European Journal of Clinical Nutrition (2014), 1–6 © 2014 Macmillan Publishers Limited All rights reserved 0954-3007/14 www.nature.com/ejcn

ORIGINAL ARTICLE

Nutrition impact symptoms and body composition in patients with COPD J Nordén1, AM Grönberg1, I Bosaeus1, H Bertéus Forslund1, L Hulthén1, E Rothenberg1, J Karlsson2,3,4, O Wallengren1 and F Slinde1 BACKGROUND/OBJECTIVES: Anorexia or lack of appetite is common in chronic obstructive pulmonary disease (COPD) and may be caused or augmented by several symptoms affecting appetite and eating. We aimed to investigate and quantify the extent of nutrition impact symptoms (NIS) in patients with COPD and to explore relationships between NIS and fat-free mass depletion. SUBJECTS/METHODS: The results in this cross-sectional study are based on 169 COPD patients (62% female subjects). Body composition was assessed using bioelectrical impedance spectroscopy and the patients reported NIS by two newly developed questionnaires: the Eating Symptoms Questionnaire (ESQ) and the Disease-Related Appetite Questionnaire (DRAQ). RESULTS: Symptoms with the highest prevalence were dry mouth (71%), stomach ache (39%), pain or aches affecting appetite (36%) and constipation (35%). Problems with diarrhoea and feeling affected by smells were more severe among women compared with men (P o 0.05). Thirty-six percent of the patients were depleted (fat-free mass index (FFMI) o 15 kg/m2 for women and FFMIo 16 kg/m2 for men). Depleted patients had more NIS (P o 0.05) and also rated appetite and taste of food as worse compared with non-depleted patients (P o 0.05). CONCLUSIONS: NIS are common in patients with COPD, and depleted patients have more severe symptoms. To investigate how these symptoms are best prevented and/or managed and whether NIS prevention/treatment can affect development of malnutrition in patients with COPD is a challenge for the future. European Journal of Clinical Nutrition advance online publication, 7 May 2014; doi:10.1038/ejcn.2014.76

INTRODUCTION Chronic obstructive pulmonary disease (COPD) is characterised by a persistent airflow limitation that is associated with an enhanced chronic inflammatory response to noxious particles and gases in the airways and lungs.1 COPD does not, however, only affect the lungs and airways, but its extrapulmonary effects include nutritional abnormalities such as weight loss, increased resting energy expenditure and/or abnormal body composition.2 Comorbidities—for example, osteoporosis, depression, ischemic heart disease, diabetes and so on—are common in COPD patients3 and the general symptom distress is high.4,5 Many of the common symptoms and problems experienced by COPD patients are likely to negatively affect a patient´s will or ability to eat and have been shown to be common in patients with COPD6–8 and even more so among malnourished patients.8 Multiple nutrition impact symptoms (NIS) are also common6 and has been associated with a lower energy intake compared with patients without NIS.6 Malnutrition is common in patients with COPD9,10 and is probably caused by a combination of several physiological and pathophysiological alterations, such as systemic inflammation, inadequate energy intake and/or increased energy expenditure. Malnutrition is associated with higher mortality10–12 in COPD patients and it has been suggested that the fat-free mass index (FFMI)—that is, fat-free mass adjusted for body height in the same way as body mass index (BMI)—should be used in the assessment of COPD, as it has been shown to be an independent predictor of mortality providing information beyond BMI.10–12

Several previous studies have reported anorexia or lack of appetite in COPD patients,4,6,7 but a few studies have widened the approach to a more comprehensive assessment of NIS. Anorexia and/or lack of appetite are often used as collective terms for all kinds of NIS; however, it could be argued that the terms really should be considered as two of the many symptoms potentially affecting a patient's desire and ability to eat. Feeling nauseated, constipated or having chewing difficulties may result in a lack of appetite; however, focus in prevention and treatment should be on the underlying issue. Therefore, we have developed two questionnaires aiming to increase our understanding of the role of NIS in COPD patients. The aim of the present study was to investigate and quantify the extent of NIS in patients with COPD and to explore relationships between NIS and fat-free mass depletion. SUBJECTS AND METHODS Subjects All patients who visited the Lung Clinic at the Sahlgrenska University Hospital in Gothenburg, Sweden during the study period (1 September 2011 to 31 December 2012) were screened for admission to this crosssectional study. Patients were eligible if they were diagnosed with COPD caused by cigarette smoking as their main diagnosis according to their medical records—for example, patients with α1-antitrypsin deficiency were not eligible. Patients with major comorbidities or extensive multimorbidities, such as malignancy in an unstable phase, metabolic disease or renal failure, were not eligible for the study, but minor comorbidities, such as hypertension, osteoporosis, hyperlipidemia or osteoarthritis, were allowed.

