University of Groningen Lungs under a cloud Maters, Gemma

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University of Groningen

Lungs under a cloud

Maters, Gemma

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Maters, G. (2019). Lungs under a cloud: Psychological aspects of COPD. Rijksuniversiteit Groningen.

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527918-L-bw-Maters 527918-L-bw-Maters 527918-L-bw-Maters 527918-L-bw-Maters Processed on: 22-1-2019 Processed on: 22-1-2019 Processed on: 22-1-2019

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Psychological aspects of COPD

Gemma A. Maters

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The research reported in this thesis was funded by the Lung Foundation Netherlands. The study was conducted within Graduate School for Health Research SHARE (University of Groningen, University Medical Center Groningen).

http://books.ipskampprinting.nl/thesis/527918-maters

Layout Bianca Pijl, www.pijlldesign.nl,

Groningen, the Netherlands

Cover design Bianca Pijl, Printed by Ipskamp Printing

Enschede, the Netherlands

ISBN 978-94-034-1371-6 (print)

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All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without prior written permission of the author, or when appropriate, of the publishers of the publications included in this thesis.

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Psychological aspects of COPD

Proefschrift

ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen

op gezag van de

rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties

De openbare verdediging zal plaatsvinden op woensdag 13 maart 2019 om 14.30 uur

door

Gemma Amarante Maters

geboren op 5 januari 1980 te Delft

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4 Promotor Prof. dr. R. Sanderman Copromotores Dr. J.B. Wempe Dr. G. Pool Beoordelingscommissie

Prof. dr. A.V. Ranchor

Prof. dr. J.E.W.C. van Gemert-Pijnen Prof. dr. P.U. Dijkstra

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Paranimfen

Sandra Brouwer Charlotte Ulenreef

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7 Chapter 1 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 General introduction

Predictors of all-cause mortality in patients with stable COPD: medical comorbid conditions or high depressive symptoms Discrepancies between patients’ and partners’ perceptions of unsupportive behavior in patients with COPD

Problems in cross-cultural use of the HADS: ‘No butterflies in the desert’ Identifying patients with COPD in need for psychosocial care

through screening with the HSCL-25 and the CCQ Mental State ‘With the best intentions’: why a psychological intervention study for patients with COPD failed to include enough patients

Cognitive-experiential therapy in patients with COPD; a protocol General discussion

Summary Samenvatting About the author Dankwoord

SHARE- previous dissertations

9 21 37 51 73 87 103 137 147 151 155 157 159

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Chapter 1

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11 The purpose of this thesis is to explore psychological aspects of experiencing and handling Chronic Obstructive Pulmonary Disease (COPD), as well as options for psychological support. With our title, ‘Lungs under a cloud’ we express the interplay between COPD and psychological issues. The disease brings psychological problems about and is influenced by psychological issues negatively. In this thesis we look into perceived distress and the consequences of distress, as well as its relationship with social support. Furthermore, we investigate needs for psychosocial care and feasibility issues concerning a psychological intervention study. In particular, this thesis discusses: a) the relationship between comorbidities (including depressive symptoms) and all-cause mortality (Chapter 2), b) the relationship between psychological distress and perceptions of spousal support (Chapter 3), c) the cross-cultural use of the Hospital Anxiety and Depression Scale (HADS; a questionnaire which we intended to use in our intervention study, until we found out there were problems with it, Chapter 4), d) the screening of an endorsed need for psychosocial care (Chapter 5) and e) difficulties encountered in the implementation of a psychological intervention study (Chapter 6). Also, we developed a psychological intervention protocol, to encounter several central issues in coping with COPD (Chapter 7).

This introduction starts off with background information on COPD; symptoms, course and medical treatment options. Subsequently, a short overview of research concerning psychosocial problems in COPD patients will be presented, as well as available research concerning studies on psychological support. At the end of this introduction an overview of the chapters of this thesis will be provided.

COPD: definition, prevalence and symptoms

The official definition of COPD, according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), is “common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases” (Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2018). In plain English: pulmonary damage causes breathing problems and this damage is caused by smoking or exposure to other harmful substances. Next to tobacco smoking or environmental exposures, the so-called ‘host factors’ (such as genetic factors) seem to play a part (Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2018). Although COPD is considered to have treatable characteristics (Houben-Wilke et al., 2018), it is a progressive disease. A diagnosis of COPD is typically suspected in patients with dyspnea (breathlessness), chronic cough or sputum production, with or without exposure to risk factors. To confirm the diagnosis of COPD, spirometry, a medical pulmonary test that determines the level of airflow limitation, is needed. Earlier, a fixed criterion of airflow limitation was used to diagnose COPD. Recently, the Global Lung Function Initiative (GLI) of the European Respiratory Society (ERS) introduced z-scores, based on age dependent reference values (European Respiratory Society, 2017). Four categories of airflow limitation severity are recognized, as indicated by the Global Initiative for Chronic Obstructive Lung Disease; the GOLD categories (Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2018). They are ranging from GOLD category 1, indicating mild airflow limitation, to category 4, indicating very severe airflow limitation. The correlation between the GOLD category and physical symptoms or impairment is, however, weak (Han et al., 2013; Jones, 2009).

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In the Netherlands, over 350.000 people suffer from COPD (Snoeck-Stroband et al., 2015). It is estimated that worldwide 65 million people suffer from COPD; in 2015 three million people died of COPD, mostly in low and middle-income countries (WHO website). This implies that COPD is an important cause of death in many countries. COPD is frequently accompanied by other diseases (comorbidities) that may influence symptoms and the course of the disease (Anecchino et al., 2007; Chatila, Thomashow, Minai, Criner, & Make, 2008; Patel & Hurst, 2011; Schnell et al., 2012). The disease typically becomes apparent after the age of 40 (World Health Organization, 2017). In earlier decades, COPD patients usually were men. Nowadays, in western countries more and more women are diagnosed with COPD. An important reason for this change is that more women started smoking during the last decennia. Women with COPD usually experience more severe symptoms and are, on average, diagnosed at a younger age than men (Snoeck-Stroband et al., 2015). COPD patients are treated with pharmacotherapy to alleviate symptoms or treat complications. In addition, they are advised on smoking cessation, physical exercise and/or are encouraged to participate in pulmonary rehabilitation, if applicable. However, non-adherence to such advices or treatments is a well-known problem in COPD patients (Blackstock, ZuWallack, Nici, & Lareau, 2016).

