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David Price,1,2 William Henley,1,3 José Eduardo Delfini Cançado,4 Leonardo M Fabbri,5 Huib AM Kerstjens,6 Alberto Papi,7 Nicolas Roche,8 Elif Şen,9 Dave Singh,10 Claus F Vogelmeier,11 Elena Nudo,12 Victoria Carter,1 Derek Skinner,1 Rebecca Vella,1 Joan B Soriano,13 Maxim Kots,12 George Georges14 1Observational and Pragmatic Research Institute, Singapore; 2Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 3Health Statistics Group, Department of Health and Community Sciences, University of Exeter Medical School, Exeter, UK; 4Santa Casa de São Paulo Medical School, São Paulo, Brazil; 5Respiratory Medicine, Department of Translational Medicine and for Romagna, University of Ferrara, Ferrara, Italy; 6Department of Pulmonary Diseases, University of Groningen and University Medical Centre Groningen, and Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands; 7Respiratory Medicine, University of Ferrara, Ferrara, Italy; 8Department of Respiratory Medicine, APHP-Centre University of Paris, Cochin Hospital and Institute (UMR1016), Paris, France; 9Department of Pulmonary Medicine, Ankara University School of Medicine, Ankara, Turkey; 10Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK; 11Department of Internal Medicine, Pulmonary and Critical Care Medicine, University of Marburg, Member of the German Centre for Lung Research (DZL), Marburg, Germany; 12Global Medical Affairs, Chiesi Farmaceutici, S.p.A, Parma, Italy; 13Respiratory Department, Hospital Universitario de La Princesa and Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; 14Global Clinical Development, Chiesi Farmaceutici, S.p.A, Parma, ItalyCorrespondence: David Price, Observational and Pragmatic Research Institute, 22 Sin Ming Lane, #06-76, Midview City, 573969, Singapore, Tel +65 3105 1489, Email dprice@opri.sgBackground: Combined ICS and long-acting bronchodilators (LABD) more effectively reduce COPD exacerbations than LABD therapy alone. Corticosteroid-related adverse effects, including pneumonia, limit ICS use. Previous data suggest this risk is lower for extrafine beclometasone (ef-BDP). We compared pneumonia risk among new users of fixed dose ICS/LABD formulations containing ef-BDP, versus patients initiating LABD without any ICS.Methods: A propensity-matched historical cohort study design used data from OPCRD. COPD patients with ≥ 1 year of continuous data who initiated LABD or ICS/LABD formulations containing ef-BDP were matched. Primary outcome was time to pneumonia event, as treated, using either sensitive (physician diagnosed) or specific (physician diagnosed and x-ray or hospital admission confirmed) definitions, with non-inferiority boundary of 15%.Results: 23,898 COPD patients were matched, who were 68± 11 years, 54.3% male and 56% current-smokers, while 43% were former-smokers. Initiation of ef-BDP/LABD was not associated with an increased risk of pneumonia versus LABD, for either a sensitive 0.89 (0.78– 1.02), P = 0.08 or a specific 0.91 (0.78– 1.05), P = 0.18 definition of pneumonia. The probability of remaining pneumonia free 1-year after ef-BDP/LABD was 98.4%, which was comparable to LABD at 97.7%, and was sustained up to 6 years of observation; non-inferiority criterion was met for both definitions. Initiation of ef-BDP/LABD was also associated with a reduced risk of developing LRTIs in the propensity matched cohort.Conclusion: Risk of pneumonia when using ICS for the management of COPD reported in several randomised controlled trials may not be relevant with ef-BDP in a diverse real-world clinical population.Keywords: inhaled corticosteroids, pneumonia, COPD, extrafine beclometasone, long-acting bronchodilators

David B Price,1,2 William Henley,1,3 José Eduardo Delfini Cançado,4 Leonardo M Fabbri,5 Huib AM Kerstjens,6 Alberto Papi,7 Nicolas Roche,8 Elif Şen,9 Dave Singh,10 Claus F Vogelmeier,11 Sara Barille,12 Elena Nudo,12 Victoria Carter,1 Derek Skinner,1 Rebecca Vella,1 George Georges13 1Observational and Pragmatic Research Institute, Singapore; 2Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 3Health Statistics Group, Institute of Health Research, University of Exeter Medical School, Exeter, UK; 4Santa Casa de São Paulo Medical School, São Paulo, Brazil; 5Respiratory Medicine, Department of Translational Medicine, University of Ferrara, Ferrara, Italy; 6Department of Pulmonary Diseases, University of Groningen and University Medical Centre Groningen, and Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, Netherlands; 7Respiratory Medicine, University of Ferrara, Ferrara, Italy; 8Department of Respiratory Medicine, APHP-Centre University of Paris, Cochin Institute, Paris, France; 9Department of Pulmonary Medicine, Ankara University School of Medicine, Ankara, Turkey; 10Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK; 11Department of Internal Medicine, Pulmonary and Critical Care Medicine, University of Marburg, Member of the German Centre for Lung Research (DZL), Marburg, Germany; 12Global Medical Affairs, Chiesi Farmaceutici, S.p.A., Parma, Italy; 13Global Clinical Development, Chiesi Farmaceutici, S.p.A., Parma, ItalyCorrespondence: David B Price, Observational and Pragmatic Research Institute, 22 Sin Ming Lane, #06-76, Midview City, 573969, Singapore, Email dprice@opri.sgBackground: Inhaled corticosteroids (ICS) afford therapeutic benefits in some COPD patients, but their widespread use is cautioned due to an increased risk of developing pneumonia. Subclass variations exist, and the risk profile differs for individual ICS. Formulation particle size has been identified as a potential effect modifier. The present study compared the risk of pneumonia among new COPD users of fixed-dose combination inhalers containing fine-particle fluticasone (fp-FDC-F) versus extrafine particle beclometasone (ef-FDC-BDP).Methods: A propensity matched historical cohort study was conducted using data from the Optimum Patient Care Research Database. COPD patients aged ≥ 40 years with ≥ 1 year of continuous medical data who initiated fp-FDC-F or ef-FDC-BDP were compared. The primary outcome was time to pneumonia event, as treated, using either sensitive (physician diagnosed) or specific (physician diagnosed and x-ray or hospital admission confirmed) definitions.Results: A total of 13,316 patients were matched. Initiation of fp-FDC-F (mean dosage furoate 99 μg; propionate 710 μg) was associated with an increased risk of pneumonia versus ef-FDC-BDP (mean beclometasone dose 395 μg), irrespective of definition (sensitive HR 1.38 95% CI 1.14– 1.68; specific HR 1.31 95% CI 1.05– 1.62).Conclusion: In the current investigation, we found that in comparison to extrafine beclomethasone, commencing a formulation containing fluticasone is associated with an increased risk of developing pneumonia. These observations support the idea that not all ICS are equal in their adverse effects and subclass variations exist and should be carefully considered in the treatment choice.Keywords: inhaled corticosteroids, pneumonia, COPD, extrafine beclomethasone, fluticasone

Erik Bathoorn,1 Feikje Groenhof,2 Ron Hendrix,1,3 Thys van der Molen,2,4 Bhanu Sinha,1 Huib AM Kerstjens,5 Alex W Friedrich,1 Janwillem WH Kocks2,4 1Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 2Department of Primary Care, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 3Department of Pulmonary Diseases and Tuberculosis, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 4Department of Medical Microbiology, Certe – Laboratory for Infectious Diseases, Groningen, the Netherlands; 5GRIAC Research Institute, Groningen, University of Groningen, University Medical Center Groningen, the Netherlands Background: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are generally treated with optimization of bronchodilation therapy and a course of oral corticosteroids, mostly without antibiotics. The Dutch guidelines recommend prudent use of antibiotics, with amoxicillin or doxycycline as first choice. Here we evaluate adherence to these guidelines with regard to antibiotic prescription in AECOPD in primary care and the use of sputum cultures. Methods: We retrospectively analyzed a longitudinal cohort of patients in three primary care practices in the north-eastern region of the Netherlands from 2009 to 2013 (n=36,172 subjects) participating in the Registration Network Groningen. Antibiotics prescribed for AECOPD -10/+28 days from the start date of corticosteroid courses were evaluated. In addition, we assessed regional data on the susceptibility of respiratory pathogens from COPD patients. Results: We identified 1,297 patients with COPD. Of these, 616 experienced one or more exacerbations, resulting in a total of 1,558 exacerbations, for which 1,594 antibiotic courses were prescribed. The recommended antibiotics doxycycline and amoxicillin accounted for 56% of the prescribed antibiotics overall and for 35% in subsequent antibiotic courses. The alternative choices were not based on culture results because only in 67 AECOPD events (2.9%) sputum samples were taken. Regional data including 3,638 sputum samples showed that pathogens relevant in AECOPD were detected in 19% of cultures. Conclusion: Our study shows that guidelines regarding the prescription of antibiotics are poorly followed, particularly in recurrent exacerbations. Sputum cultures were performed in a small minority of cases. Performing sputum diagnostics in patients with early treatment failure or a repeated exacerbation when antibiotic treatment is started may further rationalize antibiotic treatment. Keywords: COPD, exacerbation, antimicrobial stewardship, bacteria, sputum cultures

