 Heike Biller,1 Frauke Pedersen,1,4 Benjamin Waschki,1 Erika Von Mutius,5 Matthias Kopp,6,7 Gesine Hansen,8 Klaus F Rabe,1 Thomas Bahmer,1,9,&ast; Henrik Watz4,&ast; On behalf of the ALLIANCE study group1LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 2Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany; 3Department of Biomedical Informatics, Heinrich-Lanz-Center, University Medical Center Mannheim, Heidelberg University, Heidelberg, Germany; 4Pulmonary Research Institute at the LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 5Dr von Hauner Children’s Hospital, Ludwig Maximilians University of Munich, Comprehensive Pneumology Center Munich, German Center for Lung Research (DZL), and Institute of Asthma and Allergy Prevention, Helmholtz Centre, Both Munich, Germany; 6Department of Pediatric Respiratory Medicine, Inselspital, University Children’s Hospital of Bern, University of Bern, Bern, Switzerland; 7Division of Pediatric Pneumology & Allergology, University Hospital Schleswig-Holstein-Campus Luebeck, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Luebeck, Germany; 8Department of Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, Germany; 9University Hospital Schleswig-Holstein-Campus Kiel, department for Internal Medicine I, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Kiel, Germany&ast;These authors contributed equally to this workCorrespondence: Mustafa AbdoLungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Wöhrendamm 80, Grosshansdorf, 22927, GermanyTel +49 4102 601 2412Email m.abdo@lungenclinic.deRationale: Small airway dysfunction (SAD) is a frequent feature of asthma that has been linked to disease severity and poor symptom control. However, little is known about the role of SAD in nocturnal asthma.Objective: To study the association between the severity of SAD and frequency of nocturnal symptoms compared to conventional lung function testing.Methods: We assessed the frequency of self-reported nocturnal symptoms through the asthma control test. We studied the impact of nocturnal asthma using the Asthma Quality of Life Questionnaire (AQLQ) and the Multidimensional Fatigue Inventory (MFI-20). We assessed the lung function using spirometry, body plethysmography, impulse oscillometry, single and multiple inert gas washout and measured markers of T2-inflammation (blood and sputum eosinophils; fractional exhaled nitric oxide (FeNo)). We stratified the patients according to the presence and frequency of nocturnal asthma.Results: A total of 166 asthma patients were enrolled in the analysis. Eighty-seven patients (52%) reported to have nocturnal symptoms at least once in the last four weeks. The odds ratio of nocturnal asthma correlated with the severity of all non-spirometric measures of SAD, yet neither with airflow obstruction (FEV1 and FEV/FVC) nor with large airway resistance (R20). Patients with frequent nocturnal asthma (n = 29) had a numerical increase of T2 markers and more severe SAD, as indicated by all non-spirometric measures of SAD (all p-values < 0.05), worse overall asthma control, increased fatigue and reduced quality of life (all p-values < 0.01) compared to patients with infrequent nocturnal asthma (n = 58) or patients without nocturnal asthma (n = 79). We identified 63 patients without airflow obstruction, nearly 43% of them (n = 27) had nocturnal asthma. In this subgroup, only markers of air trapping and ventilation heterogeneity were significantly elevated and correlated with the frequency of nocturnal symptoms: LCI (Spearman’s coefficient = − 0.42, p < 0.001), RV% (− 0.32, p = 0.02).Conclusion: SAD is closely associated to asthma with nocturnal symptoms. Spirometry might underestimate the broad spectrum of distal lung function impairments in this population of patients.Keywords: small airway dysfunction, nocturnal asthma, ventilation heterogeneity, air trapping

Mustafa Abdo,1 Benjamin Waschki,2 Anne-Marie Kirsten,3 Frederik Trinkmann,4,5 Heike Biller,1 Christian Herzmann,6 Erika von Mutius,7 Matthias Kopp,8,9 Gesine Hansen,10 Klaus F Rabe,1 Thomas Bahmer,1,11,* Henrik Watz3,* On behalf of the ALLIANCE study group1LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 2Department of Cardiology and Pneumology at Hospital Itzehoe, Itzehoe, Germany; 3Pulmonary Research Institute at the LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 4Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany; 5Department of Biomedical Informatics, Heinrich-Lanz-Center, University Medical Center Mannheim, Heidelberg University, Heidelberg, Germany; 6Research Center Borstel, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Borstel, Germany; 7Dr von Hauner Children’s Hospital, Ludwig Maximilians University of Munich, Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research (DZL), Munich, Germany; 8Department of Pediatric Respiratory Medicine, Inselspital, University Children’s Hospital of Bern, University of Bern, Bern, Switzerland; 9Division of Pediatric Pneumology & Allergology, University Hospital Schleswig-Holstein-Campus Luebeck, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Luebeck, Germany; 10Department of Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, Germany; 11University Hospital Schleswig-Holstein-Campus Kiel, Department for Internal Medicine I, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Kiel, Germany*These authors contributed equally to this workCorrespondence: Mustafa AbdoLungenClinic Grosshansdorf GmbH, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Wöhrendamm 80, Großhansdorf, 22927, GermanyTel +49 4102 601 2412Email m.abdo@lungenclinic.deRationale: Asthma, obesity and physical activity (PA) are interrelated. However, longitudinal data with objective PA measures and direct assessment of body composition are still lacking.Objective: To study the impact of symptom control on PA and body composition.Methods: In a longitudinal cohort study of the German Center for Lung Research, we assessed the body composition of 233 asthma patients and 84 healthy controls using bioelectrical impedance analysis. PA (ie average daily steps and time of at least moderate activity, steps/min) was measured by accelerometry for one week. Asthma control was assessed by ACT score, ACQ-5 score and history of severe exacerbations. After two years of follow-up, we studied changes in physical activity and body composition in relation to asthma control.Results: Patients with uncontrolled asthma had increased fat mass and decreased muscle mass compared to patients with controlled asthma or healthy controls. Both fat mass and muscle mass correlated better with asthma control than the body mass index (BMI). In multivariate regressions adjusted for age and sex, asthma control and physical activity were independent predictors of body composition (R2 = 0.61, p&thinsp