The most salient symptoms of COPD are dyspnea (breathlessness), cough and sputum production (Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2018). Especially dyspnea is described as a very unpleasant symptom; patients feel as if they are grasping for air or breath through a straw. Other frequently occurring symptoms are fatigue, decrease in muscular strength and/or weight loss. Symptoms may be mild up to severe, depending on factors such as the stage of the disease and also the activity level of patients. Ultimately, because of the progressive character of the disease, patients may become impaired in all of their daily life activities. For instance, walking the stairs or riding a bicycle may increase dyspnea, doing home appliances or working may become impossible, sleep interruptions may frequently occur and worsen fatigue during the day. In addition, most COPD patients experience episodes of increased symptoms from time to time (exacerbations). These exacerbations may last for days or weeks and patients may seek (urgent) medical advice or care to deal with them. Exacerbations negatively influence disease progression and should be adequately treated to minimize the impact and to prevent future exacerbations from happening. The latest GOLD revision (Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2018) aims at more precisely discriminating severity of COPD by adding symptoms (low versus high) and number of exacerbations per year (0 or 1 versus 2 or more).

Psychosocial issues and options for psychological support

Due to the burdening and, ultimately, life-threatening character of the disease, COPD may induce strong emotions in patients, such as feelings of anxiety, suppressed mood, helplessness and hopelessness. Depression and anxiety disorders are frequently reported in COPD literature (Hanania et al., 2011; Kunik et al., 2005; Maurer et al., 2008) and are associated with an increase in the experienced disease burden. Some patients are afraid to suffocate or lose control. Panic attacks may occur and patients may avoid particular situations or activities, which may provoke distress or an increase in symptoms. Some COPD patients experience traumatic events, such as

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13 treatments or strong emotions during a hospitalization. A state of suspense has been found in COPD patients, because of the uncertainties the disease brings about. In Box 1.1 some interview-quotes are presented from two studies conducted by two psychology students, under our supervision, to illustrate how patients with COPD perceive and experience their disease (Hendriks, 2011; Mayer, 2011). A relationship was found between depression in patients with COPD and mortality in some studies, but not in all (Almagro et al., 2012; Groenewegen, Schols, & Wouters, 2003). Because most studies were performed in hospitalized patients, we investigated the association between co-morbidities (such as depressive symptoms) and mortality in patients with stable COPD.

Besides emotional problems, taking part in social activities may become difficult for patients suffering from COPD, because of the breath-related symptoms themselves, and/or because of sensitivity to allergen stimuli such as tobacco smoke. Therefore, social isolation is a risk factor in patients with COPD, who try to avoid the increase of symptoms. Concerning their social context, some COPD patients experience a lack of understanding from their acquaintances, leading to even more avoidance of social situations and/or to negative emotions. Patients involved in a relationship may experience role changes, due to their disease. Relational problems may occur in the partner relationship, sometimes worsened because of sexual problems experienced by patients or partners. On the other hand, a partner may positively influence adherence to medication or rehabilitation (Fischer et al., 2009; Rand, Nides, Cowles, Wise, & Connett, 1995). The way partner support is best provided has received little attention in COPD literature, as well as the way patients perceive partner support. Therefore, we look into spousal support in this thesis.

Based on the aforementioned emotional and relational issues patients with COPD may face, one would expect that many patients might experience a need for professional psychosocial support. However, it seems that the number of COPD patients that receive a psychological treatment are generally low. Therefore, in the literature concerning psychological aspects of COPD, screening for distress is encouraged (Garvey, 2012; Maurer et al., 2008; Obradovic et al., 2012); however, an association between distress levels and a need for psychosocial care has not yet been established in the literature concerning patients with COPD. We therefore investigated the association between a need for psychosocial care and distress (measured with two questionnaires). Cognitive behavioral therapy appears to improve psychological outcomes in patients with COPD, according to two systematic reviews on this issue (Coventry & Gellatly, 2008; Farver-Vestergaard, Jacobsen, & Zachariae, 2015). However, it should be stated that intervention studies in this field until now encounter problems, such as low inclusion numbers. Therefore, more research into psychological interventions is called for (Baraniak & Sheffield, 2011; Dowson, Kuijer, & Mulder, 2004; Farver-Vestergaard et al., 2015; Rose et al., 2002). This thesis discusses inclusion and dropout issues in an intervention study, as we experienced such issues in our randomized controlled trial.

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A female COPD patient (75 years old):

̏My pulmonary disease belongs to me. I learned a lot from it. It gave me confidence in life˝. A male COPD patient (71 years old):

̏ I feel down increasingly. This is related to my pulmonary disease. I know for a fact that I will die of it. My body tells me too, and I usually listen to my body. The end of my life may be far away, I don´t think I will die tomorrow. Up until now, I thought I would be fine if I just wouldn´t give up. But lately, I do no longer believe this anymore. If this worsens, what will happen when they try to help me? Will it be fine, or a long-drawn-out process? But I do not long for death. If I die of this disease, I will suffocate. Either my heart snaps, or my lungs. That is not a happy thought. To fall asleep and die will not be the case, as I had hoped for. That’s hard. At difficult moments, I tend to think of death. On the other hand, sometimes a beautiful day arrives. I get my mobility scooter and drive as far as I can. I feel a bit free, but it never lasts. Then I have to go home again and the worrying starts again … and the worrying worsens˝.

