Publications by authors named "Helgo Magnussen"

122 Publications

Withdrawal of inhaled corticosteroids versus continuation of triple therapy in patients with COPD in real life: observational comparative effectiveness study.

Respir Res 2021 Jan 21;22(1):25. Epub 2021 Jan 21.

Pneumology Department, Hospital Universitari Vall D'Hebron, Vall D'Hebron Institut de Recerca (VHIR), CIBER de Enfermedades Respiratorias (CIBERES), Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain.

Background: Inhaled corticosteroids (ICS) are indicated for prevention of exacerbations in patients with COPD, but they are frequently overprescribed. ICS withdrawal has been recommended by international guidelines in order to prevent side effects in patients in whom ICS are not indicated.

Method: Observational comparative effectiveness study aimed to evaluate the effect of ICS withdrawal versus continuation of triple therapy (TT) in COPD patients in primary care. Data were obtained from the Optimum Patient Care Research Database (OPCRD) in the UK.

Results: A total of 1046 patients who withdrew ICS were matched 1:4 by time on TT to 4184 patients who continued with TT. Up to 76.1% of the total population had 0 or 1 exacerbation the previous year. After controlling for confounders, patients who discontinued ICS did not have an increased risk of moderate or severe exacerbations (adjusted HR: 1.04, 95% confidence interval (CI) 0.94-1.15; p = 0.441). However, rates of exacerbations managed in primary care (incidence rate ratio (IRR) 1.33, 95% CI 1.10-1.60; p = 0.003) or in hospital (IRR 1.72, 95% CI 1.03-2.86; p = 0.036) were higher in the cessation group. Unsuccessful ICS withdrawal was significantly and independently associated with more frequent courses of oral corticosteroids the previous year and with a blood eosinophil count ≥ 300 cells/μL.

Conclusions: In this primary care population of patients with COPD, composed mostly of infrequent exacerbators, discontinuation of ICS from TT was not associated with an increased risk of exacerbation; however, the subgroup of patients with more frequent courses of oral corticosteroids and high blood eosinophil counts should not be withdrawn from ICS. Trial registration European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS30851).
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http://dx.doi.org/10.1186/s12931-021-01615-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818945PMC
January 2021

Effect of Inhaled Corticosteroid Withdrawal on Chronic Obstructive Pulmonary Disease Exacerbations in Patients Taking Triple Therapy at Baseline.

Int J Chron Obstruct Pulmon Dis 2020 11;15:2879-2888. Epub 2020 Nov 11.

Pulmonary Research Institute at Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany.

Purpose: In the Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management (WISDOM) trial, inhaled corticosteroid (ICS) withdrawal in patients with chronic obstructive pulmonary disease receiving triple therapy (long-acting β-agonist+long-acting muscarinic antagonist+ICS) did not change moderate/severe exacerbation risk. However, many patients were not taking triple therapy before study participation. This analysis was conducted to eliminate the impact of non-ICS users on WISDOM results by re-analyzing the data using only the subset of patients who were taking triple therapy at screening.

Patients And Methods: The effect of ICS withdrawal on moderate/severe exacerbation risk in the subgroup of WISDOM patients taking triple therapy before enrolling in the study was evaluated in this post hoc analysis. Additionally, the effect of ICS withdrawal in patients with a history of ≥2 exacerbations in the previous year and various blood eosinophil counts was assessed.

Results: Overall, 39.0% (n=970: ICS continuation, 479; ICS withdrawal, 491) of the WISDOM trial population were taking triple therapy at screening. Baseline characteristics were generally similar between groups. Moderate/severe exacerbation risk between the ICS withdrawal and continuation groups (hazard ratio [HR], 1.05; 95% confidence interval [CI]: 0.89-1.25) was not increased in patients taking triple therapy at screening versus the overall trial population (HR [95% CI]: 1.06 [0.94-1.19]). However, in patients with a history of ≥2 exacerbations, exacerbation risk (HR [95% CI]) increased nominally with blood eosinophil count from 1.07 [0.81-1.41] (≥100 cells/μL) to 1.45 [0.58-3.60] (≥400 cells/μL).

Conclusion: Consistent with results from the overall WISDOM trial population, ICS withdrawal did not increase exacerbation risk in patients taking triple therapy at screening. Patients with a history of frequent exacerbations and higher blood eosinophil counts could benefit from continuation of ICS-based therapy.
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http://dx.doi.org/10.2147/COPD.S237408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667507PMC
November 2020

Blood eosinophils as a biomarker of future COPD exacerbation risk: pooled data from 11 clinical trials.