Kris Mooren,1,2,* Eline M Atsma,1,* Eline Duinker,1 Huib AM Kerstjens,3 David Currow,4 Yvonne Engels2 1Department of Pulmonology, Spaarne Gasthuis, Haarlem, the Netherlands; 2Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; 3Department of Pulmonary Diseases and Tuberculosis, University of Groningen and University Medical Centre Groningen, Groningen, the Netherlands; 4Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia*These authors contributed equally to this workCorrespondence: Kris Mooren, Boerhaavelaan 22, Haarlem, 2035RC, the Netherlands, Tel +3123545969, Email k.mooren@spaarnegasthuis.nlPurpose: Oxygen is commonly prescribed to patients with severe COPD. However, little is known about the perspectives COPD patients, who do not yet use oxygen, have on this treatment.Patients and Methods: A total of 14 oxygen-naïve patients with COPD Gold stages 3– 4 and a high symptom burden participated in semi-structured interviews, in which their beliefs and expectations regarding oxygen therapy were explored. We used conventional content analysis to process our qualitative data.Results: Four main themes were identified: seeking information, expected impact on quality of life, expected social impact and stigma, and last phase of life.Conclusion: The message that home oxygen should be started, was regarded as bad news by most participants. The rationale behind the therapy and the way it is delivered were unknown to most participants. Some participants anticipated smoking-related stigma and social isolation. Misconceptions such as tank explosions, becoming housebound, full dependency on oxygen and an imminent death were common amongst interviewees. Clinicians should be aware of these fears and assumptions when communicating with patients on this subject.Keywords: oxygen, palliative care, breathlessness, social stigma, chronic obstructive pulmonary disease

Richard N van Zyl-Smit,1 Kenneth R Chapman,2 Huib AM Kerstjens,3 Christian Gessner,4 Hironori Sagara,5 Ana-Maria Tanase,6 Motoi Hosoe,6 Abhijit Pethe,7 David Lawrence,6 Hanns-Christian Tillmann,8 Peter D’Andrea7 1Division of Pulmonology and UCT Lung Institute, University of Cape Town, Cape Town, South Africa; 2Division of Respiratory Medicine, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; 3Department of Pulmonology, University of Groningen, University Medical Center Groningen, and Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands; 4Universitätsklinikum Leipzig, Germany POIS Leipzig GbR, Leipzig, Germany; 5Department of Medicine, Division of Respiratory Medicine and Allergology, Showa University School of Medicine, Tokyo, Japan; 6Novartis Pharma AG, Basel, Switzerland; 7Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 8Novartis Institutes for BioMedical Research, Translational Medicine, Basel, SwitzerlandCorrespondence: Ana-Maria Tanase, Novartis Pharma AG, Fabrikstrasse 4, Novartis Campus, Basel, Switzerland, Tel +41 79 899 98 22, Email ana-maria.tanase@novartis.comBackground: Once-daily, single-inhaler mometasone furoate/indacaterol acetate/glycopyrronium bromide (MF/IND/GLY, an ICS/LABA/LAMA) and MF/IND (an ICS/LABA) via Breezhaler® have been approved for the maintenance treatment of patients with asthma inadequately controlled with medium-or high-dose ICS or medium-or high-dose ICS/LABA treatment.Objective: Once-daily (o.d.) formulations of MF/IND/GLY and MF/IND at different MF dose strengths have been compared with twice-daily (b.i.d.) fluticasone propionate/salmeterol xinafoate (FLU/SAL), and b.i.d. FLU/SAL+ o.d. tiotropium (TIO) in the PALLADIUM, IRIDIUM and ARGON studies.Methods: The similarity in study design and consistent outcomes in these studies prompted the pooling of data in this review to better characterise these novel once-daily controller formulations.Results: Pooled data from PALLADIUM and IRIDIUM studies showed comparable or greater efficacy with o.d. MF/IND formulations versus b.i.d. FLU/SAL. The o.d. MF/IND/GLY was superior to b.i.d. FLU/SAL in the IRIDIUM study, and similar to, if not more efficacious than b.i.d. FLU/SAL + o.d. TIO in the ARGON study.Conclusion: These formulations therefore provide novel once-daily treatment options for patients across asthma severity and flexibility for clinicians to step-up or step-down the treatment using the same device and formulations.Keywords: mometasone/indacaterol/glycopyrronium, mometasone/indacaterol, fluticasone/salmeterol, tiotropium, bronchodilator, lung function, asthma control, exacerbation

Johanna MC Broese,1,2 Rianne MJJ van der Kleij,1 Els ML Verschuur,2 Huib AM Kerstjens,3 Ewald M Bronkhorst,4 Niels H Chavannes,1 Yvonne Engels5 1Public Health & Primary Care, Leiden University Medical Center, Leiden, the Netherlands; 2Lung Alliance Netherlands, Amersfoort, the Netherlands; 3Respiratory Medicine & Tuberculosis, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands; 4Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands; 5Anesthesiology, Pain & Palliative Medicine, Radboud University Medical Center, Nijmegen, the NetherlandsCorrespondence: Johanna MC Broese, Department of Public Health and Primary Care, Leiden University Medical Centre, Post Zone V0-P, Postbox 9600, Leiden, 2300 RC, the Netherlands, Email j.m.c.broese@lumc.nlBackground: Difficulty predicting prognosis is a major barrier to timely palliative care provision for patients with COPD. The ProPal-COPD tool, combining six clinical indicators and the Surprise Question (SQ), aims to predict 1-year mortality as a proxy for palliative care needs. It appeared to be a promising tool for healthcare providers to identify patients with COPD who could benefit from palliative care.Objective: To externally validate the ProPal-COPD tool and to assess user experiences.Methods: Patients admitted with an acute exacerbation COPD were recruited across 10 hospitals. Demographics, clinical characteristics and survival status were collected. Sensitivity, specificity, positive and negative predictive values of the tool using two cut-off values were calculated. Also, predictive properties of the SQ were calculated. In monitoring meetings and interviews, healthcare providers shared their experiences with the tool. Transcripts were deductively coded using six user experience domains: Acceptability, Satisfaction, Credibility, Usability, User-reported adherence and Perceived impact.Results: A total of 523 patients with COPD were included between May 2019 and August 2020, of whom 100 (19.1%) died within 12 months. The ProPal-COPD tool had an AUC of 0.68 and a low sensitivity (55%) and moderate specificity (74%) for predicting 1-year all-cause mortality. Using a lower cut-off value, sensitivity was higher (74%), but specificity lower (46%). Sensitivity and specificity of the SQ were 56% and 73%, respectively (AUC 0.65). However, healthcare providers generally appreciated using the tool because it increased awareness of the palliative phase and provided a shared understanding of prognosis, although they considered its outcome not always correct.Conclusion: The accuracy of the ProPal-COPD tool to predict 1-year mortality is limited, although screening patients with its indicators increases healthcare providers’ awareness of palliative care needs and encourages them to timely initiate appropriate care.Keywords: chronic obstructive pulmonary disease, prognostication, palliative care, advance care planning, Surprise Question

B Ditz,1,2 LEM Kistemaker,2– 4 M van den Berge,1,2 JM Vonk,2,5 R Gosens,2,3 HAM Kerstjens1,2 1Department of Pulmonary Diseases, University Medical Center, University of Groningen, Groningen, the Netherlands; 2Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 3Department of Molecular Pharmacology of Groningen, University of Groningen, Groningen, the Netherlands; 4Aquilo BV, Groningen, the Netherlands; 5Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsCorrespondence: HAM KerstjensDepartment of Pulmonary Diseases, University Medical Center, University of Groningen, Groningen, the NetherlandsEmail h.a.m.kerstjens@umcg.nlIntroduction: There is a great interest to identify airway biomarkers to evaluate the potential and efficacy of anti-inflammatory therapeutic interventions. In this pilot study, we compared cytokine mRNA and protein levels of IL-6, IL-8, CCL2, CCL4, and TNF-α, as well as LTB-4 expression regarding their reproducibility and responsivity in induced sputum in COPD patients.Methods: We recruited a cohort of 17 patients with a moderate COPD exacerbation, necessitating antibiotics and/or oral corticosteroids. Patients were followed for two consecutive stable phase visits. Cytokine mRNA and protein levels were measured in induced sputum samples.Results: IL-6 and CCL4 protein levels decreased from exacerbation to stable phase, whereas their mRNA expression showed the same trend (not statistically significant). Coefficients of variation were overall lower (ie, more favorable for responsiveness) at protein levels compared to mRNA levels. No significant differences were observed in the reproducibility between cytokine mRNA expression and protein measurements. IL-6, IL-8, CCL2, and TNF-α gene expression levels yielded moderate to high intraclass correlation coefficients and/or Spearman correlation coefficients between both stable phase samples in contrast to their protein levels.Conclusion: Our findings suggest that several protein levels yield better responsivity with lower noise-to-signal ratios compared to their respective mRNA levels. In contrast, cytokine mRNA expression was more reproducible as it varied less in a stable state than proteins. Future studies are needed with a larger sample size to further evaluate the differences of responsivity and reproducibility between cytokine mRNA and protein measurements, not only during exacerbations.Keywords: COPD, exacerbation, induced sputum, cytokines, mRNA and protein levels