A female COPD patient (53 years old):

̏And about the black mood, I think one will lose faith. Sometimes the disease makes me feel down. But I don’t want to be bothered by it every day. And about the fear, I do recognize is. But not every day. It surprises me, when I am busy with my daily activities. I tend to think: do I have to live the rest of my life with this disease? Sometimes it is just a feeling. I do not talk about the fear. I don’t know how to. I’d rather keep this to myself. Generally, I do not talk about my disease to others. Only if they start talking about it. This disease is an adventure. But I will continue and will not lose faith˝.

Box 1.1 Three patients with COPD about their disease (parts of interviews)

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Overview of the chapters

In this thesis we look into several of the issues described in the preceeding paragragh. In the current paragraph we introduce the research presented in this thesis.

Chapter 2. The incidence of medical and psychological comorbidities in patients with COPD is

high and an association between medical co-morbidities and mortality was demonstrated in some studies, but not in all. Most studies were performed in patients who were hospitalized. Therefore, we investigated the association between co-morbidities and mortality in patients with stable COPD. Survival analyses were performed with data collected in stable COPD patients and illness parameters, including acknowledged survival predictors, were included in the analyses.

Chapter 3. Because of the disabling character of the disease, patients with COPD may experience

a high need for support from their spouses. However, only a few studies have looked into partner support in patients with COPD. Research in patients with other diseases showed the association between patients’ wellbeing and provided support, as perceived by patients, may be either positive or negative. The aims of our study were (1) to investigate if discrepancies between patients’ and partners’ perceptions of overprotection and protective buffering are associated with distress and (2) to evaluate if the direction of the differences between patients’ and partners’ perceptions is associated with distress.

Chapter 4. In this chapter, the cross-cultural use of the HADS is discussed. This is a widely used

instrument to screen for anxiety and depression, also in COPD research. At first, we intended to use the HADS in our research on a psychological intervention. Then we found out there where four different Dutch translations of the HADS and there were problems reported in HADS literature. We decided not to use this questionnaire in our intervention study and look into the cross-cultural use of the HADS instead. Problems are reported in literature, such as discrepant optimal cut points and inconsistent factor-structures. The aim of this chapter is to examine whether these problems could be due to the translation and cross-cultural use of the HADS.

Chapter 5. In the literature until now, high levels of distress (symptoms of anxiety or depression)

are reported in COPD. Screening for distress is advocated, as a means to identify patients in need for psychosocial care. However, to our knowledge, no earlier research has focused on the association between distress levels and a need for psychosocial care. Therefore, we examined the association between the screening capacities of the Hopkins Symptoms Checklist-25 (HSCL-25) and the Mental State scale of the Clinical COPD Questionnaire (CCQ). In addition, several characteristics of patients with a need for psychosocial care were investigated.

Chapter 6. In chapter 6 we present the issues we came across in our psychological intervention

study. This study was prompted by a need for more high-quality research into psychological interventions in patients with COPD, in the literature. Because of the problems reported in COPD literature, we paid extra attention to approaching and motivating patients. Still, we encountered inclusion and dropout problems. Therefore, we were no able to report on the effectiveness of the psychological intervention. Instead, we report on the process and problems encountered during performing the study and make recommendations for future psychological intervention studies in COPD.

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Chapter 7. In this chapter we present our protocol for a cognitive-experiential intervention. We

describe the rationale for the intervention, as well as the manual for psychologists. The cognitive- experiential intervention is targeted at learning patients to get more control over; a. the physical consequence/ symptoms of the disease, b. emotions or perceptions regarding the disease and c. the consequences of the disease regarding relationships. Cognitive and experiential techniques were chosen to realize those goals.

Chapter 8. Offers the general discussion; we reflect on our overall findings, clinical implications,

methodological considerations and future research.

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References

Almagro, P., Cabrera, F. J., Diez, J., Boixeda, R., Alonso Ortiz, M. B., Murio, C. Working Group on COPD, Spanish Society of Internal Medicine. (2012). Comorbidities and short-term prognosis in patients hospitalized for acute exacerbation of COPD: The EPOC en servicios de medicina interna (ESMI) study. Chest, 142(5), 1126-1133. doi:S0012-3692(12)60613-8.

Anecchino, C., Rossi, E., Fanizza, C., De Rosa, M., Tognoni, G., Romero, M., & working group ARNO project. (2007). Prevalence of chronic obstructive pulmonary disease and pattern of comorbidities in a general population. International Journal of Chronic Obstructive Pulmonary Disease, 2(4), 567-574.

Baraniak, A., & Sheffield, D. (2011). The efficacy of psychologically based interventions to improve anxiety, depression and quality of life in COPD: A systematic review and meta- analysis. Patient Education and Counseling, 83(1), 29-36. doi:10.1016/j.pec.2010.04.010.

Blackstock, F. C., ZuWallack, R., Nici, L., & Lareau, S. C. (2016). Why don’t our patients with chronic obstructive pulmonary disease listen to us? The enigma of nonadherence. Annals of the American Thoracic Society, 13(3), 317-323. doi:10.1513/AnnalsATS.201509-600PS.

Chatila, W. M., Thomashow, B. M., Minai, O. A., Criner, G. J., & Make, B. J. (2008). Comorbidities in chronic obstructive pulmonary disease. Proceedings of the American Thoracic Society, 5(4), 549-555. doi:10.1513/ pats.200709-148ET.

Coventry, P. A., & Gellatly, J. L. (2008). Improving outcomes for COPD patients with mild-to-moderate anxiety and depression: A systematic review of cognitive behavioural therapy. British Journal of Health Psychology, 13(Pt 3), 381-400. doi:10.1348/135910707X203723

Dowson, C. A., Kuijer, R. G., & Mulder, R. T. (2004). Anxiety and self-management behaviour in chronic obstructive pulmonary disease: What has been learned? Chronic Respiratory Disease, 1(4), 213-220. European Respiratory Society. (2017). GLI-2012 excel individual calculator. Retrieved from

http://www.ers-education.org/guidelines/global-lung-function-initiative/spirometry-tools/excel-individual-calculator. aspx.