BackgroundImpulse oscillometry (IOS) allows an effort-independent evaluation of small airway function in asthma. Unfortunately, well-determined minimal clinically important differences (MCIDs) for IOS measures are lacking. Here, we provide MCIDs for frequently used IOS measures, namely frequency dependence of resistance (FDR) and area of reactance (AX), in patients with asthma.MethodsWe performed IOS at baseline and 1 year later in adult patients with mild-to-severe asthma (n=235). In a two-step approach, we first applied a distribution-based method to statistically determine the MCID. Next, we validated the proposed MCID according to patient-reported outcome measures (PROMs): Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Questionnaire-7 (ACQ-7) and Asthma Control Test (ACT). We used multivariable analyses to investigate the proposed MCIDs as predictors for improvements in PROMs compared with the established MCID of forced expiratory volume in 1 s (FEV1).ResultsThe proposed MCID was a decline of ≥0.06 kPa·L−1·s−1and ≥0.65 kPa·L−1for FDR and AX, respectively. Patients who had changes beyond the MCIDs for both FDR and AX showed greater improvements in all PROMs than those who had not. The mean improvements in PROMs were beyond the established MCIDs for ACQ-7 and AQLQ, and approximated the MCID for ACT. Multivariable analyses demonstrated the MCIDs for both FDR and AX as independent predictors for the MCIDs of all PROMs. The MCID for FDR was a stronger predictor of all PROMs than the MCID for FEV1.ConclusionsThis study provides MCIDs for IOS-derived measures in adult patients with asthma and emphasises that small airway function is a distinguished end-point beyond the conventional measure of FEV1.

Mustafa Abdo,1 Frauke Pedersen,1,2 Frederik Trinkmann,3,4 Felix JF Herth,3 Klaus F Rabe,1 Anne-Marie Kirsten,2 Henrik Watz2 1LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 2Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 3Pneumology and Critical Care Medicine, Thoraxklinik at University Hospital Heidelberg, Translational Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; 4Department of Biomedical Informatics (DBMI) at the Center for Preventive Medicine and Digital Health Baden-Württemberg (CPD-BW), University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyCorrespondence: Mustafa Abdo, LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Wöhrendamm 80, Grosshansdorf, 22927, Germany, Email m.abdo@lungenclinic.de

RationaleIn adults, personalised asthma treatment targets patients with type 2 (T2)-high and eosinophilic asthma phenotypes. It is unclear whether such classification is achievable in children.ObjectivesTo define T2-high asthma with easily accessible biomarkers and compare resulting phenotypes across all ages.MethodsIn the multicentre clinical All Age Asthma Cohort (ALLIANCE), 1125 participants (n=776 asthmatics, n=349 controls) were recruited and followed for 2 years (1 year in adults). Extensive clinical characterisation (questionnaires, blood differential count, allergy testing, lung function and sputum induction (in adults)) was performed at baseline and follow-ups. Interleukin (IL)-4, IL-5 and IL-13 were measured after stimulation of whole blood with lipopolysaccharide (LPS) or anti-CD3/CD28.Measurements and main resultsBased on blood eosinophil counts and allergen-specific serum IgE antibodies, patients were categorised into four mutually exclusive phenotypes: “atopy-only”, “eosinophils-only”, “T2-high” (eosinophilia + atopy) and “T2-low” (neither eosinophilia nor atopy). The T2-high phenotype was found across all ages, even in very young children in whom it persisted to a large degree even after 2 years of follow-up. T2-high asthma in adults was associated with childhood onset, suggesting early origins of this asthma phenotype. In both children and adults, the T2-high phenotype was characterised by excessive production of specific IgE to allergens (pConclusionsUsing easily accessible biomarkers, patients with T2-high asthma can be identified across all ages delineating a distinct phenotype. These patients may benefit from therapy with biologicals even at a younger age.

Comprehensive studies investigated the role of T-cells in asthma which led to personalised treatment options targeting severe eosinophilic asthma. However, little is known about the contribution of B-cells to this chronic inflammatory disease. In this study we investigated the contribution of various B-cell populations to specific clinical features in asthma.In the All Age Asthma Cohort (ALLIANCE), a subgroup of 154 adult asthma patients and 28 healthy controls were included for B-cell characterisation by flow cytometry. Questionnaires, lung function measurements, blood differential counts and allergy testing of participants were analysed together with comprehensive data on B-cells using association studies and multivariate linear models.Patients with severe asthma showed decreased immature B-cell populations while memory B-cells were significantly increased compared with both mild-moderate asthma patients and healthy controls. Furthermore, increased frequencies of IgAWith this study we demonstrate for the first time a significant association of increased IgA