Anna Jetske Baron,1– 3 Bertine MJ Flokstra-de Blok,1,2,4 Huib AM Kerstjens,2,3 Gineke Koopmans-Klein,5 David B Price,6,7 Andrea A Sellink,8 Ioanna Tsiligianni,9 Janwillem WH Kocks1,2,6 1General Practitioners Research Institute, Groningen, the Netherlands; 2University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, the Netherlands; 3University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, the Netherlands; 4University of Groningen, University Medical Center Groningen, Beatrix Children’s Hospital, Department of Pediatric Pulmonology and Pediatric Allergology, Groningen, the Netherlands; 5Mundipharma Pharmaceuticals, Leusden, the Netherlands; 6Observational and Pragmatic Research Institute, Singapore; 7Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 8AstraZeneca, Den Haag, the Netherlands; 9Health Planning Unit, Department of Social Medicine, University of Crete, Crete, GreeceCorrespondence: Bertine MJ Flokstra-de Blok Prof. E.D. Wiersmastraat 5, Groningen, 9713 GH, the NetherlandsTel +31 50 2113898Email bertine@gpri.nlPurpose: Many patients with asthma still have insufficient disease control, despite the availability of effective treatment options. A substantial proportion of patients appear to rely more on short-acting beta2-agonist (SABA) rather than on anti-inflammatory maintenance treatment. The aim of this study was to describe differences in indicators of asthma symptoms and exacerbations among patients using more or less SABA than the guideline-recommended threshold of < 3 times/week.Patients and Methods: Data from Dutch respondents in the European REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey were used in this post hoc analysis. The survey included asthma patients aged 18– 50 years with at least two prescriptions for their asthma in the past two years. SABA use was categorized into two groups: < 3 (low-SABA users) or ≥ 3 (high-SABA users) times in the last week.Results: Of the 736 asthma patients, 21% did not use SABA and 19% used SABA 1 to 2 times (all low SABA users) and 60% used SABA ≥ 3 times (high SABA users) in the last week. The majority of high and low SABA users also reported using an ICS-containing treatment. Significant differences were found for all indicators related to exacerbations (p< 0.001): high SABA users more frequently used antibiotics and oral steroids, more frequently visited the emergency departments or needed an overnight hospital stay. Indicators of asthma symptoms were not significantly different between both groups.Conclusion: The majority of a Dutch asthmatic population reported high SABA use and had frequent moderate/severe exacerbations. More effective interventions are needed to change healthcare providers’ and patients’ behaviours to improve care and reduce SABA (over)use.Keywords: asthma, short acting beta2-agonist, SABA, primary health care, adverse effects, guidelines

Johanna MC Broese,1,2 Rianne MJJ van der Kleij,1 Els ML Verschuur,2 Huib AM Kerstjens,3 Yvonne Engels,4 Niels H Chavannes1 1Public Health & Primary Care, Leiden University Medical Center, Leiden, the Netherlands; 2Lung Alliance Netherlands, Amersfoort, the Netherlands; 3Respiratory Medicine & Tuberculosis, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands; 4Anesthesiology, Pain & Palliative Medicine, Radboud University Medical Center, Nijmegen, the NetherlandsCorrespondence: Johanna MC BroesePublic Health and Primary Care, Leiden University Medical Centre, Post Zone V0-P, Postbox 9600, Leiden, 2300 RC, the NetherlandsEmail j.m.c.broese@lumc.nlIntroduction: Patients with advanced chronic obstructive pulmonary disease (COPD) experience significant symptom burden, leading to poor quality of life. Although guidelines recommend palliative care for these patients, this is not widely implemented and prevents them from receiving optimal care.Objective: A national survey was performed to map the current content and organization of palliative care provision for patients with COPD by pulmonologists and general practitioners (GPs) in the Netherlands.Methods: We developed a survey based on previous studies, guidelines and expert opinion. Dutch pulmonologists and GPs were invited to complete the survey between April and August 2019.Results: 130 pulmonologists (15.3%; covering 76% of pulmonology departments) and 305 GPs (28.6%) responded. Median numbers of patients with COPD in the palliative phase treated were respectively 20 and 1.5 per year. 43% of pulmonologists and 9% of GPs reported some formalized agreements regarding palliative care provision. Physicians most often determined the start of palliative care based on clinical expertise or the Surprise Question. 31% of pulmonologists stated that they often or always referred palliative patients with COPD to a specialist palliative care team; a quarter rarely referred. 79% of the respondents mentioned to often or always administer opioids to treat dyspnea. The topics least discussed were non-invasive ventilation and the patient’s spiritual needs. The most critical barrier to starting a palliative care discussion was difficulty in predicting the disease course.Conclusion: Although pulmonologists and GPs indicated to regularly address palliative care aspects, palliative care for patients with COPD remains unstructured and little formalized. However, our data revealed a high willingness to improve this care. Clear guidance and standardization of practice are needed to help providers decide when and how to initiate discussions, when to involve specialist palliative care and how to optimize information exchange between care settings.Keywords: COPD, palliative care, advance care planning, surprise question, organization

Jaco Voorham,1,2 Simonetta Baldi,3 Luigi Santoro,4 Marjan Kerkhof,1,5 Marco Contoli,6 Leonardo M Fabbri,6 Huib AM Kerstjens,7 Jose Luis López-Campos,8 Nicolas Roche,9 Dave Singh,10 Claus F Vogelmeier,11 David B Price1,12 1Observational & Pragmatic Research Institute Pte Ltd, Singapore, Singapore; 2Data to Insights Research Solutions, Lisbon, Portugal; 3Department of Global Clinical Development, Chiesi SAS, Bois Colombes Cedex, France; 4Department of Global Clinical Development, Chiesi Farmaceutici S.p.A, Parma, Italy; 5Mescio Research, Blauwestad, The Netherlands; 6Section of Respiratory Medicine, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy; 7Department of Pulmonary Diseases, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands; 8Respiratory Diseases Unit, University Hospital Virgen Del Rocío, Seville, Spain; 9Service de Pneumologie, Hôpital Cochin, APHP, Centre-Université de Paris, Paris, France; 10University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK; 11Department of Internal Medicine, Pulmonary and Critical Care Medicine, University of Marburg, Member of the German Centre for Lung Research (DZL), Marburg, Germany; 12Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UKCorrespondence: David B PriceAcademic Primary Care, Division of Applied Health Sciences University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD 198785, UKTel +65 6962 3627Email dprice@opri.sgPurpose: This study aimed to evaluate the non-inferiority of initiating extrafine beclometasone dipropionate/formoterol fumarate (BDP/FF) versus double bronchodilation (long-acting beta-agonists [LABA]/long-acting muscarinic antagonists [LAMA]) among patients with a history of chronic obstructive pulmonary disease (COPD) exacerbations.Patients and Methods: A historical cohort study was conducted using data from the UK’s Optimum Patient Care Research Database. Patients with COPD ≥ 40 years at diagnosis were included if they initiated extrafine BDP/FF or any LABA/LAMA double therapy as a step-up from no maintenance therapy or monotherapy with inhaled corticosteroids (ICS), LAMA, or LABA and a history of ≥ 2 moderate/severe exacerbations in the previous two years. The primary outcome was exacerbation rate from therapy initiation until a relevant therapy change or end of follow-up. Secondary outcomes included rate of acute respiratory events, acute oral corticosteroids (OCS) courses, and antibiotic prescriptions with lower respiratory indication, modified Medical Research Council score (mMRC) ≥ 2, and time to first pneumonia diagnosis. The non-inferiority boundary was set at a relative difference of 15% on the ratio scale. Five potential treatment effect modifiers were investigated.Results: A total of 1735 patients initiated extrafine BDP/FF and 2450 patients initiated LABA/LAMA. The mean age was 70 years, 51% were male, 41% current smokers, and 85% had FEV1 < 80% predicted. Extrafine BDP/FF showed non-inferiority to LABA/LAMA for rate of exacerbations (incidence rate ratio [IRR] = 1.01 [95% CI 0.94– 1.09]), acute respiratory events (IRR = 0.98 [0.92– 1.04]), acute OCS courses (IRR = 1.01 [0.91– 1.11]), and antibiotic prescriptions (IRR = 0.99 [0.90– 1.09]), but not for mMRC (OR = 0.93 [0.69– 1.27]) or risk of pneumonia (HR = 0.50 [0.14– 1.73]). None of the a priori defined effect modifier candidates affected the comparative effectiveness.Conclusion: This study found that stepping up to extrafine BDP/FF from no maintenance or monotherapy was not inferior to stepping up to double bronchodilation therapy in patients with a history of exacerbations.Keywords: real-world, electronic health records, observational, comparative effectiveness, heterogeneity, chronic obstructive pulmonary disease