Farver-Vestergaard, I., Jacobsen, D., & Zachariae, R. (2015). Efficacy of psychosocial interventions on psychological and physical health outcomes in chronic obstructive pulmonary disease: A systematic review and meta-analysis. Psychotherapy and Psychosomatics, 84(1), 37-50. doi:10.1159/000367635. Fischer, M. J., Scharloo, M., Abbink, J. J., van ‘t Hul, A. J., van Ranst, D., Rudolphus, A., Kaptein, A. A. (2009).

Drop-out and attendance in pulmonary rehabilitation: The role of clinical and psychosocial variables. Respiratory Medicine, 103(10), 1564-1571. doi:10.1016/j.rmed.2008.11.020.

Garvey, C. (2012). Depression in patients with chronic obstructive pulmonary disease. Postgraduate Medicine, 124(3), 101-109. doi:10.3810/pgm.2012.05.2553.

Global Initiative for Chronic Obstructive Lung Disease (GOLD). (2018). Global strategy for the diagnosis, management and prevention of COPD. Retrieved from http://www.goldcopd.org/.

Groenewegen, K. H., Schols, A. M., & Wouters, E. F. (2003). Mortality and mortality-related factors after hospitalization for acute exacerbation of COPD. Chest, 124(2), 459-467. doi:S0012-3692(15)33325-0. Han, M. K., Muellerova, H., Curran-Everett, D., Dransfield, M. T., Washko, G. R., Regan, E. A., Lynch, D. A. (2013).

GOLD 2011 disease severity classification in COPDGene: A prospective cohort study. The Lancet Respiratory Medicine, 1(1), 43-50.

Hanania, N. A., Mullerova, H., Locantore, N. W., Vestbo, J., Watkins, M. L., Wouters, E. F., Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study investigators. (2011). Determinants of depression in the ECLIPSE chronic obstructive pulmonary disease cohort. American Journal of Respiratory and Critical Care Medicine, 183(5), 604-611. doi:10.1164/rccm.201003-0472OC. Hendriks, S. (2011). Illness experience, self-perceived support and need for help in patients with chronic

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Houben-Wilke, S., Augustin, I. M., Vercoulen, J. H., van Ranst, D., bij de Vaate, E., Wempe, J. B., Franssen, F. M. E. (2018). COPD stands for complex obstructive pulmonary disease doi:10.1183/16000617.0027-2018. Jones, P. W. (2009). Health status and the spiral of decline. Copd, 6(1), 59-63. doi:10.1080/15412550802587943. Kunik, M. E., Roundy, K., Veazey, C., Souchek, J., Richardson, P., Wray, N. P., & Stanley, M. A. (2005). Surprisingly

high prevalence of anxiety and depression in chronic breathing disorders. Chest, 127(4), 1205-1211. doi:10.1378/chest.127.4.1205

Maurer, J., Rebbapragada, V., Borson, S., Goldstein, R., Kunik, M. E., Yohannes, A. M. ACCP Workshop Panel on Anxiety and Depression in COPD. (2008). Anxiety and depression in COPD: Current understanding, unanswered questions, and research needs. Chest, 134(4 Suppl), 43S-56S. doi:10.1378/chest.08-0342. Mayer, N. (2011). COPD: A breathtaking experience, interviews with COPD-patients about their illness

experience and need for psychosocial help. Unpublished Master’s Thesis. University of Groningen, Groningen.

Obradovic, L. M., Pesut, D. P., Maric, D., Maskovic, J., Maric, N. P., & Milikic, M. M. (2012). Symptoms of anxiety and depression in patients with chronic obstructive pulmonary disease. Pneumologia (Bucharest, Romania), 61(2), 92-96.

Patel, A. R., & Hurst, J. R. (2011). Extrapulmonary comorbidities in chronic obstructive pulmonary disease: State of the art. Expert Review of Respiratory Medicine, 5(5), 647-662. doi:10.1586/ers.11.62.

Rand, C. S., Nides, M., Cowles, M. K., Wise, R. A., & Connett, J. (1995). Long-term metered-dose inhaler adherence in a clinical trial. The lung health study research group. American Journal of Respiratory and Critical Care Medicine, 152(2), 580-588. doi:10.1164/ajrccm.152.2.7633711.

Rose, C., Wallace, L., Dickson, R., Ayres, J., Lehman, R., Searle, Y., & Burge, P. S. (2002). The most effective psychologically-based treatments to reduce anxiety and panic in patients with chronic obstructive pulmonary disease (COPD): A systematic review. Patient Education and Counseling, 47(4), 311-318. doi:10.1016/S0738-3991(02)00004-6

Schnell, K., Weiss, C. O., Lee, T., Krishnan, J. A., Leff, B., Wolff, J. L., & Boyd, C. (2012). The prevalence of clinically-relevant comorbid conditions in patients with physician-diagnosed COPD: A cross-sectional study using data from NHANES 1999-2008. BMC Pulmonary Medicine, 12, 26-2466-12-26. doi:10.1186/1471-2466-12-26.

Snoeck-Stroband, J., Schermer, T., van Schayck, C., Muris, J., van der Molen, T., Chavannes, N., Geijer, R. (2015). NHG-standaard COPD (derde herziening). Huisarts En Wetenschap, 58(4), 198-211.

World Health Organization (2017). Chronic obstructive pulmonary disease fact sheet. Retrieved from http:// www.who.int/news-room/fact-sheets/detail/chronic-obstructive-pulmonary- disease-(copd).