Frauke Pedersen,1,2 Frederik Trinkmann,3 Mustafa Abdo,2 Anne-Marie Kirsten,1 Klaus F Rabe,2 Henrik Watz,1 Simonetta Baraldo,4 Marina Saetta,4 Jens M Hohlfeld,5,6 Olaf Holz5 1Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 2LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 3Pneumology and Critical Care Medicine, Thoraxklinik at University Hospital Heidelberg, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany; 4Department of Cardiac, Thoracic, Vascular Sciences and Public Health, Respiratory Diseases Clinic, University of Padova, Padova, Italy; 5Fraunhofer ITEM, Clinical Airway Research - Biomedical Research in End-Stage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany; 6Department of Respiratory Medicine, Hannover Medical School (MHH), Biomedical Research in End-Stage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, GermanyCorrespondence: Frauke PedersenPulmonary Research Institute at LungenClinic Grosshansdorf, Wöhrendamm 80, Grosshansdorf, D-22927, GermanyTel +49-4102-6016845Fax +49-4102-8881114Email f.pedersen@pulmoresearch.dePurpose: 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.Keywords: sputum cell quality score, soluble biomarkers, sputum supernatant

BACKGROUND Little is known about the role of small airway dysfunction (SAD) and its complex relation with asthma control and physical activity (PA). OBJECTIVE To investigate the interrelations among SAD, risk factors for asthma severity, symptom control, and PA. METHODS We assessed SAD by impulse oscillometry and other sophisticated lung function measures including inert gas washout in adults with asthma (mild to moderate, n = 140; severe, n = 128) and 69 healthy controls from the All Age Asthma Cohort. We evaluated SAD prevalence and its interrelation with risk factors for asthma severity (older age, obesity, and smoking), type 2 inflammation (sputum and blood eosinophils, fractional exhaled nitric oxide), systemic inflammation (high-sensitivity C-reactive protein), asthma control (AC), and PA (accelerometer for 1 week). We applied a clinical model based on structural equation modeling that integrated causal pathways among these clinical variables. RESULTS The prevalence of SAD ranged from 75% to 90% in patients with severe asthma and from 53% to 64% in mild to moderate asthma. Severe SAD was associated with poor AC and low PA. Structural equation modeling indicated that age, obesity, obesity-related systemic inflammation, T2 inflammation, and smoking are independent predictors of SAD. Small airway dysfunction was the main determinant factor of AC, which in turn affected PA. Obesity affected AC directly and through its contribution to SAD and low PA. In addition, PA had bidirectional associations with obesity, SAD, and AC. Structural equation modeling also indicated interrelations among distal airflow limitation, air trapping, and ventilation heterogeneity. CONCLUSIONS Small airway dysfunction is a highly prevalent key feature of asthma that interrelates a spectrum of distal lung function abnormalities with risk factors for asthma severity, asthma control, and physical activity.

Background Anti-T2 biological therapies have proven to effectively reduce acute exacerbations and daily doses of oral steroids in severe eosinophilic asthma. Despite the remarkable clinical efficacy, there are usually only moderate improvements in airflow limitation, suggesting that other measures of lung function like small airway dysfunction (SAD) might better reflect the clinical response. We aimed to investigate if measures of small airway function would predict and correlate with the clinical response to anti-T2 therapy. Methods We studied data of patients who were previously included in the German prospective longitudinal All Age Asthma Cohort (ALLIANCE) that recruits asthma patients of all severity grades and inflammatory phenotypes. The selection criteria for this analysis were adult patients with severe eosinophilic asthma under treatment with anti-T2 biological agents. Asthma control was assessed by asthma control test (ACT) and number of severe exacerbations. Small airway function was assessed by the frequency dependence of resistance (FDR, R5-20)) derived from impulse oscillometry (IOS) and the mean forced expiratory flow between 25 and 75% of the forced vital capacity (FEF25-75). We also studied air trapping (RV and RV/TLC), blood eosinophils and FeNO. Patients were classified into responders and partial or non-responders. Clinical response was defined as at least 50% reduction in annualized severe exacerbations and daily oral steroid doses accompanied with a minimum increase of 3 points in the ACT score. We used a Receiver Operator Characteristic (ROC) to study the capacity of FDR in predicting clinical response compared to other clinical variable like blood eosinophils. We studied the correlation between FDR measures and clinical response, represented by the ACT score and number of exacerbations, using linear regressions. Results 20 patients were included (mean age, 59 ± 9 years; 60% female; mean body mass index (BMI), 27.6 ± 5.4 kg/m2; mean absolute blood eosinophils, 570 ± 389/µl; mean number of severe exacerbations 12 months prior to initiating the biological therapy, 5.0 ± 3; mean predicted FEV1, 76 ± 21%; mean predicted FDR, 224 ± 140%; mean daily prednisolone dose, 6.4 ± 4.9 mg; mean ACT score, 15 ± 5). Responders had significantly higher baseline FDR compared to partial or non-responders but similar FEV1, FEF25–75, RV and RV/TLC. ROC analysis showed that the combination of FDR and blood eosinophils had the best predictive capacity of the clinical response among all tested clinical markers (FeNO, FEV1, FDR, blood eosinophils) with an AUC of 85% [67–100%], (CI = 0.95, p = 0.01). Linear regressions indicated better associations between improvements in FDR and ACT score (R2 = 0.42, p = 0.001) than with FEV1 and ACT score (R2 = 0.25, p = 0.013). Likewise, we observed better associations between improvements in FDR and reduction of exacerbations (R2 = 0.41, p = 0.001) than with FEV1 (R2 = 0.20, p = 0.025). Conclusion Our data suggest that severe SAD may represent a distinct phenotype of eosinophilic asthma that substantially improves under anti-T2 biological therapy. Measures of small airway function might be useful in selecting appropriate patients qualifying for anti-T2 biological therapy in addition to blood eosinophil count.