1 Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; 2Centre for Health Care Sciences, Örebro University Hospital, Örebro, Sweden; 3Department of Medicine, Örebro University Hospital, Örebro, Sweden and 4School of Health and Medical Sciences, Örebro University, Örebro, Sweden. Correspondence: Dr F Slinde, Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy at University of Gothenburg, PO Box 459, SE-405 30 Göteborg, Sweden. E-mail: [email protected] Received 9 September 2013; revised 17 February 2014; accepted 24 March 2014

Nutrition impact symptoms in COPD J Nordén et al

2 Inclusion criteria also demanded that patients should be able to understand and answer the study questionnaires adequately; thus, patients who could not understand the Swedish language or patients with cognitive or psychiatric disorders that resulted in an inability to provide adequate answers were not eligible for the study. Information about comorbidities, including cognitive or psychiatric disorders, was collected from medical records. All study patients must also be able to have their body composition measured by Bioimpedance Spectroscopy (BIS). Therefore, patients with, for instance, a pacemaker or any kind of metal, such as prostheses or other implants, were not eligible for the study. Eligible patients got oral and written information about the study at the Lung Clinic. Study procedures were carried out in patients who gave consent. The study was approved by the regional ethical review board in Gothenburg (Diary number 483-11). Included patients were asked about their smoking habits and use of other nicotine- or tobacco-containing products, such as nicotinereplacement products or snuff. Information about lung function, use of pharmaceuticals and secondary diagnoses was collected from medical records as far as possible. Sickness severity was assessed according to the current Swedish guidelines for COPD treatment provided by the Swedish Medical Products Agency.13

Body composition Body height was measured using a wall-mounted stadiometer to the nearest 0.5 cm with the patients standing barefoot. Body weight was measured to the nearest 0.1 kg with the patients standing on a scale (Lindeltronic 4000, Lindells, Sweden) in light indoor clothing without shoes. Body composition was assessed using BIS (SFB7 for Body Composition, ImpediMed Ltd, Brisbane, Australia) according to the instructions of the manufacturer. BIS measurements were performed by one of the two trained dietitians involved with the study (AMG and JN). BMI was calculated as the weight in kilograms divided by the height in meters squared (kg/m2). The same height adjustment (kg/m2) was used to calculate FFMI from the fat-free mass. BMI o22 kg/m2 was used as a cutoff for underweight according to the guidelines regarding prevention and treatment of malnutrition provided by the Swedish National Board of Health and Welfare.14 Patients with BMI >30 kg/m2 were considered obese. For classification of depletion, FFMIo15 kg/m2 for women and FFMIo16 kg/m2 for men were used as suggested by Baarends et al.15

Nutrition impact symptoms NIS were assessed by the use of two questionnaires: the Eating Symptoms Questionnaire (ESQ) and the Disease-Related Appetite Questionnaire (DRAQ). Both questionnaires were developed by the research group partly through focus groups led by experienced dietitians and cognitive interviews with patients. Ten dietitians having a long experience working with different patient groups known to have NIS, most of all cancer and COPD patients, were invited to participate in two focus group occasions during 2009. Eight dietitians agreed to participate and were divided into two groups discussing the same issues. The first occasion focused on establishing a more detailed picture of the eating behaviours in malnourished patients with different medical diagnoses. The questions focused on were as follows: how can eating behaviour in different patient groups be characterised? What are the contributing factors for eating problems and loss of appetite? How is the eating behaviour influenced by, for example, environment, cognitive or emotional factors? On the second occasion, preliminary versions of the questionnaires were discussed. The discussions were noted, transcribed and analysed. The results have contributed as a foundation for the tools we have developed. In 2010, we also carried out cognitive interviews to examine how patients interpret the questions in the questionnaires. The patients read through each question and thought out loud concerning the questions—how they thought, associated and perceived each question.16 A dietitian was present and documented the expressed thoughts of the patient. This resulted in further refinement of the tow instruments. The questionnaires were created to investigate NIS mainly in patients suffering from, or in risk of developing, malnutrition. Both questionnaires are designed to be generic—that is, they can be used in different kinds of medical diagnoses. The current study is the first to test the questionnaires in patients suffering from or at risk of malnutrition. In the current study, the patients were given the choice between filling out the questionnaires at the clinic or later on at home. In case a patient European Journal of Clinical Nutrition (2014) 1 – 6