Lotte F Westbroek,1 Margot Klijnsma,1 Philippe Salomé,2 Lidewij M Sekhuis,1,3 Emiel Rolink,3 Erny Korsmit,4 Huib AM Kerstjens1,3 On behalf of the LAN COPD Care Pathway Study Group1Department of Pulmonary Diseases, University of Groningen, and University Medical Center Groningen, Groningen Research Institute for Asthma and COPD GRIAC, Groningen, The Netherlands; 2General practitioner, private practice, IJsselstein, The Netherlands; 3Lung Alliance Netherlands (LAN), Amersfoort, The Netherlands; 4Bravis Hospital, The Netherlands and Senior Advisor Healthcare Networking at Korsmit Zorgadvies, Bergen Op Zoom, The NetherlandsCorrespondence: Huib AM KerstjensDepartment of Pulmonary Diseases, University Medical Center Groningen, Room S3.131 (AA11), Postbox 30.001, Groningen 9700RB, The NetherlandsTel +31 50 361-0280Fax +31 50 36 19320Email h.a.m.kerstjens@umcg.nlBackground: Many patients with chronic obstructive pulmonary disease (COPD) experience exacerbations of symptoms, leading to a large burden on patients and the health system and costs to society. To address this burden, a 25% reduction in number of hospitalization days for COPD exacerbations was recently declared a national goal in the Netherlands, to be achieved in 5 years.Methods: A national care pathway was designed following an established managed clinical pathway setup, which involved prior national surveys and the identification of ten key elements. The concept was discussed, made locally applicable, and finally tested in eight regions containing eleven hospitals and surrounding primary-care groups in a prospective cohort study. All patients were followed for 1 year, starting at hospitalization.Results: In total, 752 patients gave informed consent and participated (mean age 70 years, 58% female). Of these, 120 (16%) died within a year. The median length of index hospitalization was 5 days, and 43% had at least one rehospitalization within 1 year (range 0– 8). There was a 19.4% reduction in number of total hospitalization days, without a decrease in health-related quality of life or perceived quality of care. Elements that contributed significantly to the reduction were contact in the first week after hospitalization, and during the year of follow-up pharmacological and nonpharmacological smoking-cessation guidance, checks on inhalation technique, and discussion of lung-attack plan.Discussion: With concerted action between patients and health workers in the hospital and in the community, a large reduction in number of hospitalization days can be achieved. The program was quite demanding for both patients and health workers. In our subsequent national implementation plan after this pilot study, we have named the major contributors to success and advocate the stepwise introduction of the elements in light of feasibility.Keywords: COPD, National Action Program, managed-care pathway, hospitalization

Karin Klooster,1,* T David Koster,1,* Christoph Ruwwe-Glösenkamp,2 Dorothea Theilig,3 Felix Doellinger,3 Jacopo Saccomanno,2 Huib AM Kerstjens,1 Dirk-Jan Slebos,1 Ralf-Harto Hübner2 1University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, Groningen, the Netherlands; 2Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Department of Pneumology, Berlin, Germany; 3Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Department of Radiology, Berlin, Germany*These authors contributed equally to this workCorrespondence: Karin Klooster Email k.klooster@umcg.nlPurpose: Lung volume reduction using one-way endobronchial valves is a bronchoscopic treatment for patients with severe emphysema without collateral ventilation between the treatment target lobe and the ipsilateral lobe(s). CT-scan fissure analysis is often used as a surrogate to predict the absence of collateral ventilation. We aimed to evaluate the predictive value of the fissure completeness score (FCS) compared to the functional Chartis measurement of collateral ventilation and to provide cut-off values of the FCS in patient selection.Patients and Methods: Multicenter study in patients eligible for treatment with one-way valves. The FCS was calculated by quantitative CT analysis (Thirona, the Netherlands) and compared to status of interlobar collateral ventilation measured with Chartis system (PulmonX, USA). Thresholds were calculated for the predictive values of the presence of collateral ventilation.Results: An FCS > 95% of the left major fissure had a positive predictive value (PPV) of 91%, with 1 in 11 fissures demonstrating collateral ventilation with Chartis measurement, whereas an FCS of ≤ 80% had a negative predictive value (NPV) of 100% for the presence of collateral ventilation. For the right major fissure, the NPV was 100% for an FCS ≤ 90%, but 69.7% for the right upper lobe fissure.Conclusion: Quantitative CT analysis is recommended in all patients evaluated for endobronchial valves. Patients with incomplete fissures (left major fissure: FCS < 80%; right major fissure: < 90%) can be excluded from Chartis measurement and endobronchial valve treatment. In patients with more complete fissures, the FCS is not specific enough for endobronchial valve treatment decisions. In this case, additional Chartis measurements are always recommended in the right lung. For the left lung, Chartis assessments may be omitted if the FCS is > 95%.Keywords: COPD, lung volume reduction, fissure, collateral ventilation, CT scan

Jorrit BA Welling,1,2 Jorine E Hartman,1,2 Sonja WS Augustijn,1 Huib AM Kerstjens,1,2 Lowie EGW Vanfleteren,3 Karin Klooster,1,2 Dirk-Jan Slebos1,2 1University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, Groningen, the Netherlands; 2Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 3COPD Center, Sahlgrenska University Medical Hospital and Institute of Medicine, Gothenburg University, Gothenburg, SwedenCorrespondence: Jorrit BA WellingDepartment of Pulmonary Diseases, University Medical Center Groningen, Groningen, the NetherlandsEmail j.b.a.welling@umcg.nlPurpose: Bronchoscopic lung volume reduction (BLVR) is a valuable treatment option for carefully selected patients with severe COPD. There is limited knowledge about the characteristics and outcomes of patients referred to a specialized center for BLVR. The study objectives were to investigate the selection rate for BLVR treatment in patients referred for this treatment and to investigate the differences between patients that were selected for BLVR and patients that were not.Patients and Methods: We performed a retrospective analysis of patients with severe COPD who were referred to our hospital to assess eligibility for BLVR treatment. Our parameters included demographics, comorbidity, chest computed tomography characteristics, reasons for rejection from BLVR treatment and patient survival.Results: In total, 1500 patients were included (mean age 62 years, 50% female and forced expiratory volume in 1 s 33% of predicted). Out of this group, 282 (19%) patients were selected for BLVR treatment. The absence of a suitable target lobe for treatment, an unsuitable disease phenotype and insufficient lung hyperinflation were the most important factors for not being selected. Patients that were selected for any BLVR option lived significantly longer than the group of patients that were not selected for BLVR (median 3060 versus 2079 days, P< 0.001).Conclusion: We found that only a small proportion of patients that are referred for BLVR treatment is eligible for a BLVR treatment, indicating a need for both better referral tools and for the development of new therapies for this group of patients. Furthermore, our data suggest that selection for BLVR is associated with a significant survival benefit.Keywords: bronchoscopic lung volume reduction, patient selection, endobronchial valves, lung volume reduction coils

Wouter H van Geffen,1,2 Bita Hajian,3 Wim Vos,4 Jan De Backer,4 Anthony Cahn,5 Omar S Usmani,6 Cedric Van Holsbeke,4 Massimo Pistolesi,7 Huib AM Kerstjens,2 Wilfried De Backer3 1Department of Respiratory Medicine, Medical Centre Leeuwarden, Leeuwarden, the Netherlands; 2Department of Pulmonary Diseases, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, University of Groningen, the Netherlands; 3Department of Pulmonary Diseases, Antwerp University Hospital, Antwerp, Belgium; 4FLUIDDA nv, Kontich, Belgium; 5GlaxoSmithKline R&D, Stevenage, UK; 6Faculty of Medicine, National Heart & Lung Institute, Imperial College London, London, UK; 7Department of Experimental and Clinical Medicine, Section of Respiratory Medicine, University of Florence, Florence, Italy Background: Exacerbations of COPD are a major burden to patients, and yet little is understood about heterogeneity. It contributes to the current persistent one-size-fits-all treatment. To replace this treatment by more personalized, precision medicine, new insights are required. We assessed the heterogeneity of exacerbations by functional respiratory imaging (FRI) in 3-dimensional models of airways and lungs. Methods: The trial was designed as a multicenter trial of patients with an acute exacerbation of COPD who were assessed by FRI, pulmonary function tests, and patient-reported outcomes, both in the acute stage and during resolution. Results: Forty seven patients were assessed. FRI analyses showed significant improvements in hyperinflation (a decrease in total volume at functional residual capacity of -0.25±0.61 L, p≤0.01), airway volume at total lung capacity (+1.70±4.65 L, p=0.02), and airway resistance. As expected, these improvements correlated partially with changes in the quality of life and in conventional lung function test parameters. Patients with the same changes in pulmonary function differ in regional disease activity measured by FRI. Conclusion: FRI is a useful tool to get a better insight into exacerbations of COPD, and significant improvements in its indices can be demonstrated from the acute phase to resolution even in relatively small groups. It clearly visualizes the marked variability within and between individuals in ventilation and resistance during exacerbations and is a tool for the assessment of the heterogeneity of COPD exacerbations. Keywords: COPD exacerbations, FRI, hyperinflation, chronic obstructive pulmonary disease, symptoms, heterogeneity

Wouter H van Geffen,1,2 Huib AM Kerstjens2 1Department of Respiratory Medicine, Medical Centre Leeuwarden, Leeuwarden, the Netherlands; 2Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Background: Static hyperinflation is known to be increased during moderate acute exacerbations of chronic obstructive pulmonary disease (COPD) (AECOPD), but few data exist in patients with severe exacerbations of COPD. The role of dynamic hyperinflation during exacerbations is unclear. Methods: In a prospective, observational cohort study, we recruited patients admitted to hospital for AECOPD. The following measurements were performed upon admission and again after resolution (stable state) at least 42 days later: inspiratory capacity (IC), body plethysmography, dynamic hyperinflation by metronome-paced IC measurement, health-related quality of life and dyspnea. Results: Forty COPD patients were included of whom 28 attended follow-up. The IC was low at admission (2.05±0.11 L) and increased again during resolution by 15.6%±23.1% or 0.28±0.08 L (mean ± standard error of the mean, p