Background: Little is known about physical activity in daily life among patients with sarcoidosis. Fatigue is a frequent and disabling symptom that might negatively affect physical activity levels. Methods: In patients with sarcoidosis, we measured physical activity (steps per day) by accelerometry (SenseWear Armband) for 1 week. We assessed lung function (DLCO, FVC), exercise capacity (6-min walking distance [6MWD]), health-related quality of life (St George’s Respiratory Questionnaire [SGRQ]), generic quality of life (12-Item Short-Form Health Survey [SF-12]), and fatigue (Multidimensional Fatigue Inventory [MFI-20]). Results: We investigated 57 patients with sarcoidosis (mean age 50 years, 56% male, mean DLCO 73% predicted, mean FVC 91% predicted, mean 6MWD 525 m, mean steps per day 7,490), of whom n = 14 (25%) had severe fatigue. The MFI-20 subscales “reduced activity” and “physical fatigue” were weakly associated with steps per day on a bivariate level (Spearman ρ = –0.274 and ρ = –0.277, respectively; p < 0.05), while the other subscales and the total score were not. 6MWD, SGRQ score, and SF-12 (physical health) score showed stronger associations with steps per day in bivariate analyses (Pearson r = 0.499, r = –0.386, and r = 0.467, respectively; p < 0.01), and were independent predictors of steps per day in multivariate linear regression analyses adjusting for confounders (p < 0.05). In ROC curve analyses, 6MWD, SGRQ score, and SF-12 (physical health) score properly identified sedentary patients (steps per day p < 0.01). Fatigue was less predictive (MFI-20 subscale “general fatigue,” AUROC 0.70; p = 0.03). Conclusion: While exercise capacity and quality of life measurements were robust predictors of physical activity in patients with sarcoidosis, associations of objectively measured physical activity with fatigue were surprisingly weak. In sarcoidosis, fatigue might not preclude affected patients from being physically active, although this symptom is subjectively perceived as highly disabling.

Background: Physical activity (PA) is associated with disease severity in idiopathic pulmonary fibrosis (IPF), but longitudinal studies evaluating its prognostic value and changes over time are lacking. Methods: We measured PA (steps per day, SPD) in a cohort of 46 IPF-patients (mean age, 67 years; mean FVC, 76.1%pred.) by accelerometry at baseline, recorded survival status during 3 years follow-up and repeated measurements in survivors. We compared the prognostic value of PA to established mortality predictors including lung function (FVC, DLCO) and 6-min walking-distance (6MWD). Results: During follow-up (median 34 months) 20 patients (43%) died. SPD and FVC best identified non-survivors (AUROC-curve 0.79, p

Jutta Beier,1 Robert Mroz,2,3 Anne-Marie Kirsten,4 Ferran Chuecos,5 Esther Garcia Gil5 1insaf Respiratory Research Institute, Wiesbaden, Germany; 2Centrum Medycyny Oddechowej, 3Medical University of Białystok, Białystok, Poland; 4Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany; 5AstraZeneca PLC, Barcelona, Spain Background: A previous Phase IIIb study (NCT01462929) in patients with moderate to severe COPD demonstrated that 6 weeks of treatment with aclidinium led to improvements in 24-hour bronchodilation comparable to those with tiotropium, and improvement of symptoms versus placebo. This post hoc analysis was performed to assess the effect of treatment in the symptomatic patient group participating in the study. Methods: Symptomatic patients (defined as those with Evaluating Respiratory Symptoms [E-RS™] in COPD baseline score ≥10 units) received aclidinium bromide 400 µg twice daily (BID), tiotropium 18 µg once daily (QD), or placebo, for 6 weeks. Lung function, COPD respiratory symptoms, and incidence of adverse events (AEs) were assessed. Results: In all, 277 symptomatic patients were included in this post hoc analysis. Aclidinium and tiotropium treatment improved forced expiratory volume in 1 second (FEV1) from baseline to week 6 at all time points over 24 hours versus placebo. In addition, improvements in FEV1 from baseline during the nighttime period were observed for aclidinium versus tiotropium on day 1 (aclidinium 157 mL, tiotropium 67 mL; P

Background: miRNAs are critically involved in asthma and are actively secreted in extracellular vesicles (EV) for inter-cell communication. We have previously shown that total extracellular miRNAs in plasma can distinguish between asthma and healthy controls (Milger, Allergy, 2017). Thus, we now aimed to investigate if miRNA profiles from plasma EVs are altered in patients with asthma. Methods: We isolated EVs from 1 mL plasma of adult subjects from the ALLIANCE cohort with mild-to-moderate (AM) or severe asthma (AS), and healthy controls (HC) (n=15/group) by size exclusion chromatography (Izon). EVs were characterized by nanoparticle-tracking analysis and flow cytometry. EV RNA was isolated and subjected to small RNA-seq (Illumina). We correlated sequencing data with clinical characteristics and confirmed candidate miRNAs in a new set of EV isolates by RT-qPCR. Results: Isolated EVs had a median size of 131.5 nm and a median concentration of 8.6x10^9 particles/mL in HC, with no significant differences among the groups. RNA-seq detected 139 EV-miRNAs, 35 of which were expressed at moderate to high levels. miR-122-5p was significantly higher in EVs from AS patients compared to HC (log2FC=1.77, padj=0.019) and we observed a trend for miR-191-5p (log2FC=0.39, padj=0.11). Both findings were confirmed by RT-qPCR. Further, miR-191-5p significantly correlated with FEV1%pred (R=-0.38 p=0.013), eosinophil (R=0.45, p=0.0056) and neutrophil (R=-0.37, p=0.027) counts in blood. Conclusion: miR-122-5p and miR-191-5p are increased in EVs from subjects with asthma, and miR-191-5p correlates with lung function impairment and inflammation. Therefore, EV miRNAs might qualify for disease subphenotyping in asthma.