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Chapter 2

Gemma A. Maters Jacob N. de Voogd Robbert Sanderman Johan B. Wempe

COPD: Journal of Chronic Obstructive Pulmonary Disease, 2014, 11:4, 468-474. DOI: 10.3109/15412555.2014.898026

with stable COPD: medical comorbid

conditions or high depressive symptoms

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Abstract

Comorbid conditions are frequently found in patients with COPD. We evaluate the association of comorbidities with mortality, in stable COPD. 224 patients, mean age 61.2 (±10.00), 48.2% female, mean FEV1 1.1 (±0.5) liters, median follow-up time 4.2 years, participated. Medical comorbidities were scored according to the Charlson Comorbidity Index (CCI). Depressive symptoms were assessed with the Hospital Anxiety and Depression Scale (HADS) and Symptom Checklist-90 (SCL-90). The Cox proportional hazard model was used for survival analyses. In our sample, 70% of all patients have a comorbid medical condition or high depressive symptoms. During follow-up 51% of all patients died, and those with heart failure have the highest mortality rate (75%). Age, fat-free mass and exercise capacity were predictive factors, contrary to CCI-scores and high depressive symptoms. An unadjusted association between heart failure and survival was found. Although the presence of comorbidities, using the CCI-score, is not related to survival, heart failure seems to have a detrimental effect on survival. Higher age and lower exercise capacity or fat-free mass predict mortality.

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Introduction

Medical and psychological comorbid conditions are frequently found in patients with Chronic Obstructive Pulmonary Disease (COPD) (Chatila, Thomashow, Minai, Criner, & Make, 2008; Patel & Hurst, 2011). Recently, Schnell et al. (Schnell et al., 2012) reported a prevalence rate of 96.4% and Anecchino et al. (Anecchino et al., 2007) found 68.4% of their cohort received medication for cardiovascular diseases, diabetes or depression. An association between medical comorbidities and mortality was demonstrated (Almagro et al., 2012), but not all investigators found an independent association (Groenewegen, Schols, & Wouters, 2003). However, many studies were performed in hospitalized patients (Almagro et al., 2002; Almagro et al., 2012; Antonelli Incalzi et al., 1997; Groenewegen et al., 2003; Holguin, Folch, Redd, & Mannino, 2005; Patil, Krishnan, Lechtzin, & Diette, 2003) and to the lesser extent in patients with stable COPD (Casanova et al., 2005; Marti, Munoz, Rios, Morell, & Ferrer, 2006; Soler-Cataluna et al., 2005). The aim of the present paper is to investigate the association between comorbidities and survival in stable COPD.

Methods

Participants

Patients were recruited from January 2004 through December 2007, before starting pulmonary rehabilitation at the Center for Rehabilitation of the University Medical Center Groningen (UMCG), the Netherlands. All patients were diagnosed with COPD according to GOLD guidelines and 242 consecutive patients participated. COPD had to be stable for at least six weeks, patients had to be able to fill out questionnaires, perform cycle ergometry and spirometry. Also, medical history had to be available. Eighteen patients were excluded: one patient refused to fill out questionnaires, fourteen patients did not have fully available medical records, and three patients could not perform cycle ergometry due to their bodyweight (≥150 kilograms). Data of 224 patients were analyzed. All measurements took place as part of usual care, and each patient approved usage of his or her data. Therefore, no formal medical ethical approval was necessary due to local regulations.

Demographic variables

Age, sex, height, weight, marital status (‘living with a partner’ or ‘living without a partner’) and smoking status (‘never smoked or ex-smoker ≥ 1 year’ or ‘current smoker or ex-smoker < 1 year’) were derived from medical records.

Physiological parameters

Spirometry (Masterlab, Viasys Healthcare) was performed to obtain FEV1 and Forced Vital Capacity (FVC). Total Lung Capacity (TLC) and Residual Volume (RV) were obtained using body plethysmography. Levels of arterial oxygen (PaO2), carbon dioxide tension (PaCO2) and lactate at rest were determined prior to cycle ergometry (OxyconPro, Viasys Healthcare). The Fat-Free Mass Index (FFMI) was determined by bioelectrical impedance analysis (Bodystat 1500).

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Exercise capacity

The Incremental Shuttle Walk Test (ISWT: Singh, Morgan, Scott, Walters, & Hardman, 1992) was used to assess walking capacity. A symptom limited cycle ergometry was performed using a 1-minute incremental schedule at 5 or 10 watts (Varray & Prefaut, 1995). Maximal workload sustained for at least 30 s (Wpeak), and maximal oxygen uptake (VO2 peak) were measured.

Vital status

The primary endpoint was all-cause mortality. Although cause of death was mentioned in death certificates, it was considered not accurate enough. Survival status was obtained from municipal registrations on June 8th 2012.

Comorbidity

Patients’ comorbidities were obtained from medical histories, using prior diagnoses and current medication. In addition, hospital records and data from the primary care physician were obtained. With respect to medications: if patients used cardiovascular medications such as b-blockers or ACE-I, it was investigated for which indication it had been prescribed, e.g. CHF or systemic hypertension. Heart disease was defined to be present in case of documented STEMI or non-STEMI myocardial infarction, cardiological interventions and evidence for heart failure by echocardiography or scintigraphy. The presence of renal failure was looked for in medical records and by calculation of the eGFR, using serum creatinine, which was present in 178/224 patients and, classified as normal (eGFR>90 ml/min.1.73m2) renal function or mild (eGFR 60-89 ml/mion.1.73 m2_{) or moderate (eGFR 30-59 ml/min.1.73 m2) renal function failure. The Charlson Comorbidity}

Index (CCI) (Charlson, Pompei, Ales, & MacKenzie, 1987) was used to classify comorbidities and assign a weighted score. No score was attributed to COPD.

Depressive symptoms were assessed with Dutch translations of the Hospital Anxiety and Depression Scale, depression subscale (HADS-D) (Van Hemert & Ormel, 1993; Zigmond & Snaith, 1983) and the 16-item depression subscale of the Symptom Checklist-90 (SCL-90) (Arrindell & Ettema, 2003; Derogatis, 1977). We used the conventional HADS-Depression cut- off (≥8) to indicate high depressive symptoms. For the SCL-90 no cut-off is available (Wagena, Arrindell, Wouters, & van Schayck, 2005).