Bita Hajian,1 Jan De Backer,2 Wim Vos,2 Wouter H van Geffen,3 Paul De Winter,1 Omar Usmani,4 Tony Cahn,5 Huib AM Kerstjens,3 Massimo Pistolesi,6 Wilfried De Backer1 1Department of Respiratory Medicine, University Hospital Antwerp, Edegem, Belgium; 2FLUIDDA nv, Kontich, Belgium; 3Department of Respiratory Medicine, University Medical Center Groningen, Groningen, the Netherlands; 4Department of Pulmonology, Brompton Hospital, London, UK; 5GSK, London, UK; 6Department of Pulmonary Diseases, University of Firenze, Florence, Italy Introduction: Severe exacerbations associated with chronic obstructive pulmonary disease (COPD) that require hospitalization significantly contribute to morbidity and mortality. Definitions for exacerbations are very broad, and it is unclear whether there is one predominant underlying mechanism that leads to them. Functional respiratory imaging (FRI) with modeling provides detailed information about airway resistance, hyperinflation, and ventilation–perfusion (V/Q) mismatch during and following an acute exacerbation. Materials and methods: Forty-two patients with COPD participating in a multicenter study were assessed by FRI, pulmonary function tests, and self-reported outcome measures during an acute exacerbation and following resolution. Arterial blood gasses and lung function parameters were measured. Results: A significant correlation was found between alveolar–arterial gradient and image-based V/Q (iV/Q), suggesting that iV/Q represents V/Q mismatch during an exacerbation (p

Rationale: Neutrophils are key players in chronic obstructive pulmonary disease (COPD), and increased numbers of neutrophils are present in sputum and lung tissue of patients with COPD. Interestingly, immunoglobulin free light chains (IgLC) are able to prolong the life of neutrophils; therefore, IgLC may contribute to the chronic state of inflammation. Objectives: In this study, the relation between IgLC and COPD has been investigated. Methods: We investigated the presence of IgLC in different murine lung emphysema models. IgLC levels in serum from mice and patients with COPD were examined by Western blot analysis and ELISA, respectively. IgLC levels in lung tissue were determined by immunohistochemistry. Fluorescence-activated cell sorter and immunofluorescent analysis were used to detect binding between IgLC and human neutrophils. Interleukin-8 (CXCL8) release by neutrophils after IgLC incubation was measured by ELISA. The effect of F991, an IgLC antagonist, was examined on the neutrophil influx in murine lungs after 5 days of smoke exposure. Measurements and Main Results: Increased levels of IgLC in serum of cigarette smoke-exposed and cigarette smoke extract-treated mice compared with control mice were observed. Patients with COPD showed increased serum IgLC and expression of IgLC in lung tissue compared with healthy volunteers. Interestingly, IgLC bound to neutrophils and activated neutrophils to release CXCL8. F991 inhibited the IgLC binding to neutrophils and reduced the smoke-induced neutrophil influx in murine lungs after smoke exposure. Conclusions: This study describes for the first time an association between neutrophils and IgLC in the pathophysiology of COPD, which could open new avenues to targeted treatment of this chronic disease. [ABSTRACT FROM AUTHOR]

Background: Inhaled corticosteroids (ICSs) and long-acting beta(2)-agonists (LABAs) are used to treat moderate to severe chronic obstructive pulmonary disease (COPD).Objective: To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD.Design: Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847)Setting: 2 university medical centers in The Netherlands.Patients: 114 steroid-naive current or former smokers with moderate to severe COPD.Measurements: Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months.Intervention: Random assignment by minimization method to receive fluticasone propionate, 500 microg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 microg twice daily, and salmeterol, 50 microg twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29).Results: 101 patients were greater than 70% adherent to therapy. Fluticasone therapy decreased counts of mucosal CD3(+) cells (-55% [95% CI, -74% to -22%]; P = 0.004), CD4(+) cells (-78% [CI, -88% to 60%]; P < 0.001), CD8(+) cells (-57% [CI, -77% to -18%]; P = 0.010), and mast cells (-38% [CI, -60% to -2%]; P = 0.039) and reduced hyperresponsiveness (P = 0.036) versus placebo at 6 months, with effects maintained after 30 months. Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium, with accompanying reductions in sputum neutrophil, macrophage, and lymphocyte counts and improvements in FEV(1) decline, dyspnea, and quality of life. Reductions in inflammatory cells correlated with clinical improvements. Discontinuing fluticasone therapy at 6 months increased counts of CD3(+) cells (120% [CI, 24% to 289%]; P = 0.007), mast cells (218% [CI, 99% to 407%]; P < 0.001), and plasma cells (118% [CI, 9% to 336%]; P = 0.028) and worsened clinical outcome. Adding salmeterol improved FEV(1) level.Limitations: The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months.Conclusion: ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD. Adding LABAs does not enhance these effects. . [ABSTRACT FROM AUTHOR]

BACKGROUND: The assessment of asthma control is pivotal to the evaluation of treatment response in individuals and in clinical trials. Previously, asthma control, severity, and exacerbations were defined and assessed in many different ways. PURPOSE: The Task Force was established to provide recommendations about standardization of outcomes relating to asthma control, severity, and exacerbations in clinical trials and clinical practice, for adults and children aged 6 years or older. METHODS: A narrative literature review was conducted to evaluate the measurement properties and strengths/weaknesses of outcome measures relevant to asthma control and exacerbations. The review focused on diary variables, physiologic measurements, composite scores, biomarkers, quality of life questionnaires, and indirect measures. RESULTS: The Task Force developed new definitions for asthma control, severity, and exacerbations, based on current treatment principles and clinical and research relevance. In view of current knowledge about the multiple domains of asthma and asthma control, no single outcome measure can adequately assess asthma control. Its assessment in clinical trials and in clinical practice should include components relevant to both of the goals of asthma treatment, namely achievement of best possible clinical control and reduction of future risk of adverse outcomes. Recommendations are provided for the assessment of asthma control in clinical trials and clinical practice, both at baseline and in the assessment of treatment response. CONCLUSIONS: The Task Force recommendations provide a basis for a multicomponent assessment of asthma by clinicians, researchers, and other relevant groups in the design, conduct, and evaluation of clinical trials, and in clinical practice. [ABSTRACT FROM AUTHOR]

BACKGROUND: Treatment with systemic corticosteroids for exacerbations of COPD results in improvement in clinical outcomes. On hospitalization, corticosteroids are generally administered IV. It has not been established whether oral administration is equally effective. We conducted a study to demonstrate that therapy with oral prednisolone was not inferior to therapy with IV prednisolone using a double-blind, double-dummy design. METHODS: Patients hospitalized for an exacerbation of COPD were randomized to receive 5 days of therapy with prednisolone, 60 mg IV or orally. Treatment failure, the primary outcome, was defined as death, admission to the ICU, readmission to the ICU because of COPD, or the intensification of pharmacologic therapy during a 90-day follow-up period. RESULTS: A total of 435 patients were referred for a COPD exacerbation warranting hospitalization; 107 patients were randomized to receive IV therapy, and 103 to receive oral therapy. Overall treatment failure within 90 days was similar, as follows: IV prednisolone, 61.7%; oral prednisolone, 56.3% (one-sided lower bound of the 95% confidence interval [CI], -5.8%). There were also no differences in early (ie, within 2 weeks) treatment failure (17.8% and 18.4%, respectively; one-sided lower bound of the 95% CI, -9.4%), late (ie, after 2 weeks) treatment failure (54.0% and 47.0%, respectively; one-sided lower bound of the 95% CI, -5.6%), and mean (+/- SD) length of hospital stay (11.9 +/- 8.6 and 11.2 +/- 6.7 days, respectively). Over 1 week, clinically relevant improvements were found in spirometry and health-related quality of life, without significant differences between the two treatment groups. CONCLUSION: Therapy with oral prednisolone is not inferior to IV treatment in the first 90 days after starting therapy. We suggest that the oral route is preferable in the treatment of COPD exacerbations. Trial registration: Clinicaltrials.gov Identifier: NCT00311961. [ABSTRACT FROM AUTHOR]

Farida F Berkhof,1 Leola Metzemaekers,1 Steven M Uil,1 Huib AM Kerstjens,2 Jan WK van den Berg11Department of Pulmonary Diseases, Isala Hospital, Zwolle, 2Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the NetherlandsBackground: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) are both common diseases that coexist frequently. Patients with both diseases have worse stable state health status when compared with patients with one of these diseases. In many outpatient clinics, health status is monitored routinely in COPD patients using the Clinical COPD Questionnaire (CCQ) and in HF patients with the Minnesota Living with Heart Failure Questionnaire (MLHF-Q). This study validated and compared which questionnaire, ie, the CCQ or the MLHF-Q, is suited best for patients with coexistent COPD and HF.Methods: Patients with both COPD and HF and aged ≥40 years were included. Construct validity, internal consistency, test–retest reliability, and agreement were determined. The Short-Form 36 was used as the external criterion. All questionnaires were completed at baseline. The CCQ and MLHF-Q were repeated after 2 weeks, together with a global rating of change.Results: Fifty-eight patients were included, of whom 50 completed the study. Construct validity was acceptable. Internal consistency was adequate for CCQ and MLHF-Q total and domain scores, with a Cronbach's alpha ≥0.70. Reliability was adequate for MLHF-Q and CCQ total and domain scores, and intraclass correlation coefficients were 0.70–0.90, except for the CCQ symptom score (intraclass correlation coefficient 0.42). The standard error of measurement on the group level was smaller than the minimal clinical important difference for both questionnaires. However, the standard error of measurement on the individual level was larger than the minimal clinical important difference. Agreement was acceptable on the group level and limited on the individual level.Conclusion: CCQ and MLHF-Q were both valid and reliable questionnaires for assessment of health status in patients with coexistent COPD and HF on the group level, and hence for research. However, in clinical practice, on the individual level, the characteristics of both questionnaires were not as good. There is room for a questionnaire with good evaluative properties on the individual level, preferably tested in a setting of patients with COPD or HF, or both.Keywords: Clinical COPD Questionnaire, Minnesota Living with Heart Failure Questionnaire, chronic obstructive pulmonary disease, heart failure