The 3-min constant speed shuttle test (CSST) was used to examine the effect of tiotropium/olodaterol compared with tiotropium at reducing activity-related breathlessness in patients with chronic obstructive pulmonary disease (COPD).This was a randomised, double-blind, two-period crossover study including COPD patients with moderate to severe pulmonary impairment, lung hyperinflation at rest and a Mahler Baseline Dyspnoea Index After 6 weeks, there was a decrease in the intensity of breathlessness (Borg dyspnoea score) at the end of the 3-min CSST from baseline with both tiotropium (mean –0.968, 95% CI −1.238– −0.698; n=100) and tiotropium/olodaterol (mean −1.325, 95% CI −1.594– −1.056; n=101). The decrease in breathlessness was statistically significantly greater with tiotropium/olodaterol versus tiotropium (treatment difference −0.357, 95% CI −0.661– −0.053; p=0.0217).Tiotropium/olodaterol reduced activity-related breathlessness more than tiotropium in dyspnoeic patients with moderate to severe COPD exhibiting lung hyperinflation.

Kai Michael Beeh,1 Anne-Marie Kirsten,2 Ana-Maria Tanase,3 Alexia Richard,3 Weihua Cao,4 Bettina Hederer,3 Jutta Beier,1 Oliver Kornmann,5 Richard N van Zyl-Smit6 1Insaf Respiratory Research Institute Wiesbaden, Wiesbaden, Germany; 2Pulmonary Research Institute at Lung Clinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany; 3Novartis Pharma AG, Basel, Switzerland; 4Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 5IKF Pneumologie, Clinical Research Centre Respiratory Diseases, Frankfurt, Germany; 6Division of Pulmonology and UCT Lung Institute, University of Cape Town, Cape Town, South Africa Background and purpose: Fixed-dose combinations of a long-acting beta agonist and an inhaled corticosteroid are more effective than the individual components in COPD. The primary study objective was to demonstrate that the combination indacaterol acetate/mometasone furoate (IND/MF [QMF149]) was non-inferior to the twice-daily combination salmeterol xinafoate/fluticasone propionate (Sal/Flu) in terms of trough FEV1 at week 12 (day 85). Secondary objectives were to compare the efficacy of IND/MF (QMF149) vs Sal/Flu with respect to other lung function parameters, COPD exacerbations, symptoms and dyspnea, health status/health-related quality of life, and rescue medication use.Materials and methods: This was a 12-week multicenter, randomized, double-blind, double-dummy, parallel-group, Phase II study in patients with moderate-to-very-severe COPD, who were randomized (1:1) to IND/MF (QMF149) (150/160 µg once daily; n=316) or Sal/Flu (50/500 µg twice daily; n=313).Results: Over 90% of patients completed the study: 94.6% in the IND/MF (QMF149) group and 92.0% in the Sal/Flu group. The primary objective of non-inferiority of IND/MF (QMF149) to Sal/Flu for trough FEV1 at week 12 (day 85) was met: the lower limit of the CI (95% CI: 27.7, 83.3 mL) was greater than -60 mL. The analysis for superiority of IND/MF (QMF149) to Sal/Flu demonstrated superiority of IND/MF (QMF149), with a difference of 56 mL (P

The efficacy and safety of twice-daily aclidinium bromide/formoterol fumarate was compared with that of salmeterol/fluticasone propionate in patients with stable, moderate-to-severe chronic obstructive pulmonary disease (COPD).AFFIRM COPD (Aclidinium and Formoterol Findings in Respiratory Medicine COPD) was a 24-week, double-blind, double-dummy, active-controlled study. Patients were randomised (1:1) to aclidinium/formoterol 400/12 µg twice-daily via Genuair/Pressair or salmeterol/fluticasone 50/500 µg twice-daily via Accuhaler. The primary end-point was peak forced expiratory volume in 1 s (FEV1) at week 24. Other end-points included Transition Dyspnoea Index (TDI) focal score at week 24, TDI and St George's Respiratory Questionnaire (SGRQ) responders, COPD Assessment Test and SGRQ scores, assessment of COPD symptoms and exacerbations, use of reliever medication, and device preference. Adverse events were monitored throughout.In total, 933 patients were eligible (mean age 63.4 years, 65.1% male). Aclidinium/formoterol was superior to salmeterol/fluticasone in peak FEV1 and noninferior in TDI. Health status and reduction in exacerbation risk were similar in both groups. While both treatments were well tolerated, pneumonia occurred less frequently with aclidinium/formoterol than salmeterol/fluticasone.In stable COPD, aclidinium/formoterol significantly improved bronchodilation versus salmeterol/fluticasone, with equivalent benefits in symptom control and reduction in exacerbation risk. Both treatments were well tolerated and treatment-related adverse events were less common with aclidinium/formoterol.