had impaired vision, the study staff assisted by reading the questions and the alternatives. The ESQ lists 13 symptoms that could all be connected to eating and/or the feelings of hunger and appetite (Table 1). The patients were asked to rate whether or to what degree (ranging in five steps from 'no problems' to 'severe problems') they had experienced each of the symptoms during the last 2 weeks. At the end of the ESQ there was an open question where the patients could report any additional symptoms they had experienced. The DRAQ was inspired by the well-known questionnaire CNAQ.17 Apart from being translated into Swedish, some of the questions have been modified and four new questions have been added, leaving the DRAQ with 12 questions concerning appetite, hunger and other eating-related issues. Some patients failed to return their questionnaires and some returned incomplete questionnaires. Missing questionnaires were interpreted as the patient did not wish to answer. When incomplete questionnaires were returned, with several questions—for example, an entire page— unanswered, the patient was contacted by phone to complete the missing questions. In case a questionnaire returned with just one or a few questions unanswered, no actions were taken.

Statistics For statistical analyses, IBM SPSS Statistics version 19.0 (SPSS Inc, Chicago, IL, USA) was used. The Student’s t-test was used to test for significant differences in the means between groups. For differences in distributions, the Χ2 test was used, and the Pearson´s r was used to test for significant correlations in parametric data. P-values o 0.05 were considered statistically significant.

RESULTS Characteristics In total, 406 patients met the inclusion criteria. Of these, 170 patients failed to be invited because of limited resources of the study. Of the 236 invited, 67 patients declined, leaving 169 study patients. Neither those who were not invited nor those who declined differed significantly in age or gender distribution from those included. No further information about the uninvited and the decliners was available. Characteristics of the 169 included patients are presented in Table 2. All patients had been smokers at some part of their life and 34 reported being active smokers at time of enrolment. Snuff, a common tobacco product in Sweden, was used by 21 patients of whom three were also active smokers. Eleven patients used some kind of nicotine-containing replacement product, six of these used nicotine gum. Fifty-five patients (33%) were underweight (BMI o22 kg/m2) and 30 (18%) were obese. Sixty-one (36%) patients were classified as depleted. The depleted patients had significantly lower BMI compared with the non-depleted (P o0.01) ones and there was a strong correlation between BMI and FFMI (Pearson’s r = 0.84). None of the obese patients were depleted. We included patients with all stages of COPD and a majority, 81 (48%), were in stage IV with 12 (7%), 36 (21%) and 38 (23%) in stages I–III, respectively. Two patients had neither any information about their stage nor results of any lung function test in their medical records, and their stage of COPD could therefore not be decided. There was a significant difference in disease severity on the basis of the stage between the depleted and the non-depleted groups with the depleted having higher severity of their disease (P = 0.02). Nine patients failed to return their questionnaires and some questionnaires were returned with one or a few missing answers. This left us with 12–15 missing answers for each question of the ESQ, and 9–11 missing answers for each question of the DRAQ. Four out of the nine (44%) patients who did not return their questionnaires were obese, which was a significantly higher proportion than among those who did return their questionnaires (P = 0.03). This resulted in a significantly higher mean BMI (31 kg/m2) among those who did not return their questionnaires. On the © 2014 Macmillan Publishers Limited