Jan Willem H Kocks,1,2 Jan Willem K van den Berg,3 Huib AM Kerstjens,2,4 Steven M Uil,3 Judith M Vonk,2,5 Ynze P de Jong,3 Ioanna G Tsiligianni,1,2 Thys van der Molen1,2 1Department of General Practice, 2Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, 3Department of Pulmonary Diseases, Isala Klinieken, Zwolle, 4Department of Pulmonary Diseases and Tuberculosis, 5Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Background: Exacerbations of chronic obstructive pulmonary disease (COPD) are a major burden to patients and to society. Little is known about the possible role of day-to-day patient-reported outcomes during an exacerbation. This study aims to describe the day-to-day course of patient-reported health status during exacerbations of COPD and to assess its value in predicting clinical outcomes. Methods: Data from two randomized controlled COPD exacerbation trials (n = 210 and n = 45 patients) were used to describe both the feasibility of daily collection of and the day-to-day course of patient-reported outcomes during outpatient treatment or admission to hospital. In addition to clinical parameters, the BORG dyspnea score, the Clinical COPD Questionnaire (CCQ), and the St George's Respiratory Questionnaire were used in Cox regression models to predict treatment failure, time to next exacerbation, and mortality in the hospital study. Results: All patient-reported outcomes showed a distinct pattern of improvement. In the multivariate models, absence of improvement in CCQ symptom score and impaired lung function were independent predictors of treatment failure. Health status and gender predicted time to next exacerbation. Five-year mortality was predicted by age, forced expiratory flow in one second % predicted, smoking status, and CCQ score. In outpatient management of exacerbations, health status was found to be less impaired than in hospitalized patients, while the rate and pattern of recovery was remarkably similar. Conclusion: Daily health status measurements were found to predict treatment failure, which could help decision-making for patients hospitalized due to an exacerbation of COPD. Keywords: health status, Clinical COPD Questionnaire, hospital, admission, prediction

Tanja W Effing,1,2 Manon Krabbenbos,3 Marcel E Pieterse,4 Paul DLPM van der Valk,3 Gerhard A Zielhuis,5 Huib AM Kerstjens,6 Job van der Palen,371Repatriation General Hospital, Department of Respiratory Medicine, Daw Park, 2Flinders University, School of Medicine, Adelaide, South Australia, Australia; 3Medisch Spectrum Twente, Department of Pulmonology, Enschede, 4Department of Psychology, Health and Technology, Enschede, 5Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen, Nijmegen, 6Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, 7Department of Research Methodology, Measurement and Data Analysis, University of Twente, The Netherlands Objective: To assess the adherence of physiotherapists to the study protocol and the occurrence of contamination bias during the course of a randomized controlled trial with a recruitment period of 2 years and a 1-year follow-up (COPE-II study).Study design and setting: In the COPE-II study, intervention patients received a standardized physiotherapeutic reactivation intervention (COPE-active) and control patients received usual care. The latter could include regular physiotherapy treatment. Information about the adherence of physiotherapists with the study protocol was collected by performing a single interview with both intervention and control patients. Patients were only interviewed when they were currently receiving physiotherapy. Interviews were performed during two separate time periods, 10 months apart. Nine characteristics of the COPE-active intervention were scored. Scores were converted into percentages (0%, no aspects of COPE-active; 100%, full implementation of COPE-active).Results: Fifty-one patients were interviewed (first period: intervention n = 14 and control n = 10; second period: intervention n = 18 and control n = 9). Adherence with the COPE-active protocol was high (median scores: period 1, 96.8%; period 2, 92.1%), and large contrasts in scores between the intervention and control group were found (period 1: 96.8% versus 22.7%; period 2: 92.1% versus 25.0%). The scores of patients treated by seven physiotherapists who trained patients of both study groups were similar to the scores of patients treated by physiotherapists who only trained patients of one study group.Conclusion: The adherence of physiotherapists with the COPE-active protocol was high, remained unchanged over time, and no obvious contamination bias occurred.Keywords: physiotherapy, guideline adherence, compliance, bias, randomized controlled trial, chronic obstructive pulmonary disease

Background: Limited data exist on the relative impact of moderate and severe exacerbations on asthma control and impairment., Objective: To explore data from the CAPTAIN trial to evaluate the relationship between first moderate or severe exacerbation and changes in lung function, symptoms, physical activity limitation scores, and short-acting β 2 -agonist (SABA) usage to determine the clinical relevance of moderate events., Methods: CAPTAIN was a phase IIIA 24- to 52-week, multicenter, international, randomized controlled trial evaluating efficacy and safety of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI in patients with uncontrolled asthma on inhaled corticosteroid/long-acting β 2 -agonist. Outcomes reported include first postrandomization exacerbation event by severity (wk 1-52), frequency and duration of moderate and severe exacerbations, and time course of changes over ± 14-day peri-exacerbation period for lung function, symptoms, limitations, and SABA use., Results: Of the intent-to-treat population (n = 2,436), 550 patients (23%) continued to 52 weeks. There were 529 moderate and 546 severe exacerbations. Lung function changes were similar, but symptom, physical activity limitation scores, and SABA use were higher, for severe versus moderate exacerbations. Lung function decline preceded increases in symptom, physical activity limitation scores, and SABA use, irrespective of exacerbation severity. Lung function variables, limitation scores, and SABA use returned to pre-exacerbation baseline after approximately 8 to 12 days for both exacerbation severities., Conclusions: Whereas severe events were associated with greater impact on symptoms, physical activity limitations, and SABA use, onset and time to resolution were generally similar for moderate and severe events. Both exacerbation severities represent clinically important deteriorations comprising clinical and functional changes., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: COPD causes high morbidity and mortality, emphasizing the need for palliative care., Aim: To assess the effectiveness of palliative care in patients with COPD., Design: Cluster randomized controlled trial (COMPASSION study; Netherlands Trial Register (NTR): NL7644, 07-04-2019). Healthcare providers within the intervention group were trained to implement palliative care components into routine COPD care. Patients completed questionnaires at baseline, after 3 and 6 months; medical records were assessed after 12 months. The primary outcome was quality of life (FACIT-Pal). Secondary outcomes were anxiety, depression, spiritual well-being, satisfaction with care, acute healthcare use, documentation of life-sustaining treatment preferences and place of death. Generalized linear mixed modelling was used for analyses., Setting: Eight hospital regions in the Netherlands., Participants: Patients hospitalized for an acute exacerbation of COPD and positive ProPal-COPD score., Results: Of 222 patients included, 106 responded to the questionnaire at 6 months. Thirty-six of 98 intervention patients (36.7%) received the intervention. Intention-to-treat-analysis showed no effect on the primary outcome (adjusted difference: 1.09; 95% confidence interval: -5.44 to 7.60). In the intervention group, fewer intensive care admissions for COPD took place (adjusted odds ratio: 0.21; 95% confidence interval: 0.03-0.81) and strong indications were found for fewer hospitalizations (adjusted incidence rate ratio: 0.69; 95% confidence interval: 0.46-1.03)., Conclusions: We found no evidence that palliative care improves quality of life in patients with COPD. However, it can potentially reduce acute healthcare use. The consequences of the COVID-19 pandemic led to suboptimal implementation and insufficient power, and may have affected some of our findings.