Statistical analyses

For all analyses SPSS 18.0.3 for Windows (SPSS inc, Chicago, Illinois) was used. Patient characteristics were calculated in terms of means, standard deviations, medians or percentages. Comparison of non-survivors to survivors was carried out with independent samples t-tests. Presence of medical comorbidities (CCI-score of 0 versus ≥1) and high depressive symptoms (HADS-D≥8) were included in regression analyses. All variables significant at p<.05 on a bivariate level were included in a multivariate analysis, adjusting for confounders (Cox proportional hazard model). Results were expressed in hazard ratios (HR) and 95% Confidence Intervals (CI).

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25

Results

Patient characteristics

Characteristics of all patients (108 women, 116 men) are presented in Table 2.1. Of the 224 participants, 114 (51%) had died at the end of the observation period. The mortality rate was highest in patients with comorbid CHF. The overall median follow-up time is 4.2 years, ranging from 14 days to 7.6 years. The cumulative mortality rate is as follows; one year 8%, two years 16%, three years 25%, four years 33%, five years 39%, six years 46% and seven years 49%. Survivors are significantly younger than non-survivors, have higher FEV1 and FEV1%predicted, less hyperinflation, and a better exercise capacity (Wpeak, VO2peak and ISWT%predicted).

Medical comorbidities are present in 56% of all patients. The most prevalent comorbidity is moderate or severe renal disease, followed by diabetes mellitus without organ damage (DM), congestive heart failure (CHF) and myocardial infarction (AMI, Table 2.2). Comorbidity scores are significantly higher in non-survivors. High depressive symptoms are present in 28% of all patients.

Predictors of mortality in all patients with stable COPD

On a bivariate level, CCI-scores or high depressive symptoms are not related with mortality (Table 2.3). Lower FEV1, lower PaO2, higher RV%TLC, higher FFMI, lower Wpeak, lower VO2peak and a lower ISWT%predicted are significantly related to mortality.

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Variable N All patients Survivors All-cause mortality p value*

Female Sex (%) 224 48.2 54.5 42.1 ns

Age (y) 224 61.2 (±10.0) 57.7 (±8.9) 65.2 (±9.8) .000

Partner yes (%) 224 69.6 69.1 70.2 .011

Smoking yes (%) 224 36.6 40.0 33.3 ns

Median f.u. time (y) 224 4.2 4.7 3.1

FEV1 (l) 224 1.1 (±0.5) 1.3 (±0.6) 1.0 (±0.4) .001 FEV1 (%pred) 224 41.0 (±15.6) 43.2 (±16.3) 37.8 (±14.1) .012 GOLD stages (%) II/III/IV 224 27.7/44.2/28.1 35.5/38.2/26.4 20.2/50.0/29.8

RV%TLC 222 57.1 (±11.1) 54.7 (±12) 59.4 (±9.8) .001 BMI (kg/m²) 224 26.2 (±6.6) 26.5 (±7.0) 25.8 (±6.3) ns FFMI (kg/m²) 212 18.8 (±4.5) 19.9 (±4.9) 17.8 (±3.9) .001 Wpeak (W) 217 45.6 (±31.2) 57.3 (±34.9) 34.6 (±22.3) .000 PaO2(kPa) 213 9.3 (±1.4) 9.4 (±1.4) 9.1 (±1.4) ns PaCO2 (kPa) 214 5.4 (±1.3) 5.2 (±0.7) 5.6 (±1.7) ns Lactate (mmol/l) 208 1.7 (±1.0) 1.5 (±0.86) 1.8 (±1.1) ns VO2peak (ml/min) 217 869 (±374) 981 (±437) 760 (±259) .000 ISWT (%predicted) 222 213 (±151) 267 (±160) 162 (±122) .000 Depressive symptoms HADS 203 6.1 (±4.1) 6.5 (±4.2) 5.8 (±4.0) ns Depressive symptoms SCL-90 224 28.7 (±10.4) 29.2 (±11.0) 28.2 (±9.9) ns Charlson Comorbidity Index 224 0.6 (±0.9) 0.5 (±0.8) 0.8 (±1.0) .011

Table 2.1 Characteristics of the total sample of patients with stable COPD

Definition of abbreviations: FEV1= forced expiratory volume in 1 second; RV= residual volume; TLC=total lung capacity; BMI=body mass index; FFMI=fat-free mass index; Wpeak= maximal workload sustained for at least 30 s during symptom limited cycle ergometry; PaO2= arterial oxygen tension; PaCO2= arterial carbon dioxide tension; VO2peak= maximal oxygen uptake during symptom limited cycle ergometry; ISWT=incremental shuttle walk test. * Independent Samples Test.

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Comorbidity N (%)* All patients _(N=224) Survivors _(N=110) All Cause Mortality _(N=114) DM without organ damage 30 (13.4) 12 (10.9) 18 (15.8)

Congestive heart failure 28 (12.5) 7 (6.4) 21 (18.4) Myocardial infarction 21 (9.4) 10 (9.1) 11 (9.6) Any tumor 18 (8.0) 7 (6.4) 11 (9.6) Cerebrovascular disease 13 (5.8) 5 (4.5) 8 (7.0) Peripheral vascular disease 7 (3.1) 2 (1.8) 5 (4.4) Connective tissue disease 6 (2.7) 2 (1.8) 4 (3.5) Mild liver disease 7 (3.1) 3 (2.7) 4 (3.5) Peptic ulcer disease 3 (1.3) 2 (1.8) 1 (0.9) Moderate or severe renal disease** 37 (20.7) 12 (10.9) 25 (21.9)

Table 2.2 Frequencies of comorbidities in the sample of patients with stable COPD, classified according to the

Charlson Comorbidity Index (CCI)

* The comorbidities dementia, hemiplegia, diabetes with organ damage, lymphoma, leukemia, moderate or severe liver disease, metastatic solid tumor and AIDS were not present in this sample **N=178, for 46 patients no data on recent renal function were available