Respir Res 2020 Sep 17;21(1):240. Epub 2020 Sep 17.

Clinical Science Centre, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.

Background: Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation and chronic inflammation. Predicting exacerbations of COPD, which contribute to disease progression, is important to guide preventative treatment and improve outcomes. Blood eosinophils are a biomarker for patient responsiveness to inhaled corticosteroids (ICS); however, their effectiveness as a predictive biomarker for COPD exacerbations is unclear.

Methods: This post hoc analysis pooled data from 11 Boehringer Ingelheim-sponsored Phase III and IV randomised COPD studies with similar methodologies. Exacerbation data were collected from these studies, excluding patients from the ICS withdrawal arm of the WISDOM® study. Patients were grouped according to their baseline blood eosinophil count, baseline ICS use and number of exacerbations in the year prior to each study.

Results: Exacerbation rate data and baseline eosinophil count were available for 22,125 patients; 45.6% presented with a baseline blood eosinophil count of ≤ 150 cells/μL, 34.3% with 150-300 cells/μL and 20.1% with > 300 cells/μL. The lowest exacerbation rates were observed in patients with ≤ 150 cells/μL, with small increases in exacerbation rate observed with increasing eosinophil count. When stratified by exacerbation history, the annual rate of exacerbations for patients with 0 exacerbations in the previous year increased in line with increasing eosinophil counts (0.38 for ≤ 150 cells/μL, 0.39 for 150-300 cells/μL and 0.44 for > 300 cells/μL respectively). A similar trend was identified for patients with one exacerbation in the previous year, 0.62, 0.66 and 0.67 respectively. For patients with ≥ 2 exacerbations, exacerbation rates fluctuated between 1.02 (≤ 150 cells/μL) to 1.10 (150-300 cells/μL) and 1.07 (> 300 cells/μL). Higher exacerbation rates were noted in patients treated with ICS at baseline (range 0.75 to 0.82 with increasing eosinophil count) compared with patients not on ICS (range 0.45 to 0.49).

Conclusion: We found no clinically important relationship between baseline blood eosinophil count and exacerbation rate. Hence, the current analysis does not support the use of blood eosinophils to predict exacerbation risk; however, previous exacerbation history was found to be a more reliable predictor of future exacerbations.

Trial Registration: ClinicalTrials.gov Identifiers: NCT00168844 , NCT00168831 , NCT00387088 , NCT00782210 , NCT00782509 , NCT00793624 , NCT00796653 , NCT01431274 , NCT01431287 , NCT02296138 and NCT00975195 .
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http://dx.doi.org/10.1186/s12931-020-01482-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499955PMC
September 2020

Point-of-care biomarkers in asthma management: Time to move forward.

Allergy 2020 04 7;75(4):995-997. Epub 2019 Oct 7.

Department of Respiratory Medicine and Allergology, Lund University, Lund, Sweden.

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http://dx.doi.org/10.1111/all.14045DOI Listing
April 2020

Genuair/Pressair Inhaler in COPD: The Patient Perspective.

COPD 2019 04 2;16(2):196-205. Epub 2019 Jul 2.

b Sofotec GmbH, a member of the AstraZeneca Group , Bad Homburg , Germany.

This article reviews the latest data pertaining to the Genuair/Pressair device, a breath-actuated, multi-dose dry-powder inhaler with a two-step inhalation process, which is marketed for the delivery of aclidinium alone or in combination with formoterol for long-term maintenance bronchodilation treatment in chronic obstructive pulmonary disease. It contains multiple feedback mechanisms to guide effective use, and safety features to avoid double-dosing or attempted use when empty. In addition to describing the design of Genuair, the article will provide an update on inhaler operability and performance, focusing on recent patient preference and satisfaction studies. The evidence suggests that patients find Genuair easy to use, with patients requiring less training and making fewer inhalation errors than with other inhalers, and that patient satisfaction with the device is high.
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http://dx.doi.org/10.1080/15412555.2019.1630807DOI Listing
April 2019

[Therapy control of COPD by Eosinophilic Granulocytes?]

Authors:
Helgo Magnussen

Dtsch Med Wochenschr 2019 07 28;144(13):917-921. Epub 2019 Jun 28.