Nutrition impact symptoms in COPD J Nordén et al

3 Table 1.

Distribution of symptoms (%) reported in the Eating Symptoms Questionnaire, n = 169

a

All

Female

Male

Nausea None Mild Moderate to severe

62 15 15

64 13 15

59 17 14

Vomiting None Mild Moderate to severe

82 5 4

80 6 7

86 5 0

Stomach ache None Mild Moderate to severe

54 18 21

56 15 22

50 22 20

Diarrhoea None Mild Moderate to severe

61 18 13

62 12 17

59 27 6

Constipation None Mild Moderate to severe

58 14 21

53 13 27

66 14 13

Pain in the mouth None Mild Moderate to severe

72 8 12

71 8 14

73 9 9

Dry mouth None Mild Moderate to severe

21 19 52

17 15 59

27 25 41

Pain or ache affecting appetite None Mild Moderate to severe

56 13 23

52 14 26

63 11 19

Difficulties chewing None Mild Moderate to severe

72 11 10

75 8 11

66 17 9

Difficulties swallowing None Mild Moderate to severe

65 15 12

63 14 15

67 16 8

Changes in taste None Mild Moderate to severe

70 10 11

71 9 11

70 11 11

Affected by smells None Mild Moderate to severe

65 9 18

59 8 25

73 11 6

Pain or aches preventing from eating None Mild Moderate to severe

65 14 14

63 13 15

67 14 11

P, genderb

Low FFMI

Normal FFMI

59 15 18

64 15 13

82 10 2

82 3 6

51 25 20

56 14 22

59 25 10

62 14 15

46 16 31

65 12 16

67 10 16

74 7 10

16 28 49

23 14 54

48 16 30

61 11 19

67 13 13

74 10 8

66 13 15

64 16 11

56 16 20

79 6 7

61 12 20

67 7 17

66 16 12

64 12 15

0.75

P, FFMIb 0.66

0.10

0.081

0.52

0.26

0.017

0.20

0.090

0.026

0.62

0.42

0.043

0.084

0.39

0.15

0.15

0.49

0.38

0.75

0.89

0.001

0.009

0.57

0.72

0.66

Abbreviation: FFMI, fat-free mass index. aMissing answers vary between 7 and 9% for different questions; thus, the sums in the columns do not sum up to 100. b 2 Χ test; female versus male and low versus normal FFMI.

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Nutrition impact symptoms in COPD J Nordén et al

4 Table 2.

Description of the patients, n = 169

Female, n (%) Male, n (%) Age, mean (s.d.) BMI (kg/m2), mean (s.d.) FFMI (kg/m2), mean (s.d.) Underweight (BMI o 22 kg/m2), n (%) Obesity (BMI > 30 kg/m2), n (%) FEV1 % predicted, mean (s.d.) COPD, stage I, n (%) COPD, stage II, n (%) COPD, stage III, n (%) COPD, stage IV, n (%) Current smokers, n (%)

ALL n = 169

Female n = 105 (62%)

Male n = 64 (38%)

Low FFMI n = 61 (36%)

Normal FFMI n = 108 (64%)

105 (62%) 64 (38%) 69.2 (7.7) 25.1 (5.5) 16.5 (3.0) 55 (33%) 30 (18%) 45.3 (19.2) 12 (7%) 36 (21%) 38 (23%) 81 (48%) 34 (20%)

— — 69.5 (7.3) 25.3 (6.0) 16.0 (2.9) 34 (32%) 20 (19%) 46.2 (17.3) 8 (8%) 22 (21%) 26 (25%) 47 (45%) 25 (24%)

— — 68.8 (8.2) 24.9 (4.6) 17.4 (2.9)b 21 (33%) 10 (16%) 43.8 (21.8) 4 (6%) 14 (22%) 12 (19%) 34 (53%) 9 (14%)

42 (69%) 19 (31%) 68.8 (7.2) 20.4 (2.7)a 13.6 (2.3)a 46 (75%)a 0 (0%)a 41.9 (20.0) 3 (5%)a 11 (18%)a 8 (13%)a 39 (64%)a 17 (28%)

63 (58%) 45 (42%) 69.5 (8.0) 27.8 (4.8) 18.2 (1.1) 9 (8%) 30 (28%) 47.2 (18.5) 9 (8%) 25 (23%) 30 (28%) 42 (39%) 17 (16%)

Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV, forced expiratory volume; FFMI, fat-free mass index. aPo0.05 compared with patients with normal FFMI. bPo 0.01 compared with female.

basis of the variables in Table 2, there were no other significant differences between those who did and those who did not return their questionnaires.

The depleted were more downhearted and less cheerful and reported more often that their disease had affected their appetite compared with the non-depleted.