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Variable B Hazard ratio 95% CI B Hazard ratio 95% CI Sex¹ 0.30 1.36 0.93-1.97 Age (y) 0.05 1.05 1.03-1.08**** 0.04 1.04 1.02-1.07**** Partner² 0.01 1.01 0.68-1.52 Smoking³ -0.17 0.84 0.57-1.25 FEV1 (l) -0.56 0.57 0.38-0.86*** -0.05 0.96 0.57-1.59 RV%TLC (%, n=216) 0.02 1.02 1.00-1.04** BMI (kg/m²) -0.03 0.98 0.95-1.01 FFMI (kg/m², n=212) -0.06 0.92 0.89-0.99** -0.08 0.93 0.88-0.98*** Wpeak (W, n=217) -0.02 0.98 0.97-0.99**** PaO2 (kPa, n=213) -0.16 0.86 0.74-0.99** PaCO2 (kPa, n=214) 0.08 1.08 0.99-1.20 Lactate (mmol/l, n=208) 0.12 1.11 0.95-1.29 VO2peak (ml/min, n=217) -0.00 0.99 0.998-0.999**** ISWT (%predicted, n=222) -0.00 1.00 0.994-0.998**** -0.03 0.997 0.995-0.999*** Depressive sympt. HADS (n=203) -0.02 0.98 0.93-1.03

Depressive sympt. SCL-90 -0.01 0.99 0.97-1.01 Charlson Comorbidity Index4 _0.28 _1.32 _0.91-1.92

Bivariate Multivariate*

Table 2.3 Predictors of mortality in all patients with stable COPD

Definition of abbreviations: FEV1= forced expiratory volume in 1 second; RV= residual volume; TLC=total lung capacity; BMI=body mass index; FFMI=fat-free mass index; Wpeak= maximal workload sustained for at least 30 s during symptom limited cycle ergometry; PaO2= arterial oxygen tension; PaCO2= arterial carbon dioxide tension; VO2peak= maximal oxygen uptake during symptom limited cycle ergometry; ISWT=incremental shuttle walk test. *Cox proportional hazard model backward stepwise (Wald) **p<0.05

***p<0.01

****p<0.001 1 0=female, 1=male

2 0=living without a partner, 1=living with a partner

3 0=never smoked or ex-smoker for ≥1 year, 1= current smoker or ex-smoker <1 year 4 0=no comorbidity, 1=one or more comorbidities

Multivariate cox regression analyses further demonstrate ISWT%predicted (hazard ratio=0.997, 95% C.I. 0.995-0.999) is an independent predictor of increased mortality, adjusting for age, FEV1 and FFMI. Analyses with Wpeak or VO2peak, substituting ISWT%predicted, show Wpeak is associated with mortality (hazard ratio=0.98, 95% C.I. 0.97-0.99) but VO2peak (hazard ratio=0.999, 95% C.I. 0.998-1.000) is not.

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29 Adjusted for age, FEV1 and ISWT%predicted, FFMI (hazard ratio= 0.93, 95% C.I. 0.88- 0.98) is independently predictive of increased mortality, whereas BMI is not. An additional bivariate analysis with three subsamples (underweight; BMI<21, normal weight; BMI≥21 and <30, overweight; BMI>30), reveals no signifi cant result either.

FEV1 does not predict survival independently (after adjusting for age, FFMI and ISWT%predicted). Additionally, RV%TLC (hazard ratio=0.99, 95% C.I. 0.97-1.01) and PaO₂ (hazard ratio=0.92, 95% C.I. 0.80-1.06) are not associated with mortality when tested in separate multivariate analyses, substituting FEV1.

Because of the high mortality rate in patients with comorbid CHF, an additional survival analysis performed with comorbid heart failure as a dichotomy (present or absent) in our total sample shows an association with increased mortality (p=.005, hazard ratio=1.97, 95% C.I. 1.23- 3.18). But, this association was no longer signifi cant after adjusting for age, ISWT and FFMI (p=.208, hazard ratio=1.39, 95% C.I. 0.83-2.32). A survival curve using Kaplan-Meier estimates was plotted for this subsample and a sample of patients without comorbid conditions, to graphically illustrate the high mortality rate (Figure 2.1).

Figure 2.1 Kaplan Meier survival plots for patients with stable COPD without

medical comorbidities or high depressive symptoms and patients with stable COPD and congestive heart failure.

Legends

Patients with COPD without medical comorbidities or high depressive symptoms (n=83) Patients with COPD and comorbid congestive heart failure (n=28)

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30

Discussion

In our sample of patients with stable COPD, 56% is diagnosed with at least one comorbid medical condition, 28% has high depressive symptoms and 70% has either at least one medical comorbid condition or high depressive symptoms. Having a comorbid condition in itself (Charlson Comorbidity Index-score) is not related to long-term mortality. However, heart failure is, unadjusted, associated with survival and this particular sample has the most unfavorable survival prospects (75% died). Acknowledged survival predictors age, exercise capacity test ISWT, cycle ergometry derived Wpeak and fat-free mass do independently predict survival. For each year a patient gains, the estimated survival chance decreases with 4%. Further, a low score increases the risk of dying per year with 3% for the ISWT (%predicted), with 2% for Wpeak (per 5 W) and with 7% for fat-free mass (per 1 kg/m2).

Our finding that the Charlson Comorbidity Index-scores did not predict mortality contradicts with the work of some (Casanova et al., 2005; Marti et al., 2006), but is in line with the results of others (Soler-Cataluna et al., 2005). One explanation for the absence of an association with mortality might lie in the possibly exponential relationship between CCI-scores and survival (Sin, Anthonisen, Soriano, & Agusti, 2006). But, our finding might as well indicate more pervasive problems with the CCI exist. Therefore the CCI should be handled carefully, especially in clinical samples. Alternative indices need to be developed (Divo et al., 2012; Patel & Hurst, 2011).