The 3-min constant speed shuttle test (CSST) was used to examine the effect of tiotropium/olodaterol compared with tiotropium at reducing activity-related breathlessness in patients with chronic obstructive pulmonary disease (COPD). This was a randomised, double-blind, two-period crossover study including COPD patients with moderate to severe pulmonary impairment, lung hyperinflation at rest and a Mahler Baseline Dyspnoea Index, Tiotropium/olodaterol reduces activity-related breathlessness versus tiotropium in COPD http://ow.ly/MVyk30niV1o

Prior to using a new multi-analyte platform for the detection of markers in sputum it is advisable to assess whether sputum processing, especially mucus homogenization by dithiothreitol (DTT), affects the analysis. In this study we tested a novel Human Inflammation Multi Analyte Profiling® Kit (v1.0 Luminex platform; xMAP®). Induced sputum samples of 20 patients with stable COPD (mean FEV1, 59.2% pred.) were processed in parallel using standard processing (with DTT) and a more time consuming sputum dispersion method with phosphate buffered saline (PBS) only. A panel of 47 markers was analyzed in these sputum supernatants by the xMAP®. Twenty-five of 47 analytes have been detected in COPD sputum. Interestingly, 7 markers have been detected in sputum processed with DTT only, or significantly higher levels were observed following DTT treatment (VDBP, α-2-Macroglobulin, haptoglobin, α-1-antitrypsin, VCAM-1, and fibrinogen). However, standard DTT-processing resulted in lower detectable concentrations of ferritin, TIMP-1, MCP-1, MIP-1β, ICAM-1, and complement C3. The correlation between processing methods for the different markers indicates that DTT processing does not introduce a bias by affecting individual sputum samples differently. In conclusion, our data demonstrates that the Luminex-based xMAP® panel can be used for multi-analyte profiling of COPD sputum using the routinely applied method of sputum processing with DTT. However, researchers need to be aware that the absolute concentration of selected inflammatory markers can be affected by DTT.

Background: Little is known about physical activity in daily life in patients with sarcoidosis. Fatigue is a frequent and disabling symptom that might negatively affect physical activity levels. Methods: In patients with sarcoidosis we measured physical activity (steps per day, SPD) by accelerometry (SenseWear Armband) for one week. We assessed lung function (DLCO, FVC), exercise capacity (6-min walk-distance, 6MWD), health-related quality of life (SGRQ), generic quality of life (SF-12), and fatigue (MFI-20). Results: We investigated 57 patients with sarcoidosis (mean age 50 years, 56% male, mean DLCO 73%pred., mean FVC 91%pred., mean 6MWD 525m, mean SPD 7,490) of whom n=14 (25%) had severe fatigue. MFI-20 subscales ‘reduced activity’ and ‘physical fatigue’ were weakly associated with SPD on a bivariate level (Spearman-rho=-0.27, and -0.28; p Conclusion: While exercise capacity and quality of life measurements were robust predictors of physical activity in patients with sarcoidosis, associations of objectively measured physical activity with fatigue were surprisingly weak. In sarcoidosis, fatigue might not preclude affected patients from being physically active, although this symptom is subjectively perceived as highly disabling.

Background: This randomized, double-blind, Phase IIIb study evaluated the 24-hour bronchodilatory efficacy of aclidinium bromide versus placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Methods: Patients received aclidinium 400 μg twice daily (morning and evening), tiotropium 18 μg once daily (morning), or placebo for 6 weeks. The primary endpoint was change from baseline in forced expiratory volume in 1 second area under the curve for the 24-hour period post-morning dose (FEV1 AUC0–24) at week 6. Secondary and additional endpoints included FEV1 AUC12–24, COPD symptoms (EXAcerbations of chronic pulmonary disease Tool-Respiratory Symptoms [E-RS] total score and additional symptoms questionnaire), and safety. Results: Overall, 414 patients were randomized and treated (FEV1 1.63 L [55.8% predicted]). Compared with placebo, FEV1 AUC0–24 and FEV1 AUC12–24 were significantly increased from baseline with aclidinium (Δ = 150 mL and 160 mL, respectively; p < 0.0001) and tiotropium (Δ = 140 mL and 123 mL, respectively; p < 0.0001) at week 6. Significant improvements in E-RS total scores over 6 weeks were numerically greater with aclidinium (p < 0.0001) than tiotropium (p < 0.05) versus placebo. Only aclidinium significantly reduced the severity of early-morning cough, wheeze, shortness of breath, and phlegm, and of nighttime symptoms versus placebo (p < 0.05). Adverse-event (AE) incidence (28%) was similar between treatments. Few anticholinergic AEs (

SummaryInduced sputum is a non-invasive sampling technique for the analysis of airway inflammation in various lung diseases and comprises valuable potential for the identification of biomarkers and therapeutic targets by molecular methods. In the context of biobanking with preservation of induced sputum samples for subsequent analyses we applied the HEPES-glutamic acid buffer-mediated organic solvent protection effect (HOPE)-technique for preparation of induced sputum samples.Induced sputum samples of 20 patients with moderate to severe chronic obstructive pulmonary disease (COPD) and 12 healthy controls were collected. Cell pellets of induced sputum samples were preserved with HOPE and subsequently embedded in paraffin. Immunostaining of paraffin-block sections for interleukin-8, interleukin-17, myeloperoxidase, matrixmetalloproteinase-9, CD68, and CD8 revealed distinct signals without antigen retrieval. Moreover, RNA was extracted and successfully used for transcription microarray analysis.Sputum samples preserved by the HOPE-technique display a tool to address scientific approaches in pulmonary research, which can enable the identification of new biomarkers and therapeutic targets in respiratory diseases.