Symptomatic patients with COPD reporting about repeated exacerbations in their history (group D according to GOLD recommendations) are treated with dual bronchodilation (LAMA/LABA) with potential benefits from additional ICS. Eosinophils in peripheral blood are considered as potential biomarkers to predict exacerbations. > 300 cells/µL or 4 % of eosinophils in peripheral blood are recommended to treat the patients with additional ICS. In clinical practice, about 10 - 15 % of patients with COPD are classified as group D according to GOLD. < 20 % have increased eosinophils in peripheral blood. Thus, ICS therapy should be restricted to a minority of patients with COPD.
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http://dx.doi.org/10.1055/a-0748-8856DOI Listing
July 2019

Spirometric changes during exacerbations of COPD: a post hoc analysis of the WISDOM trial.

Respir Res 2018 Dec 13;19(1):251. Epub 2018 Dec 13.

Institute of Ageing and Chronic Disease, Clinical Science Centre, University Hospital Aintree, Liverpool, UK.

Background: Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with loss of lung function and poor outcomes for patients. However, there are limited data on the time course of changes in forced expiratory volume in 1 s (FEV) preceding the first reported symptom and after the start of an exacerbation.

Methods: WISDOM was a multinational, randomized, double-blind, active-controlled, 52-week study in patients with severe-to-very severe COPD. Patients received triple therapy (long-acting muscarinic antagonist and long-acting β-agonist/inhaled corticosteroid [ICS]) for 6 weeks, and were randomized to continue triple therapy or stepwise withdrawal of the ICS (dual bronchodilator group). After suitable training, patients performed daily spirometry at home using a portable, battery-operated spirometer. In the present post hoc analysis, patients who continued to perform daily home spirometry and completed at least one measurement per week for a 56-day period before and after the start of a moderate or severe exacerbation were included. Missing values were imputed by linear interpolation (intermittent), backfilling (beginning) or carry forward (end). Exacerbation onset was the first day of a reported symptom of exacerbation.

Results: Eight hundred and eighty-eight patients in the WISDOM study had a moderate/severe exacerbation after the complete ICS withdrawal visit; 360 of them contributed at least one FEV measure per week for the 8 weeks before and after the event and are included in this analysis. Mean daily FEV began to decline from approximately 2 weeks before the onset of symptoms of an exacerbation, dropping from 0.907 L (mean Days - 56 to - 36 before the exacerbation) to 0.860 L on the first day of the exacerbation. After the exacerbation, mean FEV improved but did not return to pre-exacerbation levels (mean Days 36-56 after the exacerbation, 0.875 L). The pattern of FEV changes around exacerbations was similar in the triple therapy and dual bronchodilator groups, and a similar pattern was seen in moderate and severe exacerbations when analysed separately.

Conclusions: Mean lung function starts to decline prior to the first reported symptoms of an exacerbation, and does not recover to pre-exacerbation levels 8 weeks after the event.

Trial Registration: WISDOM (ClinicalTrials.gov number, NCT00975195 ).
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http://dx.doi.org/10.1186/s12931-018-0944-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293570PMC
December 2018

Physical Activity and Fatigue in Patients with Sarcoidosis.

Respiration 2018;95(1):18-26. Epub 2017 Nov 9.

Pulmonary Research Institute, LungenClinic Grosshansdorf, Grosshansdorf, Germany.

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 <5,000; AUROC 0.90, 0.81, and 0.80, respectively; 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.
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http://dx.doi.org/10.1159/000481827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804844PMC
October 2018

Triple Therapy in COPD: What We Know and What We Don't.

COPD 2017 Dec 9;14(6):648-662. Epub 2017 Nov 9.

d Airways Disease Section , National Heart and Lung Institute, Imperial College London , London , UK.

Triple inhaled therapy for chronic obstructive pulmonary disease (COPD) consists of an inhaled corticosteroid (ICS), a long-acting β-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) taken in combination. Triple therapy is recommended by the Global initiative for Chronic Obstructive Lung Disease (GOLD) for patients who experience recurrent exacerbations despite treatment with either a dual bronchodilator (preferred initial therapy) or LABA/ICS combination (alternative initial therapy). Although there is evidence for the greater efficacy of triple therapy compared with LABA/ICS and LAMA monotherapy with regards to improved lung function, health status, and exacerbation rate, the efficacy of triple therapy when compared with dual bronchodilation (LABA/LAMA) is as yet unknown. As ICS use is associated with an increased risk of developing pneumonia, it is important to assess the risk/benefit ratio of triple therapy on an individual basis, and identify patients most likely to benefit. The role of elevated blood eosinophils as a biomarker for the identification of candidates for ICS treatment is currently debated, and further prospective evidence is required. This review assesses evidence for the efficacy and safety of triple therapy and postulates on the prospective evidence from ongoing studies. The potential for treating patients who experience further exacerbations on dual bronchodilation according to phenotype is also considered, as well as withdrawal of ICS from triple therapy in patients who are unlikely to benefit.
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http://dx.doi.org/10.1080/15412555.2017.1389875DOI Listing
December 2017

Brain Activation during Perception and Anticipation of Dyspnea in Chronic Obstructive Pulmonary Disease.