Nutrition impact symptoms Table 1 shows the percentage of each group reporting each symptom divided by the reported severities in the ESQ. As 'mild' symptoms in general were the most common degree of severity, 'moderate', 'pretty severe' and 'severe' symptoms have been grouped to increase the readability of the table. Table 3 shows the percentages of each group reporting each given alternative for each question of the DRAQ. The alternatives of the questions of the DRAQ have also been regrouped to increase the readability. Symptoms with the highest prevalence, regardless of severity, were dry mouth (71%), stomach ache (39%), pain or aches affecting appetite (36%) and constipation (35%). The only symptom with a prevalence of o 20% was vomiting (10%) (Table 1). Other common NIS were early satiety, as 34% reported feeling full after eating half or less of their meal, and absence of hunger as 25% reported that they never or rarely feel hungry (Table 3). Twenty percent of the patients reported eating two times or less in a day (Table 3). The open question of the ESQ requested the patients to report any additional symptoms or problems. Most patients chose not to write anything, or just state that they had no further symptoms. Twelve patients wrote comments according to given answers, such as 'dry mouth caused by medications', or commented on their general eating habits but did not report any additional symptoms. There were 29 patients who reported one or more additional symptoms. The identified symptoms were as follows: dyspnoea while cooking, while eating and after meals, pain or aches in specific parts of the body, vertigo, anxiety, depression, flatulence, weight gain, having a hunger for sweets, bad teeth, ill-fitting denture, problems from a diaphragmatic hernia, fatigue, lack of appetite, productive cough, gastro-oesophageal reflux, blisters in the mouth, spasms and excessive side effects of osteoporosis treatment. Problems with diarrhoea and feeling affected by smells were more severe among women compared with men (Table 1). Women also felt nauseated during meals more often than men (Table 3). The depleted patients more often suffered from constipation and had more often experienced changes in taste compared with the non-depleted group (Table 1). The depleted also rated their appetite as worse than the non-depleted and did not think that food tastes as good as the non-depleted did (Table 3).

DISCUSSION To our knowledge, this is the first study to investigate NIS among COPD patients in a detailed and standardised way and to relate the results to depletion. It shows a high prevalence of several NIS among COPD patients, and our main findings include high prevalence of dry mouth, gastrointestinal discomforts, early satiety, few daily meals and troubles with pains and aches. Our findings are compatible with previous findings by, for example, Grönberg et al.,6 Odencrants et al.7 and Blindermann et al.,4 although comparisons are complicated by differences in study methods. Grönberg et al.6 investigated NIS by incorporating an open question about dietary problems in a Dietary History interview. Odencrants et al.7 asked COPD patients to write a diary including all aspects of eating—for example, dietary problems, cooking, grocery shopping and so on. The diaries were complemented by an interview.7 Although Blindermann et al.4 did use questionnaires, as we did, their focus was on the general symptom burden of COPD patients and included several symptoms that could not be defined as symptoms potentially affecting dietary intake. 7 Grönberg et al.6 and Odencrants et al. identified a number of symptoms not investigated in this study, such as tiredness,6,7 breathlessness,6,7 fungal infections,7 bloated stomach,7 forgetting to eat,6 fear of gaining weight,6 dieting6 and patients being on the same diet as a family member with different nutritional needs.6 The most common symptom in this study, dry mouth, was not reported at all in the study by Grönberg et al.6 This is interesting as dry mouth was extremely common in this study, as well as in the study by Blindermann et al.4 The study by Odencrants et al.7 did not report frequencies and included only 13 patients; however, dry mouth was reported as a 'recurrent problem'. It is reasonable to believe that dry mouth in most cases is a side effect of drugs and that new drug treatments have been implemented since the data collection by Grönberg et al. was finished in 1998. Pharmaceuticals with the active substances of Budesonide, Terbutaline and Salmeterol were the most commonly used among the patients in the study by Grönberg et al.6 None of the abovementioned substances are stated to have dry mouth as a common side effect. The study included participants between 1992 and 1998. During the 20 years that have elapsed between the start of both the studies, the recommended pharmacotherapy in case of

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Nutrition impact symptoms in COPD J Nordén et al

5 Table 3.

Answer distribution (%) of the Disease Related Appetite Questionnaire, n = 169

a

All

Female

Male

My appetite is… Poor or very poor Neither poor nor good Good or very good

14 26 54

11 30 54

19 20 55

My appetite varies from day to day Agree Neither agree nor disagree Disagree

36 19 38

40 20 35

30 19 44

When I eat... I feel full after eating 1/4 of the meal or less I feel full after eating approximately half of the meal I don't feel full or I feel full after eating all or almost all of the meal