The observed mortality (51%) is more or less similar to the mortality in two other cohorts we earlier investigated: n=121, age 61 y, follow-up 8,5 y, mortality 63% (7.5 %/y) (de Voogd, Wempe, Koeter et al., 2009) and n=122, age 61 y, follow-up 7 y, mortality 39% (5.6 %/y) (de Voogd, Wempe, Postema et al., 2009). The mortality in our cohorts is somewhat higher than in other ‘landmark’ cohorts: Moberg et al (Moberg et al., 2013): n=674, age 69 y, mean follow-up 5.5y , mortality 48.2%, (8.8%/y) , the medical group from the NETT (A randomized trial comparing lung-Volume– Reduction surgery with medical therapy for severe emphysema.2003): n=610, age 67 y, follow-up 6 y, mortality 50% (8,3 %/y) and Marin et al (Marin, Soriano, Carrizo, Boldova, & Celli, 2010): n=210, age 57 y, follow-up 9 y, mortality 24 % 2.7 %/y). Differences between the study groups with respect to age and phenotype (lung function, exacerbations) largely account for the differences in mortality between our groups and others. Our cohorts consisted of subjects specifically referred for rehabilitation, being severely ill, whilst other groups consisted of more or less stable patients. We found that 56% of all patients have at least one comorbid medical condition. This is higher than prevalence rates found in other survival studies in stable COPD-patients which used the CCI. One study found a percentage of 38% (Marti et al., 2006) and another report 43.8% of their sample has at least one comorbid condition, but they excluded patients with certain comorbidities (e.g. heart failure) (Soler-Cataluna et al., 2005). The percentages of the specific comorbidities in our study correspond to percentages in earlier studies (Patel & Hurst, 2011). We relied on a thorough retrospective analysis of medical records in our study. This is considered an accepted way to calculate CCI scores. Prevalence rates for studies that relied on analysis of medical records range from 7-23% for congestive heart failure (Noteboom et al., 2014; Sidney et al., 2005; Sin & Man, 2003; Soriano, Visick, Muellerova, Payvandi, & Hansell, 2005). In our study we found 12,5% of our sample of stable COPD patients to have a comorbid diagnosis of congestive

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31 heart failure. In COPD literature, we found two studies who relied on a prospective analysis of congestive heart failure (echocardiography) (Macchia et al., 2012; Rutten et al., 2005). Macchia et al. found 17% of their sample of stable COPD suffered from (diastolic or systolic) ventricular dysfunction. Rutten et al showed 20,5% of their sample of primary care patients with stable COPD suffered from comorbid heart failure. As far as we know, the study by Macchia et al is the only study that examined the mortality prognosis for COPD patients with or without CHF. It showed a nearly significant increase in mortality when left ventricular dysfunction was present (HR 2.3, p=0.053). Our study investigated whether comorbidity influences prognosis. We are of course aware that an analysis of medical records has limitations, compared to echocardiography, but as we found quite similar prevalences with previous studies, we are confident that the results of our study yields useful and valid information. The negative effect of heart failure on mortality in COPD was found in several studies using prior diagnosis of heart failure (Almagro et al., 2012; Slenter et al., 2012) or high levels of NT-proBNP (Hoiseth, Omland, Hagve, Brekke, & Soyseth, 2012; Medina et al., 2011). These studies were in hospitalized patients, and follow-up was up to one year. These and our findings point at awareness of adequate diagnosis and treatment of heart failure in COPD, not only in an acute situation, but also in a stable condition.

In this study, the ISWT is as strongly associated to survival as cycle ergometry derived Wpeak and performs even better than VO2peak. Our finding that the ISWT independently predicts survival is in accordance with recent findings by others (Ringbaek et al., 2010; Williams et al., 2012). The ISWT is easy to perform, relatively cheap and might in certain cases be considered as an alternative to ergometry tests (Arnardottir, Emtner, Hedenstrom, Larsson, & Boman, 2006; Luxton, Alison, Wu, & Mackey, 2008).

Fat-free mass predicts mortality in our study, whereas BMI does not. The predictive value of fat-free mass is in accordance with other studies in stable COPD outpatients (Vestbo et al., 2006; Waschki et al., 2011), or in patients following a rehabilitation program (Schols, Broekhuizen, Weling-Scheepers, & Wouters, 2005). In addition, a low fat-free mass was predictive of postoperative complications following Lung Volume Reduction Surgery (Nezu et al., 2001). BMI does not predict survival in our study, as in the study of Schols et al., perhaps partly due to overlap between low fat-free mass and low BMI. On the other hand, BMI and FFM are supposed to be of additional value to each other (Vestbo et al., 2006) and our and other results may suggest that in patients with worse COPD, e.g. those attending a rehabilitation program, the FFMI is a better predictor of mortality than the BMI.

Contrary to earlier findings of our research group (de Voogd et al., 2009; de Voogd et al., 2009) depressive symptoms are not associated to survival. One of the issues in explaining this finding is homogeneity of measures over studies. Earlier, the Beck Depression Index and the

Brief Assessment Schedule Depression Cards did not independently associate to survival (Waschki et al., 2011; Yohannes, Baldwin, & Connolly, 2005). The HADS was studied twice before and both studies generated an independent association with mortality (de Voogd et al., 2009; Ng et al., 2007). We are the first to study SCL-90 depression subscale scores as a predictor for mortality, which were not predictive.

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Conclusions

Exercise capacity parameters, fat-free mass and age independently predict survival. The Charlson Comorbidity Index (CCI) is not a significant predictor in this group with stable COPD and we question the value of the CCI in relatively small samples. Patients with comorbid heart failure have the worst outcomes in terms of survival.

Acknowledgements

We thank Eric van Sonderen, methodologist, for his assistance in the data analysis.

Declaration of interest

All authors have no conflicts of interest to disclose. The work was funded by the Lung Foundation Netherlands. The sponsor had no role in the study design, data collection, data analysis, writing and reviewing of the manuscript.

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perceptions of unsupportive behavior in

Chronic Obstructive Pulmonary Disease

Chapter 3

Evelien Snippe Gemma A. Maters Johan B. Wempe Mariët Hagedoorn Robbert Sanderman