Front Physiol 2017 23;8:617. Epub 2017 Aug 23.

Department of Systems Neuroscience, University Medical Center Hamburg-EppendorfHamburg, Germany.

Dyspnea is the impairing cardinal symptom in COPD, but the underlying brain mechanisms and their relationships to clinical patient characteristics are widely unknown. This study compared neural responses to the perception and anticipation of dyspnea between patients with stable moderate-to-severe COPD and healthy controls. Moreover, associations between COPD-specific brain activation and clinical patient characteristics were examined. During functional magnetic resonance imaging, dyspnea was induced in patients with stable moderate-to-severe COPD ( = 17) and healthy control subjects ( = 21) by resistive-loaded breathing. Blocks of severe and mild dyspnea were alternating, with each block being preceded by visually cued anticipation phases. During the perception of increased dyspnea, both patients and controls showed comparable brain activation in common dyspnea-relevant sensorimotor and cortico-limbic brain regions. During the anticipation of increased dyspnea, patients showed higher activation in hippocampus and amygdala than controls which was significantly correlated with reduced exercise capacity, reduced health-related quality of life, and higher levels of dyspnea and anxiety. This study suggests that patients with stable moderate-to-severe COPD show higher activation in emotion-related brain areas than healthy controls during the anticipation, but not during the actual perception of experimentally induced dyspnea. These brain activations were related to important clinical characteristics and might contribute to an unfavorable course of the disease via maladaptive psychological and behavioral mechanisms.
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http://dx.doi.org/10.3389/fphys.2017.00617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572159PMC
August 2017

What can we learn from pulmonary function testing in heart failure?

Eur J Heart Fail 2017 10 14;19(10):1222-1229. Epub 2017 Aug 14.

Klinik III für Innere Medizin, Herzzentrum der Universität zu Köln, Cologne, and Cologne Cardiovascular Research Center (CCRC), Heart Center at the University of Cologne, Cologne, Germany.

Pulmonary diseases frequently coexist in heart failure (HF), thus posing diagnostic and therapeutic challenges to cardiologists evaluating patients with overlapping symptoms and implementing recommended HF treatments. There is a growing body of evidence suggesting that pulmonary function testing might provide useful information for the best management of these patients. The availability of portable devices, allowing the measurement of spirometry and lung diffusion capacity for carbon monoxide outside of hospital-based pulmonary lung function laboratories, provides an opportunity for a more widespread use of these measures in the cardiology community, but their interpretation can be challenging. In this work, after a brief review of the methodologies, we discuss the interpretation of pulmonary function testing in patients with HF alone or associated with pulmonary diseases, and its contribution in differentiating cardiac and pulmonary symptoms and preventing acute cardiac decompensation. In addition, we examined recent evidence suggesting how the use of pulmonary function testing may provide independent prognostic information in HF patients with and without pulmonary disorders, and help therapeutic decisions to fill the treatment gap that still exists in HF patients with concomitant pulmonary diseases.
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http://dx.doi.org/10.1002/ejhf.946DOI Listing
October 2017

Physical activity patterns and clusters in 1001 patients with COPD.

Chron Respir Dis 2017 Aug 24;14(3):256-269. Epub 2017 Feb 24.

1 Department of Research & Education, CIRO, Horn, The Netherlands.

We described physical activity measures and hourly patterns in patients with chronic obstructive pulmonary disease (COPD) after stratification for generic and COPD-specific characteristics and, based on multiple physical activity measures, we identified clusters of patients. In total, 1001 patients with COPD (65% men; age, 67 years; forced expiratory volume in the first second [FEV], 49% predicted) were studied cross-sectionally. Demographics, anthropometrics, lung function and clinical data were assessed. Daily physical activity measures and hourly patterns were analysed based on data from a multisensor armband. Principal component analysis (PCA) and cluster analysis were applied to physical activity measures to identify clusters. Age, body mass index (BMI), dyspnoea grade and ADO index (including age, dyspnoea and airflow obstruction) were associated with physical activity measures and hourly patterns. Five clusters were identified based on three PCA components, which accounted for 60% of variance of the data. Importantly, couch potatoes (i.e. the most inactive cluster) were characterised by higher BMI, lower FEV, worse dyspnoea and higher ADO index compared to other clusters ( p < 0.05 for all). Daily physical activity measures and hourly patterns are heterogeneous in COPD. Clusters of patients were identified solely based on physical activity data. These findings may be useful to develop interventions aiming to promote physical activity in COPD.
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http://dx.doi.org/10.1177/1479972316687207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720232PMC
August 2017

Prognosis and longitudinal changes of physical activity in idiopathic pulmonary fibrosis.