Background: A novel, once-daily, fixed-dose combination of mometasone furoate/indacaterol acetate/glycopyrronium bromide (MF/IND/GLY) delivered via Breezhaler® is the first inhaled corticosteroid/long-acting ꞵ 2 -agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) therapy approved for the maintenance treatment of asthma in adults inadequately controlled on ICS/LABA combination. In patients with asthma and persistent airflow limitation (PAL), maximal treatment, especially with combination is suggested. This post hoc analysis of data from the IRIDIUM study assessed the efficacy of MF/IND/GLY in asthma patients with and without PAL., Methods: Patients with post-bronchodilator FEV 1 ≤80% of predicted and FEV 1 /FVC ratio of ≤0.7 were categorised as PAL subgroup and the remaining as the non-PAL subgroup. Lung function parameters (FEV 1 , PEF, and FEF 25%-75% ) and annualised asthma exacerbations rates were evaluated in both subgroups across the treatment arms: once-daily high-dose MF/IND/GLY (160/150/50 μg), high-dose MF/IND (320/150 μg) and twice-daily high-dose fluticasone/salmeterol (FLU/SAL; 500/50 μg)., Results: Of the 3092 randomised patients, 64% (n = 1981) met the criteria for PAL. Overall, there was no evidence of treatment difference between PAL and non-PAL subgroups (interaction P-value for FEV 1 , FEF 25%-75% , PEF, moderate or severe exacerbations, severe exacerbations and all exacerbations were 0.42, 0.08, 0.43 0.29, 0.35 and 0.12, respectively). In the PAL subgroup, high-dose MF/IND/GLY versus high-dose MF/IND and high-dose FLU/SAL improved trough FEV 1 (mean difference: 102 mL [P < 0.0001] and 137 mL [P < 0.0001]) and reduced moderate or severe (16% and 32%), severe (25% and 39%) and all exacerbations (19% and 38%), respectively., Conclusions: Once-daily fixed-dose MF/IND/GLY was efficacious in asthma patients with and without persistent airflow limitation., Competing Interests: Declaration of competing interest RVZS reports personal fees from Aspen/GSK, Pfizer, Roche, MSD, AstraZeneca, Novartis, Glenmark, Boehringer Ingelheim and Cipla, outside the submitted work. HAK reports grants and consultancy/advisory board participation from/for Novartis during the conduct of the study, grants and consultancy/advisory board participation from/for GlaxoSmithKline and Boehringer Ingelheim, and a grant from Chiesi, outside the submitted work. All were paid to his institution. JFM reports personal fees and grants from Novartis during the conduct of the study, personal fees from AstraZeneca, grants and personal fees from Sanofi and personal fees from ImmunoTek. KK reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, GSK, Novartis and Menarini; personal fees from Sanofi; and grants from NuvoAir, outside the submitted work, and was an employee of Novartis Pharma AG until October 31, 2018. KRC reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols, Sanofi, Regeneron, Novartis and Takeda; personal fees from CSL Behring, Inhibrx and Kamada; and grants from Vertex, outside the submitted work. MH, AMT, KM, DB and DL are employees of Novartis Pharma AG. PD is an employee of Novartis Pharmaceutical Corporation., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Chronic non-invasive ventilation (NIV) is increasingly being used to treat people with COPD who have respiratory failure, but the evidence supporting this treatment has been conflicting., Objectives: To assess the effects of chronic non-invasive ventilation at home via a facial mask in people with COPD, using a pooled analysis of IPD and meta-analysis., Search Methods: We searched the Cochrane Airways Register of Trials, MEDLINE, Embase, PsycINFO, CINAHL, AMED, proceedings of respiratory conferences, clinical trial registries and bibliographies of relevant studies. We conducted the latest search on 21 December 2020., Selection Criteria: We included randomised controlled trials (RCTs) comparing chronic NIV for at least five hours per night for three consecutive weeks or more (in addition to standard care) versus standard care alone, in people with COPD. Studies investigating people initiated on NIV in a stable phase and studies investigating NIV commenced after a severe COPD exacerbation were eligible, but we reported and analysed them separately. The primary outcomes were arterial blood gases, health-related quality of life (HRQL), exercise capacity (stable COPD) and admission-free survival (post-exacerbation COPD). Secondary outcomes for both populations were: lung function, COPD exacerbations and admissions, and all-cause mortality. For stable COPD, we also reported respiratory muscle strength, dyspnoea and sleep efficiency., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane. After inclusion of a study, we requested the IPD. We analysed continuous and time-to-event data using linear- and cox-regression mixed-effect models with a random effect on study level. We analysed dichotomous IPD using generalised estimating equations. We adjusted all models for age and sex. We assessed changes in outcomes after three and 12 months.  We also conducted a meta-analysis on aggregated trial data., Main Results: We included 14 new RCTs in this review update, in addition to the seven previously included. Seventeen studies investigated chronic NIV in stable COPD and four studies investigated chronic NIV commenced after a severe COPD exacerbation. Three studies compared NIV to sham continuous positive airway pressure (2 to 4 cmH 2 O). Seven studies used a nasal mask, one study used an oronasal mask and eight studies used both interfaces. Five studies did not report the interface. The majority of trials (20/21) were at high risk of performance bias due to an unblinded design. We considered 11 studies to have a low risk of selection bias and 13 to have a low risk of attrition bias. We collected and analysed the IPD from 13 stable COPD studies (n = 778, 68% of the participants included) and from three post-exacerbation studies (n = 364, 96% of the participants included). In the stable COPD group, NIV probably results in a minor benefit on the arterial partial pressure of oxygen (PaO 2 ) after three months (adjusted mean difference (AMD) 0.27 kPa, 95% CI 0.04 to 0.49; 9 studies, 271 participants; moderate-certainty evidence), but there was little to no benefit at 12 months (AMD 0.09 kPa, 95% CI -0.23 to 0.42; 3 studies, 171 participants; low-certainty evidence). The arterial partial pressure of carbon dioxide (PaCO 2 ) was reduced in participants allocated to NIV after three months (AMD -0.61 kPa, 95% CI -0.77 to -0.45; 11 studies, 475 participants; high-certainty evidence) and persisted up to 12 months (AMD -0.42 kPa, 95% CI -0.68 to -0.16; 4 studies, 232 participants; high-certainty evidence).  Exercise capacity was measured with the 6-minute walking distance (minimal clinical important difference: 26 m). There was no clinically relevant effect of NIV on exercise capacity (3 months: AMD 15.5 m, 95% CI -0.8 to 31.7; 8 studies, 330 participants; low-certainty evidence; 12 months: AMD 26.4 m, 95% CI -7.6 to 60.5; 3 studies, 134 participants; very low-certainty evidence). HRQL was measured with the Severe Respiratory Insufficiency and the St. Georges's Respiratory Questionnaire and may be improved by NIV, but only after three months (3 months: standardised mean difference (SMD) 0.39, 95% CI 0.15 to 0.62; 5 studies, 259 participants; very low-certainty evidence; 12 months: SMD 0.15, 95% CI -0.13 to 0.43; 4 studies, 200 participants; very low-certainty evidence). Lastly, the risk for all-cause mortality is likely reduced by NIV (adjusted hazard ratio (AHR) 0.75, 95% CI 0.58 to 0.97; 3 studies, 405 participants; moderate-certainty evidence). In the post-exacerbation COPD group, there was little to no benefit on the PaO 2 after three months, but there may be a slight decrease after 12 months (3 months: AMD -0.10 kPa, 95% CI -0.65 to 0.45; 3 studies, 234 participants; low-certainty evidence; 12 months: -0.27 kPa, 95% CI -0.86 to 0.32, 3 studies; 170 participants; low-certainty evidence). The PaCO 2 was reduced by NIV at both three months (AMD -0.40 kPa, 95% CI -0.70 to -0.09; 3 studies, 241 participants; moderate-certainty evidence) and 12 months (AMD -0.52 kPa, 95% CI -0.87 to -0.18; 3 studies, 175 participants; high-certainty evidence). NIV may have little to no benefit on HRQL (3 months: SMD 0.25, 95% CI -0.01 to 0.51; 2 studies, 219 participants; very low-certainty evidence; 12 months: SMD 0.25, 95% -0.06 to 0.55; 2 studies, 164 participants; very low-certainty evidence). Admission-free survival seems improved with NIV (AHR 0.71, 95% CI 0.54 to 0.94; 2 studies, 317 participants; low-certainty evidence), but the risk for all-cause mortality does not seem to improve (AHR 0.97, 95% CI 0.74 to 1.28; 2 studies, 317 participants; low-certainty evidence)., Authors' Conclusions: Regardless of the timing of initiation, chronic NIV improves daytime hypercapnia. In addition, in stable COPD, survival seems to be improved and there might be a short term HRQL benefit. In people with persistent hypercapnia after a COPD exacerbation, chronic NIV might prolong admission-free survival without a beneficial effect on HRQL. In stable COPD, future RCTs comparing NIV to a control group receiving standard care might no longer be warranted, but research should focus on identifying participant characteristics that would define treatment success. Furthermore, the optimal timing for initiation of NIV after a severe COPD exacerbation is still unknown., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Although guidelines recommend palliative care for patients with chronic obstructive pulmonary disease, there is little evidence for the effectiveness of palliative care interventions for this patient group specifically., Aim: To describe the characteristics of palliative care interventions for patients with COPD and their informal caregivers and review the available evidence on effectiveness and implementation outcomes., Design: Systematic review and narrative synthesis (PROSPERO CRD42017079962)., Data Sources: Seven databases were searched for articles reporting on multi-component palliative care interventions for study populations containing ⩾30% patients with COPD. Quantitative as well as qualitative and mixed-method studies were included. Intervention characteristics, effect outcomes, implementation outcomes and barriers and facilitators for successful implementation were extracted and synthesized qualitatively., Results: Thirty-one articles reporting on twenty unique interventions were included. Only four interventions (20%) were evaluated in an adequately powered controlled trial. Most interventions comprised of longitudinal palliative care, including care coordination and comprehensive needs assessments. Results on effectiveness were mixed and inconclusive. The feasibility level varied and was context-dependent. Acceptability of the interventions was high; having someone to call for support and education about breathlessness were most valued characteristics. Most frequently named barriers were uncertainty about the timing of referral due to the unpredictable disease trajectory (referrers), time availability (providers) and accessibility (patients)., Conclusion: Little high-quality evidence is yet available on the effectiveness and implementation of palliative care interventions for patients with COPD. There is a need for well-conducted effectiveness studies and adequate process evaluations using standardized methodologies to create higher-level evidence and inform successful implementation.