Background: Aclidinium bromide 400 µg (AB) is known to improve lung function and symptoms in moderate to severe COPD; however, sleep disturbances are common in patients with COPD. Aim: This study investigated the effects of AB on symptoms and sleep quality. Methods: This was a Phase IV, 21-day, randomized, double-blind, placebo (PBO)-controlled, two-period, crossover pilot study (NCT02153489). Assessments included FEV 1 , symptoms (cough, wheeze, sputum, dyspnoea, chest tightness, congestion), physical activity, polysomnography and adverse events (AEs). Results: Patients (n=30; mean age: 64.4 y; male: 50%; mean pre-bronchodilator FEV 1 ±standard deviation: 1.3±0.4 L) received AB or PBO twice daily (BID). Patients with obstructive sleep apnoea were excluded. After 21 days, AB improved both trough and peak FEV 1 vs PBO (p Conclusions: In this pilot study, aclidinium 400 µg BID significantly improved lung function. Improvements were also observed in sleep quality, physical activity and symptoms in patients with moderate COPD. These changes may be clinically important and therefore require confirmation in adequately powered studies.

Background Long-acting bronchodilators, including anticholinergics glycopyrronium and tiotropium, are central to symptomatic management of chronic obstructive pulmonary disease (COPD). In patients with moderate to severe COPD, glycopyrronium has demonstrated comparable efficacy to open-label and single-blinded tiotropium, but with faster onset of bronchodilation. The FAST study assessed the efficacy of glycopyrronium compared with tiotropium in serial spirometry and body plethysmography assessments to further characterize the earlier onset of action associated with glycopyrronium. Methods In this German multicentre, randomised, double-blinded, double-dummy, cross-over study, patients with moderate-to-severe COPD received single-dose of glycopyrronium 44 μg and tiotropium 18 μg via the Breezhaler® and Handihaler® devices, respectively. Primary objective was to demonstrate superiority of glycopyrronium over tiotropium in terms of improvement in forced expiratory volume in 1 s as assessed by the area under the curve from 0 to 2 h (FEV1 AUC 0–2h). Secondary endpoints were functional residual capacity (FRC), residual volume (RV), inspiratory capacity (IC), and specific airway resistance (sRaw), all measured by body plethysmography. Results Of the 152 patients randomised, 99.3% completed the study. After inhalation of the single dose, glycopyrronium demonstrated superiority over tiotropium in early bronchodilation as assessed by improvement in FEV1 AUC0–2h (least squares mean treatment difference = 37 mL; 95% CI: 16, 59 mL; p Conclusions Glycopyrronium was superior to tiotropium in terms of early bronchodilation. Although both glycopyrronium and tiotropium showed similar improvements in static lung volume parameters, glycopyrronium reduced specific airway resistance faster than tiotropium, which could in part explain the earlier FEV1 response seen with glycopyrronium. Trial registration ClinicalTrials.gov NCT01922271 .

Physical activity is reduced in severe asthma; impulse oscillometry was a better predictor than spirometry http://ow.ly/6WdN305D9aV

Background: Little is known about the consequences of idiopathic pulmonary fibrosis (IPF) for physical activity (PA). Objectives: We aimed to investigate levels of PA in IPF and to study associations of PA with lung function, exercise capacity, symptoms, and quality of life. Methods: In stable patients with IPF we measured PA (steps per day, SPD; physical activity level, PAL; minutes of moderate activity, MMA) by accelerometry (SenseWear Armband) for 1 week. We also assessed lung function (forced vital capacity, FVC; diffusing capacity for carbon monoxide, DLCO); exercise capacity (6-minute walking distance, 6MWD); dyspnea (modified Medical Research Council, mMRC); fatigue (Multidimensional Fatigue Inventory, MFI-20), and generic (12-Item Short Form Survey, SF-12) and health-related quality of life (St. George's Respiratory Questionnaire) as further clinical variables. Results: We investigated 48 patients with IPF in two centers (mean age, 67 years; 75% male; 23% on long-term oxygen therapy; mean FVC 75%pred.; mean DLCO 43%pred.; mean 6MWD 355 ± 140 m; mean SPD 5,017 ± 3,360). On a bivariate level, all clinical variables were significantly associated with SPD (p < 0.05). The associations of mMRC, MFI-20, SF-12 (physical health), and 6MWD with SPD were independent of impaired lung function (p < 0.05). At multivariate analyses, either 6MWD (total explained variance of the model, total R2: 42%) or MFI-20 (total R2: 39%) were the strongest independent predictors of SPD. Conclusion: Fatigue and exercise capacity are strong and independent predictors of PA in patients with IPF, which suggests that both measures should be assessed when the consequences of IPF for PA in daily life are studied.