BMC Pulm Med 2017 Jul 25;17(1):104. Epub 2017 Jul 25.

Pulmonary Research Institute at LungenClinic Grosshansdorf, Woehrendamm 80, 22927, Grosshansdorf, Germany.

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 < 0.01). After adjustment for confounders (sex, age, therapy), a standardized increase (i.e. one SD) in SPD, FVC%pred. or DLCO%pred. was associated with a more than halved risk of death (HR < 0.50; p < 0.01). Compared to baseline, SPD, FVC, and 6MWD annually declined in survivors by 973 SPD, 130 ml and 9 m, resulting in relative declines of 48.3% (p < 0.001), 13.3% (p < 0.001) and 7.8% (p = 0.055), respectively.

Conclusion: While PA predicts mortality of IPF patients similar to established functional measures, longitudinal decline of PA seems to be disproportionally large. Our data suggest that the clinical impact of disease progression could be underestimated by established functional measures.
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http://dx.doi.org/10.1186/s12890-017-0444-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526311PMC
July 2017

Aclidinium bromide improves symptoms and sleep quality in COPD: a pilot study.

Eur Respir J 2017 06 22;49(6). Epub 2017 Jun 22.

Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany.

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http://dx.doi.org/10.1183/13993003.00485-2017DOI Listing
June 2017

Plasminogen activator inhibitor-1 is elevated in patients with COPD independent of metabolic and cardiovascular function.

Int J Chron Obstruct Pulmon Dis 2017 22;12:981-987. Epub 2017 Mar 22.

Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany; Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany.

Introduction: Plasminogen activator inhibitor-1 (PAI-1), a major inhibitor of fibrinolysis, is associated with thrombosis, obesity, insulin resistance, dyslipidemia, and premature aging, which all are coexisting conditions of chronic obstructive pulmonary disease (COPD). The role of PAI-1 in COPD with respect to metabolic and cardiovascular functions is unclear.

Methods: In this study, which was nested within a prospective cohort study, the serum levels of PAI-1 were cross-sectionally measured in 74 stable COPD patients (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stages I-IV) and 18 controls without lung disease. In addition, triglycerides, high-density lipoprotein cholesterol, fasting plasma glucose, waist circumference, blood pressure, smoking status, high-sensitive C-reactive protein (hs-CRP), adiponectin, ankle-brachial index, N-terminal pro-B-type natriuretic peptide, and history of comorbidities were also determined.

Results: The serum levels of PAI-1 were significantly higher in COPD patients than in controls, independent of a broad spectrum of possible confounders including metabolic and cardiovascular dysfunction. A multivariate regression analysis revealed triglyceride and hs-CRP levels to be the best predictors of PAI-1 within COPD. GOLD Stages II and III remained independently associated with higher PAI-1 levels in a final regression analysis.

Conclusion: The data from the present study showed that the serum levels of PAI-1 are higher in patients with COPD and that moderate-to-severe airflow limitation, hypertriglyceridemia, and systemic inflammation are independent predictors of an elevated PAI-1 level. PAI-1 may be a potential biomarker candidate for COPD-specific and extra-pulmonary manifestations.
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http://dx.doi.org/10.2147/COPD.S128689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367764PMC
October 2017

Analysis of nocturnal actigraphic sleep measures in patients with COPD and their association with daytime physical activity.

Thorax 2017 08 12;72(8):694-701. Epub 2017 Jan 12.

Data Science Group, Philips Research, Eindhoven, The Netherlands.

Background: Sleep disturbances are common in patients with chronic obstructive pulmonary disease (COPD) with a considerable negative impact on their quality of life. However, factors associated with measures of sleep in daily life have not been investigated before nor has the association between sleep and the ability to engage in physical activity on a day-to-day basis been studied.

Aims: To provide insight into the relationship between actigraphic sleep measures and disease severity, exertional dyspnoea, gender and parts of the week; and to investigate the association between sleep measures and next day physical activity.

Methods: Data were analysed from 932 patients with COPD (66% male, 66.4±8.3 years, FEV% predicted=50.8±20.5). Participants had sleep and physical activity continuously monitored using a multisensor activity monitor for a median of 6 days. Linear mixed effects models were applied to investigate the factors associated with sleep impairment and the association between nocturnal sleep and patients' subsequent daytime physical activity.