11 23 60

10 27 59

13 17 62

I feel hungry… Never or rarely Sometimes Often or always

25 45 23

22 45 27

31 45 17

Food tastes… Bad or very bad Neither bad nor good Good or very good

1 25 69

0 28 68

2 20 72

Compared with when I was healthy, food tastes… Worse or a lot worse Neither worse nor better Better or a lot better

21 65 8

21 65 9

20 66 8

I feel nauseated when I eat Often or always Sometimes Never or rarely

3 20 72

2 26 67

5 9 80

How often do you eat anything? 0–2 Times a day 3–4 Times a day 5–6 Times a day

21 59 14

22 56 16

20 63 9

My eating varies from day to day Agree Neither agree nor disagree Disagree

56 9 28

59 9 26

52 9 33

Mostly, I feel… Downhearted or very downhearted Neither downhearted nor cheerful Cheerful or very cheerful

20 42 32

18 44 32

23 39 31

For how long has your disease affected your appetite? Less than 2 weeks or not all 2 Weeks–3 months More than 3 months

58 4 32

56 4 33

61 3 30

P, genderb

Low FFMI

Normal FFMI

31 28 39

5 25 63

39 23 34

34 18 41

18 23 56

6 23 63

33 38 26

21 49 21

2 41 56

0 16 77

28 57 12

17 69 7

5 25 67

2 17 74

26 54 15

19 61 13

56 16 25

57 6 31

31 46 20

14 40 39

44 3 49

66 4 22

P, FFMIb 0.000b

0.25

0.38

0.56

0.38

0.078

0.23

0.18

0.27

0.001

0.98

0.12

0.024

0.27

0.43

0.48

0.58

0.074

0.67

0.005

0.83

0.003

Abbreviation: FFMI, fat-free mass index. aMissing answers vary between 5 and 6% for different questions; thus, the sums in the columns do not sum up to 100. b 2 Χ test; female versus male and low versus normal FFMI.

COPD has changed. The most common active substances which the COPD patients were using in the current study are Budesonide, Formoterol, Salmeterol, Tiotropium and Ipratropium. Both Tiotropium and Ipratropium have anticholinergic properties, of which dry mouth is stated to be a common side effect. Although the prevalence of several symptoms and problems was high among all patients, this study clearly indicates a higher burden of NIS among depleted patients compared with the nondepleted. The depleted patients were more affected by constipation and more depressed. They had more serious alterations in © 2014 Macmillan Publishers Limited

taste and in general did not find food as tasty as the non-depleted patients did. The depleted also rated their appetite as worse than the non-depleted and reported that their appetite had been affected by their disease for a longer time. As this study was crosssectional, no conclusion about causality can be made; however, our findings strongly indicate that the causation between several NIS and the development and maintenance of depletion in patients with COPD requires further investigation. This conclusion is supported by the previous findings of Grönberg et al.6 who have shown that patients with multiple NIS have lower FFMI and lower European Journal of Clinical Nutrition (2014) 1 – 6

Nutrition impact symptoms in COPD J Nordén et al

6

energy intake compared with patients without NIS.6 Grönberg et al. have also shown that NIS may be reduced by nutritional intervention.18 CONCLUSION This study confirms earlier findings of NIS being common in patients with COPD and that depleted patients have more severe symptoms. Many of the investigated symptoms were common among the patients. Dry mouth was the most common and affected 71% of the patients to some degree. Problems with stomach aches affected 39% of the patients, and an additional seven symptoms affected more than one-fourth of the patients. Future research is needed to investigate how these symptoms can best be identified, prevented and treated and whether preventing and/or treating NIS can prevent or delay malnutrition in patients with COPD. CONFLICT OF INTEREST The authors declare no conflict of interest.

ACKNOWLEDGEMENTS This study was funded by the Swedish Heart and Lung Association and Agreement concerning research and education of doctors.

AUTHOR CONTRIBUTIONS JN conducted the research, analysed data and wrote the paper; AMG designed the study, conducted the research and wrote the paper; IB, HBF, LH, ER, JK and OW designed the study and wrote the paper; FS designed the study, analysed data and wrote the paper.

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