The efficacy and safety of aclidinium bromide bid, a novel, long-acting, muscarinic antagonist, was assessed in patients with moderate to severe COPD.In this phase IIa randomized, double-blind, double-dummy, crossover trial, patients with moderate to severe COPD received aclidinium 400 μg bid, tiotropium 8 μg once daily, and placebo for 15 days, with a 9- to 15-day washout between treatment periods. Treatments were administered through the Genuair or HandiHaler dry powder inhalers. The primary end point was mean change from baseline in FEV(1) AUC(0-12/12h) (area under the curve where the numbers represent the time period for which data were collected divided by the number of hours over which the data are averaged [eg, 0-12 h postdose divided by 12 h]) on day 15. Secondary end points were changes from baseline in FEV(1) AUC(12-24/12h), FEV(1) AUC(0-24/24h), morning predose FEV(1), peak FEV(1), and COPD symptom scores.Thirty patients with COPD were randomized, and 27 completed the study. Mean change from baseline in FEV(1) AUC(0-12/12h) at day 15 was significantly greater for aclidinium and tiotropium over placebo (P.0001). Mean changes from baseline in FEV(1) AUC(12-24/12h), FEV(1) AUC(0-24/24h), morning predose FEV(1), and peak FEV(1) at day 15 were significantly greater for aclidinium and tiotropium over placebo (P.0001 for all except P.001 for FEV(1) AUC(12-24/12h) tiotropium vs placebo). Improvements were significantly greater with aclidinium vs tiotropium on day 1 for all of the normalized AUC values of FEV(1) as well as on day 15 for FEV(1) AUC(12-24/12h) (P.05 for all). COPD symptoms were significantly improved from baseline with aclidinium vs placebo (P.05) but not with tiotropium.In patients with COPD, aclidinium 400 μg bid compared with placebo provided clinically meaningful improvements in 24-h bronchodilation that generally were comparable to tiotropium 18 μg daily but with significant differences in favor of aclidinium observed in the average nighttime period. Larger studies with longer treatment duration are ongoing to confirm the efficacy of aclidinium 400 μg bid on bronchodilation and COPD symptoms.ClinicalTrials.gov; No.: NCT00868231; URL: www.clinicaltrials.gov.

The term "granulomatosis” covers a variety of diseases. Known or unknown agents determine epitheloid cell granulomas of various forms and activities. Sarcoidosis is one of the most common granulomatous disorders in humans. Diagnostic procedures are difficult, especially in extrapulmonary manifestations. Treatment is only necessary in case of severe symptoms or decreased pulmonary function. The therapy of choice are corticosteroids. Berylliosis as an occupational disease is not frequently diagnosed. With common diagnostic procedures the differentiation between sarcoidosis and berylliosis is not possible, because of similarities in clinical and morphological signs. The estimated number of unreported cases is therefore high. The number of beryllium-exposed persons is rising so that increased numbers of the disease are expected. Therapy is comparable to the treatment in sarcoidosis.

Background: Aclidinium bromide/formoterol fumarate fixed-dose combination (FDC) twice daily (BID) is licensed in Europe for COPD treatment. Aim: To evaluate the efficacy of aclidinium/formoterol vs salmeterol/fluticasone propionate FDC (SAL/FLU) in patients (pts) with COPD. Methods: A randomised, double-blind, Phase IIIb, 24-week study in pts with COPD Assessment Test (CAT) score ≥10 compared aclidinium/formoterol 400/12 µg BID via Genuair® with SAL/FLU 50/500 µg BID via Accuhaler® ([NCT01908140][1]). Endpoints were peak FEV1 (primary), Transition Dyspnoea Index (TDI; secondary), CAT, device preference and exacerbations. Non-inferiority of aclidinium/formoterol vs SAL/FLU was tested for peak FEV1 and TDI. Superiority in peak FEV1 was also analysed. Results: 933 pts were randomised: mean age 63.4 years; 65.1% male; mean post-bronchodilator FEV1 1.48 L (53.2% predicted); mean CAT score 18.5. 788 pts (84.5%) completed the study. Aclidinium/formoterol achieved greater peak FEV1 vs SAL/FLU from Day 1 to Week 24 (p

Background The most prevalent phenotype of asthma is characterized by eosinophil-dominated inflammation that is driven by a type 2 helper T cell (Th2). Therapeutic targeting of GATA3, an important transcription factor of the Th2 pathway, may be beneficial. We evaluated the safety and efficacy of SB010, a novel DNA enzyme (DNAzyme) that is able to cleave and inactivate GATA3 messenger RNA (mRNA). Methods We conducted a randomized, double-blind, placebo-controlled, multicenter clinical trial of SB010 involving patients who had allergic asthma with sputum eosinophilia and who also had biphasic early and late asthmatic responses after laboratory-based allergen provocation. A total of 40 patients could be evaluated; 21 were assigned to receive 10 mg of SB010, and 19 were assigned to receive placebo, with each study drug administered by means of inhalation once daily for 28 days. An allergen challenge was performed before and after the 28-day period. The primary end point was the late asthmatic response as quantified by the change in the area under the curve (AUC) for forced expiratory volume in 1 second (FEV1). Results After 28 days, SB010 attenuated the mean late asthmatic response by 34%, as compared with the baseline response, according to the AUC for FEV1, whereas placebo was associated with a 1% increase in the AUC for FEV1 (P=0.02). The early asthmatic response with SB010 was attenuated by 11% as measured by the AUC for FEV1, whereas the early response with placebo was increased by 10% (P=0.03). Inhibition of the late asthmatic response by SB010 was associated with attenuation of allergen-induced sputum eosinophilia and with lower levels of tryptase in sputum and lower plasma levels of interleukin-5. Allergen-induced levels of fractional exhaled nitric oxide and airway hyperresponsiveness to methacholine were not affected by either SB010 or placebo. Conclusions Treatment with SB010 significantly attenuated both late and early asthmatic responses after allergen provocation in patients with allergic asthma. Biomarker analysis showed an attenuation of Th2-regulated inflammatory responses. (Funded by Sterna Biologicals and the German Federal Ministry of Education and Research; ClinicalTrials.gov number, NCT01743768.)