Results: Actigraphic estimates of sleep impairment were greater in patients with worse airflow limitation and worse exertional dyspnoea. Patients with better sleep measures (ie, non-fragmented sleep, sleeping bouts ≥225 min, sleep efficiency ≥91% and time spent awake after sleep onset <57 min) spent significantly more time in light (p<0.01) and moderate-to-vigorous physical activity (p<0.01).

Conclusions: There is a relationship between measures of sleep in patients with COPD and the amount of activity they undertake during the waking day. Identifying groups with specific sleep characteristics may be useful information when designing physical activity-enhancing interventions.
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http://dx.doi.org/10.1136/thoraxjnl-2016-208900DOI Listing
August 2017

Daily home-based spirometry during withdrawal of inhaled corticosteroid in severe to very severe chronic obstructive pulmonary disease.

Int J Chron Obstruct Pulmon Dis 2016 22;11:1973-81. Epub 2016 Aug 22.

Institute of Ageing and Chronic Disease, Aintree University Hospital, Liverpool, UK.

The WISDOM study (NCT00975195) reported a change in lung function following withdrawal of fluticasone propionate in patients with severe to very severe COPD treated with tiotropium and salmeterol. However, little is known about the validity of home-based spirometry measurements of lung function in COPD. Therefore, as part of this study, following suitable training, patients recorded daily home-based spirometry measurements in addition to undergoing periodic in-clinic spirometric testing throughout the study duration. We subsequently determined the validity of home-based spirometry for detecting changes in lung function by comparing in-clinic and home-based forced expiratory volume in 1 second in patients who underwent stepwise fluticasone propionate withdrawal over 12 weeks versus patients remaining on fluticasone propionate for 52 weeks. Bland-Altman analysis of these data confirmed good agreement between in-clinic and home-based measurements, both across all visits and at the individual visits at study weeks 6, 12, 18, and 52. There was a measurable difference between the forced expiratory volume in 1 second values recorded at home and in the clinic (mean difference of -0.05 L), which may be due to suboptimal patient effort in performing unsupervised recordings. However, this difference remained consistent over time. Overall, these data demonstrate that home-based and in-clinic spirometric measurements were equally valid and reliable for assessing lung function in patients with COPD, and suggest that home-based spirometry may be a useful tool to facilitate analysis of changes in lung function on a day-to-day basis.
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http://dx.doi.org/10.2147/COPD.S106142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5001655PMC
August 2017

Peripheral Artery Disease and Its Clinical Relevance in Patients with Chronic Obstructive Pulmonary Disease in the COPD and Systemic Consequences-Comorbidities Network Study.

Am J Respir Crit Care Med 2017 01;195(2):189-197

8 Pulmonary Research Institute at Lung Clinic Grosshansdorf, Airway Research Center North (Member of German Center for Lung Research), Grosshansdorf, Germany.

Rationale: Knowledge about the prevalence of objectively assessed peripheral artery disease (PAD) and its clinical relevance in patients with chronic obstructive pulmonary disease (COPD) is scarce.

Objectives: We aimed to: (1) assess the prevalence of PAD in COPD compared with distinct control groups; and (2) study the association between PAD and functional capacity as well as health status.

Methods: The ankle-brachial index was used to diagnose PAD (ankle-brachial index ≤ 0.9). The 6-minute-walk distance, health status (St. George's Respiratory Questionnaire), COPD Assessment Test, and EuroQol-5-Dimensions were assessed in patients enrolled in the German COPD and Systemic Consequences-Comorbidities Network cohort study. Control groups were derived from the Study of Health in Pomerania.

Measurements And Main Results: A total of 2,088 patients with COPD (61.1% male; mean [SD] age, 65.3 [8.2] years, GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages I-IV: 9.4, 42.5, 37.5, and 10.5%, respectively) were included, of which 184 patients (8.8%; GOLD stage I-IV: 5.1, 7.4, 11.1, and 9.5%, respectively, vs. 5.9% in patients with GOLD stage 0 in the COPD and Systemic Consequences-Comorbidities Network) had PAD. In the Study of Health in Pomerania, PAD ranged from 1.8 to 4.2%. Patients with COPD with PAD had a significantly shorter 6-minute-walk distance (356 [108] vs. 422 [103] m, P < 0.001) and worse health status (St. George's Respiratory Questionnaire: 49.7 [20.1] vs. 42.7 [20.0] points, P < 0.001; COPD Assessment Test: 19.6 [7.4] vs. 17.9 [7.4] points, P = 0.004; EuroQol-5-Dimensions visual analog scale: 51.2 [19.0] vs. 57.2 [19.6], P < 0.001). Differences remained significant after correction for several confounders.