Background: Blood eosinophilia is frequently encountered in patients with AECOPD. However the impact of blood eosinophilia at admission in patients with AECOPD on outcome on the short and long term has not been extensively studied which was the objective of the present study., Methods: We used data of 207 exacerbations from a randomized clinical trial on antibiotic prescription based upon CRP-levels versus GOLD guided strategy and analyzed the impact of blood eosinophils (≥2% of total white cell count and eosinophil count ≥300 cell/microliter) on clinical outcome., Results: 207 patients were included of whom 39 (18·8%) had eosinophilia ≥2%, 23 patients (11.1%) had blood eosinophil ≥300 cell/microliter. Eosinophilia was associated with shorter median length of stay in the eosinophilic groups(≥2% and ≥300 cell/microliter) compared to the non-eosinophilic groups. Early treatment failure was reduced in the both the eosinophilic groups (≥2% and ≥300 cell/microliter). Late treatment failure (day 11-30) did not differ between the groups. Relapse, was more frequent the eosinophilic groups (≥2% and ≥300 cell/microliter), however in the latter group this did not reach statistical significance. Eosinophilia ≥2% was a risk factor for having relapse (eosinophilia ≥2%: HR = 2·351; 95%CI 1·335-4·139), whereas eosinophilia <2% was associated with a lower risk factor for having early treatment failure (HR = 0·339 95%CI 0·122-0·943)., Conclusion: We showed that blood eosinophilia at admission in patients with an AECOPD is associated with higher short-term treatment success rate. However, blood eosinophilia ≥2% predicts a less favorable outcome due to an increased risk of relapse., Clinical Trial Registration: NCT01232140., (Copyright © 2017. Published by Elsevier Ltd.)

In patients with stable COPD, proadrenomedullin (MR-proADM) has been shown to be a good predictor for mortality. This study aims to provide an external validation of earlier observed cut-off values used by Zuur-Telgen et al. and Stolz.et al. in COPD patients in stable state and at hospitalization for an acute exacerbation of COPD (AECOPD). From the COMIC cohort study we included 545 COPD patients with a blood sample obtained in stable state (n = 490) and/or at hospitalization for an AECOPD (n = 101). Time to death was compared between patients with MR-proADM cut-off scores 0.71 and 0.75 nmol/L for stable state or 0.79 and 0.84 nmol/l for AECOPD. The predictive value of MR-proADM for survival was represented by the C statistic. Risk ratios were corrected for sex, age, BMI, presence of heart failure, and GOLD stage. Patients above the cut-off of 0.75 nmol/l had a 2-fold higher risk of dying than patient below this cut-off (95% CI: 1.20-3.41). The cut-off of 0.71 nmol/l showed only a borderline significantly higher risk of 1.67 (95% CI: 0.98-2.85). The corrected odds ratios for one-year mortality were 3.15 (95% CI 1.15-8.64) and 3.70 (95% CI 1.18-11.6) in patients with MR-proADM levels above versus below the cut-off of respectively 0.75 and 0.71 nmol/l measured in stable state. MR-proADM levels in samples at hospitalization for an AECOPD were not predictive for mortality in this validation cohort. MR-proADM in stable state is a powerful predictor for mortality.

Ertapenem is a broad-spectrum carbapenem antibiotic whose activity against Mycobacterium tuberculosis is being explored. Carbapenems have antibacterial activity when the plasma concentration exceeds the MIC at least 40% of the time (40% T MIC ). To assess the 40% T MIC in multidrug-resistant tuberculosis (MDR-TB) patients, a limited sampling strategy was developed using a population pharmacokinetic model based on data for healthy volunteers. A two-compartment population pharmacokinetic model was developed with data for 42 healthy volunteers using an iterative two-stage Bayesian method. External validation was performed by Bayesian fitting of the model developed with data for volunteers to the data for individual MDR-TB patients (in which the fitted values of the area under the concentration-time curve from 0 to 24 h [AUC 0-24, fit values] were used) using the population model developed for volunteers as a prior. A Monte Carlo simulation ( n = 1,000) was used to evaluate limited sampling strategies. Additionally, the 40% T MIC with the free fraction ( f 40% T MIC ) of ertapenem in MDR-TB patients was estimated with the population pharmacokinetic model. The population pharmacokinetic model that was developed was shown to overestimate the area under the concentration-time curve from 0 to 24 h (AUC 0-24 ) in MDR-TB patients by 6.8% (range, -17.2 to 30.7%). The best-performing limited sampling strategy, which had a time restriction of 0 to 6 h, was found to be sampling at 1 and 5 h ( r 2 = 0.78, mean prediction error = -0.33%, root mean square error = 5.5%). Drug exposure was overestimated by a mean percentage of 4.2% (range, -15.2 to 23.6%). When a free fraction of 5% was considered and the MIC was set at 0.5 mg/liter, the minimum f 40% T MIC would have been exceeded in 9 out of 12 patients. A population pharmacokinetic model and limited sampling strategy, developed using data from healthy volunteers, were shown to be adequate to predict ertapenem exposure in MDR-TB patients., (Copyright © 2017 American Society for Microbiology.)

Tiotropium is a long-acting inhaled antimuscarinic bronchodilator that has recently received marketing authorization for the indication of asthma with dose delivery via the Respimat ® inhaler, in addition to its widely established role in the management of chronic obstructive pulmonary disease (COPD). This report presents a combined analysis of tiotropium plasma and urine pharmacokinetics at steady state from 8 Phase II/III clinical trials in asthma and delineates the effects of patient characteristics on systemic exposure based on the parameters fe 0-24,ss (fraction of dose excreted unchanged in urine over 24 h post-dose at steady-state) and dose-normalized AUC tau,ss and C max,ss . Pharmacokinetics were also compared between asthma and COPD, incorporating data from 3 COPD Phase II/III clinical trials. Tiotropium pharmacokinetics in asthma were dose-proportional up to 5 μg dosed once daily. The following factors showed no statistically significant effects on tiotropium systemic exposure in asthma based on analysis of geometric mean ratios and 90% confidence intervals: age, asthma severity, lung function, reversibility testing, allergy status, smoking history, geographical region, and posology (5 μg once daily or 2.5 μg twice daily via Respimat ® ). Asian patients showed a moderately but significantly higher systemic exposure compared to White or Black patients. However, no differences in safety by race were observed. Total systemic exposure (AUC tau,ss ) was similar between asthma and COPD, but C max,ss was 52% lower in asthma patients compared to COPD. It is concluded that in asthma, patient characteristics have no relevant effect on tiotropium systemic exposure. Since systemic exposure to inhaled drugs is an indicator of safety, the lower C max,ss compared to COPD is not considered a concern for tiotropium therapy of asthma., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Gaining regular insight into the nature and severity of distress by a psychosocial nurse coupled with referral to psychosocial and/or paramedical healthcare provider(s) is an experimental supportive care approach. We sought to examine the effects of this approach on quality of life (QoL), patient's mood and satisfaction, end-of-life care and survival in patients with lung cancer., Methods: Patients with newly diagnosed or recurrent lung cancer starting systemic therapy were randomly assigned to receive usual care or the experimental approach. Patients were followed up at 1, 7, 13 and 25 weeks after randomisation with the EORTC-QLQ-C30, the European Quality of Life-5D, the Hospital Anxiety and Depression Scale and the Patient Satisfaction Questionnaire-III. Primary outcome was the mean change in the EORTC-QLQ-C30 global QoL-score between 1 and 25 weeks., Results: A total of 223 patients were randomised of whom 111 (50%) completed all four assessments (44% in the usual care group versus 55% in the experimental group). No significant difference was found in the mean change global QoL-score (-2.4, 95% CI: 12.1-7.2; P = 0.61), nor in the other patient-reported outcomes. Fewer patients in the experimental group received chemotherapy shortly before the end-of-life, and median survival was comparable (10.3 versus 10.1 months, P = 0.62). Of the 112 dropouts, 33 died and 79 discontinued participation for other reasons., Conclusions: This supportive care approach neither improved QoL nor other patient-reported outcomes in patients with lung cancer. However, it reduced the use of chemotherapy shortly before the end of life. Possibly, (late) side effects of systemic therapy may have obscured effects of our intervention on QoL., Clinical Trial Registration: NTR3540., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Long-term treatment with inhaled corticosteroids (ICS) might attenuate lung function decline and decrease airway inflammation in a subset of patients with chronic obstructive pulmonary disease (COPD), and discontinuing ICS treatment could result in further lung function decline. We hypothesised that airway inflammation increases after ICS withdrawal following long-term ICS treatment in COPD.In the GLUCOLD-1 study (GL1), 114 patients with moderate-severe COPD were randomised to 6-month or 30-month treatment with fluticasone propionate (500 µg twice daily), 30-month treatment with fluticasone/salmeterol (500/50 µg twice daily) or placebo. During the 5-year follow-up study (GL2), patients were followed prospectively while being treated by their physician. Bronchial biopsies and induced sputum were collected at baseline, at 30 months (end of GL1) and at 7.5 years (end of GL2) to assess inflammatory cell counts. Data were analysed using linear mixed-effects models.In patients using ICS during GL1 and using ICS 0-50% of the time during GL2 (n=61/85), there were significant increases in GL2 bronchial CD3 + (fold change per year calculated as GL2 minus GL1 2.68, 95% CI 1.87-3.84), CD4 + (1.91, 95% CI 1.33-2.75) and CD8 + cells (1.71, 95% CI 1.15-2.53), and mast cells (1.91, 95% CI 1.36-2.68). The sputum total cell counts increased significantly in GL2 (1.90, 95% CI 1.42-2.54), as did counts of macrophages (2.10, 95% CI 1.55-2.86), neutrophils (1.92, 95% CI 1.39-2.65) and lymphocytes (2.01, 95% CI 1.46-2.78).ICS discontinuation increases airway inflammation in patients with moderate-severe COPD, suggesting that the anti-inflammatory effects of ICS in COPD are not maintained after ICS discontinuation., (Copyright ©ERS 2017.)