Conclusions: In a large cohort of patients with COPD, 8.8% were diagnosed with PAD, which is higher than the prevalence in control subjects without COPD. PAD was associated with a clinically relevant reduction in functional capacity and health status.
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http://dx.doi.org/10.1164/rccm.201602-0354OCDOI Listing
January 2017

Clinical Correlates of Reduced Physical Activity in Idiopathic Pulmonary Fibrosis.

Respiration 2016 1;91(6):497-502. Epub 2016 Jun 1.

LungClinic Grosshansdorf, Pulmonology, Grosshansdorf, Germany.

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.
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http://dx.doi.org/10.1159/000446607DOI Listing
September 2017

Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial.

Lancet Respir Med 2016 05 7;4(5):390-8. Epub 2016 Apr 7.

Institute of Ageing and Chronic Disease, Aintree University Hospital, Liverpool, UK.

Background: Blood eosinophil counts might predict response to inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD) and a history of exacerbations. We used data from the WISDOM trial to assess whether patients with COPD with higher blood eosinophil counts would be more likely to have exacerbations if ICS treatment was withdrawn.

Methods: WISDOM was a 12-month, randomised, parallel-group trial in which patients received 18 μg tiotropium, 100 μg salmeterol, and 1000 μg fluticasone propionate daily for 6 weeks and were then randomly assigned (1:1) electronically to receive either continued or reduced ICS over 12 weeks. We did a post-hoc analysis after complete ICS withdrawal (months 3-12) to compare rate of exacerbations and time to exacerbation outcomes on the basis of blood eosinophil subgroups of increasing cutoff levels. The WISDOM trial is registered at ClinicalTrials.gov, number NCT00975195.

Findings: In the 2296 patients receiving treatment after ICS withdrawal, moderate or severe exacerbation rate was higher in the ICS-withdrawal group versus the ICS-continuation group in patients with eosinophil counts (out of total white blood cell count) of 2% or greater (rate ratio 1·22 [95% CI 1·02-1·48]), 4% or greater (1·63 [1·19-2·24]), and 5% or greater (1·82 [1·20-2·76]). The increase in exacerbation rate became more pronounced as the eosinophil cutoff level rose, with significant treatment-by-subgroup interaction reached for 4% and 5% only. Similar results were seen with eosinophil cutoffs of 300 cells per μL and 400 cells per μL, and mutually exclusive subgroups.

Interpretation: Blood eosinophil counts at screening were related to the exacerbation rate after complete ICS withdrawal in patients with severe to very severe COPD and a history of exacerbations. Our data suggest that counts of 4% or greater or 300 cells per μL or more might identify a deleterious effect of ICS withdrawal, an effect not seen in most patients with eosinophil counts below these thresholds.

Funding: Boehringer Ingelheim.
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http://dx.doi.org/10.1016/S2213-2600(16)00100-4DOI Listing
May 2016

Reduced physical activity in lymphangioleiomyomatosis compared with COPD and healthy controls: disease-specific impact and clinical correlates.

Thorax 2016 07 11;71(7):662-3. Epub 2016 Mar 11.

Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North, Member of the German Center for Lung Research, Grosshansdorf, Germany.

Rationale: Sporadic lymphangioleiomyomatosis (LAM) is an orphan lung disease for which daily physical activity has not been studied so far and it is unclear whether a disease-specific impact beyond airflow limitation exists. Clinical correlates indicating reduced physical activity in addition to established parameters like airflow limitation and hypoxaemia are largely undetermined.

Method: We measured physical activity (steps per day, SPD; physical activity level, PAL; minutes of moderate activity, MMA) in 34 women with LAM, 32 FEV1-matched female patients with COPD and 15 age-matched healthy women for 1 week using an accelerometer. In addition, we assessed lung function measurements, questionnaires for generic and respiratory health status (12-Item Short Form Survey, SF-12; St. George's Respiratory Questionnaire, SGRQ), dyspnoea (modified Medical Research Council dyspnoea scale, mMRC) and fatigue (Multidimensional Fatigue Inventory, MFI-20).

Results: Patients with LAM (mean age 52.7 years, mean FEV1 62.7% predicted) showed reduced SPD, PAL and MMA (p<0.01) compared with healthy controls and reduced MMA (p=0.032) compared with female patients with COPD (mean age 65.2 years, mean FEV1 62.6% predicted). In multivariate regression analyses, adjusting for FEV1 and long-term oxygen therapy, either generic health status (SF-12 physical health) or fatigue (MFI-20) were the strongest independent predictors for SPD in patients with LAM (p=0.006 and p=0.004, respectively).

Conclusions: Physical activity in daily life is substatially reduced in LAM, when compared with healthy controls and COPD - indicating a disease specific impact. The regular assessment of fatigue and generic health status may improve disease management in LAM by taking daily physical activity of patients with LAM more adequately into account.
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http://dx.doi.org/10.1136/thoraxjnl-2015-207852DOI Listing
July 2016

Current thinking and new paradigm for COPD.

Respir Med 2016 Mar 13;112:126-7. Epub 2016 Jan 13.

Department of Pneumology, Vall d'Hebron University Hospital, Barcelona, Spain. Electronic address:

During the 2015 European Respiratory Society Congress, a symposium was held on 'Current thinking and new paradigm for COPD'. Through a combination of plenary lectures and interactive panel discussions, experts discussed the recent evidence for chronic obstructive pulmonary disease (COPD) treatment and how this evidence can be applied in clinical practice.
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http://dx.doi.org/10.1016/j.rmed.2015.10.014DOI Listing
March 2016

Neutrophil extracellular trap formation and extracellular DNA in sputum of stable COPD patients.

Respir Med 2015 Oct 22;109(10):1360-2. Epub 2015 Aug 22.

Pulmonary Research Institute at Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research, Grosshansdorf, Germany.

Introduction: Chronic obstructive pulmonary disease (COPD) is characterized by neutrophilic airway inflammation. Neutrophil extracellular trap (NET) formation - a meshwork of neutrophil DNA components and neutrophil enzymes are involved in innate immunity and inflammation. Little is known about the presence of these structures in induced sputum from stable COPD patients.

Methods: Induced sputum samples of 23 COPD patients and 10 healthy controls were collected. Sputum cells were harvested, cultivated and stained for NET components. Extracellular DNA was quantified using a NanoDrop 2000 spectrophotometer.

Results: NET formation was markedly upregulated in COPD sputum compared with healthy controls, irrespective of sputum purulence or smoking status. NET formation was associated with significantly higher concentration of extracellular DNA in sputum supernatant (484 ng/μl in COPD versus 268 ng/μl in controls, p = 0.013). Log-transformed extracellular DNA correlated with log-transformed absolute neutrophil numbers in sputum (r = 0.60; p < 0.001) and airway obstruction (r = -0.43; p = 0.013).

Conclusion: NET formation associated with higher concentrations of extracellular DNA may be a pathobiological feature of COPD-derived sputum neutrophils.
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http://dx.doi.org/10.1016/j.rmed.2015.08.008DOI Listing
October 2015

Structural Brain Changes in Patients With COPD.

Chest 2016 Feb 12;149(2):426-434. Epub 2016 Jan 12.

Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Research Group Health Psychology, University of Leuven, Leuven, Belgium. Electronic address:

Background: Patients with COPD suffer from chronic dyspnea, which is commonly perceived as highly aversive and threatening. Moreover, COPD is often accompanied by disease-specific fears and avoidance of physical activity. However, little is known about structural brain changes in patients with COPD and respective relations with disease duration and disease-specific fears.

Methods: This study investigated structural brain changes in patients with COPD and their relation with disease duration, fear of dyspnea, and fear of physical activity. We used voxel-based morphometric analysis of MRI images to measure differences in generalized cortical degeneration and regional gray matter between 30 patients with moderate to severe COPD and 30 matched healthy control subjects. Disease-specific fears were assessed by the COPD anxiety questionnaire.

Results: Patients with COPD showed no generalized cortical degeneration, but decreased gray matter in posterior cingulate cortex (whole-brain analysis) as well as in anterior and midcingulate cortex, hippocampus, and amygdala (regions-of-interest analyses). Patients' reductions in gray matter in anterior cingulate cortex were negatively correlated with disease duration, fear of dyspnea, and fear of physical activity. Mediation analysis revealed that the relation between disease duration and reduced gray matter of the anterior cingulate was mediated by fear of physical activity.

Conclusions: Patients with COPD demonstrated gray matter decreases in brain areas relevant for the processing of dyspnea, fear, and antinociception. These structural brain changes were partly related to longer disease duration and greater disease-specific fears, which might contribute to a less favorable course of the disease.
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http://dx.doi.org/10.1378/chest.15-0027DOI Listing
February 2016